Conditions: Melanoma
Keywords: Melanoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to assess the anti-tumor activity of LGX818/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy, as well as the safety and tolerability of the novel triple combinations.

Detailed description:
This study consists of two parts: in Part I/Run-In, patients naïve to selective BRAF and MEK inhibitors will be treated with the LGX818/MEK162 combination until disease progression (as defined per RECIST v1.1). Based on the genetic analysis of a tumor biopsy obtained at that time, patients will enter Part II of the study for tailored combination treatment in one of four arms of LGX818/MEK162 + either BKM120, BGJ398, INC280 or LEE011 Patients with BRAF mutant melanoma treated by LGX818/MEK162 combination in other studies can be enrolled directly in Part II of CLGX818X2109 after relapse.

Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: LGX818 intervention 2: MEK162 intervention 3: LEE011 intervention 4: BGJ398 intervention 5: BKM120 intervention 6: INC280
Intervention descriptions: intervention 1: Combination of LGX818 and MEK162 (Part I) intervention 2: Combination of LGX818 and MEK162 (Part I) intervention 3: Combination of LGX818 + MEK162 + LEE011 (Part II) intervention 4: Combination of LGX818 + MEK162 + BGJ398 (Part II) intervention 5: Combination of LGX818 + MEK162 + BKM120 (Part II) intervention 6: Combination of LGX818 + MEK162 + INC280 (Part II)

Protocol document:
Prot_000.pdf: 
 
 
 
 
Clinical Development 
 
 
LGX818, MEK162, BKM120, BGJ398, INC280, LEE011 
 
Protocol CLGX818X2109 
 
 
The LOGIC 2 trial 
A phase II, multi-center, open-label study of sequential 
LGX818/MEK162 combination followed by a rational 
combination with targeted agents after progression, to 
overcome resistance in adult patients with locally 
advanced or metastatic BRAF V600 melanoma 
 
 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-004552-38 
Version number 
07 
Development phase 
II 
Document status 
Final 
Release date 
16-Dec-2019 
Property of Array BioPharma 
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 ........................................................................................................................ 6 
List of figures ....................................................................................................................... 9 
List of appendices ................................................................................................................ 9 
List of abbreviations .......................................................................................................... 10 
Amendment 7 ..................................................................................................................... 15 
Amendment 6 ..................................................................................................................... 19 
Amendment 5 ..................................................................................................................... 24 
Amendment 4 ..................................................................................................................... 28 
Amendment 3 ..................................................................................................................... 30 
Amendment 2 ..................................................................................................................... 33 
Amendment 1 ..................................................................................................................... 38 
Glossary of terms ............................................................................................................... 39 
Protocol Summary ............................................................................................................. 40 
1 
Background ........................................................................................................................ 46 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 46 
1.1.1 
Melanoma .............................................................................................. 46 
1.2 
Introduction to investigational treatment(s) ........................................................... 48 
1.2.1 
Overview of combination treatments .................................................... 48 
1.2.2 
Overview of single agent LGX818........................................................ 54 
1.2.3 
Overview of single agent MEK162 ....................................................... 57 
1.2.4 
Overview of single agent BKM120 ....................................................... 60 
1.2.5 
Overview of single agent BGJ398 ......................................................... 63 
1.2.6 
Overview of single agent INC280 ......................................................... 65 
1.2.7 
Overview of single agent LEE011 ........................................................ 69 
2 
Rationale ............................................................................................................................ 71 
2.1 
Study rationale and purpose ................................................................................... 71 
2.2 
Rationale for the study design ................................................................................ 72 
2.3 
Rationale for dose and regimen selection .............................................................. 73 
2.4 
Rationale for choice of combination drugs ............................................................ 74 
2.5 
Rationale for choice of comparators drugs ............................................................ 74 
3 
Objectives and endpoints ................................................................................................... 74 
4 
Study design ....................................................................................................................... 77 
4.1 
Description of study design.................................................................................... 77 
4.2 
Timing of interim analyses and design adaptations ............................................... 82 


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4.3 
Definition of end of the study ................................................................................ 82 
4.4 
Early study termination .......................................................................................... 82 
5 
Population .......................................................................................................................... 82 
5.1 
Patient population .................................................................................................. 82 
5.2 
Inclusion criteria (Group A, B and C).................................................................... 82 
5.3 
Exclusion criteria ................................................................................................... 84 
6 
Treatment ........................................................................................................................... 89 
6.1 
Study treatment ...................................................................................................... 89 
6.1.1 
Dosing regimen ..................................................................................... 90 
6.1.2 
Ancillary treatments .............................................................................. 92 
6.1.3 
Rescue medication ................................................................................. 92 
6.1.4 
Guidelines for continuation of treatment ............................................... 92 
6.1.5 
Treatment duration ................................................................................ 92 
6.2 
Dose escalation guidelines ..................................................................................... 94 
6.2.1 
Starting dose rationale ........................................................................... 94 
6.2.2 
Provisional dose levels .......................................................................... 96 
6.2.3 
Guidelines for dose escalation and determination of MTDs ................. 98 
6.2.4 
Definitions of dose limiting toxicities (DLTs) .................................... 101 
6.3 
Dose modifications............................................................................................... 105 
6.3.1 
Dose modification and dose delay ....................................................... 105 
6.3.2 
Follow-up for toxicities ....................................................................... 139 
6.3.3 
Anticipated risks and safety concerns of the study drug ..................... 146 
6.4 
Concomitant medications ..................................................................................... 148 
6.4.1 
Permitted concomitant therapy ............................................................ 148 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
throughout the study ............................................................................ 149 
6.4.3 
Prohibited concomitant therapy ........................................................... 152 
6.5 
Patient numbering, treatment assignment or randomization ................................ 154 
6.5.1 
Patient numbering ................................................................................ 154 
6.5.2 
Treatment assignment or randomization ............................................. 154 
6.5.3 
Part I .................................................................................................... 154 
6.5.4 
Part II ................................................................................................... 154 
6.5.5 
Treatment blinding .............................................................................. 154 
6.6 
Study drug preparation and dispensation ............................................................. 155 
6.6.1 
Study drug packaging and labeling ..................................................... 155 
6.6.2 
Drug supply and storage ...................................................................... 155 


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6.6.3 
Study drug compliance and accountability .......................................... 155 
6.6.4 
Disposal and destruction ...................................................................... 156 
7 
Visit schedule and assessments ........................................................................................ 156 
7.1 
Study flow and visit schedule .............................................................................. 156 
7.1.1 
Molecular pre-screening ...................................................................... 182 
7.1.2 
Screening ............................................................................................. 182 
7.1.3 
Run-in period (only for Group B) ....................................................... 184 
7.1.4 
Treatment period ................................................................................. 184 
7.1.5 
End of Study Treatment visit including study completion and 
premature withdrawal .......................................................................... 185 
7.1.6 
Follow up period ................................................................................. 186 
7.2 
Assessment types ................................................................................................. 187 
7.2.1 
Efficacy assessments ........................................................................... 187 
7.2.2 
Safety and tolerability assessments ..................................................... 191 
7.2.3 
Pharmacokinetics ................................................................................. 201 
7.2.4 
Biomarkers .......................................................................................... 210 
8 
Safety monitoring and reporting ...................................................................................... 215 
8.1 
Adverse events ..................................................................................................... 216 
8.1.1 
Definitions and reporting ..................................................................... 216 
8.1.2 
Laboratory test abnormalities .............................................................. 217 
8.2 
Serious adverse events ......................................................................................... 218 
8.2.1 
Definitions ........................................................................................... 218 
8.2.2 
Reporting ............................................................................................. 218 
8.3 
Emergency unblinding of treatment assignment .................................................. 219 
8.4 
Pregnancies .......................................................................................................... 219 
8.5 
Warnings and precautions .................................................................................... 220 
8.6 
Data Monitoring Committee ................................................................................ 220 
9 
Data collection and management ..................................................................................... 220 
9.1 
Data confidentiality .............................................................................................. 220 
9.2 
Site monitoring ..................................................................................................... 221 
9.3 
Data collection ..................................................................................................... 221 
9.4 
Database management and quality control .......................................................... 222 
10 Statistical methods and data analysis ............................................................................... 222 
10.1 
Analysis sets ......................................................................................................... 223 
10.1.1 
Full Analysis Set .................................................................................. 223 
10.1.2 
Safety Set ............................................................................................. 223 


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10.1.3 
Per-Protocol Set ................................................................................... 223 
10.1.4 
Dose-determining analysis set ............................................................. 224 
10.1.5 
Pharmacokinetic analysis set ............................................................... 224 
10.1.6 
Other analysis sets ............................................................................... 224 
10.2 
Patient demographics/other baseline characteristics ............................................ 225 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ...................... 225 
10.3.1 
Study treatment .................................................................................... 225 
10.3.2 
Concomitant therapies ......................................................................... 225 
10.3.3 
Compliance .......................................................................................... 225 
10.4 
Primary objective ................................................................................................. 225 
10.4.1 
Variable ............................................................................................... 225 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 226 
10.4.3 
Handling of missing values/censoring/discontinuations ...................... 226 
10.4.4 
Supportive analyses ............................................................................. 227 
10.5 
Secondary objectives ............................................................................................ 227 
10.5.1 
Key secondary efficacy objective(s) .................................................... 227 
10.5.2 
Secondary efficacy objectives ............................................................. 227 
10.5.3 
Safety objectives .................................................................................. 228 
10.5.4 
Pharmacokinetics ................................................................................. 231 
10.5.5 
Biomarkers .......................................................................................... 232 
CCI  
10.7 
10.8 
Interim analysis .................................................................................................... 233 
Sample size calculation ........................................................................................ 234 
11 Ethical considerations and administrative procedures ..................................................... 234 
11.1 
Regulatory and ethical compliance ...................................................................... 234 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 235 
11.3 
Informed consent procedures ............................................................................... 235 
11.4 
Discontinuation of the study ................................................................................ 235 
11.5 
Publication of study protocol and results ............................................................. 236 
11.6 
Study documentation, record keeping and retention of documents ..................... 236 
11.7 
Confidentiality of study documents and patient records ...................................... 237 
11.8 
Audits and inspections ......................................................................................... 237 
11.9 
Financial disclosures ............................................................................................ 237 
12 Protocol adherence ........................................................................................................... 237 
12.1 
Amendments to the protocol ................................................................................ 237 
13 References (available upon request) ................................................................................ 238 


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14 Appendices ....................................................................................................................... 242 
14.1 
Appendix 1 - Operating characteristics of the Bayesian logistic regression 
mode and hypothetical dose escalation scenarios ................................................ 242 
14.1.1 
Statistical model and prior distributions .............................................. 242 
14.1.2 
Hypothetical dose escalation scenarios ............................................... 250 
14.2 
Appendix 2 - Guidelines for the treatment of study drug combination induced 
hyperglycemia ...................................................................................................... 255 
14.3 
Appendix 3 - Guidelines for the treatment of study drug combination induced 
diarrhea ................................................................................................................ 257 
14.4 
Appendix 4 - Guidelines for the treatment of study drug combination induced 
skin toxicity .......................................................................................................... 265 
14.4.1 
Rash ..................................................................................................... 265 
14.4.2 
Hand Foot Skin Reaction..................................................................... 267 
14.5 
Appendix 5 - Phosphate-lowering therapy ........................................................... 268 
14.6 
Appendix 6 - Guidelines for the treatment of study drug induced psychiatric 
disorders ............................................................................................................... 269 
14.7 
Appendix 7 - List of prohibited and concomitant medications to be used with 
caution .................................................................................................................. 271 
14.8 
Appendix 8 - Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ...... 281 
 
 
List of tables 
Table 1-1 
Summary of drug-drug interaction assessment between 
combination partners ............................................................................. 54 
Table 1-2 
Comparison of INC280 exposure for 600 mg capsules versus 400 
mg tablets in cancer patients from CINC280X2102 .............................. 69 
Table 3-1 
Objectives and related endpoints ........................................................... 75 
Table 4-1 
Assignment of triple combination treatment based on molecular 
alteration(s) detected at progression under LGX818/MEK162 
combination ........................................................................................... 80 
Table 6-1 
Dose and treatment schedule ................................................................. 90 
Table 6-2 
Provisional dose levels for LGX818 and MEK162 (Part I and Part 
II) ........................................................................................................... 96 
Table 6-3 
Provisional dose levels for third agents (Part II) ................................... 97 
Table 6-4 
Criteria for defining dose-limiting toxicities ....................................... 101 
Table 6-5 
LEE011 dose modification guidelines ................................................. 105 
Table 6-6 
Criteria for interruption and re-initiation of LGX818/MEK162 
combination treatment ......................................................................... 107 


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Table 6-7 
Criteria for interruption and re-initiation of LGX818 and MEK162 
in combination with third agent (BGJ398, INC280, BKM120 or 
LEE011) .............................................................................................. 115 
Table 6-8 
Specific criteria for interruption and re-initiation of BKM120 
treatment in LGX818/MEK162 + BKM120 triple combination ......... 132 
Table 6-9 
Specific criteria for interruption and re-initiation of BGJ398 
treatment in LGX818/MEK162 + BGJ398 triple combination ........... 136 
Table 6-10 
Specific criteria for interruption and re-initiation of INC280 
treatment in LGX818/MEK162 + INC280 triple combination ........... 138 
Table 6-11 
Supportive care for the prevention and management of HFSR ........... 140 
Table 6-12 
Management of pneumonitis ............................................................... 142 
Table 6-13 
Follow-up evaluations for selected toxicities ...................................... 144 
Table 7-1 
Part I - Visit evaluation schedule for patients enrolled in Group A .... 158 
Table 7-2 
Run-in Visit evaluation schedule for patients enrolled in Group B .... 164 
Table 7-3 
Part II - Visit evaluation schedule for Part II (21 day cycles for 
triple combinations with INC280 and BKM120) ................................ 170 
Table 7-4 
Part II - Visit evaluation schedule for Part II (28 day cycles for 
LEE011 and BGJ398) ......................................................................... 175 
Table 7-5 
Part I - LGX818 + MEK162 Visit Evaluation Schedule for patients 
on treatment ≥ 36 months (Amendment 07) ........................................ 180 
Table 7-6 
Disease assessment collection plan ..................................................... 190 
Table 7-7 
ECOG performance status scale (WHO) ............................................. 192 
Table 7-8 
Local clinical laboratory parameters collection plan ........................... 193 
Table 7-9 
PHQ-9/GAD-7 patient self-reported questionnaire collection plan 
(BKM120 triple combination arm only) ............................................. 200 
Table 7-10 
Classification of severity based on depression and/or anxiety 
questionnaire scores ............................................................................ 200 
Table 7-11 
Pharmacokinetic blood collection log for LGX818 and MEK162 
during Part I/ Run-In (LGX818/MEK162 combination) ..................... 203 
Table 7-12 
Pharmacokinetic blood collection log for LGX818 and MEK162 
during Part II (triple combination, 28 days cycle with LEE011 and 
BGJ398) ............................................................................................... 204 
Table 7-13 
Pharmacokinetic blood collection log for LGX818 and MEK162 
during Part II (triple combination, 21 days cycle with BKM120 and 
INC280) ............................................................................................... 205 
Table 7-14 
Pharmacokinetic blood collection log for BKM120 during Part II 
(triple combination) (21 days cycle).................................................... 206 
Table 7-15 
Pharmacokinetic blood collection log for BGJ398 during Part II 
(triple combination) (28 days cycle).................................................... 207 


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Table 7-16 
Pharmacokinetic blood collection log for INC280 during Part II 
(triple combination) (21 days cycle).................................................... 208 
Table 7-17 
Pharmacokinetic blood collection log for LEE011 during Part II 
(triple combination) (28 days cycle).................................................... 209 
Table 7-18 
Biomarker sample collection plan and biomarker assessments ........... 214 
Table 10-1 
Non compartmental pharmacokinetic parameters ............................... 232 
Table 14-1 
Data from single-agent trials used to derive priors for BGJ398, 
BKM120, INC280 and LEE011 .......................................................... 245 
Table 14-2 
Prior distributions of model parameters .............................................. 249 
Table 14-3 
Summary of prior distribution of DLT rates for LGX818 = 450 mg 
(QD, for BGJ398 or BKM120 arm) / 200 mg (QD, for INC280 or 
LEE011 arm) and MEK162 = 45 mg (BID) ....................................... 250 
Table 14-4 
Hypothetical scenarios for on-study decisions with LGX818 = 
450mg QD and MEK162 = 45mg BID in combination with 
BGJ398 (cohort size: 3) ....................................................................... 251 
Table 14-5 
Hypothetical scenarios for on-study decisions with LGX818 = 
450mg QD and MEK162 = 45mg BID in combination with 
BKM120 (cohort size: 3) ..................................................................... 252 
Table 14-6 
Hypothetical scenarios for on-study decisions with LGX818 = 
200mg QD and MEK162 = 45mg BID in combination with 
INC280 (cohort size: 3) ....................................................................... 253 
Table 14-7 
Hypothetical scenarios for on-study decisions with LGX818 = 
200mg QD and MEK162 = 45mg BID in combination with 
LEE011 (cohort size: 3) ...................................................................... 254 
Table 14-8 
NCI CTCAE v4.0 grading of diarrhea for patients without 
ileostomy/colostomy ............................................................................ 259 
Table 14-9 
Uncomplicated vs. complicated diarrhea- defining symptoms ........... 260 
Table 14-10 
Treatment of diarrhea Grade 1-2 (uncomplicated) .............................. 262 
Table 14-11 
Treatment of diarrhea CTCAE Grade 3-4 or complicated diarrhea 
CTCAE Grade 1-2 ............................................................................... 264 
Table 14-12 
Recommended treatment of skin toxicity ............................................ 266 
Table 14-13 
Supportive care for the prevention and management of HFSR ........... 267 
Table 14-14 
PHQ-9 Depression Scale ..................................................................... 270 
Table 14-15 
GAD-7 Anxiety Scale .......................................................................... 271 
Table 14-16 
Prohibited concomitant therapy for LGX818/MEK162 combination 271 
Table 14-17 
Additional prohibited concomitant therapy for LGX818/MEK162 
+ BKM120 ........................................................................................... 271 
Table 14-18 
Additional prohibited concomitant therapy for LGX818/MEK162 
+ LEE011 ............................................................................................ 272 


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Table 14-19 
Additional prohibited concomitant therapy for LGX818/MEK162 
+ BGJ398 ............................................................................................. 272 
Table 14-20 
Additional prohibited concomitant therapy for LGX818/MEK162 
+ INC280 ............................................................................................. 272 
Table 14-21 
Narrow therapeutic index substrates and substrates of CYP3A4, 
CYP2B6, CYP2C8 and CYP2C9, CYPC19 and CYP1A2 ................. 273 
Table 14-22 
List of inhibitors and inducers of UGT1A1 to be used with caution .. 275 
Table 14-23 
List of CYP inhibitors.......................................................................... 275 
Table 14-24 
List of CYP inducers ........................................................................... 276 
Table 14-25 
List of BSEP inhibitors, P-gp inhibitors/inducers and P-gp, BCRP, 
MATE1, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3 
substrates ............................................................................................. 278 
Table 14-26 
List of QT prolonging drugs ................................................................ 280 
Table 14-27 
List of prohibited enzyme-inducing anti-epileptic drugs .................... 280 
Table 14-28 
List of long acting proton pump inhibitors .......................................... 280 
 
 
List of figures 
Figure 1-1 
Main mechanisms of resistance to BRAF inhibitors ............................. 47 
Figure 4-1 
Study design .......................................................................................... 78 
Figure 7-1 
Biopsy flow chart for patients in Group B .......................................... 212 
Figure 14-1 
Algorithm for the treatment of study drug combination induced 
hyperglycemia ..................................................................................... 255 
Figure 14-2 
Algorithm for management and treatment of study drug-induced 
diarrhea ................................................................................................ 258 
 
 
List of appendices 
Appendix 1 - Operating characteristics of the Bayesian Logistic Regression Model and 
hypothetical dose escalation scenarios 
Appendix 2 - Guidelines for the treatment of study drug combination induced hyperglycemia 
Appendix 3 - Guidelines for the treatment of study drug combination induced diarrhea 
Appendix 4 - Guidelines for the treatment of study drug combination induced skin toxicity 
Appendix 5 - Phosphate-lowering therapy 
Appendix 6 - Guidelines for the treatment of study drug induced psychiatric disorders 
Appendix 7 - List of prohibited medications and concomitant medications to be used with 
caution 
Appendix 8 - Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 


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List of abbreviations 
 
ADME 
Absorption, Distribution, Metabolism and Excretion 
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 
AUC0-12h,ss 
Area under the curve from 0-12 hours at steady state 
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 
BSEP 
Bile salt export pump 
CHF 
Congestive heart failure 
CK/CPK 
Creatine kinase / Creatine phosphokinase 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRC / mCRC 
Colorectal cancer / metastatic CRC 
CrCl 
Creatinine clearance 
CRO 
Contract research organization 
CSF 
Colony Stimulating Factor 
CSR 
Central serous retinopathy / Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DDI 
Drug-Drug Interaction 
DDS 
Dose determining set 
DHEA 
Dehydroepiandrosterone 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 


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DOR 
Duration of response 
DS&E 
Drug safety and epidemiology 
DTIC 
Dacarbazine 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report/record form 
EDC 
Electronic data capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOT 
End of study treatment 
ErbB 
Erythroblastic leukemia viral oncogene 
ERG 
Electroretinogram 
ERK 
Extracellular signal regulated kinase 
EWOC 
Escalation with overdose control 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin embedded 
FU 
Follow up 
GCP 
Good clinical practice 
Gen. Ass. 
Genetic Assessment 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
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(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 
IIT 
Investigator Initiated Trial 
IN 
Investigator notification 


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INR 
International normalized ratio 
IOP 
Intra ocular pressure 
IRB 
Institutional review board 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
KA 
Keratoacanthomas 
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 
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 
MATE 
Multidrug and toxin extrusion protein 
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 
MXR 
Mitoxantrone-resistant protein 
NaF PET 
Sodium fluoride positron emission tomography 
NCI 
National Cancer Institute 
NRAS 
Neuroblastoma RAS viral oncogene homolog 
NSCLC 
Non-small cell lung cancer 
NTI 
Narrow therapeutic index 
NYHA 
New York Heart Association 
OAT 
Organic anion transporter 
OCT 
Optical coherence tomography / organic cation transporter 
ORR 
Overall response rate 
OS 
Overall survival 
PAS 
Pharmacokinetic Analysis Set 
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 


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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 
PTC 
Papillary thyroid carcinomas 
PTEN 
Phosphatase and tensin homolog 
QD 
Quaque die/once daily 
QHS 
Every bed time 
QOD 
Every other day 
QTcB 
QT interval adjusted according to Bazett 
QTcF 
QT interval adjusted according to Fridericia 
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 
RBC 
Red blood cells 
REB 
Research ethics board 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase II dose 
RTK 
receptor tyrosine kinase 
RT-PCR 
Reverse-transcriptase polymerase chain reaction 
RVO 
Retinal vein occlusion 
s.a. 
Single agent 
SAE 
Serious adverse event 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SEC 
Study evaluation completion 
SUSAR 
Suspected unexpected serious adverse reactions 
TBIL 
Total bilirubin 
T/C 
Tumor volume over control volume 
T1/2 
Terminal elimination half-life 
tCa 
Total calcium 
TdP 
Torsades de Pointes 
TGI 
Tumor growth inhibition 
TID 
Three times per day 
TKIs 
Tyrosine kinase inhibitors 
TLC 
Therapeutic lifestyle change 
tmax 
Time to reach maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 


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TTR 
Time to response 
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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Amendment 7 
Amendment rationale 
In June 2018, encorafenib (LGX818) 450 mg orally QD, in combination with binimetinib 
(MEK162) 45 mg orally BID, received marketing approval in the United States and several 
jurisdictions for the treatment of patients with unresectable or metastatic BRAF V600-mutant 
melanoma with subsequent regulatory approvals in the European Union and Japan. This approval 
was based on the randomized Phase 3 COLUMBUS Study (CMEK162B2301). 
At this stage of development, the toxicity profile of encorafenib in combination with binimetinib 
has been well established. As all patients who continue to receive encorafenib and binimetinib 
under this study protocol have been treated for a minimum of 3 years, this protocol has been 
amended to reduce the frequency of safety assessments to align with study centers’ institutional 
standards for patients with BRAF V600-mutant locally advanced unresectable or metastatic 
melanoma. 
As of the release date of this amendment, 13 patients in the Part I of Study CLGX818X2109 
were receiving study treatment with encorafenib and binimetinib. There are no patients 
receiving treatment in the Part II triple combination arm with LEE011. 
The protocol has also been amended to discontinue enrollment to the triple combination arm 
containing LEE011 due to the limited efficacy and minimal interest in further clinical 
development of this combination. The BKM120 combination was closed on 10 July 2015 due 
to a significant drug-drug interaction (DDI) between LGX818 and BKM120 (Amendment 03) 
and the INC280 and BGJ398 arms were closed in Amendment 06 due to the lack of responses 
observed in the 13 patients treated in the INC280 arm or in the single patient treated in the 
BGJ398 arm. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. 
 
Section 1 
• Section 1.2.1.1.1 Overview of combination treatments, Non-clinical experience, 
LGX818/MEK162. 
• Section 1.2.2.2.1 Overview of single agent LGX818, Clinical experience, Clinical safety 
and efficacy. 
• Section 1.2.3.2. Overview of single agent MEK162, Clinical Experience 
• Section 1.2.3.2.1. Clinical Safety and Efficacy 
 
The above sections were updated with recent marketing authorization information and number 
of patients treated with LGX818 and MEK162. 


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Section 4 
• Section 4.1, Study Design; Figure 4-1, Study Design; and Table 4-1, Assignment of triple 
combination treatment [Assignment of triple combination treatment based on molecular 
alteration(s) detected at progression under LGX818/MEK162 combination]. 
Figure 4-1 and Table 4-1 were modified to close Part II of the study including the 
discontinuation of the triple combination with LEE011. The study design was also clarified 
to state patients will be followed per local standard-of-care practice and that all SAE’s 
should be reported to the Sponsor. 
 
Section 5 
• Section 5.3 Exclusion criteria enrollment in Part II, triple combination LGX181/MEK162 
+ LEE011. 
Section was amended under Part II to clarify that the enrollment of the triple combination arm 
containing LEE011 has been discontinued. 
 
Section 6 
• Section 6.1, Study treatment and 6.1.1 Dosing regimen, Table 6-1 Dose and treatment 
schedule. 
• Section 6.2.1, Part II LGX818/MEK162 + LEE011. 
• Section 6.2.2, Provisional dose levels, Table 6-2 Provisional dose levels for LGX818 and 
MEK162 [Part 1 and Part II], and Table 6-3 Provisional dose levels for third agents [Part 
II]. 
• Section 6.2.3.2, Implementation of dose escalation decisions. 
• Section 6.2.3.3, Intra-patient dose escalation. 
• Section 6.2.4, Definitions of dose limiting toxicities [DLTs]. 
• Section 6.5.4, Part II Treatment assignment or randomization. 
• 
Section 6.6, Study drug preparation and dispensation 
The above sections were amended to discontinue the enrollment of the triple combination arm 
containing LEE011. 
 
• Section 6.1.5 Treatment Duration 
Section was modified to provide guidance that safety evaluations should occur in accordance 
with local standard-of-care clinical practice for patients who have been on LGX818 + MEK162 
for ≥ 36 months until treatment discontinuation. 
• Section 7: Section 7.1 Study Flow and Visit Schedule 
 
• Table 7-5, Part 1- LGX818 + MEK162 Visit Evaluation Schedule for patient on treatment 
≥ 36 months (Amendment 07) 


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New Table 7-5 added to detail the reduction in the frequency of safety assessments in the visit 
evalution schedule for patitents that have received LGX818 + MEK162 treatment for ≥ 36 
months. Due to the addition of this new Table 7-5, subsequent table numbers were adjusted 
accordingly in Section 7. 
 
• Sections 7.1.4. Treatment Period 
• Section 7.1.5. End of Study Treatment visit including study completion and premature 
withdrawal 
• Section 7.1.6.2. Disease progresson follow-up period. 
• Section 7.2.2.4. Vital Signs 
• Section 7.2.2.5. Laboratory evaluations 
• Section 7.2.2.5.1. Hematology 
• Section 7.2.2.5.2. Clinical Chemistry 
• Section 7.2.2.5.6. Ophthalmologic evaluation 
• Section 7.2.2.6. Cardiac Assessments 
 
A reference link to new Table 7-5, Part 1- LGX818 + MEK162 Visit Evaluation Schedule for 
patient on treatment ≥ 36 months (Amendment 07), was added to the sections listing above. 
 
• Section 7.1.6.1. 30-day Follow-up period 
 
Section was amended to reduce the safety assessments at the 30-day follow-up visit to a review 
of concomitant medications, assessment of compliance with study drug administration, and a review 
of AEs with recording of all Grade 3 or 4 AEs and all SAEs (Other safety evaluations may be 
conducted if clinically indicated). 
 
• Section 7.2.1. Efficacy Assessments 
 
Section was amended to reduce the timing of the tumor lesion assessments for patients in Part 
I and the Run-in phase. 
 
• Section 7.2.2.1 Physical Exams 
 
Section was amended to add a bullet for Part I and Run-in patients on treatment ≥ 36 months to 
reduce the frequency of physical exams to per local standard of care with a Sponsor 
recommendation to occur every 4 weeks (Table 7-5). 
 
• Section 7.2.2.6.1 Electrocardiogram (ECG) 


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A reference link to Table 7-5 was added to the sections listing above. 
• Section 7.2.3. Pharmacokinetics 
The above sections were amended to discontinue the enrollment of the triple combination arm 
containing LEE011. 
• Section 7.2.4. Biomarkers 
 
Section have been amended, to remove the requirement to provide a new tumor biopsy at 
disease progression for patients in Part I who have been on the combination treatment with 
LGX818/MEK162 for ≥ 36 months. 
 
Section 8 
• Safety monitoring and reporting 
Section was clarified for Part I patients who have been on LGX818 + MEK162 for ≥ 36 months 
that only Grade 3 or 4 AEs and all SAEs will be recorded on the AE eCRF. Any AEs that meet 
these criteria until 30 days after the last dose of study drug must be recorded. All SAEs are to 
be reported to the Sponsor or designee using the SAE form. 


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Amendment 6 
Amendment rationale 
As of the release date of this amendment, 17 patients in the CLGX818X2109 study (16 in Part I 
and 1 in Part II [LGX818/MEK162/LEE011]) were receiving study treatment. There are no 
patients ongoing in the Part II triple combination arms with INC280, BGJ398, or BKM120. 
The protocol is being amended to discontinue enrollment to the triple combination arms 
containing INC280 and BGJ398 due to the lack of efficacy in these arms and because there is 
no interest in further clinical development of these combinations. The BKM120 combination 
was closed on 10 July 2015 due to a significant drug-drug interaction (DDI) between LGX818 
and BKM120 (Amendment 3). There have been no responses observed in the 13 patients treated 
in the INC280 arm or in the single patient treated in the BGJ398 arm. 
Additional revisions include the following: 
• Change in the frequency and type of ophthalmologic examinations. 
Rationale: In a 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 QD) plus MEK162 (45 mg BID) experienced a retinal vein occlusion 
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 LGX818/MEK162 ≥ 24 months 
(Cycle 25 Day 1 onward) who have not had a retinal adverse event (AE) within the past 12 
months 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. 
• Change in the frequency of ECGs. 
Rationale: In the safety analysis of pooled studies of encorafenib 450 mg once daily in 
combination with 45 mg binimetinib twice daily (Combo 450), the incidence of new QTc 
prolongation > 500 ms was 0.7% (2/268 patients) and QTc prolongation > 60 ms compared 
to pre-treatment values was observed in 4.9% of patients (13/268 patients). Based on these 
findings, and to further minimize the burden on both dual- and triple-combination patients 
who continue to derive benefit from study treatment, patients who have been receiving study 
treatment ≥ 24 months (Cycle 25 Day 1 onward) can undergo an ECG every 3 cycles (12 
weeks). 
• Removal of the collection of an unscheduled PK sample taken in the event of a QTcF change 
from baseline > 60 ms or a new absolute QTcF interval ≥ 501 ms. 
Rationale: This is being done to reduce the burden on the patients and the sites. Collection 
and analysis of unscheduled PK samples would not significantly contribute to the PK data 
already accumulated on this study. Additionally, collection of PK data in the event of QTcF 


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changes provides minimal actionable information to the investigator due to the processing 
time required for PK samples. 
• Removal of the fasting requirement for the dual- and triple-combination treatments. 
Rationale: Based on results of two dedicated clinical pharmacology studies, exposures of 
binimetinib (clinical trial CMEK162A2103) and encorafenib (clinical trial ARRAY-818- 
102) were unaffected by food, indicating patients can take the dual-combination treatment 
with or without food. Since the package insert for LEE011 indicates patients can take 
LEE011 with or without food, the fasting restriction was removed for the triple combination. 
• Removal of the restriction of agents that elevate gastric pH, including antacids, proton pump 
inhibitors, and H2 antagonists. 
Rationale: Based on available data from the results of a dedicated clinical pharmacology 
study (ARRAY-162-105), exposures of binimetinib and encorafenib were unaffected by 
rabeprazole, a proton pump inhibitor, indicating patients can take the dual-combination 
treatment with agents that elevate gastric pH. Since the package insert for LEE011 
(ribociblib) indicates patients can take LEE011 with gastric pH–elevating agents, the 
restriction was removed for the triple combination.. 
In Appendix 7 of the protocol, language was added to the appendix header regarding 
Table 14-16 through Table 14-28 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. 
Section 4 
• Section 4.1 Description of study design and Table 4-1 (Assignment of triple combination 
treatment based on molecular alteration(s) detected at progression under 
LGX818/MEK162 combination). 
Section 4.1 and Table 4.1 were modified to discontinue enrollment to the triple combination 
arms containing INC280, BGJ398, and BKM120. 
• Section 4.3 Definition of end of study 
The above section was amended to clearly define the end of study. 
Section 5 
• Section 5.3 Exclusion criteria enrollment in Part II, additional exclusion criteria for Part II 
for selected triple combination LGX181/MEK162 + INC280 and LGX818/MEK162 + 
BGJ398. 
Section was amended under Part II to clarify that the enrollment of the triple combination 
arms containing INC280 and BGJ398 has been discontinued. Patients who are eligible may 
only enroll in the LGX818/MEK162 + LEE011 arm. 


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Under LGX818/MEK162 + LEE011, added exclusion criteria to maintain consistency with 
the LEE011 program standards. 
Section 6 
• Section 6.1 Study treatment and 6.1.1 Dosing regimen, Table 6.1 Dose and treatment 
schedule. 
Amended to clarify that the enrollment of the triple combination arms containing INC280 
and BGJ398 has been discontinued. Patients who are eligible may only enroll in the 
LGX818/MEK162 + LEE011 arm. 
• Section 6.1.1.1 Instructions for administration of LGX818, MEK162, INC280, BKM120, 
LEE011 and BGJ398. 
The above section was modified to allow patients to take either the dual combination 
(LGX818 and MEK162) or the triple combination (LGX818, MEK162 and LEE011) with 
or without food. 
• Section 6.2.1 Part II LGX818/MEK162 + BGJ398 and LGX818/MEK162 + INC280; 
Section 6.2.2 Provisional dose levels 
Table 6-2 Provisional dose levels for LGX818 and MEK162 [Part 1 and Part II], 
Table 6-3 Provisional dose levels for third agents [Part II], 
Section 6.2.2.1 INC280 Dose Escalation: Capsule and Tablet Formulations, 
Section 6.2.3.2 Implementation of dose escalation decisions, 
Section 6.2.3.3 Intra-patient dose escalation, 
Section 6.2.4 Definitions of dose limiting toxicities [DLTs], 
Section 6.3.3.1 Anticipated risks and safety considerations of the study drug 
combinations, 
Section 6.5.4 Part II Treatment assignment or randomization, 
Section 6.6 Study drug preparation and dispensation 
The above sections were amended to discontinue the enrollment of the triple combination 
arms containing INC280, BKM120 and BGJ398. Patients who are eligible may only enroll 
in the Part II LGX818/MEK162 + LEE011 arm. 
• Section 6.3.1, Table 6-7 and Table 6-11 
To maintain consistency with the LEE011 program standards, Table 6-7 was updated for 
ECG QTcF interval prolongation, Table 6-7 was modified to include dose modification for 
a Grade ≥ 2 renal impairment, and Table 6-11 was removed, as the same recommended dose 
modifications for LGX818 + MEK612 + LEE011 for QTc-interval prolongation are 
contained in Table 6-7. Table numbers were updated as appropriate. 
• Section 6.4.2.1 Permitted concomitant therapy requiring caution and/or action throughout 
the study based on LGX818 and MEK162 DDI potential (Part I and Part II) 
The above section was amended to remove the restriction of agents that elevate gastric pH. 
Section 7 
• Table 7-1, Part I - Visit evaluation schedule for patients enrolled in Group A, 
Table 7-2, Run-in Visit evaluation schedule for patients enrolled in Group B, and 


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Table 7-4, Part II - Visit evaluation schedule for Part II (28 day cycles for LEE011 and 
BGJ398) 
The above visit evaluation schedule tables were amended in the row for ophthalmologic 
examination to allow patients who have received LGX818/MEK162 for ≥ 24 months (Cycle 
25 Day 1 onward) without a retinal AE in the past 12 months 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 tables were 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 LGX818 dose or 
until initiation of another antineoplastic therapy. 
The above visit evaluation schedule tables were also amended to discontinue the enrollment 
of the triple combination arms containing INC280 and BGJ398. Patients who are eligible 
may only enroll in the Part II LGX818/MEK162 + LEE011 arm. 
The above visit evaluation schedule tables were also amended to clarify that, in subsequent 
cycles, ECGs are to be obtained every 3 cycles after ≥ 24 months (Cycle 25 Day 1 onward) 
of treatment. 
• Table 7-3, Part II - Visit evaluation schedule for Part II (21 day cycles for triple 
combinations with INC280 and BKM120) 
The above visit evaluation schedule table was amended to discontinue the enrollment of the 
triple combination arms containing INC280 and BKM120. 
• Section 7.2.2.5.7 Ophthalmologic examination 
The above section was amended to allow patients who have received LGX818/MEK162 
treatment for ≥ 24 months without a retinal AE in the past 12 months to be evaluated only 
for visual acuity at each scheduled patient visit and at the End of Treatment visit. These 
patients are required to have a full ophthalmic examination if clinically indicated and at the 
End of Treatment visit. Also, additional testing for BGJ398 will no longer be required due 
to the discontinuation of enrollment to the LGX818/MEK162 + BGJ398 treatment arm. 
• Section 7.2.2.6.1 Electrocardiogram (ECG) 
The above section was amended to remove text around unscheduled PK sample collection 
when an ECG with a QTcF change from baseline > 60 ms or a new absolute QTcF ≥ 501 
ms result is observed. Also, patients who have been on study treatment for ≥ 24 months 
(Cycle 25 Day 1 onward) will have ECGs every 3 cycles. 
• Section 7.2.3. Pharmacokinetics 
Clarification was added that the enrollment was discontinued for the triple combination 
arms containing BKM120, INC280, and BGJ398. Patients who are eligible may only enroll 
in the Part II LGX818/MEK162 + LEE011 arm. 
The following section was modified as described below. 


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• Section 7.2.3.1.1 Blood collection plan 
The above section was amended to stop collection of unscheduled PK samples, and text 
was removed where this practice was discussed. This includes addition of footnotes in 
Table 7-11 Pharmacokinetic blood collection log for LGX818 and MEK162 during Part I 
Run-In (LGX818/MEK162 combination), Table 7-12 Pharmacokinetic blood collection 
log for LGX818 and MEK162 during Part II (triple combination, 28 days cycle with 
LEE011 and BGJ398), and Table 7-17 Pharmacokinetic blood collection log for LEE011 
during Part II (triple combination) (28 days cycle) denoting collection should be stopped 
upon the effective date of Amendment 06. 
Section 10 
• Section 10.8 Sample size calculation, Part II other arms 
Section amended to discontinue enrollment to the BKM120-, BGJ398-, and INC280- 
containing arms. Patients who are eligible may only enroll in the LGX818/MEK162 + 
LEE011 arm. 


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Amendment 5 
Amendment rationale 
As of 12 September 2017, 27 patients in the CLGX818X2109 study (25 in Part I and 2 in Part 
II [both on LGX818/MEK162/LEE011 combination]), 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 Part I continuing 
patients to be reduced to every 6-12 weeks based on Investigator discretion. Patients may be 
transitioned to this less frequent imaging schedule once they have completed ≥ 24 months of 
study treatment in Part I and the Run-in phase. 
In addition, this protocol is also being amended to change the freaquency 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 excluding retinal vein occlusion 
(in patients with at least one event) was 0.2 months (95% confidence interval [CI] 0.1, 0.9) 
and there were no patients with a new onset event after 24 months. Based on these findings, 
and in order to minimize the burden on patients who continue to derive benefit from study 
treatment, this amendment allows patients who have been receiving study treatment 
≥ 24 months in Part I and the Run-in phase and who have not had a retinal adverse event (AE) 
to be evaluated only for visual acuity at each scheduled patient visit (Day 15 of all cycles) 
with a full ophthalmic examination required every 12 weeks (i.e., every 4 cycles) or more 
frequently if clinically indicated, and at End of Study Treatment visit. 
Additional revisions have been to sections of the protocol that are specific to the Part II triple 
combination arm with LEE011 in order to reflect recent clinical development changes 
pertaining to patient selection and dose modification. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. 
• Synopsis and Section 5.3 – Exclusion criteria for the LGX818/MEK162/LEE011 
combination 
The above sections were amended to add additional cardiac restrictions for the eligibility of 
patients for treatment with the LGX818/MEK162/LEE011 combination. 
• Section 4.1 Description of study design 
The above section was amended to remove the requirement for an analysis when all patients 
have potentially completed at least 6 cycles of treatment in Part II or discontinued treatment. 
• Table 6-5 LEE001 Dose modification guidelines; Section 6.3.1 Dose modification and 
dose delay 
The above table was added to provide LEE001 dose modification guidelines for patients 
undergoing treatment with the LGX818/MEK162/LEE011 combination. 


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• Table 6-7 Criteria for interruption and re-initiation of LGX818 and MEK162 in 
combination with third agent (BGJ398, INC280, BKM120 or LEE011); Section 6.3.1 
Dose modification and dose delay 
The above table was updated to provide dose modification details for patients undergoing 
treatment with the LGX818/MEK162/LEE011 combination for the following: Blood and 
Lymphatic 
System 
Disorders, 
Investigations-blood, 
Investigations-hepatic 
and 
Electrocardiogram QTcF interval prolonged. 
• Table 6-11 Specific criteria for interruption and re-initiation of LEE011 treatment in 
LGX818/MEK162/ LEE011 triple combination; Section 6.3.1 Dose modification and dose 
delay 
The above table was updated to provide dose modification details for patients undergoing 
treatment with the LGX818/MEK162/LEE011 combination who experience cardiac arrhythmia 
with QTcF interval prolonged. 
• Section 6.3.2.6 – Additional follow-up for hepatic toxicities in patients receiving LEE011 
The above section was amended to add additional guidance for patients in case of AST, ALT, 
and/or bilirubin increase requiring dose interruption during treatment with the 
LGX818/MEK162/LEE011 combination. 
• Section 6.4.1 – Permitted concomitant therapy 
The above section was revised for bisphosphonates to add that prophylactic treatment is not 
allowed for bisphosphonates with the LGX818/MEK162/LEE011 combination treatment. A 
subsection was also added with guidance on the use of corticosteroids while on study. 
• Section 6.4.2.6 – Permitted concomitant therapy requiring caution and/or action during 
triple combination with LEE011 
The above section was amended to add additional guidance on the use of concomitant therapy 
requiring caution for patients during treatment with the LGX818/MEK162/LEE011 
combination. 
• Section 6.4.3 – Prohibited concomitant therapy 
The above section was amended to add additional guidance on prohibited concomintant therapy 
for patients during treatment with the LGX818/MEK162/LEE011 combination. 
• Table 7-1 Part I – Visit evaluation schedule for patients enrolled in Group A; Table 7-2 
Run-in Visit evaluation schedule for patients enrolled in Group B; Section 7.1 Study flow 
and visit schedule. 
The above tables were amended in the row for ophthalmologic examination to allow patients 
who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months (25 cycles) 
in Part I and the Run-in phase without a retinal AE to be evaluated only for visual acuity at each 
scheduled patient visit (Day 15 of all cycles) and at End of Study Treatment visit. These patients 
are also required to have a full ophthalmic examination every 12 weeks (i.e., every 4 cycles) or 
more frequently if clinically indicated, and at End of Study Treatment visit instead of Day 15 
of all cycles. 


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The above tables were 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 enrolled in Part I and the Run-in phase, who have been on the 
LGX818/MEK162 double-agent treatment for ≥ 24 months to have CT/MRI scans every 6-12 
weeks (+/- 7 days) instead of every 6 weeks. Also, this row was amended to allow patients 
enrolled in Part I and the Run-in phase who have been on the LGX818/MEK162 double-agent 
treatment for ≥ 24 months and then discontinue study treatment for any reason other than 
disease progression to have CT/MRI scans every 9-12 weeks (+/- 7 days) instead of every 9 
weeks. 
• Section 7.1.6.2 Disease progression follow-up period 
The above section was amended for tumor evaluation per RECIST by CT/MRI to allow patients 
enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 double-agent 
treatment for ≥ 24 months and then discontinue study treatment for any reason other than 
disease progression to have CT/MRI scans every 9-12 weeks (+/- 7 days) instead of every 9 
weeks. 
• Section 7.2.1 Efficacy assessments 
The above section was amended for tumor evaluation per RECIST by CT/MRI to allow patients 
enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 double-agent 
treatment for ≥ 24 months to have CT/MRI scans every 6-12 weeks (+/- 7 days) instead of every 
6 weeks. Also, this section was amended to allow patients in Group B who have been on the 
LGX818/MEK162 double-agent treatment for ≥ 24 months to be evaluated for all potential sites 
of tumor lesions every 6-12 weeks (+/- 7 days) until disease progression instead of every 6 
weeks. The above section was also amended for tumor evaluation per RECIST by CT/MRI to 
allow patients enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 
double-agent treatment for ≥ 24 months and then discontinue study treatment for any reason 
other than disease progression to have CT/MRI scans every 9-12 weeks (+/- 7 days) instead of 
every 9 weeks. 
• Table 7-5 Disease assessment collection plan; Section 7.2.1 Efficacy assessments 
The above table was amended for tumor evaluation per RECIST by CT/MRI to allow patients 
enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 double-agent 
treatment for ≥ 24 months to have CT/MRI scans every 6-12 weeks (+/- 7 days) instead of every 
6 weeks. Also, this table was amended to allow patients enrolled in Part I and the Run-in phase, 
who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months and then 
discontinue study treatment for any reason other than disease progression to have CT/MRI scans 
every 9-12 weeks (+/- 7 days) instead of every 9 weeks. 
• Section 7.2.2.5.7 Ophthalmologic evaluation 
The above section was amended to allow patients who have been on the LGX818/MEK162 
double-agent treatment for ≥ 24 months in Part I and the Run-in phase without a retinal AE to 
be evaluated only for visual acuity at each scheduled patient visit (Day 15 of all cycles) and at 
End of Study Treatment visit. These patients are also required to have a full ophthalmic 
examination every 12 weeks (i.e., every 4 cycles) or more frequently if clinically indicated, and 
at End of Study Treatment visit instead of Day 15 of all cycles after Cycle 2. 


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• Section 10 Statistical methods and data analysis 
The above section was amended to remove the requirement for an analysis when all patients 
have potentially completed at least 6 cycles of treatment in Part II or discontinued treatment, 
died or withdrew consent prior to this time. The text was revised to clarify that study data will 
be analyzed and reported at the end of the study. 
• Table 14-18 Additional prohibited concomitant therapy for the 
LGX818/MEK162/LEE011 combination; Table 14-21 Narrow therapeutic index 
substrates and substrates of CYP3A4, CYP2B6, CYP2C8 and CYP2C9, CYPC19 and 
CYP1A2; Table 14-23 List of CYP inhibitors; Appendix 7 – List of prohibited and 
concomitant medications to be used with caution 
The above tables were revised to update and expand the list of prohibited concomitant therapy 
for patients during treatment with the LGX818/MEK162/LEE011 combination, and to match 
changes made in Section 6.4 on concomitant medications. 
• Table 14-21 Narrow therapeutic index substrates and substrates of CYP3A4, CYP2B6, 
CYP2C8 and CYP2C9, CYPC19 and CYP1A2; Table 14-23 List of CYP inhibitors; 
Appendix 7 – List of prohibited and concomitant medications to be used with caution 
The above tables were revised to update and expand the list of compounds with CYP 
interactions, and to match changes made in Section 6.4 on concomitant medications. 
• Table 14-25 List of BSEP inhibitors, P-gp inhibitors/inducers and P-gp, BCRP, MATE1, 
OAT1, OAT3, OCT2, OATP1B1 and OATP1B3 substrates; Appendix 7 – List of 
prohibited and concomitant medications to be used with caution 
The above table was revised to update and expand the list of compounds with inhibitory, 
induction, or substrate activity, and to match changes made in Section 6.4 on concomitant 
medications. 
• Table 14-26 List of QT prolonging drugs; Appendix 7 – List of prohibited and 
concomitant medications to be used with caution 
The above table was revised to update and expand the list of QT prolonging drugs, and to match 
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 4 
Amendment rationale 
One of the main purposes of this protocol amendment is to provide additional information and 
guidance to investigators for the management of liver toxicities for the INC280 combination. 
Clarifications in the dose modification guidelines in case of liver toxicity, updated rules with 
regards to study treatment discontinuation for events that meet the Hy’s Law criteria and 
specific work-up guidelines for potential drug-induced liver injury (DILI) cases are added in 
the protocol. Patients with increased AST/ALT and total bilirubin (TBIL) values that may be 
indicative of potential DILI, should be considered as clinically important events; therefore, 
specific guidance for actions to be taken on study treatment (e.g. discontinuation) and for 
monitoring of liver function tests (LFTs) have been implemented and clarified. In addition, this 
protocol is amended to include the following serious adverse event (SAE): a female patient 
experienced a serious, unexpected, possibly related adverse event (AE) of abnormal LFTs 
during treatment with a combination of INC280 and gefitinib while enrolled in the 
[CINC280X2202] study (Initial Investigator Notification Letter issued 12 March 2015). The 
investigator assessed the AE as suspected to be related to the combination of INC280 and 
gefitinib. This AE met the criteria of Hy’s Law and the hepatotoxicity could not be attributed 
solely to either drug alone or to the combination. 
Secondly, this protocol amendment introduces the use of INC280 tablets with different dosage 
strengths (100 mg and 200 mg, instead of 50 mg and 200 mg) in order to improve the 
convenience of study drug administration for patients. Related to this, the protocol also allows 
for intra-patient crossover from the capsule formulation to the tablet formulation once the 
capsule formulation is no longer available. 
Thirdly, the eligibility criteria for amylase and lipase have been updated to be consistent across 
the different INC280 studies. 
Lastly, the list of prohibited and concomitant medications to be used with caution has been 
updated. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strikethrough font for deletions and red underline font for insertions. 
• Table 4.1; Section 6.1.1.1 Instructions for Administration of LGX818, MEK162, INC280, 
BKM120, LEE011 and BGH398. 
The above sections were amended to include further clarification that the 
MEK162 + LGX818 + BKM120 Arm closed on 10 July 2015 (per Amendment 03) due to drug- 
drug interaction (DDI) between LGX818 and BKM120. 
• Table 6-4; Table 6-6; Section 6.3.2.7 Additional follow-up for hepatic toxicities in 
patients receiving INC280; Section 6.3.2.8 Follow up on potential drug-induced liver 
injury cases (new sections) 
The above sections were amended to reflect the changes for INC280 safety updates. 


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• Table 6-3; Section 6.2.2.1 INC280 Dose Escalation: Capsule and Tablet Formulations 
(new section); Section 6.6 Study drug preparation and dispensation 
The above sections were amended to reflect the changes for the use of INC280 tablets. 
• Section 5.3 
The above section was amended to reflect the changes to amylase and lipase exclusion criteria 
to be consistent with the updates for INC280 dosing. 
• Table 14-17; Table 14-18; Table 14-19; Table 14-20; Table 14-21; Table 14-22; 
Table 14-23; Table 14-24; Table 14-25; Table 14-26 
The above sections were amended to reflect updates to the lists of prohibited medications and 
concomitant medications to be used with caution. 
Other minor clarification changes and corrections to typographical errors have been made. 
Study update: Study recruitment was completed on 09 November 2015. As of November 2015, 
157 patients have been treated (151 patients with LGX818 and MEK162 combination in Part I/ 
Part II Run-in). Thirty-four patients have been treated with a triple combination in Part II (20 
patients with LGX818, MEK162 and LEE011 combination; 6 patients with LGX818, MEK162 
and BKM120 combination; 1 patient with LGX818, MEK162 and BGJ398 combination; and 7 
patients with LGX818, MEK162 and INC280 combination). 
• Section 10.5.4 
The version of software used in either analysis (non-compartmental or compartmental 
approach) will be documented in the final clinical study report (CSR). Due to the sponsor 
change, the software used may be incompatible with the language in the protocol. The language 
proposed would allow for the sponsor or sponsor-designated contract research organization 
(CRO) to use any software version that would be reported in the final CSR. 
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 3 
Amendment rationale 
The main purpose of this protocol amendment is to provide additional guidance to investigators 
around management of toxicities for three of the compounds used in the study; BKM120 
(buparlisib), INC280 and LEE011, and to document a change in study sponsorship from 
Novartis to Array BioPharma. 
Alterations in LFTs have been commonly observed in clinical trials with BKM120 as an 
investigational agent. These include mostly transient increases in transaminase enzymes (ALT 
and/or AST), which often occur during the first 6 to 8 weeks of BKM120 treatment, and rarely 
are associated with signs/symptoms of impaired liver function. Current BKM120 protocols 
have conservative inclusion criteria for baseline LFTs with close monitoring guidelines to be 
followed during the treatment and stringent dose modification/interruption criteria. 
In March 2015, a search for potential drug-induced liver injury (DILI) cases in BKM120 
Novartis-sponsored trials using conservative biochemical criteria (e.g., AST/ALT >3.0x ULN 
and total bilirubin (TBL) >2.0xULN at any time during the treatment period, regardless of 
causality) has been conducted. Upon medical review, most of these occurred in the context of 
disease progression in advanced cancer patients and/or were confounded by other causes. 
However, six of these DILI candidates were consistent with Hy’s law criteria (e.g. 
AST/ALT >3.0x ULN and TBL >2.0xULN in the absence of cholestasis and other explanatory 
causes). Five of these cases were in combination with fulvestrant in study CBKM120F2302, 
and one in combination with the investigational drug LDE225 (sonidegib) in study 
CLDE225X2114. All patients have recovered upon treatment discontinuation except one 
patient for whom the outcome is not available because the patient refused to return for safety 
follow-up. Of note, with the exception of the first case reported as Investigator notification (IN) 
back in April 2014, it is unknown at this stage whether the remaining patients received BKM120 
or placebo as the trial remains blinded. Updated liver safety including the identified DILI/Hy’s 
law candidates for the randomized, blinded studies CBKM120F2302 and CBKM120F2303 
were further presented to the Data Monitoring Committee (DMC) in April-2015; the DMC 
noted no change or additional liver safety concerns and recommended continuing the respective 
studies as planned. 
An Aggregated Safety Finding Report was submitted to Health Authorities and all investigators 
participating in BKM120 studies in May 2015 informing them about the liver findings including 
a brief summary of the six Hy’s law cases. In addition, Novartis decided to update the current 
liver-related safety measures in ongoing protocols to enhance patient safety. Therefore, the 
purpose of this protocol amendment is to provide additional guidance to investigators around 
management of liver toxicities. 
A decision was taken on 10 July 2015 to halt further recruitment to the BKM120 arm, which 
was communicated to Health Authorities and sites. Pharmacokinetic analysis of the patients 
already treated with triple combination LGX818 (encorafenib), MEK162 (binimetinib) and 
BKM120 has shown a significant drug-drug interaction (DDI) between LGX818 and BKM120. 
The BKM120 exposure in triple combination was found to be substantially reduced, by up to 
80% compared to single agent BKM120 based on the preliminary PK analysis. Based on this 


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observed DDI between LGX818 and BKM120, reaching efficacious exposures of BKM120 is 
unlikely with the current doses of LGX818 and MEK162. At the time that this protocol was 
amended, one patient was still receiving treatment with triple combination LGX818, MEK162 
and BKM120; therefore, the safety updates related to BKM120 have still been implemented. 
This protocol amendment also provides additional information and guidance to investigators 
for the management of liver toxicities when taking INC280. After the cut-off date of the current 
INC280 Investigator’s Brochure (28-Sep-2014), a female patient experienced a serious, 
unexpected, possibly related adverse event of abnormal liver function tests during treatment 
with a combination of INC280 and gefitinib while enrolled in the CINC280X2202 study. This 
adverse event met the lab criteria of Hy’s Law and the hepatotoxicity could not be attributed 
solely to either drug alone or to the combination. Therefore, clarifications in the dose 
modification guidelines in case of liver toxicity and updated rules with regards to study 
treatment discontinuation for events that meet the Hy’s Law criteria are added. 
Based on the preclinical data which suggest photosensitization potential for INC280, 
precautionary measures against ultraviolet exposure are being included in this amendment, in 
addition to the information provided in the current Investigator’s Brochure. 
This amendment also updates the dose modification guidelines for QTcF prolongation by 
adding specificity for monitoring and dose adjustment in order to better manage patient safety 
in patients taking LEE011. The guidelines for QTcF prolongation have been revised following 
an event of sudden death (IN PHHO2015AR001238). This fatal case was reported from the 
MONALEESA-2 trial (NCT 01958021; LEE011 in combination with letrozole). As a result, 
new guidelines for management of QTcF prolongation were instituted throughout the LEE011 
program in order to improve safety. Life threatening hepatic toxicity has also been reported in 
patients treated with ceritinib as well as patients treated with LEE011. Due to these findings, 
the protocol has been amended to update the guidelines for the management of hepatic toxicity. 
A second purpose of this amendment is to allow patients who do not tolerate triple therapy to 
be rechallenged with dual therapy after discussion with Sponsor Medical Monitor. Furthermore, 
this amendment provides clarification regarding antineoplastic therapy, which is permitted for 
patients between Part I and Part II upon discussion with Sponsor Medical Monitor. 
The sections on concomitant medications to be used with caution have been updated to reflect 
changes to the most recent MEK162 Investigator Brochure. Non-clinical and clinical 
pharmacokinetic data have been updated to reflect recent changes to the MEK162 and LGX818 
Investigator Brochures. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Sections 1.2.4 Overview of single agent BKM120; 6.3.2.5 Management of hepatotoxicity 
(ALT and/or AST >5.0x ULN and total bilirubin >1.5x ULN) in patients receiving 
BKM120; Table 7-3 Part II - Visit evaluation schedule for Part II (21 day cycles for triple 
combinations with INC280 and BKM120); Table 7-7 Local Clinical laboratory parameters 
collection plan 


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The above sections were amended to reflect the changes for BKM120 safety updates. 
• Sections 1.2.6 Overview of single agent INC280; 6.1.1.1 Instructions for administration of 
LGX818, MEK162, INC280, BKM120, LEE011 and BGJ398; Table 6-4 Criteria for 
defining dose-limiting toxicities; Table 6-6 Criteria for interruption and re-initiation of 
LGX818 and MEK162 in combination with third agent (BGJ398, INC280, BKM120 or 
LEE011) 
The above sections were amended to reflect the changes for INC280 safety updates. 
• Sections 6.3.2.6 Additional follow-up for hepatic toxicities in patients receiving LEE011l; 
Section 6.4.3 Prohibited concomitant therapy; Table 6-6 Criteria for interruption and re- 
initiation of LGX818 and MEK162 in combination with third agent (BGJ398, INC280, 
BKM120 or LEE011); Table 7-4 Part II - Visit evaluation schedule for Part II (28 day 
cycles for LEE011 and BGJ398); Table 7-7 Local Clinical laboratory parameters 
collection plan 
The above sections were amended to reflect the changes for LEE011 safety updates. 
• Section 6.1.5 Treatment duration 
The above section was amended to allow patients who do not tolerate triple therapy to be re- 
challenged with dual therapy 
• Section 6.4.3 Prohibited concomitant therapy 
The above section was amended to clarify that antineoplastic therapy between Parts I and II is 
permitted upon discussion with Sponsor Medical Monitor. 
• Table 1-1 Summary of Drug-Drug Interaction assessment between combination partners; 
Section 1.2.2 Overview of single agent LGX818; Section 1.2.3 Overview of single agent 
MEK162; Section 6.4.2 Permitted concomitant therapy requiring caution and/or action 
throughout the study; Table 14-22 List of inhibitors and inducers of UGT1A1 to be used 
with caution; Table 14-24 List of P-gp inhibitors and BCRP, OAT1, OAT3, OCT2, 
OATP1B1 and OATP1B3 substrates 
The above sections were amended to reflect the changes in pharmacokinetic data. 
Other minor changes/corrections in the protocol text, tables and footnotes were made for 
consistency and/or clarifications. 
 
IRB/IEC/HA 
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 purpose of this amendment is to allow patients who have already received treatment 
with any BRAF and/or MEK inhibitor to begin treatment in the trial with the dual therapy, 
LGX818 and MEK162 prior to disease progression and upon consultation between the 
Investigator and the Sponsor Medical Monitor. The current protocol requires that only patients 
who have progressed on either single-agents or double combinations of BRAF and MEK 
inhibitors may begin treatment with the LGX818/MEK162 combination in this study. 
Specifically, this amendment will allow patients who received LGX818 and/or MEK162 in 
other trials to enter LOGIC 2 prior to progression. In addition, the amendment will allow 
patients who have received other BRAF and/or MEK inhibitors, and have not progressed, but 
are not tolerating their treatment, to receive LGX818/MEK162 combination in this trial. The 
combination of a BRAF and a MEK inhibitor appears to improve efficacy and also seems to 
ameliorate some of the known BRAF-inhibitor related adverse events, such as skin and 
musculoskeletal (Flaherty, NEJM 2012). Approvals have been recently granted for the 
combination of the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib 
(Tafinlar) by the Therapeutic Goods Administration (TGA) in Australia (i.e. March 2014) and 
by the Food and Drug Administration (FDA) in the United States (i.e. Accelerated Approval in 
January 2014) for melanoma patients. 
A second purpose of this protocol amendment is to allow patients who develop brain metastasis 
during Part I of the study to continue treatment on Part II of the study, at the discretion of the 
Investigator and the Sponsor Medical Monitor. This is because preliminary activity has been 
reported in brain tumors with INC280 and BGJ398. Moreover, BKM120 is known to cross the 
blood brain barrier, thereby ensuring brain metastasis are reached. 
Moreover, DDI risk assessments as well as the list of concomitant medications for some study 
treatments have been updated due to emerging data. Preliminary PK data for LEE011X2105 
study was based on very few patients and will be updated in the LEE011 IB when more 
definitive data are available. Please refer to the PK data provided in the most recent LEE011 
IB. Lastly, changes and clarifications have been made following health authority requests, 
namely: 
• Clarification that patient minimum age must be 18 years at time of informed consent 
signature 
• The end of study definition has been expanded to clarify that the End of study (Last 
Patient Last Visit [LPLV]) will be upon completion of the safety follow-up, disease 
progression follow-up and survival follow-up (only for Part II), whichever comes later, or 
if the study is terminated early. 
• Clarification has been provided to the exclusion criterion for Enrollment in Part 2 as the 
word “all” has been replaced by “any” in the following sentence: “if they meet any 
exclusion criteria listed above, and any of the applicable additional exclusion criteria 
listed below”. 


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• Clarification has been provided indicating that patients who become pregnant must 
discontinue the study (Section 7.1.5). Wording has been added to the exclusion criterion 
10 to explain that total abstinence (one of the highly effective contraception methods) 
should be considered only “when this is in line with the preferred and usual lifestyle of the 
subject”. 
• The word “non-malignant” was deleted because it is incorrectly associated to SCC/KA 
skin (Squamous cell carcinoma/keratoacanthoma) lesions in Section 6.3.1, Treatment 
discontinuation. 
• Molecular pre-screening was modified to clarify that for patients in the US, for whom 
BRAF status is assessed during molecular pre-screening, an FDA-approved BRAF assay 
must be used. 
Other changes/corrections in the protocol text, tables and footnotes were made for consistency 
and/or clarifications: 
• Additional text has been provided to allow MRI to be used 
• Collection of blood for PK CCI 
assessments has been increased to 3ml 
and 10ml respectively due to requirements of the study for analysis. 
• The instructions for fasting before and after drug administrations were clarified. 
Other minor changes/corrections in the protocol text, tables and footnotes were made for 
consistency and/or clarifications. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary 
• All changes made in the body of the protocol are reflected in the Protocol Summary. 
Sections 2.2; 4.1, Description of Study Design; 5.2, Inclusion Criteria; 7.1, Study flow and 
visit schedule; 5.3, Exclusion Criteria; 7.2.4 Biomarkers ; 7.1.3 Run-in period (only for 
Group B) 
The above sections were updated to allow patients who had previously been treated with any 
BRAF and/or MEK inhibitors (included LGX818/MEK162 combination). 
• Table 1-1 Summary of Drug-Drug Interaction assessments between combination partners. 
LEE011X2105 PK data were deleted from this section. 
• Section 4.3, Definition of the End of Study and Section 10, Statistical methods and data 
analysis 
These sections were updated to clarify the end of study definition 
• Section 5.2 Inclusion Criteria 


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This section has been updated to reflect the change in Inclusion Criterion #2. Inclusion criterion 
#10 was added to include also patients who did not progress on their prior BRAF and/or MEK 
inhibitor regimen. 
• Section 5.3 Exclusion Criteria 
This section was updated to reflect changes in requirements for patients regarding abstinence 
and for patients who develop brain metastases during Part I of the study. 
• Clarification in the exclusion criteria for Enrollment in Part II section has also been 
provided. Moreover, additional exclusion criteria for LGX818/MEK162 + INC280 
combination arm have been provided due to new data available in the latest IB. Section 
6.3.1, Treatment discontinuation. 
The word “non-malignant” was deleted. 
• Section 6.1.1.1 Instructions for administration of LGX818, MEK162, INC280, BKM120, 
LEE011 and BGJ398. 
This section was modified to clarify the fasting condition before or after drug administration. 
In addition, one sentence was deleted because not appropriate. 
• Section 6.3.3.1.5, LGX818/MEK162 + LEE011- Main anticipated adverse events 
This section was modified to add thrombocytopenia and rash. 
• Section 6.2.1 Starting Dose Rationale (LGX818/MEK162 + LEE011) 
LEE011X2105 PK data were deleted from this section. 
• Section 6.3.3.1.5, LGX818/MEK162 + LEE011 
This section was updated with additional anticipated AEs for LEE011. 
• Section 6.4.2.6 Permitted concomitant therapy requiring caution and/or action during 
triple combination with LEE011. 
This section was modified to include recent findings from other ongoing studies. 
• Section 6.4.3 Prohibited concomitant therapy 
This 
section 
was 
updated 
with 
additional 
prohibited 
concomitant 
therapy 
for 
LGX818+MEK162+INC280 combination. 
• Appendix 7 List of prohibited and concomitant medications to be used with caution 
Tables in the Appendix 7 were updated to be consistent with the new information provided in 
the related protocol Sections 6.4.2.6 and 6.4.3 
• Section 7.1.1 Molecular pre-screening 
It was modified to implement the use of FDA-approved BRAF test for US patients without 
documented BRAF mutation. Moreover, this section was modified to allow patients previously 
treated with any BRAF and/or MEK inhibitors to have their tumor samples fully characterized 
through a comprehensive genomic analysis at pre-screening. 
• Section 7.1.2.2 Information to be collected on screening failures 


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This Section was modified to allow collection of LGX818/MEK162 in the eCRF for patients in 
group C during the genetic assessments in the screening, if they become screen failure during 
that time. 
• Section 7.1.5 Criteria for Premature Patient Withdrawal 
• This section was updated to clarify requirements for end of treatment in the event of 
patient pregnancy. 
• Section 7.2.1 Efficacy Assessments 
This section was updated to allow MRI for patients where CT imaging is more restrictive 
• Sections 7.2.3 Pharmacokinetics, 7.2.4 Biomarkers 
These sections were updated to reflect changes in the amount of blood collected for PK CCI  
CCI 
samples in Part I/Run-in and Part II. In addition, some minor consistency edits 
were also implemented in the above sections. 
• Table 7-1, Visit evaluation schedule (Group A), Table 7-2, Visit evaluation schedule 
(Group B); Table 7-3, Part II - Visit evaluation schedule for Part II (21 day cycles), Table 
7-4, Part II - Visit evaluation schedule for Part II (28 day cycles) and Table 7-5, Disease 
Assessment collection plan 
These sections have been modified to clarify the brain CT/MRI scans requirements and that 
color photography is required if skin lesions are present. These were already described in 
Section 7.2.1, Efficacy assessments; therefore, no additional assessments were implemented 
with these changes. In addition, Tables 7-3 and 7-4 have been updated to delete Cycle 2 Day 8 
visit because no assessments were scheduled in that visit. 
• Section 7.2.2.5.2, Clinical chemistry 
It was clarified that the cardiac enzyme (CK) must be analyzed at the same timepoint s as the 
other clinical chemistry parameters. 
• Table 7-7, Local Clinical laboratory parameters collection plan. 
Fasting plasma glucose and Hemoglobin HbA1c were added to Table 7-7. Moreover, amylase 
and LDH were added to the list of parameters to be analyzed, while LDL and BUN were 
removed because not informative. 
• Section 8.1.1, Definitions and reporting 
This section was updated to indicate that an AE is defined as “Ongoing” when not resolved by 
the end of the 30 day Safety Follow-up period. 
• Section 10.5.4, Pharmacokinetics 
Pharmacokinetic parameters will be determined for all PK-evaluable patients using either non- 
compartmental method(s), using Phoenix WinNonlin® Pro 6.2 (Pharsight, Mountain View, 
CA), and/or compartmental method(s). 
• Section 13, References, was updated 


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• Appendix 5 - Phosphate-lowering therapy, was modified to be consistent with Section 
6.1.2.1 Phosphate-lowering therapy for LGX818/MEK162 + BGJ398 combination 
Other minor changes/corrections in the protocol text, tables and footnotes were made for 
consistency and/or clarifications. 
 
IRB/IEC/HA 
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 1 
Amendment rationale 
The reason for the current amendment is to comply with health authority request to better define 
some DLT criteria by excluding only Grade ≥3 cutaneous squamous cell carcinoma, rather than 
SCC (squamous cell carcinoma), from the DLT definition. Moreover, Grade ≥3 laboratory 
abnormalities, which are clearly drug related, will also be considered DLT. 
In addition, minor changes for consistency and clarification were implemented. 
 
Changes to the protocol 
1. In Table 6-4, Criteria for defining dose-limiting toxicities, “Other Adverse Events” was 
moved from a subcategory under “General Disorders” to the first column of a new row in 
the table to define “any other Grade ≥3 toxicity” as a DLT. 
2. In Table 6-4, Criteria for defining dose-limiting toxicities, the exclusion of cutaneous 
squamous cell carcinoma rather than SCC (squamous cell carcinoma) from the “Other 
Adverse Events” category was specified in the footnote c. 
3. In Table 6-4, Criteria for defining dose-limiting toxicities, in “Other Adverse Events” 
exclusion of grade 3 laboratory abnormalities was removed from DLT definition. Any 
grade 3 laboratory abnormalities which are clearly drug related will be considered a DLT. 
4. In the footnote c of the Table 6-5, Criteria for interruption and re-initiation of 
LGX818/MEK162 combination treatment, and Table 6-6, Criteria for interruption and re- 
initiation of LGX818 and MEK162 in combination with third agent (BGJ398, INC280, 
BKM120 or LEE011), reference to electrolyte abnormalities and study-drug related fever 
are removed. 
5. In the footnote c of Table 6-5, Criteria for interruption and re-initiation of 
LGX818/MEK162 combination treatment, and Table 6-6, Criteria for interruption and re- 
initiation of LGX818 and MEK162 in combination with third agent (BGJ398, INC280, 
BKM120 or LEE011), it was specified that cutaneous squamous cell carcinoma, rather 
than SCC, may not require dose modification. 
6. The Appendix 14.1.1, Statistical model and prior distributions, was modified to specify 
that the doses related to INC280 in Table 14-3 are the total daily doses (INC280 is 
administered BID). 
 
IRB/IEC/HA 
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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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: 21 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient who enrolls in 
the study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non- 
investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoint s 


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Protocol Summary 
Protocol number 
CLGX818X2109 
Title 
A phase II, multi-center, open-label study of sequential LGX818/MEK162 
combination followed by a rational combination with targeted agents after 
progression, to overcome resistance in adult patients with locally advanced 
or metastatic BRAF V600 melanoma 
Brief title 
Study with selected triple combinations to overcome resistance after 
treatment with LGX818/MEK162 in melanoma patients. 
Sponsor and Clinical 
Phase 
Array BioPharma 
Interventional 
Investigation type 
Drug 
Study type 
Interventional LGX818, MEK162, BKM120, BGJ398, INC280, LEE011 
Purpose and rationale 
The combination to be evaluated in an individual patient will be based on 
the molecular alteration(s) detected at progression after LGX818/MEK162 
combination treatment 
Primary Objective(s) 
The primary objective for this study is to assess the anti-tumor activity of 
LGX818/MEK162 in combination with third targeted agents after 
progression on LGX818/MEK162 combination therapy. 
Secondary Objectives 
To estimate the MTD/RP2D of triple combinations after progression on 
LGX818/MEK162 therapy 
To characterize the safety and tolerability of LGX818/MEK162 in 
combination with targeted agents 
To further assess anti-tumor activity of LGX818/MEK162 combination, and 
in combination with targeted agents after progression on LGX818/MEK162 
combination 
To characterize genomic alterations in tumor tissue at baseline and at 
tumor progression. 
To determine the PK profiles of LGX818,MEK162 and the third agents 
when given in combination and to assess drug-drug interaction 
Study design 
This study consists of two parts: in Part I, naïve patients to selective BRAF 
and MEK inhibitors will be treated with the LGX818/MEK162 combination 
until disease progression (as defined per RECIST v1.1). Based on the 
genetic analysis of a tumor biopsy obtained at that time, patients will enter 
Part II of the study for tailored combination treatment in one of four arms of 
LGX818/MEK162 + either BKM120, BGJ398, INC280 or LEE011. 
Note: As of Protocol Amendment 06, enrollment to the BKM120-, 
BGJ398- and INC280-containing arms in Part II is closed. As of 
Amendment 07, enrollment to the LEE011-containing arm in Part II is 
closed. 
Population 
This study will enroll approximately 140 patients with BRAF mutant locally 
advanced unresectable or metastatic melanoma 


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Inclusion criteria 
• 
Patients (males and females) age ≥ 18 years 
• 
Histologically confirmed diagnosis of unresectable stage III or 
metastatic melanoma (stage IIIC to IV per American Joint Committee 
on Cancer [AJCC]) 
• 
Documented evidence of BRAF V600 mutation. 
• 
Newly obtained tumor biopsy at baseline, and patient agrees to a 
mandatory biopsy at the time of progression, if not medically 
contraindicated. 
• 
Evidence of measurable disease, as determined by RECIST v1.1. 
Inclusion criteria (for 
triple combinations) 
Progressive disease following prior treatment with LGX818/MEK162 
combination. 
A pre-LGX818/MEK162 combination archival tumor sample must be 
available 
Exclusion criteria 
Symptomatic or untreated leptomeningeal disease. 
• 
Symptomatic brain metastases. Patients previously treated or 
untreated for brain metastases that are asymptomatic in the absence 
of corticosteroid therapy or on a stable dose of steroids for four weeks 
are allowed to enroll. 
Brain metastases must be stable at least 4 weeks 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. 
• 
Known acute or chronic pancreatitis. 
• 
History or current evidence of retinal vein occlusion (RVO) or current 
risk factors for RVO (e.g. uncontrolled glaucoma or ocular 
hypertension, history of hyperviscosity or hypercoagulability 
syndromes); 
• 
Clinically significant cardiac disease including any of the following: 
• 
CHF requiring treatment (NYH grade ≥ 2), 
• 
LVEF < 50% as determined by MUGA scan or ECHO 
• 
History or presence of clinically significant ventricular arrhythmias 
or atrial fibrillation 
• 
Clinically significant resting bradycardia 
• 
Unstable angina pectoris ≤ 3 months prior to starting study drug 
• 
Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting 
study drug, 
• 
QTcF > 480 msec. 
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 
• 
AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver 
metastases are present 


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Additional Exclusion 
Patients who have developed brain metastases during Part I of the study 
criteria (for triple 
may continue to Part II upon discussion with the Sponsor Medical Monitor. 
combinations) 
The brain metastasis must be either asymptomatic or treated and stable 
for at least 4 weeks and on a stable or tapering dose of steroids for at least 
2 weeks. 
Note: As of Protocol Amendment 06, enrollment to the BKM120-, 
BGJ398- and INC280-containing arms in Part II is closed. As of 
Amendment 07, enrollment to the LEE011-containing arm in Part II is 
closed. 
LGX818/MEK162/BKM120: 
• 
Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 
8 %. 
• 
Patient has any of the following mood disorders as judged by the 
Investigator or a Psychiatrist: 
• 
Patient has a score ≥ 12 on the PHQ-9 questionnaire 
• 
Patient has ≥ CTCAE grade 3 anxiety 
LGX818/MEK162/BGJ398: 
• 
History and/or current evidence of significant ectopic mineralization/ 
calcification with the exception of calcified lymph nodes and 
asymptomatic vascular calcification. 
• 
Current evidence of corneal disorder/ keratopathy incl. but not limited 
to bullous/ band keratopathy, corneal abrasion, 
inflammation/ulceration, keratoconjunctivitis etc., confirmed by 
ophthalmologic examination 
LGX818/MEK162/LEE011: 
• 
Patients with uncontrolled hypertension (please refer to WHO-ISH 
guidelines) are excluded from study. 
• 
QTcF ≥450 ms 
• 
Mean resting heart rate < 50 or >90 bpm 
• Patient with the following laboratory abnormalities unless corrected to 
within normal limits with supplements before the first dose of study 
medication: sodium, potassium, magnesium, total calcium (corrected 
for serum albumin), and phosphorus 
• Total bilirubin ≥ ULN except for patients with Gilbert’s syndrome who 
may only be included if the total bilirubin is ≤ 3.0 × ULN or direct 
bilirubin ≤ 1.5 × ULN. 
• Aspartate transaminase (AST) ≥ 2.5 × ULN, ≥ 5 × ULN in patients with 
liver metastasis 
• Alanine transaminase (ALT) ≥ 2.5 × ULN, ≥ 5 × ULN in patients with 
liver metastasis 
• Long QT syndrome or family history of idiopathic sudden death or 
congenital long QT syndrome or any of the following before the first 
dose of the triple combination: 
• Risk factors for TdP including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
• Concomitant medication(s) with a known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe that cannot be 


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discontinued or replaced by safe alternative medication (e.g., within 5 
half-lives or 7 days prior to starting study drug) 
• 
Inability to determine the QTcF interval. 
• Any heart disease that requires the use of a cardiac pacemaker or 
implantable cardioverter defibrillator ≤ 3 months prior to starting study 
drug. 
• Unstable atrial fibrillation (ventricular response >100 bpm). 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade AV block (e.g., 
bifascicular block, Mobitz type II, and third degree AV block) 
• Systolic blood pressure (SBP) > 160 or < 90 mmHg 
• Patients who are currently receiving treatment with agents that are 
known to cause QTc prolongation in humans. See LEE011 
Investigators Brochure for a complete list of agents that are known to 
cause QTc prolongation in humans. 
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 
according to the Modification of Diet in Renal Disease (MDRD) 
formula. 
• Patient is currently receiving any of the following substances and 
cannot be discontinued 7 days prior to Cycle 1 Day 1: 
• Concomitant medications, herbal supplements, and/or fruits (e.g., 
grapefruit, pummelos, star fruit, Seville oranges) and their juices that 
are strong inducers or inhibitors of CYP3A4/5 
• Medications that have a narrow therapeutic window and are 
predominantly metabolized through CYP3A4/5. 
• 
History of documented myocardial infarction (MI), angina pectoris, 
symptomatic pericarditis, or coronary artery bypass graft (CABG) 
within 6 months prior to study entry 
• 
Documented cardiomyopathy 
• 
Current evidence of brain metastasis or brain metastasis detected by 
mandatory CT/MRI at screening 
• 
PT/INR or aPTT > 1.5xULN 
LGX818/MEK162/INC280: 
• Patients unable to stop known CYP3A4, CYP1A2, CYP2C8 or 
CYP2C19 substrates with narrow therapeutic index. These 
medications should be stopped 7 days prior to first dose of study 
treatment (refer to Section 6.4.3 and Appendix 7 for prohibited 
medications for this combination treatment). 
• Patients receiving treatment with long-acting proton pump inhibitors, 
and unable to discontinue them 3 days prior to the start of study 
treatment and during the course of the study. 
• Asymptomatic serum amylase > CTCAE Grade 2 (1.5-2.0xULN). 
Patients with Grade 1 or Grade 2 serum amylase at the beginning of 
the study must be confirmed to have no signs or symptoms suggesting 
pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal 
imaging findings of pancreas, etc.) 
• 
Serum lipase > ULN 


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Investigational and 
reference therapy 
LGX818/MEK162 
LGX818/MEK162 + BKM120 
LGX818/MEK162 + BGJ398 
LGX818/MEK162 + INC280 
LGX818/MEK162 + LEE011 
Efficacy assessments 
Tumor response per RECIST v1.1: Overall Response Rate (ORR) (Part II), 
Progression Free Survival (PFS) (Part I and II), Duration of Response 
(DOR) (Part I and II) and Overall Survival (OS) (Part II), Time to Response 
(TTR) (Part I and II), Disease Control Rate (DCR) (Part I and II). 
As of Protocol Version 7, the Sponsor recommends assessing efficacy 
every 8 to 12 weeks or per institution local standard-of-care clinical 
practice. 
Safety assessments 
Physical examinations 
Vital signs 
Laboratory evaluations 
Cardiac assessments 
Dermatologic evaluations 
Ophthalmologic evaluations 
As of Protocol Version 7, for patients who have been on treatment in Part I 
for ≥ 36 months, safety evaluations should occur in accordance with local 
standard-of-care clinical practice and may receive treatment until treatment 
discontinuation criteria are met. 
It is recommended that safety evaluations occur approximately every 
4 weeks, unless otherwise specified. Safety should be monitored by 
assessing physical examination, hematology, chemistry laboratory testing 
and other pertinent testing as required as part of the safety profile of the 
compound (dermatological examinations, ophthalmic exams, cardiac 
profiles) until discontinuation. Adverse events should be reviewed at every 
visit. Investigators will be required to record all Grade 3 or 4 AEs, including 
SAEs, in the clinical database. All SAEs are to be reported to the Sponsor 
or designee using the SAE form. 
Other assessments 
LGX818 and MEK162, or BKM120, or BGJ398, or INC280, or LEE011 
pharmacokinetic evaluations 
Baseline molecular status in tumor tissue of potential predictive markers 
Changes from baseline in pharmacodynamic markers in tumor tissue 
Gene alteration/expression profiles (e.g. baseline, progression) in tumor 
tissue 


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Data analysis 
The primary objective of the study is to assess the anti-tumor activity of 
LGX818/MEK162/LEE011 after progression on LGX818/MEK162 
combination therapy. For patients receiving other triple combinations, an 
initial assessment of the anti-tumor activity of LGX818/MEK162 in 
combination with targeted agents after progression on LGX818/MEK162 
combination therapy. 
Best Overall Response (BOR) assessed per RECIST v1.1 during Part II 
will be used to evaluate the tumor response in terms of Overall Response 
Rate (ORR) for combinations of LGX818, MEK162 and the third agents. 
This will be based on investigator-assessed tumor evaluations per RECIST 
v1.1 
MTD/RP2D of LGX818/MEK162 in combination with targeted agents after 
progression on LGX818/MEK162 therapy will be assessed. Estimation of 
the MTD of the treatment will be based upon the estimation of the 
probability of DLT in Cycle 1 for patients in the dose-determining set 
(DDS), using an adaptive BLRM guided by the EWOC principle 
Safety and tolerability of LGX818/MEK162 and their combination with third 
target agents will be assessed for incidence and severity of adverse drug 
reactions and serious adverse drug reactions (as assessed by CTCAE 
Version 4.03), changes in hematology and chemistry values, physical 
examinations, vital signs, electrocardiogram, cardiac monitoring, 
ophthalmological and dermatological examinations. 
For Part I, the Full Analysis Set (FAS) consists of all patients who received 
at least one dose (partial or full) of LGX818 or MEK162. 
For Part II, the FAS consists of all patients who have received at least one 
dose of LGX818 or MEK162 or the assigned third agent following the 
assignment of the triple combination treatment. 
The pharmacokinetic analysis set (PAS) consists of all patients who have 
at least one blood sample providing evaluable pharmacokinetic (PK) data 
Key words 
BRAF inhibitor; RAF kinase inhibitor; LGX818; MEK162; Mek Inhibitor; 
BKM120; PI3K inhibitor; BGJ398; FGFR inhibitor; INC280; c-Met inhibitor; 
LEE011; CDK4/6 inhibitor; metastatic melanoma; BRAF; V600 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Melanoma 
 
1.1.1.1 
Drug resistance in melanoma 
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); (Ferlay et al 2010), faster than that of all solid tumors, constituting 
a significant and growing health burden. It is estimated that 76,250 men and women will be 
diagnosed with melanoma of the skin in 2012 in the United States alone (Siegel et al 2012). 
Overall incidence rates in USA have increased for both men and women, whereas death rates 
have increased in men (+3.3% 2001-2006) but have decreased in women (-0.6% 1992-2006) 
(annual percent change in age–standardized rates). Similarly, the number of new skin 
melanomas in the world, for all ages, in 2010 was 208,251 men and women (Jemal 2011; Ferlay 
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 et al 2009). 
Currently, the existing therapeutic options for patients with melanoma comprise of 6 therapies 
approved by the Food and Drug Administration (FDA): dacarbazine (DTIC), interleukin-2 (IL- 
2), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (BRAF inhibitors) as well as 
trametinib (MEK inhibitor). Single agent (s.a.) therapy with dacarbazine (DTIC), a cytotoxic 
chemotherapy, is generally well tolerated, but results in an overall response rate of only 10% 
and no survival benefit for patients with metastatic disease (median PFS of 2-3 months and OS 
of 6-10 months) (Anderson 1995, Serrone 2000, Chapman 1999). Ipilimumab (Yervoy® Bristol- 
Myers Squibb) was approved by the FDA (25 March 2011) for the treatment of unresectable or 
metastatic melanoma. The selective BRAF inhibitors vemurafenib (Zelboraf®, Roche) and 
dabrafenib (Tafinlar, GSK), were recently approved for the treatment of patients with 
unresectable or metastatic melanoma with the BRAF V600E mutation. The selective MEK 
inhibitor trametinib (Mekinist, GSK) was recently approved for the treatment of patients with 
unresectable or metastatic melanoma with the BRAF V600E and V600K mutations. 
In addition to approved therapies, the concept of a simultaneous, dual, vertical pathway 
inhibition of the RAF/MEK/ERK pathway to prevent the emergence of resistance to single 
agent small molecule inhibitor therapy (Emery 2009, Fremin 2010) is currently being explored 
by the combination treatment of a selective BRAF- and a MEK1/2-inhibitor in cancer patients 
with advanced BRAF mutation-positive tumor types. Results of the first phase I/II study Study 
NCT01072175 have been recently reported (Flaherty et al 2012a). A total of 247 patients with 
metastatic melanoma and BRAF V600 mutations were treated with dabrafenib +/- trametinib, 
and in the phase II part, 162 patients were randomly assigned to receive dabrafenib (150 mg) 
plus trametinib (1 or 2 mg) or dabrafenib monotherapy (150mg). ORR was 50 %, 76% and 


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54%, with a median PFS of 9.2 months, 9.4 and 5.8 months for dabrafenib plus trametinib 
(150/1, 150/2) and dabrafenib monotherapy respectively. Results from theNCT01072175 study 
also show that a selective BRAF inhibitor combines safely with a MEK inhibitor with a 
decreased occurrence of cutaneous side effect, such as rash and squamous cell carcinoma (SCC) 
of the skin in comparison to single agent therapy (Flaherty et al 2012a). 
 
Figure 1-1 
Main mechanisms of resistance to BRAF inhibitors 
 
Adapted from Alcalá et al (2012). 
Despite the demonstrated clinical efficacy of BRAF and MEK inhibitors, in most cases tumors 
become resistant to treatment. Although there are multiple paths to resistance, the main 
mechanisms result in reactivation of the RAF/MEK/ERK signaling pathway in the presence of 
an inhibitor (see Figure 1-1). This reactivation can occur via (i) increased activity of receptor 
tyrosine kinases (RTKs) via gene amplification, and overexpression and/or ligand production 
(Straussman 2012, Villanueva 2010, Wilson 2012), (ii) acquisition of mutations in the NRAS 
and MEK1 genes, (iii) bypass of BRAF via overexpression of kinases such as COT and RAF- 
1 (CRAF), (iv) expression of splice variants of the mutant BRAF allele, and (v) increased 


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expression of the mutant BRAF allele due to, e.g. gene amplification (Emery 2009, Johannessen 
2010, Nazarian 2010, Poulikakos 2011, Shi 2012, Trunzer 2013). Consistent with the 
observation that RAF/MEK/ERK pathway re-activation underlies the majority of cases of 
BRAF inhibitor resistance, combining selective RAF and MEK inhibitors confers a more 
durable response than do single agent treatments, although most patients ultimately progression 
in this case as well. Although the mechanisms of resistance to combined inhibitor treatment are 
not well understood at present time, initial reports suggest that many of the same mechanisms 
that confer resistance to single agent RAF inhibitors, such as RTK activation and mutations in, 
e.g. MEK1/2 and NRAS, also confer resistance to RAF/MEK inhibitor combinations 
(Abel 2013, Wagle 2013, Villanueva 2013). In addition, activation of survival pathways such 
as the PIK3Cα signaling system that are distinct from the MAPK pathway, either via activation 
RTKs such as PDGFR-β and IGF-1R or loss of the PTEN gene have also been demonstrated to 
confer resistance to BRAF inhibitors, and by extension are likely to promote resistance to 
combinations of BRAF and MEK inhibitors as well (Johannessen 2010, Nazarian 2010, 
Villanueva 2010, Wilson 2012). The findings described above highlight the importance of 
identifying mechanisms of resistance in real time in order to initiate rational combination 
therapy soon after progression. By comparing the set of genetic alterations present in a 
progressing tumor at the time of relapse to the alterations present in the tumor prior to treatment, 
it should be possible to identify the likely molecular mechanisms underlying resistance. This 
comparison could then be used to direct the selection of a drug combination therapy for an 
individual patient that is most likely to overcome resistance. In this CLGX818X2109 study, a 
rational combination treatment approach informed by comparing the genetic profiles of relapsed 
and treatment naive tumors will be taken to expand and improve the therapeutic options for 
patients with BRAF-mutant advanced or metastatic melanoma that have very poor prognosis 
after the development of resistance to combined BRAF/MEK inhibitor treatment. 
 
1.2 
Introduction to investigational treatment(s) 
1.2.1 
Overview of combination treatments 
 
1.2.1.1 
Non-clinical experience 
 
1.2.1.1.1 LGX818/MEK162 
Re-activation of MAPK signaling in the presence of inhibitor occurs in the majority of cases of 
acquired resistance to BRAF inhibitors. Often, this re-activation is the direct result of molecular 
alterations in genes that encode components of the MAPK pathway such as NRAS, BRAF, and 
MEK1 (Nazarian 2010, Poulikakos 2011, Shi 2012, Wagle 2011). Clinical data for the 
dabrafenib/trametinib as well as the LGX818/MEK162 combination prove the hypothesis, that 
inhibition of more distal components of the MAPK pathway provides at least a partial benefit 
in treating BRAF mutant melanomas. In vitro, the combination of LGX818 and MEK162 either 
additively or synergistically inhibited the proliferation of a set of 16 BRAF mutant melanoma- 
derived cell line models (Report RD-2011-50576). In vivo, this combination significantly 
increased the conditional survival of mice implanted with a BRAF-mutant primary human 
melanoma xenograft. Although most single agents, and all combination treatments effectively 
inhibited tumor growth, increased survival resulted from reductions in the overall rates (and in 


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some cases complete prevention) of the emergence of resistant tumors in the combination 
relative to the single agent treatment groups (Data on file). 
LGX818 (encorafenib, BRAFTOVI®) in combination with MEK162 (binimetinib, 
MEKTOVI®), has received marketing approval in several jurisdictions for the treatment of 
patients with BRAF-mutant melanoma, based on results from a Phase 3 clinical trial 
CMEK162B2301 (COLUMBUS). 
For further details on non-clinical experiences, refer to the current [LGX818 and MEK162 
Investigator’s Brochures] 
 
1.2.1.1.2 LGX818/MEK162 + BKM120 
Signaling through the PIK3C pathway, induced via RTK activation, PTEN loss, or activating 
alleles of PIK3Cα may also contribute to both intrinsic and acquired resistance to BRAF 
inhibitors and combinations of BRAF and MEK1/2 inhibitors in BRAF-mutant melanoma 
(Hodis 2012, Paraiso 2011, Villanueva 2010, Villanueva 2013). This observation provides a 
rationale for pairing RAF inhibitors and RAF/MEK inhibitor combinations with PIK3C 
inhibitors in some instances of clinical resistance. The effects of combining LGX818 with the 
pan-PIK3C inhibitor BKM120 have been measured in a set of BRAF-mutant melanoma cell 
lines in vitro. In these studies the combination inhibited proliferation in a moderately synergistic 
manner in a subset of cell lines (data on file). In vivo, this combination strongly inhibited the 
growth of the A-375 melanoma tumors implanted orthotopically into the brain of 
immunocompromised mice. Moreover, the combination improved the conditional survival of 
mice relative to comparable single agent treatments (data on file). 
Recently, (Villanueva et al 2013) reported that addition of a mTOR/PI3K inhibitor was able to 
overcome resistance to BRAF/MEKi combination in vivo. These data suggest that blockading 
PIK3CA-pathway signaling in combination with MAPK-pathway inhibition, either via single 
agent BRAF or combined BRAF/MEK1/2 inhibition may provide clinical benefit. 
For further details on non-clinical experiences, refer to the current [LGX818 and BKM120 
Investigator’s Brochures] 
 
1.2.1.1.3 LGX818/MEK162 + INC280 
Stimulation of the MAPK and/or the PIK3C pathways via RTK activation has been shown to 
confer resistance to BRAF inhibitors in melanoma-derived cell lines in vitro, and has been 
linked to resistance in the clinic (Nazarian 2010, Straussman 2012, Vergani 2011, 
Villanueva 2010, Wilson 2012). In particular, activation of the c-MET and FGFR family of 
RTKs have proven to robustly promote resistance to BRAF inhibitors in several melanoma 
models in vitro (Straussman 2012, Wilson 2012) (Novartis data on file). In addition to 
conferring resistance to RAF inhibitors, activation of c-MET by its cognate ligand HGF has 
also been demonstrated to confer resistance to a combination of the RAF inhibitor LGX818 and 
MEK1/2 inhibitor MEK162 in BRAFV600E mutant cell lines in vitro. Critically, in cell lines 
rendered resistant to LGX818 and the LGX818/MEK162 combination by exogenously added 
HGF, the addition of the c-MET inhibitor INC280 completely restored sensitivity to LGX818 
(Novartis data on file). 


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For further details on non-clinical experiences, refer to the current [LGX818 and MEK162 
Investigator’s Brochures] 
 
1.2.1.1.4 LGX818/MEK162 + BGJ398 
Ligand mediated activation of FGFRs can promote resistance to RAF inhibitors 
(Straussman 2012, Wilson 2012, RD-2013-50040). Moreover, FGFR activation is also able to 
confer resistance to the combination of LGX818 and MEK162 in BRAFV600E mutant models 
of melanoma (data on file). However, FGFR-activation-mediated resistance to both LGX818 
and the combination of LGX818 and MEK162 could be prevented via addition of the selective 
FGFR inhibitor BGJ398, which does not affect the growth of BRAFV600E cell lines as a single 
agent. These data suggest that BGJ398 could be useful in instances of FGFR-mediated 
resistance to combined RAF and MEK inhibition in the clinic. 
For further details on non-clinical experiences, refer to the current [LGX818, MEK162 and 
BGJ398 Investigator’s Brochures] 
 
1.2.1.1.5 LGX818/MEK162 + LEE011 
Several lines of evidence suggest that targeting the CDK4 and CDK6 kinases may be an 
effective means to combat resistance to RAF inhibitors and/or combinations of RAF and MEK 
inhibitors. First, the CyclinD/CDK4/6 complex represents a key downstream convergence point 
for many mitogenic signaling pathways including the RAS/RAF/MEK/ERK pathway. Elevated 
levels of cyclinD induced by activated signaling through this pathway serves to increase 
CyclinD/CDK4/6 activity and in doing so promotes transition from the G1 to S phases of the 
cell cycle as this complex is responsible for phosphorylating, and thereby inactivating, the 
tumor suppressor pRB. The majority of cases of clinical resistance to RAF inhibitors result in 
reactivated 
signaling 
and 
by 
extension 
re-establish 
cell 
proliferation 
via 
the 
CyclinD/CDK4/6/pRB axis. Second, CDK4/6 inhibitors have been demonstrated to effectively 
combine with inhibitors of RAF and MEK in preclinical models of melanoma that harbor BRAF 
and NRAS mutation, respectively, suggesting that such combinations behave in a manner akin 
to “dual vertical” pathway inhibition (Kwong et al 2012, RD-2012-50370, RD-2013-50169). 
Third, co-overexpression of the CDK4 and CCND1 genes is sufficient to confer resistance to 
BRAF inhibitors in BRAF-mutant cell lines in vitro (Smalley et al 2009). 
Combinations between LGX818, MEK162 and LEE011 have been examined in a variety of 
BRAFV600E melanoma cell lines including models engineered to express alleles of the NRAS, 
BRAF and MEK1 genes, known to promote resistance to RAF inhibitors in the clinic. In both 
the parental and engineered models, the addition of LEE011 to the LGX818/MEK162 
combination resulted in either additional synergistic or additive anti-proliferative effects. 
Collectively these data suggest that the CDK4/6 inhibitor LEE011 may be an effective means 
to combat resistance that emerges against the LGX818/ MEK162 as a result of pathway re- 
activation (RD-2013-50245). 
For further details on non-clinical experiences, refer to the current [LGX818, MEK162 and 
LEE011 Investigator’s Brochures] 


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1.2.1.2 
Clinical experience 
 
Clinical studies with combinations of MEK162 
The experience with MEK162 in cancer patients in combination studies comprises 8 ongoing 
Phase I studies with overall 216 patients as of 7 January 2013. MEK162 is combined with a 
PI3K inhibitor in [CMEK162X2101] (MEK162 and BKM120), and it is combined with RAF 
inhibitors in [CMEK162X2110] (MEK162 and LGX818). In addition, as of October 2013 
MEK162 is combined with LEE011 (inhibitor of CDK4/6), and enrolled 7 patients in 
[CMEK162X2114]. 
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. 
For further details, please refer to the current [MEK162 Investigator’s Brochure]. 
 
1.2.1.2.1 LGX818 + MEK162 and LGX818 + MEK162 + LEE011 
The ongoing clinical study [CMEK162X2110] is an open label, dose finding, phase Ib/II study 
to determine the maximum tolerated dose (MTD) and/or recommended dose for Phase II 
(RP2D) of LGX818 in combination with MEK162 in patients with locally advanced or 
metastatic melanoma, mCRC or any other solid tumor positive for a V600 BRAF mutation. 
As of March 8, 2013, enrolled patients were treated with LGX818 QD + MEK162 BID at the 
following dose levels (DLs): 50 mg + 45mg, 100 mg + 45 mg, 200 mg + 45 mg, 400 mg + 
45 mg, 450 mg + 45 mg, and 600 mg + 45 mg (Kefford et al 2013). 
At the time of data cutoff, 30 patients with BRAF V600 mutant tumors have been enrolled 
across 6 DLs. There were no dose-limiting toxicities (DLTs) in the first 5 DLs. One DLT was 
reported at the 600 mg + 45 mg DL (grade 3 alanine aminotransferase (ALT) elevation). 
The MTD has not yet been determined in this study and the dose of 450mg QD LGX818 + 
45mg BID MEK162 has been selected for further development. 
The LGX818 + MEK162 + LEE011 arm has been recently added to this study and started 
enrolling patients. 
A Phase 3 study comparing MEK162/LGX818 to LGX818 or Vemurafenib single agent has 
started in October 2013. 
 
Safety 
The combination of LGX818 and MEK162 in [CMEK162X2110] was well tolerated with no 
substantial increase in adverse events (AEs) for the combination vs single-agent therapy. The 
combination may decrease the severity and frequency of some on-target AEs common with 
BRAFi monotherapy including cutaneous toxicities (no events of HFSR, hyperkeratosis, and 
KA/SCC), myalgia, and arthralgia. No febrile or photosensitivity events have been reported to 
date. The most common AEs were grade 1/2 gastrointestinal toxicities, visual disturbances, 
headache, and fatigue. Five patients (16.7%) had grade 3 AEs suspected to be treatment related 
(2 with transaminase increases, 2 with lipase increase, 1 with retinal vein occlusion, and 1 with 
maculopapular rash). 


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In the on-going [CMEK162X2110] study, preliminary PK results indicated that there was no 
pharmacokinetic drug-drug interaction between LGX818 and MEK162. The PK exposures of 
LGX818 and MEK162 were similar to those observed in the corresponding monotherapy 
studies (see Section 1.2.3.2.1) 
 
Efficacy 
In [CMEK162X2110] the disease control rate was 100% for BRAFi naïve and 64% for BRAFi 
pretreated melanoma patients, 33% for mCRC (metastatic colorectal cancer) patients, and 100% 
for PTC (papillary thyroid carcinomas) patients. The overall response rate was 88% for BRAFi 
naïve and 18% for BRAFi pretreated melanoma patients and 67% for PTC patients. 
For further details on clinical experience, refer to the current [MEK162 Investigator’s 
Brochure]. 
 
1.2.1.2.2 BKM120 + MEK162 
Study [CMEK162X2101] is a Phase Ib, open-label, multi-center, dose escalation and expansion 
study of an orally administered combination of MEK162 plus BKM120 in adult patients with 
selected advanced solid tumors. The study is still ongoing. As of 07 January 2013, 48 patients 
had received at least one dose of MEK162 in combination with BKM120. As of the data-cutoff 
date, 40 patients had discontinued from the study and 8 were still ongoing in the dose escalation 
phase. Seven dose levels were evaluated. The most frequently reported treatment-related AEs 
regardless of Grade occurring in ≥ 10% of patients were CK elevation (56%), diarrhea (54%) 
and AST elevation (50%). Twenty-five (25) out of 48 enrolled patients (52%) experienced at 
least one CTCAE Grade 3-4 AE suspected to be treatment related. The most common treatment- 
related CTCAE Grade 3-4 AEs were CK elevation (19%) and maculo-papular rash (10%). 
Thirty-five out of 48 enrolled patients (73%) experienced one or more AEs requiring a dose 
interruption and/or reduction. Fifteen out of 48 enrolled patients (31%) experienced one or more 
AEs leading to discontinuation from the study. 
For further details on clinical experience, refer to the current [MEK162 Investigator’s 
Brochure]. 
 
1.2.1.2.3 MEK162 + LEE011 
[CMEK162X2114] is a phase Ib/II, multicenter dose escalation study of LEE011 in 
combination with MEK162 in adult patients with NRAS mutant melanoma. As of October 
2013, 7 patients were enrolled and DLTs include CTCAE Grade 3 elevated creatinine and a 
CTCAE Grade 4 CPK elevation. 
For further details on clinical experience, refer to the current [MEK162 and LEE011 
Investigator’s Brochures]. 
 
Clinical studies with combinations of LGX818 
 
1.2.1.2.4 LGX818 + LEE011 
[CLEE011X2105] is a phase Ib dose escalation study to estimate the MTD and/or RP2D for the 
combination of LEE011 and LGX818, followed by a Phase II study to assess the clinical 


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efficacy and to further evaluate the safety of the combination in patients with locally advanced 
or metastatic BRAF mutant melanoma. As of October 2013, 6 patients were enrolled; in two 
patients the following DLTs were observed: CTCAE Grade 3 myalgia and CTCAE Grade 3 
acute liver injury. In another patient CTCAE Grade 2 elevated creatinine was reported. 
For further details on clinical experience, refer to the current [LGX818 and LEE011 
Investigator’s Brochures] 
 
1.2.1.2.5 LGX818 in combination with MEK162, BKM120, BGJ398, INC280 or 
LEE011 
[CLGX818X2102] is a phase II, two part multi-center, open-label study in adult patients with 
locally advanced unresectable or metastatic BRAF V600 melanoma. Upon progression on 
single agent LGX818 in Part I of the study, patients are assigned to a combination treatment in 
Part II. Based on targeted sequencing of a tumor biopsy obtained at progression, patients are 
assigned to one of five combination arms: LGX818 + MEK162, BKM120, BGJ398, INC280, 
or LEE011 to assess the clinical efficacy and to further evaluate the safety of the drug 
combinations. As of 14th of November, this study has started enrolling patients. 
For further details on clinical experience, refer to the current [LGX818 Investigator’s Brochure] 
 
1.2.1.3 
Assessment of pharmacokinetic drug-drug interaction DDI 
Brief summaries of the potential drug-drug interactions between different study drug 
combinations are listed in Table 1-1. 
The single agent non clinical and clinical pharmacokinetics data are described in Section 1.2. 


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Table 1-1 
Summary of drug-drug interaction assessment between combination 
partners 
 
Combination 
Potential 
Perpetrators 
Potential Victims 
Assessments 
LGX818+MEK162 
LGX818 is a 
CYP3A4 
inducer. 
LGX818 is a 
CYP3A4 substrate 
No significant DDI observed 
so far in the LGX818 and 
MEK162 combination study 
MEK162X2110. 
LGX818+MEK162+BKM120 
LGX818 is a 
CYP3A4 
inducer. 
LGX818 and 
BKM120 are 
CYP3A4 substrates 
Simcyp simulation predicted 
minimal DDI between LGX818 
and BKM120. 
In the ongoing combination 
study CMEK162X2101, 
preliminary data showed no 
effect of BKM120 on the PK of 
MEK162 and its metabolite; 
mean Cmax and AUC of 
BKM120 were reduced by 
more than 50% when given in 
combination with MEK162 
LGX818+ 
MEK162+BGJ398 
BGJ398 is a 
TDI (time 
dependent 
inhibitor) of 
CYP3A4. 
LGX818 is a 
CYP3A4 
inducer. 
LGX818 and 
BGJ398 are 
CYP3A4 substrates 
Simcyp simulation predicted 
minimal change in LGX818 
exposure and reduced 
BGJ398 exposure. 
Change in the PK of MEK162 
and its metabolite is expected 
to be minimal. 
LGX818+ MEK162+INC280 
INC280 is a 
strong TDI of 
CYP3A4. 
LGX818 is a 
CYP3A4 
inducer. 
LGX818 and INC280 
are CYP3A4 
substrates 
Simcyp simulation predicted 
increased LGX818 exposure 
and reduced INC280 
exposure. 
Change in the PK of MEK162 
and its metabolite is expected 
to be minimal. 
LGX818+ MEK162+LEE011 
LEE011 is a 
TDI of 
CYP3A4. 
LGX818 is a 
CYP3A4 
inducer. 
LGX818 and 
LEE011 are CYP3A4 
substrates 
Simcyp simulation predicted 
increased LGX818 exposure 
and reduced LEE011 
exposure. 
Change in the PK of MEK162 
and its metabolite is expected 
to be minimal. 
 
1.2.2 
Overview of single agent LGX818 
 
1.2.2.1 
Non-clinical experience 
 
1.2.2.1.1 Non-clinical pharmacodynamics 
LGX818 is a highly selective ATP-competitive small molecule RAF kinase inhibitor, which 
suppresses the RAF/MEK/ERK pathway in tumor cells expressing BRAFV600E. 


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Similar to the in vitro profile of LGX818, its 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 pharmacodynamics, please refer to the current [LGX818 Investigator’s 
Brochure]. 
 
1.2.2.1.2 Non-clinical pharmacokinetics and metabolism 
The oral bioavailability (F) of encorafenib was ~40 to~50% in the mouse, rat, and dog. In the 
monkey ADME study F was low (22%). Encorafenib showed low plasma clearance (CL) in the 
rat and mouse and a moderate to high plasma clearance in the monkey and dog. The estimated 
volume of distribution at steady state (Vss) was low in the rodents and moderate in the dog and 
monkey. In the monkey 13-week toxicity study, encorafenib increased proportionally with dose 
and no accumulation upon multiple dosing. 
Encorafenib is a substrate of P-glycoprotein (P-gp) with a high apparent passive permeability. 
Binding to human plasma proteins was ~86%. 
Distribution into rat tissues was rapid. There was no distribution to the central nervous system 
(brain and spinal cord) and no retention in the melanin-rich tissues. For all species investigated, 
monohydroxylation, N-dealkylation and subsequent glucuronidation represented the major 
metabolic pathways. Glucuronidation, both direct and indirect, occurred more readily in human 
than in other species. Encorafenib is metabolized by CYP3A4, CYP2C19 and CYP2D6. 
CYP3A4 was predicted to be the major enzyme contributing to total oxidative clearance of 
encorafenib in human liver microsomes (~83.3%), followed by CYP2C19 and CYP2D6 
(~16.0% and 0.71%, respectively). 
The predominant route of excretion of [14C] encorafenib in monkeys was via fecal excretion 
while the urinary excretion was a minor route of elimination. Encorafenib is predominantly 
excreted as metabolites. 
In vitro experiments indicate that encorafenib is a relatively potent reversible inhibitor of 
UGT1A1, CYP2B6, CYP2C9, and CYP3A4/5, and also a time-dependent inhibitor of 
CYP3A4. Encorafenib induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary 
hepatocytes. Finally, encorafenib was found to be a weak inhibitor of BCRP, and a potent 
inhibitor of renal transporters OCT2, OAT1, OAT3 and hepatic transporters OCT1,OATP1B1 
and OATP1B3. 
For further details on non-clinical pharmacokinetics and metabolism, please refer to the current 
[LGX818 Investigator’s Brochure]. 
 
1.2.2.1.3 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 dose 
of 400 mg/kg/day, a dose well above the MTD. Other findings included hyperplasia and 


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hyperkeratosis in the skin (plantar surface of feet) and non-glandular stomach in rat, which was 
apparent at all dose levels and presented with recovery 4 weeks after stopping treatment, and 
an absence of the later stages of spermatid maturation in the male rats. In the 13-week monkey 
toxicology study (No. 1370471) 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. 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-week GLP rat and monkey studies that would indicate an effect on the central nervous 
system or respiratory system. 
No teratogenicity studies have been completed to date. There were no effects in a rat safety 
pharmacology study on the CNS or respiratory system. 
For further details on non-clinical pharmacology and toxicology, please refer to the current 
[LGX818 Investigator’s Brochure]. 
 
1.2.2.1.4 Genotoxicity study 
For details on non-clinical pharmacology and toxicology, please refer to the current [LGX818 
Investigator’s Brochure]. 
 
1.2.2.2 
Clinical experience 
 
1.2.2.2.1 Clinical safety and efficacy 
As of 11 May 2019, a total of 1549 healthy subjects and patients had received LGX818 either 
as a single agent or in combination with other targeted agents. These patients constitute the 
LGX818 safety population, which includes 97 healthy subjects, 7 subjects with hepatic 
impairment and 1445 patients with advanced cancer (410 patients who received single-agent 
LGX818 and 1046 patients who received encorafenib combination therapy, with 11 patients 
who received both single-agent LGX818 and LGX818 + MEK162 combination therapy and 4 
patients who received LGX818 + MEK162 combination therapy in 2 different studies). 
For further details, please refer to the current [LGX818 (encorafenib) Investigator’s Brochure]. 
 
1.2.2.2.2 Clinical pharmacokinetics 
The human ADME study in healthy subjects showed that encorafenib is at least 86% absorbed 
based on recovered radioactivity and has a preferential distribution to plasma as compared to 
blood. The predominant biotransformation reaction of encorafenib was N-dealkylation (other 
major metabolic pathways involved hydroxylation, carbamate hydrolysis, indirect 
glucuronidation and glucose conjugate formation.). The most abundant circulating component 
was encorafenib, ranging from 17.9% to 36.4% of the radioactivity in plasma. 
Encorafenib was mainly eliminated via metabolism, with low levels of unchanged encorafenib 
detected in urine and feces. The dose was equally recovered in urine and feces (47.2% in each 
matrix) and the renal clearance was estimated to be 1.8%. 


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Encorafenib as a single-agent in patients with locally advanced or metastatic BRAF-mutant 
melanoma [CLGX818X2101] in the dose-escalation phase showed that the Day 15 exposures 
were consistently decreased by 30 to 60% compared to those at Day 1, probably due to induction 
of CYP450 enzymes. AUC and Cmax ratios at steady state (Day 15) relative to Day 1 did not 
appear to change with dose. The dose expansion phase in patients with locally advanced or 
metastatic BRAF-mutant melanoma or metastatic colorectal cancer (mCRC) showed exposure 
of encorafenib in terms of Cmax and AUCtau was within the range observed at the 300-mg 
dose level for the dose-escalation phase. The results of the dose-proportionality assessment in 
patients with locally advanced or metastatic BRAF-mutant melanoma suggest that encorafenib 
exposure was approximately dose proportional over the dose range studied. In combination 
studies, when administered with binimetinib, PK parameters of encorafenib were similar to 
those observed in the single-agent study. When co-administered with cetuximab and BYL719, 
the mean Cmax and AUC of encorafenib at steady state were higher when co-administered with 
higher doses of BYL719. Encorafenib 200 mg in combination with 300 mg LEE011, showed 
that exposure of encorafenib was higher than single-agent data, though the available data is 
limited. When encorafenib 200 mg was dosed in combination with escalating doses of LEE011 
and binimetinib 45 mg, the AUC and CL/F of encorafenib was higher on Day 1 at higher doses 
of LEE011. This was not observed at steady state. The possibility of drug-drug interactions in 
combinations requires further assessment. 
For further details on clinical pharmacokinetics, please refer to the current [LGX818 
Investigator’s Brochure] 
 
1.2.3 
Overview of single agent MEK162 
 
1.2.3.1 
Non-clinical experience 
 
1.2.3.1.1 Non-clinical pharmacodynamics 
MEK162 is a potent and highly selective allosteric, ATP competitive inhibitor of MEK1/2. 
Overall, single agent anti-tumor activity of MEK162 has been demonstrated in vivo in xenograft 
models derived from a variety of cancer types including melanoma, CRC, pancreatic, and lung, 
that harbor an array of know oncogenic drivers including (but not limited to) activating lesions 
in BRAF, NRAS and KRAS. 
Overall, MEK162 has demonstrated potent activity against MEK1/2 and broad anti- 
proliferative activity in vitro and in vivo. 
For further details on pharmacodynamics, refer to the current [MEK162 Investigator’s 
Brochure]. 
 
1.2.3.1.2 Non-clinical pharmacokinetics and metabolism 
The oral bioavailability (F) in rat and monkey absorption, distribution, metabolism and 
excretion (ADME) studies is moderate (48%) and similar to the fraction absorbed (based on 
radioactivity excreted) suggesting a minimal first pass effect. Binimetinib shows a low total 
systemic plasma clearance and volume of distribution at steady state after intravenous (IV) 
administration. Mean plasma terminal half-life (T1/2) ranges from 2 to 9 hours in preclinical 
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In vitro experiments indicate that binimetinib has moderate to high membrane permeability and 
is a substrate of P-gp and BCRP. 
Binimetinib is highly bound to plasma proteins (humans: 97.2%). 
Binimetinib is more distributed in plasma than blood. The blood-to-plasma concentration ratios 
of binimetinib ranges from 0.652 to 0.994 in the species tested. In humans, the blood-to-plasma 
ratio is 0.718. 
[14C]-Binimetinib-derived radioactivity is absorbed and widely distributed to tissues in both 
pigmented rats and albino rats following a single oral (PO) dose. 
With multiple routes of metabolism, binimetinib is metabolized primarily by glucuronidation 
pathways (mainly via UGT1A1, 1A3 and 1A9) and to a lesser extent by oxidation pathways 
(mainly via CYP1A2 and 2C19). UGT1A1 was shown to be the major contributor (90%) to the 
formation of the direct glucuronide. 
Following IV dosing in the rat, fecal and urinary excretion accounts for 46% and 45% of total 
radioactivity, respectively. Approximately 15% of binimetinib is excreted unchanged in urine 
and 16 % in feces. Total recovery of radioactivity in the excreta of monkey is 99% and 85% 
following PO and IV dosing, respectively. The most abundant drug-related components in 
monkey excreta included binimetinib, the 2 glucuronides and the amide. 
In vitro, binimetinib reversibly inhibits CYP2B6 and is a weak reversible inhibitor of CYP1A2 
and CYP2C9. Binimetinib is not considered a time-dependent inhibitor of CYP1A2, CYP2C9, 
CYP2D6 or CYP3A4/5. Binimetinib induces CYP3A, but this was not confirmed in a human 
DDI study. 
For detailed information regarding non-clinical pharmacokinetics, refer to the [MEK162 
Investigator’s Brochure]. 
 
1.2.3.1.3 Non-clinical safety pharmacology and toxicology 
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies 
were completed to support the chronic administration of MEK162 to adult cancer patients. The 
toxic effects of MEK inhibitors in humans are similar to the toxic effects observed in monkeys. 
The toxic effects include gastro-intestinal intolerance and diarrhea, rash, central serous 
retinopathy (only seen in humans) and retinal vein occlusion (rarely seen in humans). In vitro 
and in vivo phototoxicity studies conducted in mice indicate that MEK162 has a very low risk 
of weak phototoxic potential at therapeutic doses. Furthermore, there has been no evidence of 
phototoxicity or photosensitivity in humans being treated with MEK162 for cancer or for 
rheumatoid arthritis. This includes 686 patients and healthy volunteers who have received at 
least one dose of MEK162 and is based on data as of January 7, 2013. 
For details on non-clinical safety pharmacology and toxicology, refer to the current [MEK162 
Investigator’s Brochure]. 


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1.2.3.1.4 Genotoxicity study 
Teratogenic effects were seen in rats and rabbits. MEK162 should not be used in pregnant 
women and women of child-bearing potential must be advised to use highly effective 
contraception methods. 
For details on non-clinical safety pharmacology and toxicology, refer to the current [MEK162 
Investigator’s Brochure]. 
 
1.2.3.2 
Clinical experience 
 
1.2.3.2.1 Clinical safety and efficacy 
As of 20 January 2019, a total of 2907 healthy subjects and patients had received at least 
MEK162 either as a single agent or in combination with other targeted agents, standard 
chemotherapy agents or immunomodulating agents. These patients constitute the MEK162 
safety population, which includes 229 healthy subjects, 17 subjects with hepatic dysfunction, 6 
subjects with renal dysfunction, 164 patients with rheumatoid arthritis and 2491 patients with 
advanced cancer. 
For further details, please refer to the current [MEK162 (binimetinib) Investigator’s Brochure]. 
 
1.2.3.2.2 Clinical pharmacokinetics 
The pharmacokinetics of binimetinib are characterized by moderate to high variability, 
accumulation of approximately 1.5-fold, and steady state concentrations reached within 15 
days. Binimetinib has been shown to be approximately dose proportional (study 
[ARRY-162-111]). The human ADME study showed that about 50% of binimetinib dose is 
absorbed. The primary metabolic pathways include glurucronidation (up to 61.2% via 
UGT1A1), N-dealkylation, amide hydrolysis (up to 17.8% via CYP1A1 and CYP2C19). The 
excretion route is 31.7% of unchanged binimetinib in feces and 18.4% in urine. Estimated renal 
clearance of unchanged binimetinib is 6.3% of total dose. The impact of UGT1A1 inhibitors or 
inducers has not been clinically assessed. 
Food-effect clinical studies have shown influence of food on PK of binimetinib is mild and not 
clinically relevant; therefore, binimetinib can be taken with food. A drug interaction study with 
binimetinib and midazolam was conducted; the results suggest that continuous intake of 
binimetinib produces no relevant CYP3A4 induction. Binimetinib solubility in vitro has been 
shown to be pH dependent but the effects of the impact of pH modifying agents on the PK of 
binimetinib in vivo is unknown. In vitro studies also demonstrated that binimetinib is a P-gp 
and BCRP substrate, but the effects of inhibitors of these substrates on the PK of binimetinib in 
vivo is unknown. In the cases where the extent of a drug interaction is unknown, it is 
recommended to co-administer drugs with caution. 
A hepatic impairment study is on-going, preliminary results indicate that the exposure of 
binimetinib in healthy subjects and those with mild hepatic impairment is comparable. Exposure 
in moderate and severe hepatic impairment is to be determined. 
For further details on clinical pharmacokinetics, refer to the current [MEK162 Investigator’s 
Brochure]. 


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1.2.4 
Overview of single agent BKM120 
 
1.2.4.1 
Non-clinical experience 
 
1.2.4.1.1 Non-clinical pharmacodynamics 
NVP-BKM120 (BKM120) is a potent oral pan-class I PI3K inhibitor that is a 2,6-dimorpholino 
pyrimidine derivative. BKM120 inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50-fold 
selectivity towards this target compared to other protein kinases as well as against somatic 
PI3Kα activating mutants (H1047R-, E542K-, and E545K-p110α). 
For further details on non-clinical pharmacodynamics, refer to the current [BKM120 
Investigator’s Brochure]. 
 
1.2.4.1.2 Non clinical pharmacokinetics and metabolism 
In animals, BKM120 has moderate to high bioavailability, moderate volume of distribution and 
was found to cross the blood brain barrier in rats with a tissue-to-plasma ratio of about 2. 
BKM120 is moderately bound to plasma protein across all species examined (fup in human 
plasma of about 15%). 
Oxidative metabolism of BKM120 is predominantly mediated by CYP3A4 (estimated fraction 
metabolized >0.9). Direct phase II metabolism (glucuronidation) via UGT1A4 is also observed 
in human liver microsomes supplemented with UDPGA. Recombinant human CYP1A1 also 
has the capacity to metabolize BKM120. However, its endogenous expression in the human 
liver is negligible and therefore it should not have any impact on hepatic BKM120 metabolism. 
BKM120 was identified to be a weak reversible inhibitor of CYP3A4 (Ki 13.6 μM,) and it also 
weakly inhibited the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 35- 
65 μM. BKM120 did not show time dependent inhibition of CYP450 enzymes. Experiments 
also showed a potential for BKM120 to induce UGT1A1 at concentrations between 0.5 and 100 
µM. 
BKM120 is neither an inhibitor nor a substrate of P- gp, MRP-2, BCRP, or OCT2. BKM120 
can inhibit hMATE1 and hMATE2K in vitro at concentrations above 10 µM. 
Further information on the non-clinical pharmacokinetics may be found in the [Investigator’s 
Brochure for BKM120]. 
 
1.2.4.1.3 Safety pharmacology and toxicology 
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory 
functions. Cardiac safety studies, conducted in vitro and in vivo did not indicate a prominent 
electrophysiological risk. No relevant electrophysiological effect was seen in dogs. The only 
effect considered relevant was a trend towards an increase in systolic and diastolic blood 
pressure, which was observed in two dog telemetry studies. In rats and dogs, clinical pathology 
and histopathology findings showed quantitative reductions of lymphoid and erythroid counts 
and lymphoid tissue hypoplasia. The pancreas was seen to be affected by treatment with 
BKM120, particularly in dogs, where acinar cell toxicity was seen in the exocrine part of this 
organ. At higher doses in the 2-week dose-range-finding study in rats, there were 


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histopathological findings in both the endocrine as well as the exocrine pancreas. Male sexual 
organs and associated tissues were found to be targets of toxicity in both rats and dogs. Changes 
included minimal to slight germ cell depletion, formation of spermatic giant cells and abnormal 
spermatids, and cellular debris in epididymal tubules. Testicular toxicity did not fully reverse 
after the 4-week treatment-free period in rats (highest dose), although a clear trend towards 
recovery was seen. In individual female rats, minimal to slight cyst formation occurred in the 
Graafian follicles. In dogs, there was no effect on female sexual organs. Glucose homeostasis 
was affected in various species (mice, rats, dogs), as expected from the mode of action of 
BKM120. However, these effects were minimal in both rats and dogs at the doses used in the 
4-week studies. 
Further information on the safety pharmacology and toxicology may be found in the 
[Investigator’s Brochure for BKM120]. 
 
1.2.4.1.4 Genotoxicity study 
No evidence for a direct DNA interaction was found in an Ames test and two chromosome 
aberration tests in vitro with BKM120. However, a potential for genotoxicity was identified 
based on the observation of an aneugenic potential and was confirmed by fluorescence in situ 
hybridization of centromeric sequences within micronuclei induced in human peripheral 
lymphocytes in vitro. In summary, evidence of a genotoxic potential with BKM120 has been 
seen in vitro and in vivo and is likely due to an aneugenic effect. 
 
1.2.4.2 
Clinical experience 
As of 15 September 2013, approximately 1469 patients and healthy volunteers have been 
enrolled into twenty two Novartis sponsored clinical studies of BKM120, including 3 blinded 
phase II and III studies. 
The maximum tolerated dose (MTD) was determined to be 100 mg/day BKM120 in Caucasian, 
Japanese and Chinese patient population. The recommended Phase II dose (RP2D) was 
confirmed at 100mg daily for Caucasian and for Japanese population and is under evaluation in 
Chinese patients. 
For further details, refer to the current [BKM120 Investigator’s Brochure]. 
 
1.2.4.2.1 Clinical safety and efficacy 
As of 15 September 2013, DLTs events were reported in 3 single agent trials. In 
[CBKM120X2101] (62 patients) 9 DLTs were observed in 9 patients: 2 grade 4 hyperglycemia 
(150 mg/d), 1 grade 3 hyperglycemia (100 mg/d), 1 grade 3 arthralgia (100 mg/d), 1 grade 3 
abdominal pain upper (100 mg/d), 1 grade 3 rash (100 mg/d), 1 grade 3 mood altered (100 
mg/d), 1 grade 2 mood altered (100 mg/d), 1 grade 2 mood altered (80 mg/d). In 
[CBKM120X1101] (15 patients) 1 DLT was observed: 1x grade 4 hepatic function abnormal 
(100 mg/d). In [CBKM120Z2102] (24 patients) 1 DLT was observed: 1 x grade 3 depression 
(80 mg/d). Most frequent events in single agent BKM120 studies (occurring in about ≥ 20% of 
patients) include, but may not be limited to: nausea, vomiting, diarrhea, decreased appetite, 
hyperglycemia, abdominal pain, constipation, asthenia, fatigue, macular-papular rash with or 
without pruritus, mucosal inflammation including stomatitis, increase in liver transaminases, 


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anxiety and depression. Other frequent events (about ≥10% of patients) include: anemia, altered 
mood, confusion, dizziness, headache, insomnia, dry skin, back pain, arthralgia, cough, 
peripheral 
edema, 
dyspepsia, 
fever, 
hypokalemia, 
hyponatremia, 
hypocalcemia, 
hypophosphatemia, eosinophilia, increase in blood alkaline phosphatase, lipase increase, 
dysgeusia and dyspnea. Other uncommon events are described in the current [BKM120 
Investigator’s Brochure]. 
In the [CBKM120X2101] study in adult patients with advanced solid malignancies, as of 
15 September 2013 and among 83 patients analyzed, the best overall response according to 
RECIST criteria reported as per investigator assessment was as follows: partial response 1 
patient (1.2%), stable disease 33 patients (39.8%), progressive disease 38 patients (45.8%), and 
unknown 11 patients (13.3%). 
In the [CBKM120C2201] study in patients with advanced endometrial carcinoma, as of 
15 September 2013, out of 70 patients analyzed, the best overall response distribution according 
to RECIST criteria reported as per investigator assessment was: complete response 1 patient 
(1.4%), partial response 1 patient (1.4%), stable disease 26 patients (37.1%), progressive 
disease 29 patients (41.4%), and unknown 13 patients (18.6%). 
For further details on clinical efficacy data of BKM120, refer to the current [BKM120 
Investigator’s Brochure]. 
 
Liver toxicity 
Approximately 25 to 45% of patients treated with single agent BKM120 reported liver toxicity 
(all grades, regardless of study drug relationship, 100 mg/d dose) based on a search of multiple 
MedDRA event terms (e.g. SMQ preferred terms). The incidence of grade 3 and 4 events was 
approximately 10 to 30%. Liver function test (LFT) alterations observed during ongoing and 
completed studies have been mostly transaminase enzyme increases (ALT and/or AST). Data 
suggest a slightly higher rate of grade 3 and 4 liver enzyme elevations in Japanese patients 
(44%) in the [CBKM120X1101] study, however, the number of patients treated at 100 mg in 
this study was limited (n=9). Transaminase elevations typically occur during the first 6 to 8 
weeks of treatment start. 
Although transaminase increases are relatively common, only a few of the patients had other 
simultaneous observations related to impaired liver function (e.g. bilirubin increase or clinical 
symptoms). 
Based on these findings, guidelines to monitor and follow patients with LFT alterations 
(including dose and schedule modifications) have been implemented. 
A recent liver safety review across Novartis-sponsored trials with BKM120 identified several 
potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT >3.0 x ULN and TBIL >2.0 
x ULN at any time during the treatment, regardless of causality. Upon medical review, most of 
these cases occurred in the context of disease progression in terminally ill, advanced cancer 
patients and/or were confounded by other causes. However, six of these DILI candidates were 
consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and TBIL >2.0xULN in the 
absence of cholestasis and other explanatory causes) with probable causal relationship to study 
treatment. Five of these cases were enrolled in study CBKM120F2302 in combination with 
fulvestrant, and one in combination with the investigational drug LDE225 (sonidegib). All 


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patients have recovered upon treatment discontinuation except one patient for whom no data is 
available since the patient refused to return for safety follow-up. 
 
1.2.4.2.2 Clinical pharmacokinetics and metabolism 
The pharmacokinetic data reveals that BKM120 single agent is rapidly absorbed after oral 
administration with a median time to reach maximum concentration (Tmax) between 0.5 and 3 
hours at steady-state. The variability in exposure and maximum plasma concentration (Cmax) 
at steady-state for the maximum tolerated dose (MTD) of 100 mg qd is moderate: 33% and 28% 
respectively. BKM120 accumulated in a linear fashion (~ 3-fold) and reached steady-state after 
8 days of treatment. At steady-state the median accumulation half-life was estimated between 
35.7 hours and 58.5 hours, calculated based on an accumulation ratio between 3 and 4-fold 
For further details on pharmacokinetics and metabolism of BKM120, refer to the current 
[BKM120 Investigator’s Brochure]. 
 
1.2.5 
Overview of single agent BGJ398 
 
1.2.5.1 
Non-clinical experience 
 
1.2.5.1.1 Non-clinical pharmacodynamics 
BGJ398 is orally bio-available, selective and ATP competitive pan FGFR kinase inhibitor 
which has demonstrated anti-tumor activity in preclinical, in vitro and in-vivo-xenograft tumor 
models. 
In mice, BGJ398 administered p.o. at doses of 10 to 50mg/kg qd for 7 days shows a significant, 
dose-dependent anti-tumor activity against NIH3T3/FGFR3S249C and NIH3T3/FGF- 
R3K650E xenografts, with stasis and regression at doses ≥ 30 mg/kg qd. In rats, BGJ398 led to 
a dose-dependent inhibition of RT112 tumor growth with tumor stasis/regression at 10mg/kg 
qd. 
For further details on non-clinical pharmacodynamics, refer to the current [BGJ398 
Investigator’s Brochure]. 
 
1.2.5.1.2 Non-clinical and pharmacokinetics and metabolism 
In all species tested, BGJ398 exhibited a high plasma CL and a large Vss. The compound is 
highly bound to plasma proteins (~ 98%) but does not preferentially distribute to red blood cells. 
BGJ398 is widely distributed to tissues in the rat and has a high affinity to melanin containing 
tissues. 
In human liver microsomes, BJG398 is mainly metabolized by CYP3A4/5 with partial 
contribution by FMO3 (6%).The major circulating component in rat plasma after a single [14C] 
BGJ398 dose was parent compound, accounting for 35.7% (i.v.) and 25.9% (p.o.). There were 
two main biotransformations in all species investigated: N-oxidation and N-deethylation to 
yield the pharmacologically active metabolites BQR917 and BHS697, respectively. The 
predominant reaction in dog was N-oxidation while N-deethylation was the main 
biotransformation product in rat and human. Minor reactions were observed in rat and human 
included glucuronic acid and glutathione conjugation. BGJ398 is a potent reversible inhibitor 


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of CYP3A4 (Ki 0.26µM). The compound also reversibly inhibits CYP2C9 and CYP2C19 with 
Ki values of 6.09µM and 4.1µM, respectively. BGJ398 was found not to be a CYP3A4 inducer 
at concentrations up to of 10 μM. 
BGJ398 is a P-gp and BCRP substrate and also inhibits BCRP mediated transport with an IC50 
value of 0.21µM. 
The active metabolite CQM157 showed a reversible CYP inhibition profile similar to BGJ398. 
CQM157 was shown to be a potent inhibitor of CYP2C8, CYP2C9 and CYP3A4 (IC50 less 
than 10 µM) and CYP2C19 (IC50 12 µM). CQM157 was not a time dependent inhibitor of 
CYP1A2, 2C9, 2D6 and 3A4/5.CQM157 was found to be an inhibitor of P-gp with an IC50 of 
2.7 µM and of BCRP with an IC50 of 3.4 µM and uptake transporters OATP1B1 with an IC50 
of 3.5 µM and of OATP1B3 with an IC50 of 2.8 µM. Active metabolite BHS697 did not inhibit 
efflux transporters P-gp and BCRP and was an inhibitor of OATP1B1 (IC50 = 6.0 µM) and 
OATP1B3 (IC50 = 1.6). 
For further details on nonclinical drug metabolism and pharmacokinetics, refer to the current 
[BGJ398 Investigator’s Brochure]. 
 
1.2.5.1.3 Non-clinical safety and genotoxicity 
In conclusion, multiple biological effects were observed in nonclinical safety studies and mainly 
consisted of effects on the phosphate and/or calcium homeostasis, corneal opacity associated 
with keratopathy, ectopic mineralization, changes in renal function parameters, bone growth 
plate thickening / retention of the primary spongiosa and a potential for QTc prolongation. 
For further details on non- clinical safety pharmacology and toxicology, refer to the current 
[BGJ398 Investigator’s Brochure]. 
 
1.2.5.2 
Clinical experience 
 
1.2.5.2.1 Clinical safety and efficacy 
The treatment emergent adverse events as of the cutoff date of 24 September 2013 that were 
suspected to be related to BGJ398 that occurred in 20% or more of patients who received 
BGJ398 in [CBGJ398X2101] study are increases in phosphorous levels (71.3%) decreased 
appetite (26.6%), fatigue (25.5%), stomatitis (24.5%), and alopecia (21.3%). Twenty-eight 
percent of patients (26/94) experienced a least one suspected related grade 3 or 4 event, which 
is consistent with the value reported in the previous version of the IB (24.4%, 11/45 patients). 
Overall, most adverse events reported have been mild to moderate in severity, reversible, and 
unrelated to BGJ398. 
Ten of the 94 patients who received BGJ398 experienced a total of 15 adverse events during 
the first cycle of treatment that met the protocol-defined DLT criteria. Of these events, four 
occurred in four patients enrolled in the dose escalation part of the study. The MTD has been 
determined as125mg QD. 
None of the 18 patients treated with BGJ398 at 125 mg QD on the 3 week on/1 week off dosing 
regimen  have  experienced  a  DLT.  Furthermore  fewer  dose  interruptions  due  to 


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hyperphosphatemia occurred in patients enrolled to this cohort. Subsequently this intermittent 
schedule is considered the RP2D for BGJ398. 
Preliminary antitumor efficacy has been detected in patients with FGFR1-amplified lung SCC, 
FGFR1-amplified squamous cell carcinoma of the head and neck, FGFR1-amplified breast 
cancer, FGFR3-mutated bladder cancer, and cholangiocarcinoma with FGFR2 gene fusion. 
While all patients who responded had increases in blood phosphorous levels, not all patients 
who experienced increases in blood phosphorous levels responded to treatment with BGJ398. 
For further details on clinical efficacy, refer to the current [BGJ398 Investigator’s Brochure]. 
 
1.2.5.2.2 Clinical pharmacokinetics 
As of 24 September 2013, the pharmacokinetics (PK) of BGJ398 and active metabolites were 
evaluated following single and repeat daily doses in the ongoing phase 1 study 
([CBGJ398X2101]). 
The median apparent Tmax value across all dose levels tended to be 2-3 hours post-dose. 
Accumulation was observed following multiple doses. The mean Cmax and AUC0-24 for Cycle 
1 Day 1 at 125 mg was 111 ng/mL and 816 h.ng/mL and for Cycle 1 Day 15 was 318 ng/mL 
and 5301 h.ng/mL respectively. The mean AUC0-24 ratios between Cycle 1 Day 1 and Cycle 
1 Day 15 ranged between 1.5 to 6.5, indicating some changes in BGJ398 exposure following 
multiple dosing. The inter-patient variability was moderate to high for BGJ398. 
For further details on clinical pharmacokinetics, refer to the current [BGJ398 Investigator’s 
Brochure]. 
 
1.2.6 
Overview of single agent INC280 
 
1.2.6.1 
Non-clinical experience 
 
1.2.6.1.1 Non-clinical pharmacodynamics 
INC280 is a small ATP competitive, reversible inhibitor of the c-MET receptor tyrosine kinase. 
The proto-oncogene c-MET, a member of the receptor tyrosine kinase family, encodes the high- 
affinity receptor for hepatocyte growth factor (HGF), the only ligand for the receptor. 
INC280 possesses potent inhibitory activity against the c-MET kinase in vitro (IC50 = 0.13 ± 
0.05 nM) and is both ATP competitive and reversible (Liu et al 2011). INC280 is highly specific 
for c-MET with > 10,000-fold selectivity over a panel of 56 other human kinases tested. 
Collectively, the data demonstrate that INC280 possesses potent in vitro and in vivo 
pharmacological activity against c-MET dependent advanced solid tumors. 
More detailed information can be found in the current [INC280 investigator’s brochure]. 
 
1.2.6.1.2 Non-clinical pharmacokinetics and metabolism 
INC280 is highly bound to human plasma protein. After a single oral dose of [14C]-INC280 in 
rats, radioactivity was widely and rapidly distributed into all tissues. INC280 penetrates the 
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INC280 is predominantly metabolized by cytochromes P450. CYP3A4 is the major P450 
enzyme to metabolize INC280 (~fm 99.6%) with very low contribution from other enzymes 
(~0.4%). Other than CYP3A4, the strong metabolic activity of recombinant CYP1A1 was also 
identified. The hydroxylated metabolite M8 and the imidazo-triazinone M16 were two 
prominent metabolites in hepatocyte incubations of all species except for the dog, and were the 
main metabolites observed in rat plasma, feces and urine. Information on metabolism and drug- 
drug interaction potential of M8 and M16 is not available. 
INC280 showed inhibitory potency in vitro against CYP1A2 (IC50 = 20 µM; KI = 18.5 µM, 
kinact = 0.033 min-1), 2C8 (IC50 = 1.7 µM), 2C9 (IC50 = 7.6 µM), 2C19 (IC50 = 11.3 µM) and 
3A4/5 (IC50 = 9.9 µM; KI = 13.2 µM, kinact = 0.030 min-1). 
INC280 also displayed inhibition of MDR1/P-gp, MXR/BCRP, OATP1B1 and OATP1B3 
mediated substrate efflux or uptake with IC50 values of 12, 16.4, 6.5 and 6.2 µM, respectively. 
For further details on non-clinical metabolism and pharmacokinetics, refer to the current 
[INC280 Investigator’s Brochure]. 
 
1.2.6.1.3 Non-clinical safety and toxicology 
Repeat dose toxicity studies conducted revealed the following target organs or systems: 
kidneys, pancreas, central nervous system (CNS), and potentially liver data are summarized in 
the IB. Additionally; INC280 has shown photosensitization potential in in vitro and in vivo 
assays. 
For further details on non-clinical safety and toxicology, refer to the current [INC280 
Investigator’s Brochure]. 
 
1.2.6.1.4 Genotoxicity 
INC280 is not genotoxic. INC280 is considered potentially teratogenic to human. Therefore, 
males must be willing to abide by protocol permitted methods of contraception to avoid 
fathering a child from the time of screening through follow-up. Women of child-bearing 
potential who agree to participate in initial clinical studies must agree to abide by permitted 
methods of contraception defined in the clinical protocol to avoid pregnancy from screening 
through follow-up. 
For further details on genotoxicity, refer to the current [INC280 Investigator’s Brochure]. 
 
1.2.6.2 
Clinical experience 
 
1.2.6.2.1 Clinical safety and efficacy 
The INC280 film-coated tablet formulation has been developed and tested to improve patient 
convenience and compliance over the INC280 capsule formulation. 
 
As of 28-Sep-2015 (cut-off date of the INC280 Investigator’s Brochure, edition 6), 
a total of 500 cancer patients and 90 non-cancer subjects have received INC280. A total of 271 
patients with solid tumors have been treated with INC280 as a single agent (198 patients 
received the capsule formulation only, 66 patients received tablet formulation only, and 7 


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patients switched from capsule to tablet formulation during treatment with INC280), and 229 
patients have been treated with INC280 in combination therapies (139 patients received the 
capsule formulation only and 90 patients received tablet formulation only). In addition, 90 non- 
cancer subjects have received INC280 (6 subjects received the capsule formulation only, 60 
subjects received the tablet formulation only, and 24 subjects received both capsule and tablet 
formulations). 
Overall, the majority of the reported AEs are of mild or moderate severity. 
The most frequent AEs suspected to be related to INC280 of any grade reported in the 
[CINC280X2102] study, which is considered as the reference study for the safety profile of 
INC280 as a single agent, were nausea (38 patients [32.2%]), vomiting (31 patients [26.3%]), 
fatigue (29 patients [24.6%]), edema peripheral (27 patients [22.9%]) and decreased appetite 
(22 patients [18.6%]), and the majority were Grade 1/2. The most frequently occurring 
Grade 3/4 AEs suspected to be related to INC280 included fatigue (6 patients [5.1%]); lipase 
increased (4 patients [3.4%]); ALT increased (4 patients [3.4%]); AST increased (3 patients 
[2.5%]); anemia, nausea, neutropenia, dehydration and hypophagia (each in 2 patients [1.7%]); 
and thrombocytopenia, vomiting, diarrhea, edema peripheral, blood bilirubin increased, 
amylase increased, lymphocyte count decreased, decreased appetite, hypoalbuminemia, 
hypophosphatemia, hyperlipasemia, hyperlipidemia, cerebral venous thrombosis and rash 
maculopapular (each in 1 patient [0.8%]). 
 
The MTD for INC280 capsules as single agent was not reached. The RP2D for INC280 as 
a single agent has been determined to be 600 mg BID in capsule formulation and 400 mg BID 
in tablet formulation. 
 
A female patient experienced a serious, unexpected, possibly related adverse event of abnormal 
liver function tests during treatment with a combination of INC280 and gefitinib while enrolled 
in the [CINC280X2202] study. The initial Investigator Notification (IN) for the event was 
issued on 12 March 2015). The patient experienced concurrent elevations of total 
bilirubin >2×ULN and ALT/AST >3×ULN with alkaline phosphatase (ALP) <2×ULN. The 
patient permanently discontinued study drugs. The liver function alterations were reversible and 
improved after the discontinuation of both drugs. At the time of the follow-up Investigator 
Notification (IN), the outcome of the adverse event of abnormal liver function tests was reported 
as completely recovered. The investigator assessed the AE as suspected to be related to the 
combination of INC280 and gefitinib. This AE met the criteria of Hy’s Law and the 
hepatotoxicity could not be attributed solely to either drug alone or to the combination. The 
recommended phase II dose (RP2D) of INC280 in combination therapy with gefitinib is 400mg 
BID in tablet formulation. The maximum tolerated dose (MTD) for single agent INC280 has 
not been defined. 
For further details on clinical safety and efficacy, refer to the current IB [INC280 Investigator’s 
Brochure]. 


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1.2.6.2.2 Clinical pharmacokinetics 
As of 28-Sep-2015, INC280 single agent steady state PK data are evaluable in four studies 
with tablet and/or capsule formulations ([CINC280X2101T], [CINC280X1101], 
[CINC280X2102] and [CINC280X2201]). Study [CINC280X2101T] only included Western 
patients, the majority of whom were Caucasian. Study [CINC280X1101] was performed in 
Japanese cancer patients while studies [CINC280X2102] and [CINC280X2201] included both 
Asian and Western cancer patients. 
The mean plasma exposures (Cmax and AUC) of INC280 capsules were increased with dose 
following QD administration up to 600 mg/day in studies [CINC280X2101T] and 
[CINC280X1101], no further increase in the mean exposure was observed at 800 mg QD in 
[CINC280X1101]). 
A single dose relative bioavailability study in healthy subjects, [CINC280X2103], was 
conducted to compare the relative bioavailability of INC280 tablets to INC280 capsules. The 
outcome of this study showed that following a single oral administration of 600 mg INC280 
in healthy subjects, both formulations had similar Tmax values; tablets however provided 
higher systemic exposures at a dose of 600 mg. The AUC geometric mean ratios (tablet vs. 
capsule) were 2.4 to 2.6, and the Cmax geometric mean ratio (tablet vs. capsule) was 3.0. 
Additionally lower inter-subject variability was observed when administering the tablet 
formulation of INC280. 
In clinical studies with cancer patients, the INC280 tablet formulation provided slightly higher 
exposures than the INC280 capsule formulation at the same doses tested, with generally lower 
inter-subject variability. The mean plasma exposures of INC280 tablet appeared to increase 
dose proportionally from 200 to 400 mg twice per day ([CINC280X1101] and 
[CINC280X2102]). The apparent terminal half-life T1/2 of INC280 estimated from 
[CINC280X1101] QD treatment is 4.4 h, ranging, from 2.8 to 9.0 across the cohorts. Steady 
state INC280 exposure is expected to be reached by the third day of consecutive dosing. 
Accumulation of INC280 tablet following repeated administration at 400 mg BID is low with 
an accumulation ratio of up to 2-fold in [CINC280X1101] and [CINC280X2102]; however, 
some subjects had higher accumulation ratios up to 10-fold in [CINC280X1101]. 
Study [CINC280X2102] investigated the MTD or RP2D, safety and tolerability of the 
INC280 capsule and tablet formulations in the cancer patient target population. The INC280 
400 mg BID tablet formulation had comparable tolerability, safety profile, and exposure 
compared to the 600 mg BID capsule formulation. A comparison of exposure (Cmax and 
AUC0-12,ss) between tablets administered at 400 BID and capsules administered at 600 BID 
is shown below (Table 1-2). 


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Table 1-2 
Comparison of INC280 exposure for 600 mg capsules versus 400 mg 
tablets in cancer patients from CINC280X2102 
 
Dose Regimen (Dosage Form) 
[N] 
Mean Cmax ± Standard 
Deviation [N] 
Mean 
AUC0-12,ss 
± 
Standard Deviation [N] 
600 mg BID (capsule) [N=45] 
4790 ± 3440 ng/mL 
24700 ± 13500 
[N=45] 
[N=21] 
400 mg (tablet) [N=8] 
5860 ± 2780 ng/mL 
25500 ± 14400 
[N=8] 
[N = 4] 
In summary, the exposure data in the cancer patient target population [CINC280X2102] 
supports a dose ratio of approximately 3:2 (i.e., 600 mg capsules: 400 mg tablets) in the relevant 
treatment population for converting the capsule formulation to the tablet formulation. 
For further details on clinical pharmacokinetics, refer to the current IB [INC280 Investigator’s 
Brochure]. 
 
1.2.7 
Overview of single agent LEE011 
 
1.2.7.1 
Non-clinical experience 
 
1.2.7.1.1 Non-clinical pharmacodynamics 
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits highly 
specific inhibitory activity against CDK4/cyclin D1 and CDK6/cyclinD3 complexes, with 
concentrations 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. LEE011 inhibits the 
growth of many tumor cell types in vitro and in vivo, including mantle cell lymphoma, 
liposarcoma, rhabdoid tumors, neuroblastoma, melanoma and carcinomas of the esophagus, 
breast, lung and pancreas. Furthermore, in patient-derived primary V600E BRAF mutated 
melanoma xenograft models, combining LEE011 with LGX818 (a potent and selective RAF 
inhibitor), both improved initial anti-tumor effects relative to LGX818 alone, and 
delayed/prevented the emergence of resistance to observed with single agent LGX818. Lastly, 
regardless of the various genetic aberrations that may be present in the cancer cells, the anti- 
tumor activity of LEE011 requires the presence of functional retinoblastoma protein (Rb). More 
detailed information can be found in the current [LEE011 investigator’s brochure]. 
 
1.2.7.1.2 Non-clinical pharmacokinetics and metabolism 
In human hepatocytes, LEE011 is mainly metabolized by CYP3A4 with partial contribution by 
FMO3 (15-26%). CYP3A4 metabolized LEE011 mainly by hydroxylation and N- 
demethylation, whereas FMO3 produced a hydroxylamine metabolite. In hepatocytes, LEQ803 
(N-demethylation) was a major metabolite in the rat, monkey, and humans, and the only 
metabolite in dogs. This metabolite was found to interact with hERG channels in vitro. In the 
rat ADME studies, LEQ803 was found only in minor amounts. LEE011 is a time-dependent 
CYP3A4 inhibitor and a reversible inhibitor of CYP1A2. CYP2E1 was inhibited with an IC50 
value of 62 µM. Time- dependent inhibition of CYP3A4 was observed with a KI value of 5 µM 
and a kinact value of 0.0245 min-1. LEE011 displayed no capacity to inhibit CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at concentrations up to 50 µM and was not 


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identified as time-dependent inhibitor of CYP1A2, CYP2C9, and CYP2D6. LEE011 is a low- 
affinity p-gp substrate.LEE011 was identified as inhibitor of the efflux transporter MDR1 and 
MXR with IC50 values of 143 µM and 24 µM, respectively. LEE011 inhibited the human BSEP 
(bile salt export pump) transporter with an IC50 value of 4.7 µM, but did not inhibit rat and dog 
BSEP at concentration up to 200 µM. 
For further details on non-clinical pharmacokinetics, refer to the current [LEE011 Investigator’s 
Brochure]. 
 
1.2.7.1.3 Non-clinical toxicology and genotoxicity 
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. 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. 
Extensive distribution into the rat thyroid gland occurred following an oral dose of LEE011. 
Although no abnormalities of thyroid function were identified in the preclinical studies, this 
high distribution of LEE011 into the thyroid gland provides the rationale for monitoring thyroid 
function tests in patients enrolled into this first clinical trial of LEE011. 
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. 
For further details on non-clinical toxicology and genotoxicity, refer to the current [LEE011 
Investigator’s Brochure]. 
 
1.2.7.2 
Clinical experience 
LEE011 is currently being investigated as single agent in 3 studies: [CLEE011X1101], 
[CLEE011X2101], [CLEE011X2102] and in combination in 4 studies: [CLEE011X2105], 
[CLEE011X2106], [CLEE011X2107], [CMEK162X2114]. 
 
1.2.7.2.1 Clinical safety and efficacy 
As of 2 July 2013, 78 patients have been treated with increasing doses of LEE011 orally, once 
daily for 21 days followed by a 1 week rest (28-day cycle). Doses ranging from the starting 
dose of 50 mg to 1200 mg were evaluated on this schedule. In addition, continuous dosing of 
LEE011 at 600 mg was evaluated (once daily for 28 days of a 28-day cycle). A total of 10 
events meeting DLT criteria were observed at the indicated doses and include grade 3 
mucositis/stomatitis (n=1) at 50 mg, grade 3 pulmonary embolism (n=1) at 280 mg, grade 3 
hyponatremia (n=1) and prolonged grade 3/4 neutropenia (n=1) at 400 mg, prolonged grade 2 
elevated creatinine (n=1) at 600 mg, grade 4 thrombocytopenia (n=1) at 750 mg, grade 3 
asymptomatic QTcF prolongation with grade 3 neutropenia in one patient at 900 mg and grade 
4 febrile neutropenia (n=1) and grade 4 thrombocytopenia (n=1) at 1200 mg. There was also 1 
DLT, grade 3 neutropenia at 600 mg on the continuous dosing schedule. Grade 1/2 neutropenia 


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was observed at doses of 280 mg or higher (23%) and grade 3/4 neutropenia was seen at doses 
of 400 mg and higher (21%). 
Asymptomatic grade 2 QTc prolongation was observed with increasing frequency starting at 
600 mg with grade 3 prolongation in 2 patients. The majority of all reported adverse events 
were mild or moderate (grade 1-2) and reversible. There have been no deaths related to LEE011 
reported. There have been no deaths related to LEE011 reported. The MTD of LEE011 is 
identified as 900 mg QD in a 3 weeks on/1 week off schedule while the RP2D is 600 mg QD 
in a 3 weeks on/1 week off schedule. 
For further details on clinical safety and efficacy, refer to the current [LEE011 Investigator’s 
Brochure] 
 
1.2.7.2.2 Clinical pharmacokinetics 
Following oral dosing, LEE011 is rapidly absorbed with median time to reach maximum plasma 
concentrations (Tmax) ranging from 1 to 5 hours (range of median Tmax values). LEE011 
plasma exposure (maximum plasma concentration [Cmax] and AUC) exhibit slightly over- 
proportional increases in exposure across the dose range tested (50 to 1200 mg), with no clear 
evidence of time-dependent auto-inhibition of its clearance mediated by CYP3A4. Steady-state 
is generally reached by Day 8 and the arithmetic mean effective T1/2 based on accumulation 
ratio (i.e., T1/2, acc) range from 15.9 to 43.1, hours across the 50 to 1200 mg dose cohorts. The 
accumulation ratio based on AUC obtained in a dosing interval (Racc) across the studied doses 
ranged from 1.55- to 3.13-fold. 
For further details on clinical pharmacokinetics, refer to the current [LEE011 Investigator’s 
Brochure] 
 
2 
Rationale 
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. The response to single agent BRAF or MEK inhibitors is often short lived 
(median PFS ~ 5 to 7 months), with resistance developing quickly. More recently, promising 
data have been reported for the vertical pathway inhibition of the RAF/MEK/ERK pathway 
with Dabrafenib and Trametinib leading to the FDA approval of this combination in January 
2014. The decreased occurrence of SCC in the Dabrafenib/Trametinib 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 (Heidorn 2010; Poulikakos 2010; Hatzivassiliou 
2010). 
Similar preliminary efficacy and tolerability has been seen for the combination of LGX818 and 
MEK162 with overall response rates of 88% for BRAFi naïve and 18% for BRAFi pretreated 
melanoma patients. The combination was well tolerated with no substantial increase in adverse 
events (AEs) for the combination vs single-agent therapy (Kefford et al 2013). 


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Despite further improvements of response and PFS for BRAF/MEK inhibitor combinations, 
virtually all patients eventually show progressive disease. Mechanisms for resistance to this 
combination are currently under investigation. It is however hypothesized that similar 
mechanisms are responsible for treatment failure after dual combination therapy as reported for 
single agent BRAF inhibitor treatment. 
(Wagle et al 2013) recently reported on resistance mechanisms in 5 patients treated with the 
dabrafenib/trametinib combination and identified new MEK mutations in 2 patients as well as 
BRAF amplification in a third patient while no known resistance mechanisms could be 
identified in the two other patients. Similarly, in a second publication, (Villanueva et al 2013) 
identified MEK2 mutation and BRAF amplification as a resistance mechanism in a patient 
treated with the dabrafenib/trametinib combination. 
This provides a strong rationale for a systemic analysis of the genetic alterations present in a 
patient’s tumor at progression. By using the results of such analysis, it will be possible to 
characterize the possible mechanisms of resistance that emerge in an individual patient, and 
propose a tailored rational combination therapy to potentially circumvent resistance and achieve 
more prolonged responses. Such a combination approach would build on a backbone of 
BRAF/MEK inhibition and add a third agent based on the individual patient’s resistance profile. 
The validity of this concept is supported by data from a xenograft model resistant to 
BRAF/MEK inhibitor combination, where persistent pS6 was observed and addition of a 
mTOR/PI3K inhibitor resulted in sustained tumor growth inhibition (Villanueva et al 2013). 
The primary purpose of this study is to assess the anti-tumor activity of novel triple 
combinations of LGX818/MEK162 plus either BKM120, BGJ398, INC280 or LEE011 in 
patients who have progressed on prior BRAF and/or MEK inhibitor treatment. 
In addition, safety and tolerability of the novel triple combinations will be assessed. The triple 
combination to be evaluated in an individual patient will be based on the molecular alteration(s) 
detected at progression after BRAF/MEK inhibitor combination treatment (see Table 4-1). 
 
2.2 
Rationale for the study design 
This design was chosen in order to evaluate whether a selected combination partner for 
LGX818/MEK162, based on genetic alterations identified in a tumor at progression, can 
effectively overcome resistance to dual BRAF/MEK inhibition in adult patients with locally 
advanced or metastatic BRAF V600 melanoma. Tumor biopsies will be collected at baseline 
and at the time of progression following LGX818/MEK162 treatment in order to identify the 
molecular alteration(s) that predominate in an individual patient’s tumor at progression. 
Molecular alterations identified in this manner would then be used to select the appropriate drug 
to combine with LGX818/MEK162. 
Three different patient populations are eligible for participation in this study (see Figure 4-1): 
a. Patients naïve to treatment with BRAF inhibitors (Group A). 
b. Either patients who progressed after single agent BRAF or MEK inhibitors; or patients 
who progressed after combination of BRAF and MEK inhibitors other than the 
combination of LGX818/MEK162; or patients receiving LGX818 and/or MEK162, who 
have not progressed yet; or, in consultation with the Sponsor, patients who received any 


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BRAF and/or MEK inhibitor other than LGX818 and/or MEK162 and have not 
progressed yet (Group B). 
c. Patients who progressed after LGX818/MEK162 combination therapy (Group C). 
Treatment naïve patients (Group A) will receive the dual combination of LGX818/MEK162 
during Part I until progression. In Part II, patients will be assigned to a rational combination 
treatment of LGX818/MEK162 and a third investigational agent. 
For Group B: 
• Patients who progressed after treatment with single agent BRAF or MEK inhibitor or after 
a BRAFi/MEKi combination therapy will enter Part II after a brief Run-in with the 
LGX818/MEK162 combination. However, if a response is achieved at the time of the first 
CT/MRI scan on LGX818/MEK162 the patient will remain on the LGX818/MEK162 
combination. 
• Patients who have been treated and not progressed on BRAF and/or MEK inhibitor 
regimen may enter the Run-in and continue LGX818/MEK162 combination until evidence 
of disease progression. At that time, a tumor biopsy will be taken and analyzed to guide 
assignment to a triple combination arm in Part II. 
During the Run-in period, tolerability of the LGX818/MEK162 combination will be 
established. Patients who progressed after LGX818/MEK162 combination therapy (Group C) 
can be enrolled directly into a triple combination in Part II after analysis of their tumor sample 
after progression. 
 
2.3 
Rationale for dose and regimen selection 
During Part I and the Run-in, patients will be treated with the LGX818/MEK162 combination 
at the recommended Phase 2 dose (RP2D) of 450mg QD LGX818 and 45mg BID MEK162. 
During Part II, patients will be treated with LGX818/MEK162 in combination with a third 
targeted 
agent 
(i.e. 
LGX818/MEK162 
+ 
BKM120, 
LGX818/MEK162+BGJ398, 
LGX818/MEK162+INC280, LGX818/MEK162+LEE011). Please, see Section 6.2.1 and 
Section 6.2.2 for details on starting dose rationale and provisional dose levels. The escalation 
of the third agent and LGX818 in the respective triple combinations will be based on BLRM, 
unless a RP2D for that combination is already established. 
If the proportion of patients eligible for one of the triple combinations is too low, it is possible 
that the trial will complete enrollment before a MTD/RP2D has been established for this 
combination. 
The 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 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. 


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Intra-patient dose escalation will be permitted after the first cycle for patients who have not 
experienced a DLT. Intra-patient dose escalation will also be guided by the BLRM with a 
modified EWOC criteria that reflects individual patient tolerability. 
LGX818/MEK162 and LGX818/MEK162 + INC280 or BKM120 will be administered on a 
continuous schedule. In the triple combination arms of LGX818/MEK162 + LEE011 and 
BGJ398, LGX818/MEK162 will be administered on a continuous schedule while LEE011 and 
BGJ398 will be administered on a 3 weeks on 1 week off schedule (see Section 6.1.1) as it was 
found to improve tolerability. 
 
2.4 
Rationale for choice of combination drugs 
Preclinical data suggest that simultaneous, triple inhibition of the RAF/MEK/PI3K pathway 
with the LGX818/MEK162/BKM120 combination could lead to increased clinical efficacy and 
possibly overcome early resistance to the BRAF/MEK combination in patients with BRAF 
V600 mutant advanced melanoma (see Section 1.2.1.1.2). Moreover, other mechanisms that 
reactivate MAPK signaling or activate alternate pathways such as PI3K/AKT signaling pathway 
may play a role in primary and/or acquired resistance to dual BRAF/MEK inhibition. Thus the 
antitumor activity of LGX818/MEK162 in combination with selected agents BKM120, 
BGJ398, INC280, and LEE011 that target PI3K, FGFR, c-met and CDK4/6 kinase respectively, 
will be assessed. The selection of the LGX818/MEK162 triple combination given to an 
individual patient will be based on the molecular alteration(s) identified in this patient’s tumor 
sample upon progression on BRAF/MEK combination treatment (see Section 1.2.1.1). 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
To assess the anti-tumor activity of LGX818/MEK162 in 
combination with third targeted agents after progression on 
LGX818/MEK162 combination therapy. 
Overall response rate (ORR) 
Refer to Section 10.4. 
Secondary 
To estimate the MTD/RP2D of triple combinations after 
progression on LGX818/MEK162 therapy 
To characterize the safety and tolerability of 
LGX818/MEK162 in combination with targeted agents 
Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 of 
Combination Part (Part II) 
Adverse Events (AEs), serious AEs (SAEs), changes in 
hematology and chemistry values, vital signs, 
electrocardiograms (ECGs), dose interruptions, reductions 
and dose intensity. 
Refer to Section 10.5.3. 
To further assess anti-tumor activity of LGX818/MEK162 
combination, and in combination with targeted agents after 
progression on LGX818/MEK162 combination 
PFS, DOR, TTR, DCR, and OS (Part II only) 
Refer to Section 10.5.2. 
To characterize genomic alterations in tumor tissue at 
baseline and at tumor progression. 
Genomic alteration status (e.g. mutation, amplification, 
deletion, overexpression, ligand activation and splice variants) 
of pre-defined markers 
Refer to Section 10.5.5. 
To determine the PK profiles of LGX818,MEK162 and the 
third agents when given in combination and to assess drug- 
drug interaction 
Plasma concentration and derived parameters of LGX/MEK, 
and targeted agents 
Refer to Section 10.5.4. 


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4 
Study design 
4.1 
Description of study design 
Note: As of Protocol Amendment 06, enrollment to the BKM120-, BGJ398- and INC280- 
containing arms in Part II is closed. As of Amendment 07, enrollment to the LEE011 arm 
in Part II is closed. 
This is a multicenter, open-label, phase II study which will enroll approximately 140 patients 
with BRAF mutant locally advanced unresectable or metastatic melanoma. 
This study consists of two parts: in Part I, patients naïve to selective BRAF and MEK inhibitors 
will be treated with the LGX818/MEK162 combination until disease progression (as defined 
per RECIST v1.1). Based on the genetic assessment of a tumor biopsy obtained at progression 
of disease (PD), patients will enter Part II of the study for tailored combination treatment in one 
of four arms: LGX818/MEK162 + BKM120, BGJ398, INC280 or LEE011 (Figure 4-1). 
New triple combination arms will be introduced in the study via substantial protocol 
amendment which will require submission, review and approval by Health Authority (HA) and 
Ethic Committees (EC) or Institutional Review Boards (IRB) following local regulatory 
requirements. As of 10 July 2015, the triple combination of LGX818/MEK162 + BKM120 is 
no longer being explored, due to decreased exposure of BKM120 given with LGX818/MEK162 
as compared to exposures achieved with single agent BKM120. It is assumed that this is 
attributable to LGX818, which is a known inducer of the CYP enzymes. 
During Part I, patients will be treated with LGX818/MEK162 at RP2D of the dual combination. 
In Part II, dose escalation for the triple combination will occur unless a RP2D for the respective 
combination is already established. 
Non-naïve patients for BRAF and/or MEK inhibitor treatment who are relapsing will be 
enrolled into Part II. Depending on the previous treatment, patients may receive a brief Run-in 
with LGX818/MEK162 combination. 


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Figure 4-1 
Study design 
 
*Single agents: i.e. Vemurafenib, Dabrafenib, LGX818, Trametinib, MEK162; Combos: i.e. 
Dabrafenib/Trametinib, LGX818/MEK162 combination 
**Patients who progressed on a previous BRAFi and/or MEKi regimen will continue on 
LGX818/MEK162 if PR is observed, followed by new Biopsy at progression. Patients who did not 
progress on their prior BRAFi/MEKi regimen may continue LGX818/MEK162 combination until 
evidence of disease progression at which point a tumor biopsy will be taken and analyzed to guide 
assignment to a triple combination arm in Part II. 
***LEE011 cohort might start directly at the RP2D established in CMEK162X2110, if available. 
Note: The triple combination arms containing BKM120, INC280, BGJ398 and LEE011 in Part II are 
closed to enrollment as these combinations are no longer being explored. 
BRAF V600 mutant melanoma patients can enter different parts of this study (Part I, Run-in 
or Part II) according to their previous treatments: 
 
Group A 
Patients naïve to selective BRAF and MEK inhibitors will enter the Part I and be treated 
with LGX818/MEK162 combination at the RP2D of 450 mg/QD and 45 mg/BID, respectively, 
until disease progression (as defined per RECIST v1.1), or no clinical benefit. At the time of 
disease progression, newly obtained tumor sample will be analyzed for a selected panel of genes 
(Table 4-1) in order to assign patients to a triple combination arm in Part II. 
 
Group B 
Patients who progressed after treatment with single agent BRAF or MEK inhibitor or the 
combination of BRAF/MEK inhibitors (excluding LGX818/MEK162 combination) will 
receive LGX818/MEK162 combination in a brief Run-in phase (at least 3 weeks) followed by 
early disease assessment after 3 weeks. Patients achieving at least a PR from this treatment at 
the time of the first CT/MRI scan (during the Run-in phase) will continue on LGX818/MEK162 
combination until progression. At this time, a newly obtained tumor biopsy will be mandatory 


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and patients will be assigned to a triple combination arm in Part II on the basis of the tumor 
sample’s genetic assessment (Table 4-1). Patients not deriving clinical benefit from 
LGX818/MEK162 combination therapy will be assigned to a treatment arm in Part II on the 
basis of the analysis of their most recent tumor biopsy. 
Patients who did not progress on their prior BRAF and/or MEK inhibitor regimen (including 
LGX818 and/or MEK162), may enter the Run-in and continue LGX818/MEK162 combination 
until evidence of disease progression at which point a tumor biopsy will be taken and analyzed 
to guide assignment to a triple combination arm in Part II. 
 
Group C 
Note: As of Amendment 07, the triple combination arms containing BKM120, INC280, 
BGJ398 and LEE011 in Part II are closed to enrollment as these combinations are no 
longer being explored, therefore no additional patients will be enrolled from Group C. 
Patients who progressed after treatment with LGX818/MEK162 combination in other 
Sponsor studies (e.g. [CMEK162X2110], [CLGX818X2102] and [COLUMBUS] or IITs) are 
eligible to enter Part II directly on the basis of the molecular analysis of their last progressive 
tumor sample. 
Important note: In Groups B and C, progressive disease (PD) after previous treatment should 
be documented per RECIST v1.1 and determined using radiological assessments. 
During the molecular analysis, all patients (Groups A, B and C) may be treated with 450mg/QD 
of LGX818 and 45mg/BID of MEK162 or their last tolerated dose, not exceeding 450mg/QD 
of LGX818 and 45mg/BID of MEK162, until assigned to a triple combination arm, as indicated 
by Table 4-1. However, these patients must meet the related inclusion criteria (see Section 5.2) 
in order to continue to be treated with LGX818/MEK162 combination during the tumor genetic 
assessment. Moreover, patients should not discontinue LGX818/MEK162 combination for 
more than 6 weeks for AEs related to this combination prior to entering Part II of this study. All 
AEs related to LGX818/MEK162 combination should resolve to at least grade 2 before the first 
dose of triple combination. 
Progressive disease assessment is deemed to be confirmed from the previous study (e.g. 
[COLUMBUS], [CMEK162X2110] and [CLGX818X2102] or IITs) and may be used as 
baseline tumor evaluation for Part II of this study, only if the time interval before start of Part 
II study treatment is no longer than 28 days. 


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Assignment of triple combination treatment 
 
Table 4-1 
Assignment of triple combination treatment based on molecular 
alteration(s) detected at progression under LGX818/MEK162 
combination 
Priority* 
Molecular alteration identified on biopsy at progression** 
Drug to be given in 
combination with 
LGX818/MEK162 
Amplification 
Mutation 
Loss 
CCND1 
CDK4 
1 
B/CRAF 
No alteration in any gene 
listed in this table. 
HER2 
2 
IGF-1R 
EGFR 
CDK4 
MAP2K1/K2 
N/KRAS 
HRAS 
 
PTEN 
PIK3CA 
EGFR 
 
 
P16 
LEE011*** 
 
 
 
PTEN 
BKM120*** 
 
3 
cMET 
INC280*** 
FGFR1 
4 
FGFR2 
FGFR3 
FGFR1 
FGFR2 
FGFR3 
 
BGJ398*** 
 
* Priority order may be revised based on data arising from this study or from other internal or external 
research. 
** Other alterations arising from internal or external research may be considered in the future. 
*** BKM120 (Amendment 03), BGJ398, INC280 (Amendment 06), and LEE011 (Amendment 07) triple 
combination arms were closed to enrollment as these combinations are no longer being explored. 
Assignment to the specific triple combination is based on the results of genetic profiling of the 
tumor biopsy obtained at progression from LGX818/MEK162 combination, as described in 
Table 4-1. 
If a patient is assigned to one triple combination arm due to his/her molecular alteration, but 
he/she meets the additional exclusion criteria for that arm, then the investigator and the Sponsor 
will come to agreement on which group is most appropriate for the patient. 
If a patient does not fit any of the criteria specified in Table 4-1, or if the biopsy is medically 
contra-indicated for the patient, other relevant data may be considered, and the investigator and 
the Sponsor may decide to assign the patient to the LEE011 triple combination treatment group. 
 
Molecular pre-screening 
To enter the screening phase for Part I, Run-in and Part II of this study, patients must complete 
the molecular pre-screening assessment and provide written documentation of BRAF V600 
mutation (see Section 7.1.1 for details). 


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Screening 
Only once the BRAF V600 mutational status is known, the patient is allowed to sign the Main 
Study Informed Consent Form and start the screening for the appropriate study part. All 
screening evaluations are required to be performed before administration of study treatment. 
 
Treatment periods 
There will be two treatment parts: Part I and Part II: 
Part I = LGX818/MEK162 combination treatment phase that will begin on Cycle 1 Day 1 until 
disease progression and initiation of triple combination treatment. 
Part II = triple combination treatment that should be initiated once the genetic alterations from 
tumor biopsy collection at the time of progression are known. 
Important note: patients in group B will have to undergo a three-week Run-in period with 
LGX818/MEK162. Please, see the flowchart in Figure 7-1. 
Study treatment will be administered as 21-day cycles (except LGX818/MEK162/LEE011 and 
LGX818/MEK162/BGJ398 combination arm of 28-day cycles) and will continue until disease 
progression (on triple combination treatment), unacceptable toxicity, withdrawal of informed 
consent, or death. 
Eligible patients may continue treatment beyond the data cutoff. 
Once a patient has received 3 cycles of treatment a reduced schedule of assessments for the 
subsequent cycles will be followed. Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5 
define the reduced schedule of assessments. 
Since the safety and efficacy of the dual combination of binimetinib and encorafenib has been 
extensively assessed, patients who have been on treatment in Part I for ≥ 36 months will be 
followed as per local standard-of-care practice for patients with BRAF V600-mutant 
unresectable or metastatic melanoma or other advanced solid tumors and only limited data will 
be collected (see Section 7.2). 
 
30-day safety follow-up assessments 
Patients must complete the safety follow-up assessments 30 days after the last dose of the study 
treatment (see also Section 7.1.5 and Section 7.1.6). For patients who have been on treatment in 
Part I for ≥ 36 months, the 30 day follow-up will include a review of concomitant medications and 
assessment of compliance with administration of LGX818 (encorafenib) and MEK162 
(binimetinib). There will also be review of AEs with recording of all Grade 3 or 4 AEs and all SAEs 
(SAEs, follow-up of SAEs to continue as described in Section 8). Other safety evaluations may be 
conducted if clinically indicated. 
 
Disease progression, survival follow-up assessments 
Patients enrolled in Part I, Run-in and Part II 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 Part II of the study will be followed for survival (Section 7.1.6.3). 


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4.2 
Timing of interim analyses and design adaptations 
No formal interim analyses are planned. However, the dose-escalations are planned for Part II. 
The dose-escalation design foresees that decisions based on the DLT data are taken before the 
end of the study. More precisely, after each cohort in the dose-escalation phase, the next dose 
combination has to be chosen depending on the observed data. Details of this procedure and the 
process for communication with Investigators are provided in Section 6.2.3. 
 
4.3 
Definition of end of the study 
End of study (Last Patient Last Visit [LPLV]) will occur once all patients have discontinued 
treatment and all eligible patients (patients who have not withdrawn consent and are not lost to 
follow-up) have completed their 30-day follow-up visit. 
 
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. The same assessments for a prematurely 
withdrawn patient should be performed as described in Section 7.1.6.1. The investigator may 
be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
 
5 
Population 
5.1 
Patient population 
Study CLGX818X2109 will be conducted in adult patients with locally advanced or metastatic 
melanoma harboring a confirmed BRAF V600 mutation. Moreover patients fitting group A, B 
or C (see Section 4.1), and meeting all the inclusion criteria in Section 5.2 are eligible to start 
with either LGX818/MEK162 combination or with one of the triple combinations 
(LGX818/MEK162 + third agent, as described in Figure 4-1) 
Patients enrolled in this study are not permitted to participate in parallel investigational drug or 
device studies. Additionally, patients who have been permanently discontinued from study 
medication 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 treatment in the study. 
 
5.2 
Inclusion criteria (Group A, B and C) 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. For Group A only: patients who are naïve to selective BRAF and MEK inhibitors and 
might have received other allowed treatments such as chemotherapy, biological therapy 
(e.g., antibodies) (see related exclusion criterion in Section 5.3) 
2. Patients (male and female) age ≥ 18 years 


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3. Able to understand and voluntarily sign the informed consent form prior to any screening 
procedure, and ability to comply with the study visit schedule and other protocol 
requirements. 
4. Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma 
(stage IIIC to IV per American Joint Committee on Cancer [AJCC]). 
5. Documented evidence of BRAF V600 mutation. 
6. For Group A only: Patients must provide either archival or newly obtained tumor sample 
at baseline. In addition, patients must agree to a mandatory biopsy at the time of 
progression from LGX818/MEK162 combination, if not medically contraindicated. 
7. Evidence of measurable disease, as determined by RECIST v1.1. 
Note: Lesions in areas of prior radiotherapy or other locoregional therapies (e.g., 
percutaneous ablation) should not be considered measurable, unless lesion progression has 
been documented since the therapy. 
8. ECOG Performance Status ≤ 2. 
9. Negative serum pregnancy test within 72 hours prior to the first dose of study treatment in 
all women of childbearing potential. 
10. For Group B only: Patients who progressed after treatment with single agent BRAF or 
MEK inhibitor or the combination of BRAF/MEK inhibitors (excluding 
LGX818/MEK162 combination) and patients who did not progress on their prior BRAF 
and/or MEK inhibitor regimen (including LGX818 and/or MEK162 inhibitor), but did not 
tolerate this treatment, may enter the Run-in (Group B) upon consultation with the 
Sponsor. 
11. For Group B only: Patients with progressive disease following any single or double- 
agent BRAF and MEK inhibitors other than LGX818 and /or MEK162 must discontinue 
these treatments for a period of at least five half-lives before the first day of dosing in the 
Run-in, and the drug related AE’s from the previous treatment must have normalized to at 
least grade 2. 
12. For Group B only: The most recent biopsy sample collected, either before starting 
treatment with any BRAF and/or MEK inhibitor, or after progression from any previous 
BRAF and/or MEK inhibitor (other than LGX818 and MEK162 combination) must be 
available before entering the Run-in. In addition, patients must agree to a biopsy at the 
time of progression from LGX818/MEK162 combination (see Figure 7-1), if necessary 
and not medically contraindicated. 
 
Additional inclusion criteria for Part II (Group C) 
Group C patients are eligible for inclusion in the triple combination part (Part II) of this study, 
if they meet the above inclusion criteria from N. 2 to N. 9 and all of the following criteria: 
13. Progressive disease documented per RECIST v 1.1 and determined using radiological 
assessments, following prior treatment with LGX818/MEK162 combination. 
14. A pre-LGX818/MEK162 combination archival tumor sample must be available. 
15. A biopsy sample at disease progression, post-LGX818/MEK162 combination, must be 
either already available from previous studies or collectable at screening/baseline of this 
study. This tumor sample will be analyzed in order to determine which third 


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investigational drug patients will be administered as described in Section 4.1 of the 
protocol. 
16. Patients are allowed to continue receiving LGX818/MEK162 combination (at their highest 
tolerated doses) during their tumor genetic assessment if all inclusion and exclusion 
criteria (Section 5.3) are met at Screening as well as the following conditions: 
• Absence of symptoms and signs indicating clinically significant progressive disease 
not compatible with continued participation in this study, 
• No clinically significant decline in ECOG performance status, 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
17. Progressive disease documentation, produced at the last tumor assessment in the previous 
study, must be provided. The last progressive disease assessment visit must have been 
performed within 4 weeks (28 days) from the scheduled first dose administration in this 
study. If this is not the case, a new tumor assessment should be performed. 
 
5.3 
Exclusion criteria 
Enrollment in Part I and Run-in 
Patients eligible for Part I or Run-in of this study must NOT meet any of the following criteria: 
1. Symptomatic or untreated leptomeningeal disease. 
2. Symptomatic brain metastasis. Patients previously treated or untreated for brain metastasis 
that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of 
steroids for four weeks are allowed to enroll. Brain metastases must be stable at least 4 
weeks with verification by imaging (e.g. brain MRI completed at screening demonstrating 
no current evidence of progressive brain metastases). 
3. Patients are not permitted to receive enzyme inducing anti-epileptic drugs. 
4. Known acute or chronic pancreatitis. 
5. History or current evidence of retinal vein occlusion (RVO) or current risk factors for 
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes); 
6. Clinically significant cardiac disease including any of the following: 
• CHF requiring treatment (NYH grade ≥ 2) 
• LVEF < 50% as determined by MUGA scan or ECHO or uncontrolled hypertension 
(please refer to WHO-ISH guidelines) 
• History or presence of clinically significant ventricular arrhythmias or uncontrolled 
atrial fibrillation 
• Clinically significant resting bradycardia 
• Unstable angina pectoris ≤ 3 months prior to starting study drug 
• Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting study drug 
• QTcF > 480 msec. 
7. Patients with any of the following laboratory values at Screening/baseline: 
• Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L] 


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• 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 
• AST/SGOT or ALT/SGPT > 3 x ULN, or > 5 x ULN if liver metastases are present 
8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection). 
9. Patients treated with warfarin or other coumadin derived anti-coagulant, for treatment, 
prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), 
or fondaparinux is allowed. 
10. 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 first dose administration. 
11. 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 
serum hCG laboratory test. 
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 when this is in line with the preferred and usual lifestyle of the 
patient or 
• Male or female sterilization 
• Combination of any two of the following (a+b) 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b. 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. 
12. Sexually active males must use a condom during intercourse while taking the drug and 
for 3 months 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 
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13. History of thromboembolic or cerebrovascular events within the last 6 months, including 
transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary 
embolism. 
14. 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). 
15. 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. 
16. Known Human Immunodeficiency Virus (HIV) infection. 
17. 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. 
18. Patients unable to stop treatment with strong CYP3A4 inhibitors and CYP2C9 substrates 
with narrow therapeutic index (e.g. warfarin, phenytoin). These medications should be 
stopped 7 days prior to first dose of study treatment (refer to Section 6.4.3 and Appendix 7 
for prohibited medications for this combination treatment). 
 
Enrollment in Part II 
Note: Enrollment to the BKM120- (Amendment 03), BGJ398- and INC280- 
(Amendment 06) and LEE011 (Amendment 07)-containing arms in Part II is closed. 
Patients are NOT eligible for enrollment in Part II of this study if they meet any exclusion 
criteria listed above, and/or any applicable additional exclusion criteria listed below. Please 
note, patients who have developed brain metastases during Part I of the study may continue to 
Part II upon discussion with the Sponsor Medical Monitor. The brain metastasis must be either 
asymptomatic or treated and stable for at least 4 weeks and on a stable or tapering dose of 
steroids for at least 2 weeks. Patients with brain metastasis are not eligible for the combination 
with LEE011. 
19. Patients who discontinued LGX818/MEK162 for more than 6 weeks prior to the 
scheduled first dose of triple combination (Part II), and AEs related to the above treatment 
are not resolved to at least grade 2. 
 
Additional exclusion criteria for Part II for selected triple combination 
 
LGX818/MEK162 + INC280: This arm is closed to enrollment as this 
combination is no longer being explored (Amendment 06). 
20. Patients unable to stop known CYP3A4, CYP1A2, CYP2C8 or CYP2C19 substrates with 
narrow therapeutic index. These medications should be stopped 7 days prior to first dose 
of study treatment (refer to Section 6.4.3 and Appendix 7 for prohibited medications for 
this combination treatment). 


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21. Patients receiving treatment with long acting proton pump inhibitors, and unable to 
discontinue them 3 days prior to the start of study treatment and during the course of the 
study. 
22. Asymptomatic serum amylase > CTCAE Grade 2 (1.5-2.0xULN). Patients with Grade 1 
or Grade 2 serum amylase at the beginning of the study must be confirmed to have no 
signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, 
abnormal imaging findings of pancreas, etc.) 
23. Serum lipase > ULN 
 
LGX818/MEK162 + BKM120: This arm was closed to enrollment due to DDI 
between LGX818 and BKM120 (Amendment 03). 
24. Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %. 
25. Patient has any of the following mood disorders as judged by the Investigator or a 
Psychiatrist: 
• Patient has a score ≥ 12 on the PHQ-9 questionnaire 
• Patient selects a response of “1, 2 or 3” to question number 9 on the PHQ-9 
questionnaire regarding potential for suicidal thoughts or ideation (independent of the 
total score of the PHQ-9) 
• Patient has a GAD-7 mood scale score ≥ 15 
• Patient has a medically documented history of or active major depressive episode, 
bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of 
suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or 
others), or patients with active severe personality disorders (defined according to 
DSM- IV) are not eligible. Note: for patients with psychotropic treatments ongoing at 
baseline, the dose and the schedule should not be modified within the previous 6 
weeks prior to start of study drug. 
• Patient has ≥ CTCAE grade 3 anxiety 
26. Patients with uncontrolled hypertension (please refer to WHO-ISH guidelines) 
27. Patient is currently receiving treatment with medication that has a known risk to prolong 
the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued 
or switched to a different medication prior to randomization. Please refer to Section 6.4.3 
and Appendix 7 for a list of prohibited drugs. 
Patients currently receiving treatment with strong and moderate inhibitors or inducers of 
isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one 
week and must have discontinued strong inhibitors before the treatment is initiated. 
Switching to a different medication prior to randomization is allowed. Please refer to 
Appendix 7 for prohibited medication of this combination treatment. 
 
LGX818/MEK162 + BGJ398: This arm is closed to enrollment as this 
combination is no longer being explored (Amendment 06). 
28. History and/or current evidence of significant ectopic mineralization/ calcification with 
the exception of calcified lymph nodes and asymptomatic vascular calcification. 


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29. Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/ band 
keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis etc., 
confirmed by ophthalmologic examination 
30. Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis. 
31. History of congenital long QT- syndrome and/or hypokalemia CTCAE Grade ≥ 3 and/or 
magnesium levels below the clinically relevant lower limits before the first dose of triple 
combination. 
32. QTcF > 470 msec 
33. Use of medications that are known to prolong the QT interval and/or are associated with a 
risk of Torsades de Pointes 7 days prior to first dose. (Refer to Appendix 7) 
34. Ionized (i) calcium (Ca) > ULN 
35. Serum inorganic phosphorus (Pi) > ULN 
36. Patients who are currently receiving treatment with agents that are known CYP3A4 strong 
inducers or inhibitors. (Refer to Appendix 7 for prohibited medications). 
 
LGX818/MEK162 + LEE011: This arm is closed to enrollment as this 
combination is no longer being explored (Amendment 07). 
37. Uncontrolled hypertension (please refer to WHO-ISH guidelines) are excluded from 
study. 
38. Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI 
at screening 
39. PT/INR or aPTT > 1.5xULN 
40. QTcF ≥450 ms on screening ECG 
41. Mean resting heart rate < 50 or > 90 bpm (determined from ECG) 
42. Patients with abnormalities of the following laboratory tests unless corrected to within 
normal limits with supplements before the first dose of study medication: 
• Sodium 
• Potassium 
• Magnesium 
• Total Calcium (corrected for serum albumin) 
• Phosphorus 
43. Total bilirubin ≥ ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN. 
44. Aspartate transaminase (AST) ≥ 2.5 × ULN, ≥ 5 × ULN in patients with liver metastasis 
45. Alanine transaminase (ALT) ≥ 2.5 × ULN, ≥ 5 × ULN in patients with liver metastasis 
46. Long QT syndrome or family history of idiopathic sudden death or congenital long QT 
syndrome or any of the following before the first dose of the triple combination: 
• Risk factors for TdP including uncorrected hypokalemia or hypomagnesemia, history 
of cardiac failure, or history of clinically significant/symptomatic bradycardia 
• Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by safe 
alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) 


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• Inability to determine the QTcF interval. 
47. Any heart disease that requires the use of a cardiac pacemaker or implantable cardioverter 
defibrillator ≤ 3 months prior to starting study drug. 
48. Unstable atrial fibrillation (ventricular response >100 bpm). 
49. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II, and 
third degree AV block) 
50. History of documented myocardial infarction (MI), angina pectoris, symptomatic 
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry 
51. Documented cardiomyopathy 
52. Systolic blood pressure (SBP) > 160 or < 90 mmHg 
53. Patients who are currently receiving treatment with agents that are known to cause QTc 
prolongation in humans. See LEE011 Investigators Brochure for a complete list of agents 
that are known to cause QTc prolongation in humans. 
54. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 according to the 
Modification of Diet in Renal Disease (MDRD) formula. 
55. Patient is currently receiving any of the following substances and cannot be discontinued 
7 days prior to Cycle 1 Day 1: 
• Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, 
star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of 
CYP3A4/5 
• Medications that have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5. 
 
6 
Treatment 
6.1 
Study treatment 
 
The investigational drugs to be used in this study are LGX818, MEK162, BKM120, BGJ398, 
INC280, and LEE011. 
The study treatments are: 
• Part I : dual combination LGX818 (QD) and MEK162 (BID) 
• Part II: triple combinations: 
• LGX818 (QD) and MEK162 (BID) and BKM120 (QD) LGX818 (QD) and MEK162 
(BID) and BGJ398 (QD)LGX818 (QD) and MEK162 (BID) and INC280 
(BID)LGX818 (QD) and MEK162 (BID) and LEE011 (QD) (the triple combinations 
containing BKM120, BGJ398, INC280, and LEE011 are no longer being explored). 


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6.1.1 
Dosing regimen 
 
Table 6-1 
Dose and treatment schedule 
Study 
treatments 
Pharmaceutical form and 
route of administration 
Starting Dose and Schedule 
LGX818 
Capsule for oral use 
450 mg QD (Part I), or highest tolerated dose (Run-in 
or Part II) 
200 mg QD (in combination with INC280 and LEE011 
in Part II) (continuous) 
MEK162 
Tablet for oral use 
45mg BID (Part I) or highest tolerated dose (Run-in 
or Part II) (continuous) 
BKM120*** 
Capsule for oral use 
60 mg QD (Part II) (continuous) 
BGJ398*** 
Capsule for oral use 
75 mg QD (Part II) (three week on, one week off) 
INC280*** 
Capsule for oral use 
200 mg BID (Part II) (continuous) 
INC280*** 
Tablets for oral use* 
400 mg BID (Part II) (continuous) 
LEE011*** 
Capsule for oral use 
100 mg QD (Part II) (three week on, one week off) 
*Note: For INC280, tablets will be provided when available. 
*** BKM120 (Amendment 03), BGJ398, and INC280 (Amendment 06) and LEE011 (Amendment 07) 
triple combination arms were closed to enrollment. 
For all treatments the first dose of study drug defines Day 1 of Cycle. 
For Part I a complete treatment cycle is defined as 21 days of daily continuous treatment with 
LGX818/MEK162 combination. 
For Part II a complete treatment cycle is defined as 21 days continuous treatment for 
LGX818/MEK162 plus BKM120 or INC280. 
For LGX818/MEK162 plus LEE011 or plus BGJ398 a complete treatment cycle is defined as 
28 days. 
LEE011 or BGJ398 will be taken for 21 consecutive days followed by a 7-day planned 
break (called also 3 weeks on, 1 week off schedule), while LGX818 and MEK162 are always 
taken on a continuous schedule. 
 
6.1.1.1 
Instructions for administration of LGX818, MEK162, INC280, BKM120, 
LEE011 and BGJ398 
Study treatments will be administered as a flat-fixed dose, and not by body weight or body 
surface area. On all dose administration days patients can take the dual combination (LGX818 
and MEK162) or the triple combination (LGX818 and MEK162 and LEE011) with or without 
food. 
LGX818 capsules will be co-administered orally, once daily (QD), with MEK162 tablets, twice 
daily (BID). 
BKM120 will be administered orally on a daily schedule (QD). LEE011 and BGJ398 will be 
administered orally, once daily for 21 days followed by a 1 week rest (QD). INC280 will be 
administered orally, twice daily (BID, 21-day cycle) 


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• QD Dosing: Patients should be instructed to take LGX818 or BKM120 or BGJ398 or 
LEE011 capsules daily in the morning. 
• BID Dosing: MEK162 and INC280 will be administered orally on a twice daily schedule 
(BID). The doses of MEK162, or INC280, should be taken 12 ± 2 hours apart. 
• Note that all drugs (LGX818 + MEK162, or LGX818 + MEK162 + INC280) should be 
taken together in the morning and only the BID administered drug (MEK162 or INC280) 
should be taken in the evening. 
 
Instructions for administration on days when PK sampling is performed: 
Pre-dose PK samples should be collected just prior to intake of dose. Exact dates and clock 
times of administration of the first capsule or tablet of LGX818, MEK162 and third agent will 
be recorded on the appropriate eCRF. 
 
For combination arm LGX818/MEK162 with BKM120 only: 
Instructions for administration on days when a fasting plasma glucose monitoring is performed: 
On the days of fasting plasma glucose monitoring, patients must be fasting overnight for at least 
8 hours prior to the blood collection. A light breakfast/snack may be consumed after fasting 
plasma glucose draw. Nonetheless, study drugs should be administered on an empty stomach 
and eating is not allowed for one hour after drug administration. Please, note that if the patient 
has eaten, he/she must wait two hours until taking the drug 
 
6.1.1.1.1 General instructions 
• Patients must be instructed to take MEK162, LGX818, and the 3rd combination agent for 
Part II, together with a large glass of water (~250 ml) daily in the morning at 
approximately the same time every day. 
• Patient must take the third agent immediately after LGX818/MEK162 (Part II). 
• Doses should be taken at approximately the same time each day, except on the days when 
blood collection is scheduled at the clinic, at which time the patients should take their 
morning doses at the clinic. 
• On days when blood collection is scheduled at the clinic, patients will take oral study 
drugs in the clinic under the supervision of the investigator or designee. On all other days 
patients will take oral study drugs at home. 
• At each visit, responsible site personnel will ensure that the patient is provided with the 
correct amount of study drug(s) for the duration of the treatment cycle. 
• Patients will be instructed to return unused study drugs to the site at the end of each cycle. 
• Patients should be instructed to swallow the capsules/tablets whole and not to chew, crush 
or open them. 
• If the patient forgets to take a dose, then he/she should take the dose within 6 hrs from the 
normally scheduled dose time. If more than 6 hours has passed from the previous dose, 
then the dose should be withheld that day and the patient should continue treatment with 
the next scheduled dose. 
• Patients must avoid consumption of grapefruit, pomelos, pomegranates, star fruits, Seville 
oranges or products containing the juice of each during the entire study and preferably 7 


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days before the first dose of study medications, due to potential CYP3A4 interaction with 
the study medications. Orange juice is allowed. 
• 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 increased stool frequency) must be noted in the AE section of the eCRF. In 
addition, on the days of full PK sampling, the onset time of any episodes of vomiting 
within the first 4 hours post-dosing on that day must be noted in the corresponding Dose 
Administration Record PK page of the eCRF. 
• During the entire duration of treatment with INC280, the patient is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a sunlamp or tanning bed). 
 
6.1.2 
Ancillary treatments 
 
6.1.2.1 
Phosphate-lowering therapy for LGX818/MEK162 + BGJ398 
combination 
Since the administration of BGJ398 may be associated with hyperphosphatemia and given the 
potential role of phosphorus and calcium in vascular calcifications, accepted limits of serum 
phosphorus and tCa x Pi have been predefined. 
The in-vivo-solubility product of tCa x Pi is about 58mg2/dL2 and higher values involve a 
significant risk of calcium phosphate precipitation. Phosphorus retention of serum Pi > 6.5 
mg/dL is associated with a significantly increased mortality rate of ESRD patients and several 
studies in this population have reported that tCa x Pi values > 55-60 mg2/dL2 significantly 
increase the risk of cardiovascular calcification, suggesting that these levels should be the upper 
limit of acceptability. 
For the purpose of this study, in LGX818/MEK162 + BGJ398 combination arm, prophylactic 
phosphate lowering therapy is recommended according to institutional standards. 
 
6.1.3 
Rescue medication 
Not applicable 
 
6.1.4 
Guidelines for continuation of treatment 
See Section 6.1.5. 
 
6.1.5 
Treatment duration 
Patients enrolled in Part I and Run-in (Group A and B) of CLGX818X2109 study will be treated 
with LGX818/MEK162 combination until progression and/or experiencing unacceptable 
toxicity, and/or the treatment is discontinued at the discretion of the investigator or withdrawal 
of consent. In particular, pre-treated patients with BRAF and MEK inhibitors single or dual- 
agent treatment (Group B) will enter the Run-in part and will be treated with LGX818/MEK162 
combination at RP2D for at least 3 weeks (one cycle). 
At disease progression from LGX818/MEK162 combination, all patients (Groups A, B and C) 
will be requested to provide a tumor biopsy in order to be assigned to a triple combination in 


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Part II (LGX818/MEK162 double agent + third agent) according to the genetic alterations 
profile identified in the biopsy sample. During this time, patients progressing on 
LGX818/MEK162 combination (Group A, B and C) can continue to be treated with 
LGX818/MEK162 combination at the RP2D or highest tolerated dose, until assigned to the 
appropriate triple-agent therapy arm, as indicated by Table 4-1, and after discussion between 
the Investigators and the Sponsor. The following criteria must be met: 
• Absence of symptoms and signs indicating clinically significant PD not compatible with 
continued participation in this study, 
• No clinically relevant decline in ECOG performance status, 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention. 
Moreover, patients should not discontinue LGX818/MEK162 combination for more than 6 
weeks for AEs, or any other reason, related to treatment with LGX818/MEK162 combination 
prior to entering Part II of this study. All AEs should resolve to at least grade 2 before 
commencing treatment in Part II. Please, refer to Section 6.3.1 for additional guidance on 
treatment discontinuation 
In all cases, continued treatment beyond progression of disease will be allowed in Parts I and II 
only if a patient meets the above listed criteria and only under special circumstances, for 
example, cystic lesions, mixed responses, and new brain metastasis which are treatable with 
stereotactic radiotherapy or surgery, but not requiring whole brain radiotherapy. It is judged by 
the investigator, in agreement with the Sponsor, whether or not a patient may remain on study 
treatment as long as he/she continues to benefit from the study drug treatment per investigator 
assessment. 
Patients treated in Part II of the study (LGX818/MEK162 double agent + third agent) who do 
not tolerate therapy with the third agent may be retreated with LGX818/MEK162 upon 
discussion with the Sponsor Medical Monitor. 
At the time of the data cutoff for the primary analysis, those patients who are continuing to 
receive clinical benefit may continue to be treated with the current combination, or, if 
progressing on LGX818/MEK162 combination, they are allowed to receive a triple 
combination treatment in Part II. Reduced schedule of assessments will be followed from 
Cycle 3 onward as defined in Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 
For patients who have been on treatment in Part I for ≥ 36 months, safety evaluations should 
occur in accordance with local standard-of-care clinical practice and may receive treatment until 
treatment discontinuation criteria are met. 
It is recommended that safety evaluations occur approximately every 4 weeks, unless otherwise 
specified. Safety should be monitored by assessing physical examination, hematology, 
chemistry laboratory testing and other pertinent testing as required as part of the safety profile 
of the compound (dermatological examinations, ophthalmic exams, cardiac profiles) until 
discontinuation. Adverse events should be reviewed at every visit. Investigators will be required 
to record all Grade 3 or 4 AEs, including SAEs, in the clinical database. All SAEs are to be 
reported to the Sponsor or designee using the SAE form. 


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6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
Part I 
The RP2D for the LGX818 and MEK162 dual combination has been determined as 450 mg 
LGX818 QD and 45 mg MEK162 BID ([MEK162X2110]). This dose will be used for patients 
enrolled in the first part of this trial. 
 
Part II 
In the second part of this trial, the starting doses for LGX818 are set at 450 mg QD for the triple 
combinations with BGJ398 and BKM120, and at 200 mg QD for the triple combinations with 
INC280 and LEE011. MEK162 starting doses are kept at 45 mg BID for all the triple 
combinations (see Table 6-2). 
 
LGX818/MEK162 + BKM120 
Note: Due to the DDI between LGX818 and BKM120 (Amendment 03), the BKM120- 
containing arm is closed to enrollment as this combination is no longer being explored. 
Qualitative DDI assessment (Section 1.2.1.3) predicts potential decrease in BKM120 exposure 
and no significant impact on LGX818 and MEK162 exposure when LGX818, MEK162 and 
BKM120 are co-administered. Quantitative analysis using SimCYP simulation predicted no 
change in LGX818 or BKM120 exposure when the two drugs are co-administered. Preliminary 
PK data from the ongoing clinical study using combination of MEK162 and BKM120 
[CMEK162X2101] showed that the pharmacokinetics of MEK162 and its metabolite were not 
altered by BKM120. When combined with MEK162, overall BKM120 systemic drug exposure 
was found to be lower than expected from the single agent data. Therefore the starting dose for 
this triple combination is selected to be the currently established RP2D for LGX818/MEK162 
combination and 60% of the BKM120 single agent MTD (i.e. 100mg): 450 mg QD LGX818, 
45 mg BID MEK162 and 60mg QD BKM120. 
 
LGX818/MEK162 + BGJ398 
Note: The BGJ398-containing arm is closed to enrollment as this combination is no longer 
being explored (Amendment 06). 
Qualitative DDI assessment (Section 1.2.1.3) predicts potential decrease in BGJ398 exposure 
and no significant impact on LGX818 and MEK162 exposure when LGX818, MEK162 and 
BGJ398 are co-administered. Quantitative DDI assessment using SimCYP simulation predicts 
minimal changes in LGX818 exposure when co-administered with BGJ398. At LGX818 dose 
of 450 mg QD, it predicts 17% decrease in BGJ398 AUC and minimal change in BGJ398 Cmax 
at BGJ398 75 mg QD, and 24% decrease in AUC and minimal change in Cmax at BGJ398 125 
mg QD (MTD of BGJ398 as single agent). Therefore the starting dose for the triple combination 
is selected to be the currently established RP2D for LGX818/MEK162 combination and 60% 
of the BGJ398 MTD (i.e. 125mg): 450 mg QD LGX818, 45 mg BID MEK162, and 75 mg QD 
BGJ398. 


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LGX818/MEK162 + INC280 
Note: The INC280-containing arm is closed to enrollment as this combination is no longer 
being explored (Amendment 06). 
Qualitative DDI assessment (Section 1.2.1.3) predicts potential decrease in INC280 exposure, 
increase in LGX818 exposure, and no significant change in MEK162 exposure when LGX818, 
MEK162 and INC280 are co-administered. Quantitative DDI assessment using SimCYP 
simulation predicts 100% and 50% increase in AUC and Cmax of LGX818, respectively, as 
well as 57% and 38% decrease in AUC and Cmax of INC280, respectively when 450 mg QD 
LGX818 and 200 mg BID INC280 are co-administered. Moreover, quantitative DDI assessment 
using SimCYP simulation predicts 144% and 61% increase in AUC and Cmax of LGX818, 
respectively, as well as 50% and 33% decrease in AUC and Cmax of INC280, respectively 
when 200 mg QD LGX818 and 200 mg BID INC280 are co-administered. Based on that, the 
starting dose for the triple combination is selected to be 200 mg QD LGX818, 45 mg BID 
MEK162, and 200 mg BID INC280 capsules. This is 44% of the RP2D of LGX818 in 
combination with MEK162 and 1/3 of the RP2D of INC280 (600 mg BID). 
 
LGX818/MEK162 + LEE011 
The LEE011-containing arm is closed to enrollment as this combination is no longer being 
explored (Amendment 07). 
Qualitative DDI assessment (Section 1.2.1.3) predicts potential decrease in LEE011exposure 
when it is co-administered with LGX818/MEK162, potential increase in LGX818 exposure, 
and no significant impact on MEK162 exposure when LGX818, MEK162 and LEE011 are co- 
administered. 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. Moreover, quantitative DDI assessment using Simcyp simulation predicts 
43% and 18% increase in AUC and Cmax of LGX818, respectively, as well as 40% and 26% 
decrease in AUC and Cmax of LEE011, respectively when 200 mg QD LGX818 and 200 mg 
QD LEE011 are co-administered. Therefore, the starting dose for this triple combination is 
selected to be 200 mg QD LGX818, 45 mg BID MEK162, and 100 mg QD LEE011. This is 
44% of the RP2D of LGX818 in combination with MEK162 and ~11% of the MTD of LEE011 
dose (i.e. 900 mg QD). If the RP2D/MTD for LGX818/MEK162/LEE011 triple combination is 
established in [CMEK162X2110], that dose will be administered in the LEE011 arm of this 
study. 
In this study, the pharmacokinetics of all combination partners as well as their active 
metabolites (if applicable) will be evaluated as soon as possible at steady-state and compared 
with those obtained in the respective monotherapy studies for assessment of the potential drug- 
drug interaction. 
Before the first patient is dosed in any combination, the Bayesian model for this combination 
will be updated with the most recent data from the ongoing double or triple agent trial, to 
confirm that the proposed starting doses for LGX818/MEK162 and triple agent are still 
appropriate (i.e. fulfills the EWOC criteria). If the proposed starting dose does not meet the 
criteria, a lower dose combination that satisfies the EWOC criteria will be used. In addition, 


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emerging clinical data from other combination trials may also be considered for the purpose of 
selecting a starting dose. However, patients will be treated at the determined triple combination 
MTD/RP2D if it becomes available from other clinical trials. This is to allow treating patients 
directly at the most appropriate dose without intra-patient dose escalation once results become 
available for each triple combination arm. 
 
6.2.2 
Provisional dose levels 
Table 6-2 and Table 6-3 describe the starting doses and the provisional dose levels of study 
treatments for the combinations that may be evaluated during this trial. Additional dose levels 
not currently specified may be added and additional patients may be enrolled at a dose level 
already tested if such changes are deemed necessary to provide optimal safety and tolerability, 
pharmacokinetic, and pharmacodynamic data, and satisfy the EWOC criteria. 
 
Table 6-2 
Provisional dose levels for LGX818 and MEK162 (Part I and Part II) 
 
Dose level* (mg) 
LGX818 QD 
(Part I and Part II in 
combo with BKM120 or 
BGJ398)*** 
MEK162 BID 
(Part I and Part II in 
combo with each third 
agent) 
LGX818 QD 
(Part II in combo with 
INC280 or LEE011)*** 
-2** 
150 
15 
50 
-1** 
300 
30 
100 
1 (starting dose) 
450 (RP2D) 
45 (RP2D) 
200 
+1 
- 
- 
- 
+2 
- 
- 
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. 
Dose level may be added below the MTD in order to better understand safety, PK or PD. Doses can 
be modified individually (see Section 6.3.1 for details) 
**Dose level -1 and -2 will also be used for patients requiring a dose reduction from the starting dose 
level. No dose reduction below dose level -2 is permitted for this study. 
***Triple combination arms containing BKM120 (Amendment 03), INC280, BGJ398 (Amendment 06), 
and LEE011 (Amendment 07) are closed to enrollment as these combinations are no longer being 
explored. 


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Table 6-3 
Provisional dose levels for third agents (Part II) 
 
Dose level1 
BKM120 QD* 
BGJ398 
INC280 BID 
INC280 BID 
LEE011 QD* 
QD* 
(capsules)* 
(tablets)* 
(mg) 
-22 
30 
25 
50 
- 
-12 
40 
50 
100 
50 
1 (starting 
60 
75 
200 
1003 
dose) 
2a 
200 
2b 
80 
100 
400 
300 
200 
3 
100 (MTD)4 
125 (MTD)4 
600 (RP2D)4,5 
400 (RP2D)4,5 
300 
4 
- 
- 
- 
400 
1. It is possible for additional and/or intermediate dose levels to be added during the course of the 
study Dose level may be added below the MTD in order to better understand safety, PK or PD. 
2. Dose level -1 and -2 will also be used for patients requiring a dose reduction from the starting 
dose level. No dose reduction below dose level -2 is permitted for this study. 
3. Note that the starting dose for LEE011 may be higher. The LEE011 starting dose will be at or 
below a dose used for a completed cohort of the [CMEK162X2110] study. This dose level must 
satisfy the EWOC criteria under the BLRM used in [CMEK162X2110] as well as the EWOC criteria 
under the BLRM used in this study. 
4. Note that escalation beyond the single agent MTD/RP2D may be considered if satisfying the 
EWOC criteria. 
5. INC280 capsules will be used in dose level 3. Due to a change in formulation, subsequent dose 
levels will evaluate the INC280 tablets. The 600 mg BID capsule dose is equivalent in the relevant 
patient population to the 400 mg BID tablet dose. 
* Triple combination arms containing BKM120 (Amendment 03), INC280, BGJ398 (Amendment 06) 
and LEE011 (Amendment 07) are closed to enrollment as these combinations are no longer being 
explored . 
 
6.2.2.1 
INC280 Dose Escalation: Capsule and Tablet Formulations 
Note: The INC280-containing arm is closed to enrollment as this combination is no longer 
being explored (Amendment 06). 
For detailed relative bioavailability of INC280 capsules and INC280 tablets refer to Section 
1.2.6.2.2. 
The exposure data in cancer patients [CINC280X2102] suggest a dose ratio of approximately 
3:2 (capsules:tablets) for converting the capsule formulation to the tablet formulation. Once the 
INC280 capsule formulation RP2D (600 mg BID) in combination with LGX818 and MEK 162 
has been completed, no further escalations with the capsule formulation will be investigated. 
Subsequent recruitment of patients will occur at the tablet formulation RP2D (400 mg BID) in 
combination with LGX818 and MEK162 with no further escalation beyond the tablet 
formulation RP2D (400 mg BID). 
Ongoing patients will continue with capsule formulation unless otherwise authorized by the 
Sponsor Medical Monitor. Patients will have the opportunity to switch from the INC280 capsule 
formulation to the INC280 tablet formulation only if the capsule formulation is no longer 
available. The investigators are required to consult with the Sponsor Medical Monitor to 


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determine the appropriate dose conversion based on the current available PK and safety data 
for the table formulation. 
 
6.2.3 
Guidelines for dose escalation and determination of MTDs 
 
6.2.3.1 
MTD definition 
The MTD for a combination treatment is defined as the highest combination drug dosage not 
causing medically unacceptable, dose-limiting toxicity (DLT) in 35% or more of the treated 
patients in the first cycle of treatment. AEs and laboratory abnormalities considered to be DLTs 
are defined in Table 6-4. Note that more than one MTD may be identified for a given 
combination treatment. 
For each combination treatment, the applied adaptive Bayesian methodology provides an 
estimate of the dose levels for each third agent not exceeding the MTD. Typically the MTD is 
a tested dose with maximum probability of targeted toxicity (DLT rate between 16% to less 
than 35%). The use of the EWOC principle limits the risk that a potential next dose will exceed 
the MTD (Section 10.5.3.2). 
 
6.2.3.2 
Implementation of dose escalation decisions 
The BKM120- (Amendment 03), INC280-, BGJ398- (Amendment 06), and LEE011 
(Amendment 07)-containing arms are closed to enrollment as these combinations are no 
longer being explored. 
The dose escalation process will be implemented stepwise and will proceed with cohorts of at 
least 3 patients at the current dose of triple combination arm in Part II (see also Section 10.8). 
In particular, LGX818/MEK162 in combination with LEE011 will be administered at the 
MTD/R2PD found in the [CMEK162X2110] study, if available. In that case, no further dose 
escalations will be performed. 
The decision to escalate to a higher dose level will occur after evaluation of individual patients’ 
tolerability of the triple combination during the first 21 days of the cycle (except for 
LGX818/MEK162 + LEE011 and LGX818/MEK162 + BGJ398 combination arms which will 
be 28 days) upon agreement between the investigators and the Sponsor. 
Patients must complete a minimum of one cycle of treatment with the minimum safety 
evaluation and drug exposure or have had a DLT within the first cycle of treatment to be 
considered evaluable for dose escalation decisions. Dose escalation decisions will occur when 
at least 3 patients treated at a dose level not tested before have met these criteria. However, if 
only 2 patients are evaluable and neither patient has experienced a treatment-related toxicity > 
CTCAE grade 1, dose escalation decisions may be considered. 
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK and PD information will all be evaluated by the Investigators and 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 


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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. 
The recommended combination doses for the next patients will be guided by the Bayesian 
logistic regression model (BLRM) with EWOC principle. 
The adaptive Bayesian methodology provides an estimate of all dose levels of the combination 
that do not exceed the MTD and incorporates all DLT information at all dose levels for this 
estimation. In general, the next dose will have the highest chance that the DLT rate will fall in 
the target interval (16 to less than 35%) and will always satisfy the EWOC principle. For the 
escalations of BKM120, BGJ398, and INC280, the next dose will not exceed a 100% increase 
from the previous dose. Should escalation of LEE011 be required in this study, the next dose 
may exceed a 100% increase from the previous dose, but only if that dose both satisfies the 
EWOC criteria for the BLRM used in this study, and is a dose that has been used and shown to 
satisfy the EWOC criteria in the LGX818/MEK162/LEE011 dose escalation taking place in the 
[CMEK162X2110] study. Smaller increases in dose may be recommended by the Investigators 
and Sponsor upon consideration of all of the available clinical data if necessary. To better define 
the dose-toxicity relationship additional patients may be enrolled to the current dose level, to a 
preceding dose level, or to an intermediate dose level before proceeding with further dose 
escalation. 
If the first two patients in a previously untested dose level experience a DLT, enrollment to that 
dose will stop, the BLRM will be updated and the next patients will be enrolled at the next 
lower dose level or an intermediate dose level that satisfies the EWOC criteria. If the two 
consecutive patients treated at a previously tested dose level experience a DLT, further 
enrollment will stop, the BLRM will be updated with this new information and re-evaluation of 
the available safety, PK, and PD data will occur. By incorporating all information available, 
additional patients may be enrolled into the current dose only if the combination still meets the 
EWOC criteria and as agreed by Investigators and Sponsor personnel. Alternatively, if 
recruitment to the same dose may not resume, new patients may be recruited to a lower dose 
combination as agreed by Investigators and Sponsor personnel and if the BLRM predicts that 
the risk for this lower dose combination to exceed the MTD remains below 35% (EWOC). Re- 
escalation may then occur if data in subsequent patients supports this (EWOC criteria are 
satisfied) and Investigators and Sponsor personnel agree. 
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. 
The dose-escalation in each combination arm will continue until identification of the MTD or 
completion of the study (if the required total number of patients has been enrolled). 
Identification of the MTD will occur when the following conditions are met: 
1. At least six patients have been treated at this dose 
2. This dose satisfies one of the following conditions: 
a. The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or 
b. A minimum of 12 patients have already been treated with the combination. 


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3. It is the dose recommended for patients, either per the model or by review of all clinical 
data by the Sponsor and Investigators in a dose-escalation teleconference. 
Patients may enter the Part II of the study at an LGX818 dose below 450 mg QD, and at a 
MEK162 dose lower than 45 mg BID if they previously required a dose reduction, but data 
from at least 3 patients treated at the assigned dose level of LGX818, MEK162 and third agent 
are required before escalation to the next dose level is allowed. Please note that doses of 
LGX818 higher than 200mg may be explored in the triple combination arms with LEE011 or 
INC280, if permissible by BLRM. 
 
6.2.3.3 
Intra-patient dose escalation 
The BKM120- (Amendment 03), INC280-, BGJ398- (Amendment 06) and LEE011- 
(Amendment 07)-containing arms are closed to enrollment as these combinations are no 
longer being explored. 
Intra-patient dose escalation is not permitted at any time within the Part I of treatment with 
LGX818/MEK162 combination because this combination is administered at the RP2D. 
Intra-patient dose escalation of the third agent in the combination treatment is permitted during 
Part II. Intra-patient dose escalation will not be permitted for patients in the LGX818/MEK162 
+ LEE011 arm in the event that an RP2D of this combination has been declared in study 
[CMEK162X2110]; in this case these patients will be treated at the declared RP2D. 
In order for a patient to be treated at a higher dose of BKM120, BGJ398, INC280, or LEE011, 
he or she must have tolerated the lower dose combination for at least 1 cycle of therapy (e.g., 
he or she must not have experienced at the lower dose originally assigned, a toxicity of CTCAE 
grade ≥ 2 for which relationship to study drug cannot be ruled out). Moreover, the new higher 
dose of triple combination which the patient is to be treated with, must meet the modified 
EWOC criteria used for intra-patient escalation. 
Patients will have the opportunity to switch from the INC280 capsule formulation to the INC280 
tablet formulation only if the capsule formulation is no longer available. The investigators are 
required to consult with the Sponsor Medical Monitor to determine the appropriate dose 
conversion based on the current available PK and safety data for the tablet formulation. 
The intra-patient dose escalation will be limited to 50% and will be guided by the BLRM 
according to the following modified EWOC criterion which reflects individual patient 
tolerability: a patient will be able to intra-escalate to a dose for which there is less than a 40% 
chance of excessive toxicity. Furthermore, if treatment-related toxicities of CTCAE grade 2 are 
observed in 2 or more patients at a dose level or if any patient experiences a grade 3 or greater 
toxicity, then the increase in dose of the third agent will be ≤ 25% for any subsequent increase 
in dose. (See Appendix 1) 
Should any of the other combinations have a RP2D identified from an alternative study, then 
this will be used for all patients transitioning from double-agent (Part I) into that particular triple 
combination (Part II) from the time it is identified and no intra-patient escalation will be 
permitted above this dose. Any patients ongoing with that combination at the time the RP2D is 
identified may be escalated to the RP2D at the end of their ongoing cycle if, after review of the 
safety data, both the investigator and the Sponsor agree. 


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These changes must be recorded on the Dosage Administration Record CRF. 
 
6.2.4 
Definitions of dose limiting toxicities (DLTs) 
The BKM120- (Amendment 03), INC280-, BGJ398- (Amendment 06) and LEE011 
(Amendment 07)-containing arms are closed to enrollment as these combinations are no 
longer being explored. 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first cycle (first 21 days for BKM120, and INC280, 28 days 
for LEE011 and BGJ398) of treatment initiation and meets any of the criteria included in Table 
6-4. 
The rules for treatment re-initiation and dose modification of LGX818, MEK162, BKM120, 
BGJ398, INC280 or LEE011 treatment are outlined in Section 6.3. 
National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
version 4.03 will be used for all grading, unless otherwise noted. For the purpose of dose 
escalation decisions, DLTs will be considered and included in the BLRM. 
The investigator must notify the Sponsor immediately of any unexpected ≥ CTCAE grade 3 
adverse events or laboratory abnormalities. 
 
Table 6-4 
Criteria for defining dose-limiting toxicities 
Toxicity 
Any of the following criteria: 
Hematologic 
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 with signs 
of bleeding 
Platelet count CTCAE Grade 4 
Dermatologic 
Skin and subcutaneous tissue 
disorders: 
Rash, HFSR and/or 
photosensitivity 
Rash, HFSR or photosensitivity CTCAE 
Grade 3 despite skin toxicity treatment (as 
per local practice) 
Rash, HFSR or photosensitivity CTCAE 
Grade 4 
GI 
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 
Grade 4 
Pancreas 
Pancreatitis CTCAE Grade 3 
Renal 
Investigations (Renal) 
Serum creatinine CTCAE Grade ≥ 3 


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Toxicity 
Any of the following criteria: 
Hepatic 
Investigations (Hepatic) 
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 
Hepatic – for INC280 
combination therapy 
only 
Investigations 
(Hepatic) 
Isolated* total bilirubin Grade 2 > 7 
consecutive days 
Isolated* total bilirubin Grade ≥ 3 
Isolated* AST or ALT Grade ≥ 3 for > 7 
consecutive days 
AST or ALT Grade 4 
For patients with normal baseline ALT or 
AST or total bilirubin value: 
AST or ALT > 3 x ULN combined** with 
total bilirubin >2.0 x ULN without evidence 
of cholestasis*** 
OR 
For patients with elevated baseline AST or 
ALT or total bilirubin value: 
[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] 
* “Isolated total bilirubin” increase defined as: 
total bilirubin increase without ALT or AST 
increase; “isolated AST or ALT” increase 
defined as: AST or ALT increase without total 
bilirubin increase 
** “Combined” defined as: total bilirubin increase 
to the defined threshold concurrently with 
ALT/AST increase to the defined threshold 
*** “Cholestasis” defined as: ALP elevation 
[>2xULN and R value < 2] in patients without 
bone metastasis, or elevation of ALP liver 
fraction in patients with bone metastasis) 
Note: (The R value is calculated by dividing the 
ALT by the ALP, using multiples of the ULN for 
both values. It denotes the relative pattern of 
ALT and/or ALP elevation is due to cholestatic 
or hepatocellular liver injury) 


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Toxicity 
Any of the following criteria: 
Metabolic 
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 
Cardiac disorders 
CTCAE Grade ≥ 3 
Vascular disorders 
Persistent hypertension CTCAE Grade ≥ 3 
requiring more than one drug or more 
intensive therapy than previously 
Investigations 
(Cardiac) 
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 
Serum CK-MB CTCAE grade 4 
QTcF interval ≥ 501 ms on at least two 
separate ECGs (only for triple combination) 
Ophthalmologic 
Eye disorders - RVO 
Any grade 
Eye disorders- Retinal events 
and Uveitis 
CTCAE Grade 3, if not resolved within 21 
days 
CTCAE Grade 4 
Eye disorders- any other 
CTCAE Grade 3, if not resolved within 21 
days 
CTCAE Grade 4 
General disorders 
Fatigue 
Fatigue CTCAE Grade 3 for > 7 
consecutive days 
CTCAE Grade 4 fatigue (asthenia) 
Edema 
Edema CTCAE Grade 3 for > 14 
consecutive days 
Other Adverse 
Eventsc 
Any other CTCAE Grade ≥ 3 toxicity 
(except cutaneous SCCc, CTCAE Grade 3 
alopecia, CTCAE Grade 3 fatigue/asthenia 
<7 days, 
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 Cutaneous SCC has been reported to be an on-target side-effect that is manageable and will not be 
considered a DLT. 


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Toxicity 
Any of the following criteria: 
Specific criteria for defining dose-limiting toxicities in combination arm with BKM120 
Endocrine 
A grade 3 hyperglycemic event (> 250 
mg/dL) should result in continuous dosing 
(case-by-case basis) of the drug, but the 
patient should have immediate access to 
consultation with an endocrinologist or 
specialist. 
If the event continues for > 2 week after 
consultation and management, consider 
this a DLT. (Busaidy et al 2012) 
Pneumonitis 
CTCAE grade ≥3 symptomatic pneumonitis 
Psychiatric 
Mood alteration 
CTCAE grade 2 mood alteration that does 
not resolve to ≤ grade 1 within 14 days 
despite medical treatment (for Anxiety only, 
if worsened from baseline) 
CTCAE grade ≥ 3 mood alteration 
Psychiatric disorders: 
Agitation, anxiety, 
depression, suicide ideation 
Psychiatric disorders: Agitation, anxiety, 
depression, suicide ideation CTCAE Grade 
2 despite mood stabilizing therapy for at 
least 14 days; for anxiety only, if worsened 
from baseline. Psychiatric disorders 
CTCAE Grade ≥ 3 
Specific criteria for defining dose-limiting toxicities in combination arm with BGJ398 
Renal 
Investigations (Renal) 
Creatinine CTCAE Grade 2 for > 7 
consecutive days. 
Metabolic 
Investigations (Metabolic) 
Hyperphosphatemia (serum-high) 
Serum Pi>7.0mg/dL for > 7 consecutive 
days despite phosphorus lowering therapy 
for at least 14 days 
Serum Pi > 9.0 mg/dL, despite phosphorus 
lowering therapy for at least 14 days 
Serum Pi > 10.0 mg/dL 
Hypercalcemia (serum-high) 
Serum calcium CTCAE Grade 2 for > 7 
consecutive days. 
Serum calcium CTCAE Grade ≥ 3. 
Ocular/visual 
Clinical evidence of corneal disorder/ 
disease of any grade (CTCAE grade ≥ 2) 
including but not limited to corneal edema, 
abrasion, bullous/band keratopathy, 
inflammation/ ulceration, 
keratoconjunctivitis confirmed by 
ophthalmologic examination during any 
cycle. 
Specific criteria for defining dose-limiting toxicities in combination arm with INC280 
Any Neurological 
Toxicity 
Grade ≥ 2 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
If a patient develops a toxicity, the dose may be adjusted or delayed as outlined in this section. 
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 6.3.3. 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/MEK162 combination or 
LGX818/MEK162 + third agent 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 6-5, Table 6-6, Table 6-7, Table 6-8, 
Table 6-9 and Table 6-10 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, once a dose level reduction has occurred, the dose level may not be re-escalated 
during subsequent treatment cycles. Table 6-5 lists the dose modification guidelines for 
LEE011. 
 
Table 6-5 
LEE011 dose modification guidelines 
 
Dose 
Number of Capsules and Strength 
Starting dose 
600 mg 
3 x 200 mg capsules 
First dose reduction 
400 mg 
2 x 200 mg capsules 
Second dose reduction 
200 mg 
1 x 200 mg capsules 
 
 
If a patient requires a dose delay of > 21 consecutive days of LGX818, MEK162, BKM120, 
BGJ398, LEE011, or INC280 from the intended day of the next scheduled dose, then the patient 
should be discontinued from the study treatment. In exceptional situations, if the patient is 
clearly benefiting from the study treatment (i.e. stable disease, partial response, complete 
response), and in the opinion of the investigator no safety concerns are present, after discussion 
with the Sponsor Medical Monitor, the patient may remain on the study treatment at a dose 
level adjusted based on safety. 
 
Treatment discontinuation 
In addition, a patient must discontinue study treatment if, after treatment is resumed at a lower 
dose, the same toxicity reoccurs with the worse severity during the first cycle (except for 
hyperglycemia, hyperphosphatemia, or for CK not clinically significant elevation, where 
explicit rules are provided in appendices, and for skin lesions such as SCC/KA, squamous cell 
carcinoma/keratoacanthoma). If after resolution, treatment is resumed at the same dose 
following the criteria in Table 6-5 to Table 6-10, and the same toxicity reoccurs with the same 
severity, next treatment re-initiation must resume at the next lower dose level irrespective of 
duration. 


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For each patient, once a dose level reduction of LGX818, MEK162, BKM120, BGJ398, 
LEE011, or INC280 has occurred, the dose level may not be re-escalated during subsequent 
treatment cycles with the study drugs. Dose reduction for LGX818 MEK162, BKM120, 
BGJ398, LEE011, or INC280 means treatment at the next lower, previously tested dose level 
of the respective study drug. 
In the LGX818/MEK162 combination part of the study, treatment beyond progression is 
allowed for the assignment of the combination treatment (see Section 6.1.5). 


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Table 6-6 
Criteria for interruption and re-initiation of LGX818/MEK162 combination treatment 
 
Recommended Dose Modifications for LGX818/MEK162 combination 
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 disorder 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C)b 
Omit dose until resolved, then  1 dose level of LGX818 and MEK162 
Investigations (Blood) 
Neutropenia (neutrophil count (ANC) 
decreased) 
Grade 1 (ANC < LLN - 1.5 x 109/L) or Grade 2 
(ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level of LGX818 and MEK162 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit dose of LGX818 and MEK162 until resolved to ≤ Grade 2, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days, then  1 dose level* of LGX818 and maintain dose level of MEK162 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose of LGX818 and MEK162 until resolved to ≤ Grade 2, then  1 dose level* of LGX818 and 
MEK162 
Thrombocytopenia (platelet count decreased) 
Grade 1 (PLT < LLN - 75 x 109/L) or Grade 2 
Maintain dose level of LGX818 and MEK162 
(PLT < 75 - 50 x 109/L) 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose of LGX818 and MEK162 until resolved to ≤ Grade 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days and/or with signs of bleeding, then  1 dose level* of LGX818 and MEK162 
Grade 4 (PLT < 25 x 109/L) 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment. 


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Recommended Dose Modifications for LGX818/MEK162 combination 
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, but initiate anti-diarrhea treatment (see Appendix 3). 
Grade 2 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1 and then maintain dose level of 
LGX818 and MEK162 
- For 2nd occurrence of diarrhea Grade 2 within 15 days, omit dose of LGX818 and MEK162 until 
resolved to Grade ≤ 1, then reduce MEK162 by 1 dose level* and maintain dose level of LGX818 
Grade 3 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1, then reduce dose of LGX818 and 
MEK162 by 1 dose level*. 
Grade 4 
Omit dose of LGX818 and MEK162 and 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 or 2 
Maintain dose level of LGX818 and MEK162 
Grade 3 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1, then  1 dose level* of LGX818 and 
MEK162 
Grade 4 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment. 
Note: Omit dose 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 or 2 
Grade ≥ 3 
Maintain dose level of LGX818 and MEK162 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment 
Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level of LGX818 and MEK162 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose of LGX818 and MEK162 until resolved to ≤ Grade 1, then maintain dose level of LGX818 
and MEK162 
Grade ≥3 (> 3.0 x ULN) 
Omit dose of LGX818 and MEK162 and discontinue patient from study treatment. 


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Recommended Dose Modifications for LGX818/MEK162 combination 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic) 
Bilirubin 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level of LGX818 and MEK162 
Grade 2 (> 1.5 – 3.0 x ULN) 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 
Grade ≥ 3 (> 3.0 x ULN) 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug 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 
Grade 1 
Maintain dose level of LGX818 and MEK162 
Grade 2 or Grade 3 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver 
metastasis), then 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 
Grade 4 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment. 
AST or ALT and Bilirubin 
AST or ALT > 3.0 - 5.0 x ULN and total blood 
bilirubin ≥ Grade 2 
AST or ALT > 5.0 x ULN and total blood 
bilirubin ≥ Grade 2 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1, then 
- If resolved in ≤ 7 days,  1 dose level* of LGX818 and MEK162 
- If resolved in > 7 days, discontinue patient from study drug treatment. 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment. 


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Recommended Dose Modifications for LGX818/MEK162 combination 
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) or Grade 2 (> 1.5 
- 2.0 x ULN) 
Maintain dose level of LGX818 and MEK162 
Grade 3 (> 2.0 - 5.0 x ULN) 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 2, then : 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 
Grade 4 (> 5.0 x ULN) 
Omit dose of LGX818 and MEK162 and 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 benefiting from study therapy, they may remain on- 
study at a reduced dose following discussion between investigator and Sponsor. If asymptomatic 
Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be 
discontinued permanently from study treatment. 
Cardiac disorders 
Cardiac general 
Grade 1 or 2 
Maintain dose level of LGX818 and MEK162 
Grade 3 
Omit dose of LGX818 and MEK162, until resolved to Grade ≤ 1, then  1 dose level* of LGX818 and 
MEK162 
Grade 4 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment. 


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Recommended Dose Modifications for LGX818/MEK162 combination 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Cardiac) 
Creatine phosphokinase (CPK) 
Grade 1 (> ULN – 2.5 x ULN) or Grade 2 (> 2.5 
- 5.0 x ULN) 
Maintain dose level of LGX818 and MEK162 
Grade 3 (> 5.0 - 10.0 x ULN) 
If asymptomatic: Maintain dose level of LGX818 and MEK162 
If symptomatic: Omit dose of MEK162 and maintain dose of LGX818 until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 14 days, then  1 dose level* of MEK 162 and maintain dose level of LGX8182 
- If resolved in > 14 days, then discontinue patient from study drug treatment with LGX818 and 
MEK162 
Grade 4 (> 10.0 x ULN) 
Omit dose of MEK162 and maintain dose of LGX818 until resolved to CTCAE Grade ≤ 1, then: 
- If resolved in ≤ 14 days, then  1 dose level of MEK162 and maintain dose level of LGX818 
- If resolved in > 14 days, then discontinue patient from study drug treatment with LGX818 and 
MEK162 
LV systolic dysfunction (not according CTCAE) 
Asymptomatic decrease of > 10% in LVEF 
compared to baseline and the ejection fraction 
is below the institution’s lower limit of normal 
and CTCAE Grade 2 
Omit dose of MEK162 until LVEF recovers (defined as ≥ LLN and decrease ≤ 10% compared to 
baseline). 
- If the LVEF recovers ≤ 21 days, then  1 dose level of MEK162, maintain dose of LGX818 and 
monitor LVEF 2 weeks after restarting on MEK162, every 4 weeks for 12 weeks and subsequently as 
per protocol 
- If the LVEF recovers >21 days, then discontinue patient from study drug treatment with MEK162 and 
LGX818, and closely monitor LVEF until resolution (or for 16 weeks). 
Grade ≥ 3 
Omit dose of MEK162 and LGX818 and discontinue patient from study drug treatment. 
Vascular disorders 
Hypertension 
Grade 1 or 2 
Grade 3 (requiring more than one drug or more 
intensive therapy than previously) 
Grade 4 (life-threatening) 
Maintain dose level of LGX818 and MEK162 
Omit dose of LGX818 and MEK162, until resolved to Grade ≤ 1, then  1 dose level* of LGX818 and 
MEK162 
Omit dose of LGX818 and MEK162, and discontinue patient from study drug treatment 


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Recommended Dose Modifications for LGX818/MEK162 combination 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Eye disorders 
Eye disorders – RVOe 
Any Grade 
Note: Results of ophthalmic examinations must be made available upon request. This includes 
scans/images of fluorescein angiography. 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatmentc 
Eye disorders – Retinal events, Uveitise 
Note: Results and images of ophthalmic examinations must be made available upon request. This 
includes scans/images of OCTs. 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Maintain dose of LGX818 and MEK162 and increase frequency of ophthalmic monitoring by 
ophthalmologist to at least every 14 days 
Maintain dose of LGX818 and MEK162 and refer the patient to ophthalmologist within one week. 
Reassess the patient weekly (ophthalmic examination) until resolution to Grade ≤ 1: 
- If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of LGX818 and MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of LGX818 and MEK162 
At any time if symptoms worsen, or persist with the same severity for more than 7 days, reduce 1 dose 
leveld of LGX818 and MEK162 
Interrupt dose of LGX818 and MEK162 and refer the patient to ophthalmologist monitoring within one 
weeke: 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose levelb of LGX818 and MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue LGX818 and MEK162, and refer 
the patient to ophthalmologist monitoring 
Permanently discontinue LGX818 and MEK162, and refer the patient to ophthalmologist monitoringe 


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Recommended Dose Modifications for LGX818/MEK162 combination 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Eye disorders – any other (i.e. retinal 
detachment) 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 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 
leveld of LGX818 and MEK162 
Interrupt dose of LGX818 and MEK162 and refer patient to ophthalmologist monitoring within one 
weeke: 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of LGX818 and MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue LGX818 and MEK162, and refer 
the patient to ophthalmologist monitoringe 
Permanently discontinue LGX818 and MEK162, and refer the patient to ophthalmologist Monitoringe 
Skin and subcutaneous tissue disorders 
Rash/ HFSR/ photosensitivity 
Grade 1 
Grade 2 
Grade 3, despite skin toxicity therapy 
Grade 4, despite skin toxicity therapy 
Maintain dose level of LGX818 and MEK162, but consider initiating appropriate skin toxicity therapy 
(see Appendix 4) 
Maintain dose level of LGX818 and MEK162, but initiate/intensify appropriate skin toxicity therapy 
Omit dose of LGX818 and MEK162, until resolved to Grade ≤ 1 then: 
- If resolved in ≤ 7 days,  1 dose level* of LGX818 and MEK162 
- If resolved in > 7 days, discontinue patient from study drug treatment with LGX818 and MEK162 (see 
Appendix 4) 
Omit dose LGX818 and MEK162, and discontinue patient from study drug treatment with LGX818 and 
MEK162 
General disorders and administration site conditions 
Fatigue 
Grade 1 or 2 
Grade 3 
Maintain dose level of LGX818 and MEK162 
Omit dose of LGX818 and MEK162, until resolved to Grade ≤ 1, then : 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 


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Recommended Dose Modifications for LGX818/MEK162 combination 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Edema 
Grade 1 or 2 
Grade 3 
Maintain dose level of LGX818 and MEK162 
Omit dose of LGX818 and MEK162 until resolved to Grade ≤ 1, then : 
- If resolved in ≤ 14 days,  1 dose level* of MEK162 and maintain dose of LGX818 
- If resolved in > 14 days, discontinue patient from study drug treatment with LGX818 and MEK162 
Other adverse eventsc 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 
Omit dose of LGX818 and MEK162, until resolved to Grade ≤ 1, then  1 dose level* of LGX818 and 
MEK162 
Omit dose of LGX818 and MEK162 and discontinue patient from study drug treatment 
a All dose modifications should be based on the worst preceding toxicity. 
b Not CTCAE grading 
c 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. 
d Dose reduction below 50 mg QD for LGX818, and below 15 mg BID for MEK162 is not allowed 
e Ophthalmic monitoring mandated for retinal event, posterior uveitis, RVO: further evaluation with specialized retinal imaging (e.g. ocular coherence 
tomography, angiography) 
*  1 dose level refers to: next lower dose level of LGX818, MEK162 (please see Table 6-2). 


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Table 6-7 
Criteria for interruption and re-initiation of LGX818 and MEK162 in combination with third agent (BGJ398, 
INC280, BKM120 or LEE011) 
 
Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
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 disorder 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C)b 
If the third agent is LEE011: 
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 
Omit dose until resolved, then  1 dose level 
Omit dose of LGX818 and MEK162 and LEE011 until improvement of ANC ≥ 1.0 x 109/L and no fever. 
Restart at the next lower dose level. 
If febrile neutropenia recurs, discontinue LGX818 and MEK162 and third agent if it is LEE011. 
Discontinue LGX818 and MEK162 and LEE011. 
Investigations (Blood) 
Neutropenia (neutrophil count (ANC) 
decreased) 
Grade 1 (ANC < LLN - 1.5 x 109/L) or Grade 2 
(ANC < 1.5 - 1.0 x 109/L) 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent until resolved to ≤ Grade 2, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent 
- If resolved in > 7 days,  1 dose level* of LGX818 and LEE011 and maintain dose level of MEK162 
and third agent (if not LEE011) 
Omit dose of LGX818 and MEK162 and third agent until resolved to ≤ Grade 2,  1 dose level* of 
LGX818 and MEK162 and third agent 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Thrombocytopenia (platelet count decreased) 
Grade 1 (PLT < LLN - 75 x 109/L) or Grade 2 
(PLT < 75 - 50 x 109/L) 
Grade 3 (PLT < 50-25 x 109/L) 
Grade 4 (PLT < 25 x 109/L) 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent until resolved to ≤ Grade 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent. 
- If resolved in > 7 days and/or with signs of bleeding,  1 dose level* of LGX818 and MEK162 and 
third agent 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment. 
Gastrointestinal disorders 
Diarrhea 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 and third agent, but initiate anti-diarrhea treatment. 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 1 and then maintain dose 
level of LGX818 and MEK162 and third agent 
- For 2nd occurrence of diarrhea Grade 2 within 15 days, omit dose of LGX818 and MEK162 and third 
agent until resolved to Grade ≤ 1, then reduce MEK162 by 1 dose level* and maintain dose level of 
LGX818 and third agent. If in the opinion of the investigator the toxicity is unrelated to LGX818 but 
may be related to MEK162 and the third agent, maintain dose level of LGX818 and reduce MEK162 
and third agent by 1 dose level. 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 1, then reduce dose of 
LGX818 and MEK162 and third agent by 1 dose level*. 
Omit dose of LGX818 and MEK162 and third agent and 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 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1, then  1 dose level* 
of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment. 
Note: Omit dose for ≥ grade 3 vomiting or nausea only if the vomiting or nausea cannot be controlled 
with optimal antiemetics (as per local practice). 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Pancreatitis 
Grade 2 
Grade ≥ 3 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment 
Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN – 1.5 x ULN) 
Grade 2 (> 1.5 - 3.0 x ULN) 
Grade ≥3 (> 3.0 x ULN) 
Maintain dose level of LGX818 and MEK162 (and INC280, BKM120 and LEE011). For BGJ398 triple 
combination, please, also refer to Section 6.3.1 Table 6-8. 
Omit dose of LGX818 and MEK162 and third agent until resolved to ≤ Grade 1, then maintain dose 
level of LGX818 and MEK162 and third agent. 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study treatment. 
Grade ≥2 renal impairment 
Discontinue treatment and follow-up patient for safety assessments. 
Investigations (Hepatic***)- for BGJ398, BKM120 only 
Bilirubin 
Grade 1 (> ULN – 1.5 x ULN) 
Grade 2 (> 1.5 – 3.0 x ULN) 
Grade ≥ 3 (> 3.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent- If resolved in > 
7 days,  1 dose level* of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug 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* of LGX818 and MEK162 and Third 
agent and continue treatment at the discretion of the investigator. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
AST or ALT 
Grade 1 
Grade 2 or Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 and third agent. 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 1 (or Grade ≤ 2 in case 
of liver metastasis), then 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent. 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 and third agent. 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment. 
AST or ALT and Bilirubin 
AST or ALT > 3.0 - 5.0 x ULN and total blood 
bilirubin ≥ Grade 2 
AST or ALT > 5.0 x ULN and total blood 
bilirubin ≥ Grade 2c 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 1, then 
- If resolved in ≤ 7 days,  1 dose level* of LGX818 and MEK162 and third agent 
- If resolved in > 7 days, discontinue patient from study drug treatment. 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**)- for LEE011 only 
Total Bilirubin without ALT/AST increase above 
baseline value (confirmed 48-72hr later) 
Grade 1 (> ULN – 1.5 x ULN) 
Grade 2 (> 1.5 – 3.0 x ULN) 
Grade ≥ 3 (> 3.0 x ULN) 
Grade 4 (> 10.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and LEE011 with LFTs monitored bi-weekly. 
Omit dose of LGX818 and MEK162 and LEE011 until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and LEE011 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 and LEE011 
- If resolved in > 28 days, discontinue patient from all study drug treatment 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. 
Omit dose of LGX818 and MEK162 and LEE011 and discontinue patient from all study drug 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* of LGX818 and MEK162 and 
LEE011 and continue treatment at the discretion of the investigator. Repeat liver enzyme and bilirubin 
tests twice weekly for 2 weeks after dose resumption. 
Discontinue patient from all study drug treatment. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**)- for LEE011 only 
(con’t). 
AST or ALT without bilirubin elevation > 2 ULN 
(confirmed 48-72hr later) 
Grade 1 
Grade 2 (> 3.0 – 5.0 x ULN) 
Grade 3 (> 5.0 – 20.0 x ULN) 
Grade 4 (> 20.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and LEE011. Monitor LFT bi-weekly. 
Omit dose of LGX818 and MEK162 and LEE011 until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of 
liver metastasis), then 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and LEE011. 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 and LEE011. 
- If resolved in > 28 days, discontinue patient from all study drug treatment 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. 
Omit dose of LGX818 and MEK162 and third agent until resolved to ≤ baseline grade, then lower 1 
dose level of dose level of LGX818 and MEK162 and LEE011. If recovery to ≤ baseline grade 
is > 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. 
Discontinue patient from all study drug treatment. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**)- for LEE011 only 
(con’t). 
AST or ALT and Bilirubin 
For patients with normal ALT and AST and 
total bilirubin at baseline: AST or ALT > 3.0 x 
ULN combined with total bilirubin > 2 x ULN 
without evidence of cholestasis 
Or 
For patient with elevated AST or ALT or total 
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) 
Discontinue patient from all study drug treatment. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**)- for INC280 only 
Isolated Bilirubin increase 
Grade 1 (> ULN – 1.5 x ULN) 
Grade 2 (> 1.5 – 3.0 x ULN) 
Grade ≥ 3 (> 3.0 x ULN -10.0xULN) 
Grade 4 (> 10.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and INC280 with LFTs*** monitored 
Omit dose of LGX818 and MEK162 and INC280 with weekly monitoring of LFTs***, or more frequently 
as clinically indicated, until resolved to ≤ Grade 1, then 
-If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and INC280 
-If resolved in > 7 days,  1 dose level of LGX818 and MEK162 and INC280 
Omit dose of LGX818 and MEK162 and INC280 with weekly monitoring of LFTs***, or more frequently 
as clinically indicated, until resolved to ≤ Grade 1, then 
-If resolved in ≤ 7 days,  1 dose level of LGX818 and MEK162 and INC280 
If resolved in > 7 days, discontinue patient from study drug treatment 
Discontinue patient from study drug treatment. 
The patient should be monitored weekly (including LFTs***), or more frequently if clinically indicated, 
until total bilirubin have resolved to baseline or stabilization over 4 weeks. 
Isolated AST or ALT increase 
Grade 1 or 2 (> ULN - 5.0 x ULN) 
Grade 3 (>5.0 x ULN - 20.0 x ULN) 
Grade 4 (> 20.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and INC280 with LFTs monitored 
Omit/delay dose of LGX818 and MEK162 and INC280 until resolved to ≤ Grade 1 or ≤ grade 2 if grade 
2 elevation at baseline, then 
-If resolved in ≤ 7 days, resume treatment at the same dose level 
-If resolved in > 7 days, resume treatment at ↓ 1 dose level 
Permanently discontinue patient from study drug treatment 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations (Hepatic**)- for INC280 only 
Combined elevations of AST or ALT, and Total 
Bilirubinb,d 
For patients with normal baseline ALT or AST 
or total bilirubin value: 
AST or ALT > 3.0 x ULN combined with total 
bilirubin > 2.0 x ULN without evidence of 
cholestasise 
OR 
For patients with elevated baseline AST or ALT 
or total bilirubin value: 
[AST or ALT > 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] 
Permanently discontinue patient from study drug treatment. 
Repeat LFTs as soon as possible, preferably within 48 hours from awareness of the abnormal results, 
then with weekly monitoring of LFTs, or more frequently if clinically indicated, until AST, ALT, or 
bilirubin have resolved to baseline or stabilization over 4 weeks. Refer to Section 6.3.2.8 for 
additional follow-up evaluations as applicable. 
Investigations (Metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) or Grade 2 (> 1.5 
- 2.0 x ULN) 
Grade 3 (> 2.0 - 5.0 x ULN) 
Grade 4 (> 5.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent until resolved to Grade ≤ 2, then : 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 and third agent. 
Omit dose of LGX818 and MEK162 and third agent and 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. If 
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 LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Cardiac disorders 
Cardiac general 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1, then  1 dose level* 
of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent and discontinue patient from study drug treatment. 
Investigations (Cardiac) 
Creatine phosphokinase (CPK) 
Grade 1 (> ULN – 2.5 x ULN) or Grade 2 (> 2.5 
- 5.0 x ULN) 
Grade 3 (> 5.0 - 10.0 x ULN) 
Grade 4 (> 10.0 x ULN) 
Maintain dose level of LGX818 and MEK162 and third agent 
If asymptomatic: Maintain dose level of LGX818 and MEK162 and third agent 
If symptomatic: Omit dose of MEK162 and maintain dose of LGX8181 and third agent until resolved to 
Grade ≤ 1, then: 
- If resolved in ≤ 14 days,  1 dose level* of MEK 162 and maintain dose level of LGX8182 and third 
agent 
- If resolved in > 14 days, discontinue patient from study drug treatment with LGX818 and MEK162 
and third agent 
Omit dose of MEK162 and maintain dose of LGX8181 and third agent until resolved to CTCAE Grade 
≤ 1, then: 
- If resolved in ≤ 14 days,  1 dose level of MEK162 and maintain dose level of LGX8182 and third 
agent 
- If resolved in > 14 days, discontinue patient from study drug treatment with LGX818 and MEK162 
and third agent 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
LV systolic dysfunction (not according 
CTCAE) 
Asymptomatic decrease of > 10% in LVEF 
compared to baseline and the ejection fraction 
is below the institution’s lower limit of normal 
and CTCAE grade 2 
Omit dose of MEK162 until LVEF recovers (defined as ≥ LLN and decrease ≤ 10% compared to 
baseline). 
- If the LVEF recovers ≤ 21 days, then  1 dose level of MEK162, maintain dose of LGX818 and third 
agent and monitor LVEF 2 weeks after restarting on MEK162, every 4 weeks for 12 weeks and 
subsequently as per protocol 
- If the LVEF recovers > 21 days, then discontinue patient from study drug treatment with MEK162 and 
LGX818 and third agent, and closely monitor LVEF until resolution (or for 16 weeks). 
Grade ≥ 3 
Omit dose of MEK162 and LGX818 and third agent and discontinue patient from study drug treatment. 
Electrocardiogram QTcF interval prolonged 
(only for LEE011) 
For all grades 
Grade 1 QTcF 450-480 msh 
Grade 2 QTcF 481-500 msh 
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, hold 
LEE011, 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 LEE011. 
Perform all the steps “For All Grades” and check compliance with correct dose and administration of 
LEE011. No dose adjustment required 
Omit dose of LGX818 and MEK162 and LEE011. Perform all the steps above “For All Grades.” 
Perform repeat triplicate ECGs within one hour after the first QTcF of ≥ 481 ms. 
If QTcF < 481 ms, restart study treatment with LEE011 dose reduced by 1 dose level. 
If QTcF remains ≥ 481 ms, repeat ECG as clinically indicated until the QTcF returns to < 481 ms and 
then restart study treatment with LEE011 dose reduced by 1 dose level. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Electrocardiogram QTcF interval prolonged 
(only for LEE011 con’t.) 
Grade 3h 
QTcF interval ≥ 501 ms on at least two 
separate ECGs 
Grade 4h 
QT/QTcF ≥ 501 or > 60 ms change from 
baseline and Torsades de pointes or 
polymorphic ventricular tachycardia, or 
signs/symptoms of serious arrhythmia 
If QTcF ≥ 481 ms recurs, again  1 dose level* of LEE011. 
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. 
Omit dose of LGX818 and MEK162 and LEE011. Perform all the steps above for “For All Grades.” 
Transmit ECG immediately and confirm prolongation/abnormalities with central assessment. 
Perform repeat triplicate ECGs one hour after the first QTcF of ≥ 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat cardiac 
monitoring as indicated until the QTcF returns to < 481 ms. 
• 
If QTcF returns to < 481 ms, LEE011 will be reduced by 1 dose level (Table 6-5). 
• 
If QTcF remains ≥ 481 ms after performing steps as directed in “For All Grades,” discontinue 
LEE011. 
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 all study treatment 
Discontinue patient from LGX818, MEK162, and LEE011 treatment. Perform all the steps above for 
“For All Grades.” 
Transmit ECG immediately and confirm prolongation/abnormalities with central assessment. 
Obtain local cardiologist (or qualified specialist) consultation and perform repeat cardiac monitoring as 
indicated until the QTcF returns to <481 ms.. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Electrocardiogram QTcF interval prolonged 
(only for BGJ398, INC280 and BKM120) 
Grade 1 or 2 
Grade 3 (QTcF interval ≥ 501 ms on at least 
two separate ECGs) 
Grade 4 
Maintain dose level 
Omit dose of LGX818 and MEK162 and third agent 
Perform frequent ECGs until the QTcF is < 501 msec. 
Address electrolyte, calcium and magnesium abnormalities. Restart LGX818, MEK162 and either 
BGJ398, INC280 or BKM120 at the same dose level. 
If QTcF is not < 501 ms within 5 days reduce LGX818, MEK162 and either BGJ398, INC280 or 
BKM120 by 1 dose level. 
If findings recur at the lower dose, omit dose of LGX818 and MEK162 and third agent until resolve to ≤ 
Grade 1, and restart at the next lower dose. 
Discontinue patient from LGX818 and MEK162 and third agent 
Vascular disorders 
Hypertension 
Grade 1 or 2 
Grade 3 (requiring more than one drug or more 
intensive therapy than previously) 
Grade 4 (life-threatening) 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1, then  1 dose level* 
of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, and discontinue patient from study drug treatment 
Eye disorders 
Eye disorders – Retinal events, Uveitisi 
Note: Results and images of ophthalmic examinations must be made available upon request. This 
includes scans/images of OCTs. 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Maintain dose of LGX818/MEK162 and combination partner and increase frequency of ophthalmic 
monitoring by ophthalmologist to at least every 14 days 
Maintain dose of LGX818/ MEK162 and combination partner and refer the patient to ophthalmologist 
within one week. Reassess the patient weekly (ophthalmic examination) until resolution to Grade ≤ 1: 
- If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of LGX818/ MEK162 and combination partner 
- If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of LGX818 and MEK162 and maintain 
combination partner 
At any time if symptoms worsen, or persist with the same severity for more than 7 days, reduce 1 dose 
leveld of LGX818/ MEK162 and maintain combination partner 
Interrupt dose of LGX818 and MEK162 and refer the patient to ophthalmologist monitoring within one 
weeki: 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose levelb of LGX818/ MEK162 and maintain 
combination partner 
- If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue LGX818/MEK162 and 
combination partner, and refer the patient to ophthalmologist monitoring 
Permanently discontinue LGX818/ MEK162 and combination partner, and refer the patient to 
ophthalmologist monitoringi 
Eye disorders – RVOi 
Any Grade 
Note: Results of ophthalmic examinations must be made available upon request. Omit dose of 
LGX818 and MEK162 and third agent and discontinue patient from study drug treatment 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
Eye disorders (con’t.) 
Eye disorders – any other (i.e. retinal 
detachment) 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 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 
leveld of LGX818/ MEK162 and maintain combination partner 
Interrupt dose of LGX818 and MEK162 and refer patient to ophthalmologist monitoring within one 
weeki: 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of LGX818/ MEK162 and maintain 
combination partner 
- If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue LGX818/ MEK162 and 
combination partner and refer the patient to ophthalmologist monitoringi 
Permanently discontinue LGX818/ MEK162 and combination partner, and refer the patient to 
ophthalmologist Monitoringi 
Skin and subcutaneous tissue disorders 
Rash/ HFSR/ photosensitivity 
Grade 1 
Grade 2 
Grade 3, despite skin toxicity therapy 
Grade 4, despite skin toxicity therapy 
Maintain dose level of LGX818 and MEK162 (and BGJ398, INC280 and LEE011), but consider 
initiating appropriate skin toxicity therapy (see Appendix 4). For BKM120 triple combination, please, 
refer to Table 6-10 for the specific dose modification recommendation (see also Appendix 4). 
Maintain dose level of LGX818 and MEK162 and third agent, but initiate/intensify appropriate skin 
toxicity therapy (see Appendix 4) 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1 then: 
- If resolved in ≤ 7 days,  1 dose level* of LGX818 and MEK162 
- If resolved in > 7 days, discontinue patient from study drug treatment with LGX818 and MEK162 and 
third agent 
Omit dose LGX818 and MEK162 and third agent, and discontinue patient from study drug treatment 
with LGX818 and MEK162 and third agent 


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Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
General disorders and administration site conditions 
Fatigue 
Grade 1 or 2 
Grade 3 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1, then : 
- If resolved in ≤ 7 days, maintain dose level of LGX818 and MEK162 and third agent 
- If resolved in > 7 days,  1 dose level* of LGX818 and MEK162 and third agent 
Other adverse eventsj 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, until resolved to Grade ≤ 1, then  1 dose level* 
of LGX818 and MEK162 and third agent 
Omit dose of LGX818 and MEK162 and third agent, and discontinue patient from study drug treatment 


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Protocol No. CLGX818X2109 
 
 
 
Recommended Dose Modifications for LGX818 and MEK162 in combination with a third agent (BGJ398, INC280, BKM120 or LEE011) 
Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified)a 
Recommended Dose Modifications any time during a cycle of therapy 
a All dose modifications should be based on the worst preceding toxicity. 
b Not CTCAE grading 
c 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 6.3.2.5 and 
Section 6.3.2.6. 
d “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold 
e “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in patients without bone metastasis, or elevation of ALP 
liver fraction in patients with bone metastasis 
f If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total 
bilirubin and isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for dose 
reduction 
g Dose reduction below 50 mg QD for LGX818, and below 15 mg BID for MEK162 is not allowed 
h All values refer to the average of triplicate measurements. 
i Ophthalmic monitoring mandated for retinal event, posterior uveitis, RVO: further evaluation with specialized retinal imaging (e.g. ocular coherence 
tomography, angiography). 
j 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. 
*  1 dose level refers to: next lower dose level of LGX818, MEK162 and third agents (please see Table 6-2 and Table 6-3). 
** 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. 
*** LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin ≥ grade 2), alkaline phosphatase (fractionated if alkaline phosphatase is 
grade 2 or higher) and GGT. 


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Table 6-8 
Specific criteria for interruption and re-initiation of BKM120 treatment in LGX818/MEK162 + BKM120 triple 
combination 
 
Recommended Dose Modifications for BKM120 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
No toxicity 
Maintain dose level 
Metabolism and Nutrition disorders 
Hyperglycemia - Fasting Plasma Glucose 
(FPG) 
According Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K- 
Akt-mTOR Pathway, (Busaidy et al 2012) 
Grade 1 (> ULN - 160 mg/dL) [ULN - 8.9. 
mmol/L] 
Maintain dose level of LGX818/MEK162 and BKM120 
If appropriate in clinical context, refer to nutritionist for dietary education on diabetic diet, increase 
aerobic exercise, and refer to diabetes educator for comprehensive diabetic education on 
nonpharmaceutical interventions or therapeutic lifestyle change (TLC) 
Grade 2 (> 160 - 250 mg/dL) [> 8.9 - 13.9 
mmol/L] 
Maintain dose level of LGX818/MEK162 and BKM120 
Initiate plasma glucose (PG) monitoring and PG lowering therapy (Metformin*). 
After 2 weeks: If fasting glucose grade 2 or random glucose > 200 mg/dL, continue metformin*, add 
sulfonylurea and titrate. 
After additional 1 week: If fasting glucose > 160 mg/dL or random glucose > 200 mg/dL, continue two 
oral agents and add basal insulin. 
Stop oral agents. Begin basal bolus insulin four injections/day. 
Asymptomatic Grade 3 (> 250 - 500 mg/dL) [> 
13.9 - 27.8 mmol/L] 
Maintain dose level of LGX818/MEK162 and BKM120 
Start home glucose monitoring before meals twice per day and TLC. 
Begin metformin* and sulfonylurea and rapidly titrate. 
After 1 week: If fasting glucose > 160 mg/dL or random glucose > 200 mg/dL, add basal insulin to oral 
agents, and titrate basal insulin to fasting glucose. 
After additional 1 week: If fasting glucose > 160 mg/dL or random glucose > 200 mg/dL, stop oral 
agents; add premeal insulin, and check glucose before meals three times a day (TID) and at every bed 
time (QHS). 


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Recommended Dose Modifications for BKM120 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
Symptomatic Grade 3, (> 250 - 500 mg/dL) [> 
13.9 – 27.8 mmol/L], or asymptomatic grade 4: 
fasting glucose > 500 mg/dL [27.8 mmol/L] 
Consider intravenous fluids (IVF) and/or admit if hypovolemic signs/symptoms, diabetes consultation, 
four-injection basal bolus insulin regimen, check home glucose before meals TID and QHS 
After 1 week: If fasting or random glucose > 250 mg/dL, DLT and hold BKM120. 
Restart when glucose < 250 mg/dL and no symptoms 
The occurrence of grade 3 hyperglycemia (> 250 mg/dL) or asymptomatic grade 4 hyperglycemia (> 
500 mg/dL) should result in a rapid review by the team endocrinologist (by telephone or in person) or 
the respective algorithm should be followed. 
Symptomatic Grade 4: fasting glucose > 500 
mg/dL [27.8 mmol/L] 
The study drug BKM120 should be held without attempting intervention if a patient experiences a 
symptomatic grade 4 (>500 mg/dL) hyperglycemic event and refer to endocrinology or diabetes 
treating specialist. 
Any hyperglycemia leading to diabetic keto- 
acidosis, hospitalization for intravenous insulin 
infusion, or non-ketotic coma. 
Omit dose of LGX818/MEK162 and BKM120 and discontinue patient from study drug treatment. 
(*) Do not use metformin if creatine > 1.3 mg/dL (women) or > 1.4 mg/dL (men) or if any state of 
decreased tissue perfusion or hemodynamic instability is present (eg, heart failure); hold metformin for 
computed tomography scans; GI symptoms may occur with initiation but usually subside after first 
week. 
Stomatitis/Oral mucositis 
Grade 1 / Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash 
Intolerable Grade 2 or Grade 3 
First occurrence: hold BKM120 until ≤ G1 and  1 dose level (if stomatitis is readily manageable with 
optimal management, re-introduction at the same level might be considered at the discretion of the 
investigator). 
Second occurrence: hold BKM120 until ≤ G1 and  1 dose level. 
Grade 4 
Permanently discontinue patient from BKM120. 
Skin and subcutaneous tissue disorders 
Rash/HFSR/photosensitivity 
Grade 1 
Maintain dose level of LGX818/MEK162 + BKM120; but consider initiating appropriate skin toxicity 
therapy (such as antihistamines, topical corticosteroids, and low-dose systemic corticosteroids) (see 
Appendix 4) 


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Recommended Dose Modifications for BKM120 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
Grade 2 
First occurrence: Omit dose of LGX818/MEK162 + BKM120 until resolved to grade ≤ 1 then: 
• 
If resolved in ≤ 2 weeks, maintain dose level. 
• 
If resolved in more than 2 weeks, ↓ 1 dose level LGX818/MEK162 + BKM120. 
Second occurrence:  1 dose level of LGX818/MEK162 + BKM120. 
Initiate/intensify appropriate skin toxicity therapy (such as antihistamines, topical corticosteroids) (see 
Appendix 4) 
Grade 3, despite skin toxicity therapy 
First occurrence: omit dose of LGX818/MEK162 + BKM120 until resolved to CTCAE Grade ≤ 1; then  
1 dose level. 
Second occurrence: permanently discontinue patient from LGX818/MEK162 + BKM120 
According to the investigators discretion, a paired skin biopsy could be obtained (from both an affected 
and an unaffected skin area for local histopathology assessment) if clinically appropriate. 
Grade 4, despite skin toxicity therapy 
Permanently discontinue patient from LGX818/MEK162 + BKM120. 
According to the investigators discretion, a paired skin biopsy could be obtained (from both an affected 
and an unaffected skin area for local histopathology assessment) if clinically appropriate. 
Psychiatric disorders 
Mood alteration (Depression, Anxiety) 
(for BKM120 combination arm only) 
Questionnaire scores should be considered when assigning the AE Grade but psychiatric consult, if 
required, may determine the grade (refer to Section 7.2.2.7). 
Grade 1* (or Grade 2 anxiety if present at 
Cycle 1 Day-1 of BKM120 combination arm) 
Maintain dose level 
Consider psychiatric consultation at the investigator’s discretion and introduce optimal management 
Grade 2* (for Anxiety only, if worsened from 
Cycle 1 Day-1 of BKM120 combination arm) 
Omit BKM120 dose until resolved to ≤ Grade 1 or baseline status 
Consider psychiatric consultation at the investigator’s discretion and introduce optimal management 
First event: if the condition resolved to Grade ≤ 1 or to baseline status, continue to co-medicate and 
then maintain the dose level 
Second and further events: if the condition resolved to Grade ≤ 1 or to baseline status, continue to co- 
medicate and then  1 dose level 
Grade 3* 
Omit BKM120 dose until resolved to ≤ Grade 1 or baseline status, then  1 dose level (co-medicate) 
Psychiatric consultation should be performed 
Introduce optimal management 


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Recommended Dose Modifications for BKM120 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
Grade 4* 
Permanently discontinue patient from BKM120 
Psychiatric consultation should be performed 
Introduce optimal management 
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting "1", "2", or "3"), omit study drug and refer patient for 
psychiatric consult regardless of the total questionnaire score or CTCAE grading to confirm if study drug should be interrupted or permanently 
discontinued. 
Pneumonitis 
Please see Section 6.3.2.4 and Table 6-12. 
* 1 dose level refers to: next lower dose level previously treated. 
a All dose modifications should be based on the worst preceding toxicity. Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03). 


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Table 6-9 
Specific criteria for interruption and re-initiation of BGJ398 treatment in LGX818/MEK162 + BGJ398 triple 
combination 
 
Recommended Dose Modifications for BGJ398 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
No toxicity 
Maintain dose level 
Investigations (Renal) 
Serum creatinine 
For elevations of serum creatinine associated with hyperphosphatemia, see below guidelines for management 
of elevated phosphate. For serum creatinine elevation see the recommended dose modification for 
LGX818/MEK162 + third agent (Table 6-6). 
Ocular 
Corneal disorder/disease* 
Grade ≥ 2 
*confirmed by ophthalmologic 
examination 
Omit dose and discontinue patient from study. 
Investigations (metabolic) 
Hyperphosphatemia (For serum 
creatinine = Grade 2 with any degree 
of hyperphosphatemia) 
Hold dose to allow for resolution to <=Grade 1 or baseline, and subsequently reduce BGJ398 dose and 
maintain MEK162 and LGX818 dose. 
Serum phosphorus ULN ≤ 5.5 mg/dL. 
Maintain dose level. 
Serum phosphorus lowering therapy consisting of dietary phosphate intake restriction and oral phosphate 
binders should be applied prophylactically as follows: 
From Cycle Day 1 (it could be started in the evening of C1D1): 
-Restriction of dietary phosphate intake to 600 - 800 mg/day, if BMI ≥ 21kg/m2. 
-Sevelamer 1 tablet (800mg) per meal; i.e. 3 x 800 mg/day 
Serum phosphorus > 5.5 - 7.0 mg/dL. 
Maintain dose level, increase the dose of sevelamer up to 1200mg every 8 hours. 
Serum phosphorus > 7.0 - 9.0 mg/dL 
despite phosphorus lowering therapy 
for at least 14 days. 
At >7.0 mg/dL maintain dose level and: 
- Increase the dose of sevelamer up to 1600mg (2 tablets per meal) every 8 hours. 
If serum phosphorus increases further despite phosphorus lowering therapy over at least 14 days the BGJ398 
dose must be held until resolution to ≤5.5 mg/dL, subsequently BGJ398 dose reduced (maintain dose level of 
LGX818/MEK162), and permanently discontinued if not decreased to ≤ 5.5 mg/dL within 7 days after 
suspending BGJ398. All patients will continue to be followed-up until resolution to serum phosphorus ≤ 5.5 
mg/dL or baseline or stabilization. 


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Recommended Dose Modifications for BGJ398 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
Serum phosphorus > 9.0 mg/dL 
Omit dose until resolution to ≤5.5 mg/dL, subsequently dose reduce (maintain dose level of LGX818/MEK162), 
and permanently discontinue if not decreased to ≤ 5.5 mg/dL within 7 days after suspending BGJ398. All 
patients will continue to be followed-up until resolution to serum phosphorus ≤ 5.5 mg/dL or baseline or 
stabilization. 
Serum Pi > 10.0 mg/dL 
Omit dose and discontinue patient from study 
Hypercalcemia 
Serum calcium CTCAE Grade 1 
Maintain dose level. 
Serum calcium CTCAE Grade 2 
Omit dose until resolved to ≤ CTCAE Grade 1or baseline, then: 
-If resolved by ≤ 7 days after suspending BGJ398, maintain dose level. 
-If resolved by > 7 days after suspending BGJ398,  1 dose level (maintain dose level of LGX818/MEK162),. 
Serum calcium CTCAE Grade ≥ 3 
Omit dose and discontinue patient from study. 
* 1 dose level refers to: next lower dose level previously treated. 
a All dose modifications should be based on the worst preceding toxicity. Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03). 


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Table 6-10 
Specific criteria for interruption and re-initiation of INC280 treatment in LGX818/MEK162 + INC280 triple 
combination 
 
Recommended Dose Modifications for INC280 in combination with LGX818/MEK162 
Worst toxicity gradea (value) 
Recommended Dose Modifications any time during a cycle of therapy 
No toxicity 
Maintain dose level 
Any Neurological Toxicity 
Grade ≥ 2 
Discontinue dose. 
Neurological assessments must be repeated at least twice a week until resolution to < CTCAE grade 1. 
Unscheduled MRI and gadolinium enhanced T1 imaging may also be conducted to evaluate patients for 
intramyelinic edema like lesions, brain metastases and other unanticipated CNS occurrences. An EEG may be 
performed to monitor for physiological changes in brain activity. 
* 1 dose level refers to: next lower dose level previously treated. 
a All dose modifications should be based on the worst preceding toxicity. Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03). 


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6.3.2 
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 or dermatologist should be consulted 
as deemed necessary. Further guidelines and recommendations for the management of specific 
study drug combination induced toxicities are provided in sub-sections below. 
 
6.3.2.1 
Management of hand foot skin reaction (HFSR) 
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 6-11. Furthermore the patient should be treated at the first 
symptoms according the institutional standards of care. A visit to a podiatrist may also be 
recommended at the discretion of the investigator. 


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Table 6-11 
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 regularly 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 
• 
Minimize 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 (Von Moos et al 2008). 


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6.3.2.2 
Follow up evaluations for appearance of keratoacanthoma (KA) and/or 
squamous cell carcinoma (SCC) 
The skin of patients treated with the LGX818/MEK162 combination or LGX818/MEK162 + 
third agent 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. 
Dermatologic evaluations for this adverse effect will be performed at Screening/baseline, every 
2 months thereafter and at End of Study Treatment. 
In case of occurrence of KA and/or SCC, patients will undergo complete surgical excision of 
the skin lesion following institutional standards. 
 
6.3.2.3 
Follow up evaluations for appearance of visual toxicity 
The patients treated with the LGX818/MEK162 combination or LGX818/MEK162 + third 
agent combination will be examined regularly to monitor for the possible development of visual 
toxicity. Ophthalmologic examinations to check for this adverse effect will be performed in Part 
I, Run-in and Part II at the timepoint s indicated in Section 7.2.2.5.7. Patients developing a 
CTCAE grade 1 or 2 retinal disorders (eg. retinal detachment) can be maintained on the study 
drug combination as is detailed in Table 6-5 and Table 6-6. For these patients it is recommended 
to follow up the event with an ophthalmological exam every two weeks for 8 weeks, and 
subsequently at approximately a 4-weeks interval. The study drug dosages of patients 
developing retinal event (eg. uveitis or retinal detachment) > CTCAE grade 2 should be 
interrupted/modified according to Table 6-5 and Table 6-6 and should be followed as described 
above. Patients developing a CTCAE grade 1 uveitis) can be maintained on the study drug 
combination as is detailed in Table 6-5 and Table 6-6. For these patients it is recommended to 
follow up the event with an ophthalmological exam every two weeks for 8 weeks, and 
subsequently at approximately a 4-weeks interval. For patients developing a CTCAE grade 2 
uveitis, drug dosages should be modified according to what is described in Table 6-5 and Table 
6-6, and the ophthalmological monitoring detailed above should be followed. The study drug 
dosages of patients developing uveitis ≥ CTCAE grade 3 should be interrupted/modified 
according to Table 6-5 and Table 6-6 and should be followed as described above. 
 
6.3.2.4 
Management of pneumonitis in patients receiving BKM120 
All patients participating in clinical trials with BKM120 will be routinely asked about and 
observed for the occurrence of adverse events which could include new or changed pulmonary 
symptoms (consistent with lung abnormalities). Pulmonary function tests and radiology 
assessment should be done, as clinically indicated, or if there are symptoms that indicate that 
the patient has developed pneumonitis. In case of a documented pneumonitis, the guidelines 
(including dose modifications) in Table 6-12 should be followed. Consultation with a 
pulmonologist is highly recommended for any pneumonitis case during the study treatment. 


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Table 6-12    Management of pneumonitis 
 
Worst Grade 
Pneumonitis 
Recommended/Required 
Investigations 
Management of 
Pneumonitis 
BKM120 Dose Adjustment 
Grade 1 
CT scans with lung 
windows. Repeat at least 
every 6 weeks until return to 
within normal limits. 
No specific therapy 
is required 
Administer 100% of BKM120 
dose. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
Carbon monoxide diffusing 
capacity (DLCO), and room 
air O2 saturation at rest. 
Repeat at least every 6 
weeks until return to within 
normal limits. Consider a 
bronchoscopy with biopsy 
and / or Bronchoalveolar 
lavage (BAL). 
Symptomatic only. 
Consider 
corticosteroids if 
symptoms are 
troublesome. 
Reduce BKM120 dose by 1 
dose level (see Table 6-3) until 
recovery to ≤ Grade 1. Study 
treatment may also be 
interrupted if symptoms are 
troublesome. Patients will 
discontinue study treatment if 
they fail to recover to ≤ Grade 1 
within 3 weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat at 
least every 6 weeks until 
return to within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment with BKM120 
until recovery to < Grade 1. 
May restart study treatment 
within 3 weeks at a reduced 
dose (by one level) if evidence 
of clinical benefit. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing, if possible, 
includes: spirometry, DLCO, 
and room air O2 saturation 
at rest. Repeat at least 
every 6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment with 
BKM120. 
 
 
6.3.2.5 
Management of hepatotoxicity (ALT and/or AST >5.0x ULN and total 
bilirubin >1.5x ULN) in patients receiving BKM120 
Criteria for interruption and re-initiation of BKM120 treatment in case of the occurrence of 
AST, ALT or bilirubin increase are detailed in Section 6.3 Dose Modification (Table 6-7). 
Patients with clinically significant liver test abnormalities should perform liver-directed 
medical history, physical examination and other tests as medically indicated to assess potential 
relationship with study treatment and rule out other underlying causes (e.g. disease 


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progression/obstruction, infection/hepatitis or other liver diseases, sepsis, metabolic diseases 
including diabetes, concomitant medications including herbals, alcohol, drug-drug interaction, 
cardiovascular disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions or 
risk factors should be reported in the respective medical history and concomitant medication 
CRF pages (if not done already). 
All patients with ALT or AST >5.0 x ULN and total bilirubin > 1.5x ULN in the absence of 
cholestasis (elevation of ALP in patients without bone metastasis or if bone metastasis are 
present elevation of 5’-nucleotidase and ALP liver fraction) must be immediately withdrawn 
from treatment, and every attempt should be made to carry out locally the liver event follow- 
up assessments as described below: 
• Inform the sponsor about the event immediately after its occurrence by reporting the event 
immediately in the clinical database if it meets the criteria for an AE or SAE. 
• Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis 
or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia, or other organ involvement. 
• Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess 
eosinophilia. 
• Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease including metastasis or new lesions, obstruction/compression, etc. 
• Perform viral hepatitis and other serology tests: 
• Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology and viral 
DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV total 
• Hepatitis E (HEV) serology: IgM and IgG, viral RNA 
• Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) 
serology 
• Obtain PK sample, as close as possible to last dose of study drug. Record the date/time of 
the PK blood sample draw and the date/time of the last dose of BKM120 prior to blood 
sample draw on the eCRF 
• Verify and record the use of concomitant medications, acetaminophen, and other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report 
form. 
• Consultation with a specialist(s) or a hepatologist(s) is recommended. 
• Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury 
• LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilization 
(no CTCAE grade change over 4 weeks) and outcome documented on the respective AE 
and lab chemistry pages. 
 
6.3.2.6 
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 


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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. 
 
6.3.2.7 
Additional follow-up for hepatic toxicities in patients receiving INC280 
In case of isolated elevations in total bilirubin, AST or ALT, additional follow-up evaluations 
are recommended as outlined in Table 6-13: 
 
Table 6-13 
Follow-up evaluations for selected toxicities 
 
TOXICITY 
FOLLOW-UP EVALUATION 
HEPATIC 
Isolated total bilirubin elevation 
CTCAE Grade 1 
Monitor LFTs per protocol or more frequently if clinically indicated 
CTCAE Grade 2 
Weekly monitoring of LFTs, or more frequently if clinically indicated, 
until resolved to ≤ 1.5 x ULN 
CTCAE Grade 3 
Weekly monitoring of LFTs, or more frequently if clinically indicated, 
until resolved to ≤ 1.5 x ULN. If resolved in > 7 days, after discontinuing 
the patient from INC280 permanently, the patient should be monitored 
weekly (including LFTs), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks 
CTCAE Grade 4 
After discontinuing the patient from INC280 permanently, the patient 
should be monitored weekly (including LFTs), or more frequently if 
clinically indicated, until total bilirubin have resolved to baseline or 
stabilization over 4 week 


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TOXICITY 
FOLLOW-UP EVALUATION 
HEPATIC 
Isolated AST/ALT elevation 
CTCAE Grade 2 
For patients with baseline value 
≤ 3.0 x ULN 
For patients with baseline value > 
3.0 - 5.0 x ULN 
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 x ULN 
Monitor LFTs per protocol or more frequently if clinically indicated 
CTCAE Grade 3 -For elevation > 
5.0 - 10.0 x ULN: 
For patients with baseline value ≤ 
3.0 x ULN 
For patients with baseline value > 
3.0 - 5.0 x ULN: 
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN 
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs, weekly, or more frequently if 
clinically indicated, until resolved to ≤ 5.0 x ULN 
CTCAE Grade 3 
For AST/ALT elevation > 10.0 - 
20.0 x ULN: 
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ baseline 
CTCAE Grade 4 
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to baseline or stabilization 
over 4 weeks. 
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table for dose 
modifications required for applicable toxicities 
 
 
6.3.2.8 
Follow up on potential drug-induced liver injury cases 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
values; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 
x ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis. 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 


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history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
• Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline 
phosphatase. 
• A detailed history, including relevant information, such as review of ethanol, 
concomitant medications, herbal remedies, supplement consumption, history of any pre- 
existing liver conditions or risk factors, should be collected. 
• Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary 
tract) may be warranted. 
• Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
• Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
 
6.3.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study- 
drug induced adverse events, i.e., hyperglycemia, skin toxicity and diarrhea are provided in 
Appendices. Refer to preclinical toxicity and or clinical data found in the Investigator’s 
Brochures of the study drugs. 
 
6.3.3.1 
Anticipated risks and safety considerations of the study drug 
combinations 
 
6.3.3.1.1 LGX818/MEK162 combination 
Note: INC280-, BKM120- and BKM120-containing arms are closed to enrollment as these 
combinations are no longer being explored (Amendment 06). 
 
Main adverse events for LGX818/MEK162 
The most common AEs observed in the on-going [CMEK162X2110] were grade 1/2 
gastrointestinal toxicities, visual disturbances, headache, and fatigue. Five patients (16.7%) had 
Grade 3 AEs suspected to be treatment related (2 with transaminase increases, 2 with lipase 
increase, 1 with retinal vein occlusion, and 1 with maculopapular rash) (see Section 1.2.1.2.1). 
 
6.3.3.1.2 LGX818/MEK162 + BKM120 combination 
 
Main anticipated adverse events for LGX818/MEK162 + BKM120 
The most frequently reported treatment-related AEs in MEK162 + BKM120 combination study 
[CMEK162X2101] were CK elevation (56%), diarrhea (54%) and AST elevation (50%). 


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Preliminary clinical data available from ongoing [CMEK162X2101] study with MEK162 and 
BKM120 as combination showed that the most frequently reported treatment-related AEs were 
CK elevation (56%), diarrhea (54%) and AST elevation (50%) (see Section 1.2.1.2.2). 
Based on the most frequent observed adverse events described above for LGX818 and MEK162 
dual combination and single agent and for MEK162 and BKM120 as dual combination and 
single agent (see also current LGX818, MEK162 and BKM120 Investigator Brochure), 
overlapping toxicities, which may potentially be dose-limiting, includes skin (i.e. rash) and 
fatigue/asthenia, CK and AST elevation, diarrhea and maculopapular rash for the proposed 
combination. 
 
6.3.3.1.3 LGX818/MEK162 + INC280 
 
Main anticipated adverse events for LGX818/MEK162 + INC280 
Fatigue, headache, nausea, tremor, vomiting and pain in extremity are associated with INC280 
as single agent. 
Based on the most frequent observed adverse events described above for the LGX818 and 
MEK162 dual combination (see also current LGX818 or MEK162 Investigator Brochure) and 
for INC280 as single agent, overlapping toxicities, which may potentially be dose-limiting, 
includes fatigue, nausea, peripheral edema and pain in extremity for the proposed combination. 
 
6.3.3.1.4 LGX818/MEK162 + BGJ398 
 
Main anticipated adverse events for LGX818/MEK162 + BGJ398 
Hyperphosphatemia, diarrhea, nausea, pain in extremity, fatigue/asthenia, mucositis/stomatitis, 
decreased appetite, blood, dyspepsia, dry mouth, transaminase increase and lipase increase are 
associated with BGJ398. 
Based on the most frequent observed adverse events described for the LGX818 and MEK162 
dual combination (see current LGX818 or MEK162 Investigator Brochure) and for BGJ398 as 
single agent, overlapping toxicities, which may potentially be dose-limiting, includes 
fatigue/asthenia, nausea and myalgia/arthralgia, corneal or retinal adverse events, headache and 
confusional state for the proposed combination. 
 
6.3.3.1.5 LGX818/MEK162 + LEE011 
 
Main anticipated adverse events for LGX818/MEK162 + LEE011 
Mucositis, vomiting, hematological toxicities (i.e. neutropenia, leucopenia, thrombocytopenia), 
and rash are associated with LEE011. 
Based on the most frequent observed adverse events described above for the LGX818 and 
MEK162 dual combination (see current LGX818 or MEK162 Investigator Brochure) and for 
LEE011 (See current [LEE011 Investigators Brochure]), overlapping toxicities can be expected 
for gastrointestinal events (such as nausea, vomiting, diarrhea), as well as fatigue. 


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6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted, unless otherwise specified in the IBs. 
Patients receiving medications outlined below 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. Refer to Appendix 7 for a list of medications to be used with caution as mentioned 
above. 
 
Antiemetics 
Use of antiemetics is allowed. Prophylactic antiemetics should be started only once the patient 
experiences nausea or vomiting and at the discretion of the investigator. It is recommended that 
patients use drugs that do not cause QT prolongation. Note that some anti-emetics have a known 
risk for Torsade de Pointes (TdP) (Appendix 7). 
 
Bisphosphonates 
The use of bisphosphonates regardless of indication is allowed for the LGX818 and MEK162 
dual combination and triplet combinations other than LEE011 (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. 
 
Oral antidiabetics 
Patients who develop diabetes mellitus during the study should be treated according to the ADA 
(American Diabetes Association) guidance. It is recommended to start treatment with 
glimepiride, glibenclamide or metformin. Patients receiving oral antidiabetics which are 
predominantly metabolized by CYP2C9 and CYP2C8, including but not limited to, repaglinide, 
rosiglitazone, glipizide and tolbutamide, must be carefully monitored for hypoglycemia as 
BKM120 has been found to be a moderate reversible inhibitor of these enzymes (Appendix 7). 
 
Corticosteroids 
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: 


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• Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways 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). 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
throughout the study 
 
6.4.2.1 
Permitted concomitant therapy requiring caution and/or action 
throughout the study based on LGX818 and MEK162 DDI potential 
(Part I and Part II) 
 
CYP and UGT substrates and inhibitors 
LGX818 has been identified to be primarily metabolized by CYP3A4 and to a lesser extent by 
CYP2C19 in vitro. Moderate inhibitors of CYP3A4 and strong inhibitors of CYP2C19 (see 
Appendix 7) should be taken with caution when co-administered with LGX818. 
MEK162 has been identified to be primarily metabolized by UGT1A1 in vitro. It is advised that 
inhibitors and inducers of UGT1A1 should be taken with caution when co-administered with 
MEK162. Patients should be closely monitored for the occurrence of adverse events. Please 
refer to Table 14-22 for a list of these known drugs but this list may not be exhaustive 
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. 
LGX818 is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and 
CYP3A and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma 
concentrations. Permitted medications to be used with caution in this study include those that 
are sensitive substrates of these UGT and CYP enzymes or those substrates that have a narrow 
therapeutic index (NTI) except those prohibited in Section 6.4.3. 
There is a potential for LGX818 to induce CYP2B6, CYP2C9, and CYP3A4. Induction of these 
enzymes may result in reduced efficacy for drugs that are major substrates for these CYP 
enzymes. Additionally, CYP3A4 induction may reduce the effectiveness of hormonal 
contraception methods. Therefore, the use of at least one form of non-hormonal contraception 
is needed during the participation in this study. See study exclusion criterion for use of 
contraception methods required for this study. 
 
Transporter substrates and inhibitors 
In vitro data showed that LGX818 is a substrate of P-gp. Thus, the use of drugs that are known 
to inhibit or induce P-gp and/or BCRP should be used with caution. LGX818 is a P-gp and 
BCRP inhibitor. It is also a potent inhibitor of the renal transporters, OAT1, OAT3, and OCT2 
and the hepatic transporter OATP1B1 and OATP1B3. The co-administration of drugs that are 


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known to be sensitive or NTI substrates of BCRP, P-gp, OAT1, OAT3, OCT2, OATP1B1 and 
OATP1B3 should be used with caution. 
In vitro data showed that MEK162 is a substrate of P-gp and BCRP and thus the use of drugs 
that are known to inhibit these transporters should be used with caution. 
 
Hematopoietic growth factors 
Hematopoietic growth factors (e.g. erythropoietin, G-colony stimulating factor (CSF) and GM- 
CSF) are not to be administered prophylactically. Use of these drugs should be reserved for 
patients requiring this therapy as per the labeling of these agents or as dictated by local practice 
(see also the guidelines established by the American Society of Clinical Oncology). 
 
Drugs with a conditional or possible risk to induce Torsade de Pointes 
If a patient requires the concomitant use of any medication with a possible or conditional risk 
for TdP (Appendix 7), then investigators, at their discretion, may co-administer such 
medications with LGX818/MEK162, LGX818/MEK162 + INC280 or LGX818/MEK162 + 
BGJ398.  For  LGX818/MEK162  +  BKM120  and  LGX818/MEK162  +  LEE011  see 
Section 6.4.3. Patients receiving such medications must however be monitored. 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications. 
 
6.4.2.2 
Additional permitted concomitant therapy requiring caution and/or 
action during Part II 
In addition to the cautions and/or actions to be taken throughout the study based on LGX818 
and MEK162 DDI potential (see Section 1.2.1.3), the following cautions and/or actions must 
be taken when administering the triple combinations with BKM120, BGJ398, INC280, or 
LEE011. 
 
6.4.2.3 
Additional permitted concomitant therapy requiring caution and/or 
action during triple combination with BKM120 
In vitro metabolism studies performed to examine the direct and metabolism-dependent 
inhibition of P450 enzymes showed that BKM120 is a weak, reversible inhibitor of CYP3A4/5 
and a weak inhibitor of CYP2C8/2C9/2C19. Note that with the data available, we are not able 
to confirm whether such interactions will occur in patients. Therefore, investigators, at their 
discretion, may administer concomitant medications known to be metabolized by CYP3A4/5, 
CYP2C8, CYP2C9 and CYP2C19, except those were prohibited in Section 6.4.3. Patients 
receiving such medications must be carefully monitored for potentiation of toxicity due to any 
individual concomitant medications, and may require dose titration or reduction of the drug 
substrate. Particularly, caution is advised when BKM120 is co-administered with: 
• drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which have 
a narrow therapeutic index 


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• oral anti-diabetics which are metabolized by CYP2C8 or CYP2C9, possibly resulting in 
hypoglycemia. 
 
6.4.2.4 
Permitted concomitant therapy requiring caution and/or action during 
triple combination with BGJ398 
In vitro data show that BGJ398 is a likely inhibitor of BCRP (IC50 = 0.21 μM), suggesting an 
increased risk for drug-drug interactions with BCRP substrates. In the absence of data 
confirming whether such an interaction occurs in patients, investigators at their discretion may 
co-administer known BCRP substrates. However, patients receiving such medications must be 
carefully monitored for potentiation of toxicity and may require dose titration or reduction of 
the BCRP substrate. (including but not limited to rosuvastatin, sulfasalazine, zidovudine and 
lamivudine). 
In in-vitro-assays, BGJ398 was shown to inhibit the cytochrome P450 isoenzyme CYP3A4 with 
a Ki = 0.26μM, thereby suggesting an increased risk of drug interactions with concomitant 
medications that are also metabolized by CYP3A4. Accumulation of BGJ398 following 
multiple dosing in patients likely due to auto-inhibition of CYP3A4 mediated clearance 
pathways was observed. No clinical DDI studies for BGJ398 have been done. Concomitant 
medications known to be metabolized by CYP3A4 should be administered with caution. 
Patients receiving such medications must be carefully monitored for potentiation of toxicity due 
to any individual concomitant medications, and may require dose titration or reduction of the 
CYP3A4 substrate. In particular, caution is advised when BGJ398 is to be co-administered with 
CYP3A substrates with a narrow therapeutic index, including but not limited to alfentanil, 
fentanyl, astemizole, cisapride, diergotamine, ergotamine, pimozide, quinidine and terfenadine. 
 
6.4.2.5 
Permitted concomitant therapy requiring caution and/or action during 
triple combination with INC280 
Medications that are weak and moderate inducers or inhibitors of CYP3A4 are permitted but 
should be administered with caution. Refer to Appendix 7 for a list of these medications. 
Short acting gastric acid modulators containing aluminium hydroxide and magnesium 
hydroxide, (e.g., Maalox®) or calcium carbonate (e.g., TUMS®) can be taken. However, it is 
recommended to take these drugs at least 4 hours before or 4 hours after administration of 
INC280. H2 receptor antagonists should be avoided when possible. If patients have to take H2 
receptor antagonists during the course of this study, patients should take INC280 at least 2 hours 
before H2 receptor antagonists administration. In addition, the interval of H2 receptor 
antagonist administration to next dose schedule of INC280 should be at least 8 hours apart. For 
example, if patient take twice daily dose of H2 receptor antagonist and twice daily dose of 
INC280, patient can take morning dose of INC280 at 8 am and morning dose of H2 receptor 
antagonist at 10 am. Afternoon dose of INC280 should be taken approximately 12 hours after 
the morning dose (8pm) and evening dose of H2 receptor antagonist can be taken at 10pm. 
 
6.4.2.6 
Permitted concomitant therapy requiring caution and/or action during 
triple combination with LEE011 
Medications to be used with caution during triplet combination treatment with LEE011 in this 
study are listed below (see Appendix 7, this list is not comprehensive and is only meant to be 


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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). 
 
6.4.3 
Prohibited concomitant therapy 
Prohibited concomitant therapy for LGX818/MEK162 combination 
Other investigational and antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy (that includes > 30% of the bone marrow 
reserve) and surgery) other than the study treatments must not be given to patients while the 
patient is on the study medication. If such agents are required for a patient then the patient must 
be discontinued from the study. Patients requiring antineoplastic therapy after Part I but prior 
to Part II of the study may receive treatment upon discussion with the Sponsor medical monitor, 
as long as guidelines specified in Exclusion Criterion 14 are adhered to. 
 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study. Patients should stop 
using these herbal medications 7 days prior to first dose of study treatment. 
 
Warfarin and Coumadin derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other Coumadin-derivative 
anticoagulants are not permitted. Warfarin has a narrow therapeutic range and LGX818, 
BGJ398 and INC280 are possible inhibitors of 2C9, the major metabolizing enzyme of warfarin. 
Therapeutic anticoagulation may be accomplished using low-molecular weight heparin. 
 
Strong inhibitors of CYP3A4 
LGX818 has been identified to be primarily metabolized by CYP3A4 and to a lesser extent by 
CYP2C19 in vitro. Systemic use of strong inhibitors of CYP3A4 is prohibited. Below lists 
current examples of strong CYP3A4 inhibitors that are not permitted (see Appendix 7): 


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• Antibiotics: clarithromycin, telithromycin, troleandomycin 
• Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
• Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
• Antivirals: boceprevir, telaprevir 
• Others: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
These medications should be stopped 7 days prior to first dose of study treatment. 
 
Enzyme inducing anti-epileptic drugs (EIAEDs) 
Use of EIAEDs is not permitted. Below lists current examples of enzyme-inducing anti- 
epileptic drugs that are prohibited: carbamazepine, ethotoin, felbamate, fosphenytoin 
Phenobarbital, phenytoin, primidone, topiramate. 
 
Additional prohibited concomitant therapy for LGX818/MEK162 + BKM120 
combination 
• In vitro metabolism studies suggest that oxidative metabolism of BKM120 is 
predominantly mediated by CYP3A4, with only minor contributions of CYP1A1 and 
UGT1A4. Co-administration with strong and moderate CYP3A4 inhibitors and CYP3A4 
inducers (except LGX818) is prohibited. 
• Drugs with a known risk for TdP as well as sensitive CYP3A substrates with a possible or 
conditional risk for TdP are prohibited. Please see Appendix 7 for a list of prohibited 
medication for this combination. 
 
Additional prohibited concomitant therapy LGX818/MEK162 + LEE011 
combination 
• Prophylactic treatment of bisphosphonates is not allowed with LEE011. 
• Strong inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease 
LEE011 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 Appendix 7 and LEE011 
Investigators 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. 
Please see Appendix 7 for a list of prohibited medication for this combination. 


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Additional prohibited concomitant therapy LGX818/MEK162 + BGJ398 
combination 
• Use of medications that are known to prolong the QT interval and/or are associated with a 
risk of Torsades de Pointes is prohibited and these medications must be stopped 7 days 
prior to first dose. 
• Treatment with agents that are known strong inducers or inhibitors CYP3A4 are 
prohibited. Caution should be used during administration of moderate inhibitors. 
Please see Appendix 7 for a list of prohibited medication for this combination 
 
Additional prohibited concomitant therapy LGX818/MEK162 + INC280 
combination 
• Known CYP3A4, CYP1A2, CYP2C8 or CYP2C19 substrates with narrow therapeutic 
index. 
• Long acting proton pump inhibitors 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient Number 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. Upon signing the Molecular pre-screening Informed Consent Form (if applicable) or 
Study Informed Consent Form, the patient is assigned to the next sequential Patient Number 
available to the investigator. 
Once assigned, the Patient No. must not be reused for any other subject and the Patient No. for 
that individual must not be changed. 
 
6.5.2 
Treatment assignment or randomization 
 
6.5.3 
Part I 
No randomization will be performed in this study. 
 
6.5.4 
Part II 
Patients will be assigned to one of the 4 treatment arms according the molecular alterations 
detected at progression under LGX818/MEK162 combination treatment (see Table 4-1). 
Note: Enrollment to the BKM120- (Amendment 03), BGJ398-, INC280- (Amendment 06) 
and LEE011 (Amendment 07)-containing arms in Part II is closed. 
 
6.5.5 
Treatment blinding 
Not applicable. 


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6.6 
Study drug preparation and dispensation 
Note: Enrollment to the BKM120- (Amendment 03), BGJ398-, INC280-, (Amendment 06) 
and LEE011(Amendment 07)-containing arms in Part II is closed. 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. 
All medication will be provided by the Sponsor and other drug strengths may become available. 
LGX818 will be supplied as capsules of 50 mg, and 100 mg dosage strength. 
MEK162 is supplied as tablets of dosage strength 15 mg. 
BKM120 is supplied as capsules of dosage strength 10 mg, and 50 mg. 
BGJ398 is supplied as capsules of dosage strengths 25 mg and 100 mg. 
INC280 is supplied as capsules of dosage strength 50 mg or tablets of dosage strength 100 mg 
and 200 mg. 
LEE011 is supplied as capsules of dosage strength of 50 mg, and 200 mg 
LGX818, BKM120, BGJ398, and LEE011 will be dosed once a day on a flat scale of mg/day 
and not adjusted to body weight or body surface area. 
MEK162 and INC280 will be dosed on a flat scale of mg twice a day and not individually 
adjusted by weight or body surface area. 
 
6.6.1 
Study drug packaging and labeling 
Study Drug labels will comply with the legal requirements of each country and will be printed 
in the local language. They will supply no information about the patient. The storage conditions 
for study drug will be described on the study drug label. 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, LGX818, MEK162, BKM120, BGJ398, INC280 and 
LEE011 should be stored according to the instructions specified on the drug labels and in the 
[Investigator’s Brochures]. 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 


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Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee, and will be verified by determinations of LGX818 and 
MEK162, BKM120, BGJ398, INC280, and LEE011 in plasma. 
At the day of a scheduled visit to the clinic, the patient will take LGX818 + MEK162, or 
LGX818 + MEK162 + BKM120, or LGX818 + MEK162 + BGJ398, or LGX818 + MEK162 
+ INC280, or LGX818 + MEK162 + LEE011 at the clinic under supervision of the Investigator 
or designee. The time of dose administrations must be recorded in the Dosage Administration 
Record eCRF. 
For all other study days, the patient will take LGX818 + MEK162, or LGX818 + MEK162 + 
BKM120, or LGX818 + MEK162 + BGJ398, or LGX818 + MEK162 + INC280, or LGX818 
+ MEK162 + LEE011 at home. The dose administrations must be recorded in the Dosage 
Administration Record eCRF. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Sponsor monitor or to the Sponsor address provided in the investigator 
folder at each site. 
 
6.6.4 
Disposal and destruction 
The drug supply can be destroyed at the local Sponsor facility, Drug Supply group or third 
party, 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 
7.1 
Study flow and visit schedule 
The assessments are listed in Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5 and are 
indicated with an “X”, the visits when they are performed. All data obtained from these 
assessments must be supported in the patient’s source documentation. The table indicates which 
assessments produce data to be entered into the database (D) or remain in source documents 
only (S) (“Category” column). 
Patients in Group A and B will enter the screening phase (Part I or Run-in) and move to the 
treatment phase (Part I or Run-in), if eligible to be treated, or continue to be treated, with 
LGX818/MEK162 combination. Once the patients progressed on the double combination, a 
new biopsy sample will be collected for the genetic assessment. At the time when the genetic 
assessment results are available, the patients will go through the End of Study Treatment 


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assessments (Part I and Run-in), which will include some specific assessments (e.g. HbA1c, 
fasting glucose, thyroid function and others in Table 7-1 and Table 7-2) to determine the 
patients’ eligibility for the assigned triple combination. If eligible, the patients in Group A and 
B will move from the End of Study Treatment visit (Part I or Run-in) to the treatment phase 
(Part II). Therefore, the safety and tolerability, as well as the tumor evaluation, End of Study 
Treatment assessments (Part I or Run-in) will be considered the baseline assessments for Part 
II. All Safety and tolerability assessments must be completed within 14 days before the first 
triple combination dose, with the exception of pregnancy test, which must be performed within 
72 hours before the first triple combination dose. For patients in Group C progressing while 
treated with LGX818/MEK162 combination in other studies (e.g. [CMEK162X2110] and 
[COLUMBUS]), and patients in Group B, who already received LGX818/MEK162 in other 
studies (e.g. [CMEK162X2110], and [COLUMBUS]), the End of Study Treatment assessments 
(e.g. tumor evaluation) performed in the previous study will be used as baseline assessments 
for this study. 
For all patients the screening assessments must be completed within 14 days before the first 
study treatment dose, with the exception of pregnancy test, which must be performed within 72 
hours before the first study treatment dose. Part I Screening/baseline CT/MRI scans must be 
completed within 21 days prior to the first study treatment dose. 
Assessments which are indicated to be performed at Screening/baseline, or at End of Study 
Treatment (Part I and Run-in) for patients moving to treatment phase Part II, and on Cycle 1 
Day 1, need to be repeated at Cycle 1 Day 1 only if the Screening/baseline assessments, or the 
End of Study Treatment assessments, were performed more than 3 days before Day 1 Cycle 1. 
For all patients the last CT/MRI must be completed within 28 days before receiving the first 
triple combination treatment dose. If the time interval between the last CTI/MRI tumor 
evaluation assessment documenting the disease progression and the first dose of the triple 
combination is more than 4 weeks (28 days), a new tumor evaluation should be performed. 
For PK sampling the samples may be obtained on the day of dosing +/- 3 days from the 
scheduled date (except for Day1 PK profile, which must take place on Day 1). All samples from 
the same PK profile (e.g. C1D15 PK samples) should be shifted together (e.g., if visit for C1D15 
actually occurs on C1D16, all the PK samples for this PK profile should be shifted of one day, 
accordingly, and all <24hr PK samples will be taken on C1D16 and 24 hr sample on C1D17). 
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. Every effort must be made to follow the 
schedule outlined in Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 


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Table 7-1 
Part I - Visit evaluation schedule for patients enrolled in Group A 
Note: For patients on dual combination treatment for ≥ 36 months, refer to Table 7-5. 
Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
Molecular pre-screening Informed 
Consent 
D 
7.1.1 & 
4.1. 
X 
Main study Informed Consent 
D 
7.1.2. 
X 
Documented BRAF V600 mutation 
D 
7.1.1 & 
4.1. 
X 
Demography 
D 
7.1.2.3. 
X 
Inclusion/exclusion criteria 
D 
5.2 & 5.3. 
X 
Additional exclusion criteria for third 
agent (only patients moving to Part 
II) 
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 
Physical examination 
S 
7.2.2.1. 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status (WHO) 
D 
7.2.2.2. 
X 
X 
X 
X 
X 


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Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
 
 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
Height 
D 
7.2.2.3. 
X 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.4. 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
7.2.2.5. 
Hematology 
D 
7.2.2.5.1. 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.5.2. 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
D 
7.2.2.5.3. 
X 
If clinically relevant 
X 
Ophthalmologic examination 
D 
7.2.2.5.7. 
X 
X 
X2 
X 
Urinalysis 
D 
7.2.2.5.5. 
X 
If clinically relevant 
Pregnancy test 
D 
7.2.2.5.8. 
X 
X 
X 
X 
X 
Dermatologic evaluation 
D 
7.2.2.5.6. 
X 
X 
HbA1c (only patients moving to 
BKM120 arm Part II) 
D 
7.2.2.5.4. 
X 
Fasting plasma glucose 
(only patients moving to BKM120 
arm Part II) 
D 
7.2.2.5.4. 
X 
Thyroid Function 
(only patients moving to LEE011 
arm Part II) 
D 
7.2.2.5.9. 
X 


Array BioPharma 
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Protocol No. CLGX818X2109 
 
 
 
Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
 
 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
Imaging 
7.2.1. 
Brain CT/MRI with contrast 
(patients assigned to LEE011 arm 
in Part II) 
D 
7.2.1. 
X 
Brain CT/MRI with contrast 
(patients with baseline brain 
metastases) 
D 
7.2.1. 
X 
Every 6 
weeks 
X 
Tumor evaluation (RECIST) - 
CT/MRI 
Color photography if skin lesions 
are present 
D 
7.2.1. 
X 
X 
Every 6 
weeks, 
every 6-12 
weeks after 
≥ 24 months 
of treatment3 
X 
Every 
9 
weeks, 
every 
9-12 
weeks 
after 
≥ 24 
months 
of 
treat- 
ment4 


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Protocol No. CLGX818X2109 
 
 
 
Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
 
 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
ECG5 (triplicate only at Day 1 
Cycle1) 
D 
7.2.2.6.1. 
X 
X 
X 
X 
X 
X C3, C5 
every 2 
cycles, every 
3 cycles 
after ≥ 24 
months of 
treatment 
X 
Cardiac imaging 
D 
7.2.2.6.2. 
X 
X 
C5, C8, C11 
and every 3 
cycles 
thereafter 
X 
GAD-7 and PHQ-9 Questionnaires 
(only patients moving to BKM120 
arm Part II) 
D 
7.2.2.7. 
X 
Additional Ophthalmologic exam 
(only patients moving to BGJ398 
arm Part II) 
D 
7.2.2.5.7. 
X 
Safety 
7.2.2. 
Adverse events 
D 
X6 
X 
Continuous 
Biomarkers 
7.2.4. 
Collection of archival paraffin 
blocks/slides & corresponding 
pathology report 
D 
X, if 
needed 
X, if not collected at 
molecular 
screening 


Array BioPharma 
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Protocol No. CLGX818X2109 
 
 
 
Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
 
 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
Collection of newly obtained tumor 
sample from biopsy 
D 
7.2.4. 
X, if 
needed 
X, if not collected at 
molecular 
screening 
At progression 
Report genetic assessments results 
of progression biopsy (only patients 
moving to Part II) 
D 
7.2.4. 
X 
CCI 
Study Drug Administration 
LGX818 QD/MEK162 BID 
administration 
D 
6.1.1. 
Continuous 
PK Blood Sampling 
D 
7.2.3. 
X 
X 
X pre- 
dose 
X pre- 
dose 
X Up to C5 
only 
X 
Meal Record 
D 
7.2.3.1. 
X 
Antineoplastic therapies since 
discontinuation of study treatment 
D 
7.1.6.2. 
X 
X 
X 


Array BioPharma 
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Protocol No. CLGX818X2109 
 
 
 
Part I 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
 
 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
8 
21 
15 
30 days 
from 
last 
dose 
1. EOT assessments will take place for patients who discontinue study treatment during Part I and will not move into Part II of the trial, and for patients moving to Part II 
at the time the genetic assessment results are available. EOT for patients permanently discontinuing the study treatment will occur within 14 days of the last dose of 
study treatment or within 14 days of date of decision to discontinue study treatment. 
2. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months (Cycle 25 Day 1 onward) without a retinal AE within the past 12 months 
should be evaluated only for visual acuity at each scheduled patient visit and at End of Study Treatment visit. A full ophthalmic examination is required if clinically 
indicated and at End of Study Treatment visit. 
3. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months will have CT/MRI scans every 6-12 weeks (+/- 7 days). 
4. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months and then discontinue study treatment for any reason other than disease 
progression will have CT/MRI scans every 9-12 weeks (+/- 7 days). 
5. All ECGs should be taken before a blood sample or at least 0.5 hours after a blood sample. 
6. To collect only the Pre-screening Procedure Related SAEs. 
7. 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-cutaneuous secondary malignancies for up to 6 months after the last LGX818 dose or until initiation of another antineoplastic 
therapy. 


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Protocol No. CLGX818X2109 
 
 
 
Table 7-2 
Run-in Visit evaluation schedule for patients enrolled in Group B 
Note: For patients on dual combination treatment for ≥ 36 months, refer to Table 7-5. 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
Molecular pre-screening 
Informed Consent 
D 
7.1.1 & 
4.1. 
X 
Main study Informed 
Consent 
D 
7.1.2. 
X 
Documented BRAF V600 
mutation 
D 
7.1.1 & 
4.1. 
X 
Demography 
D 
7.1.2.3. 
X 
Inclusion/exclusion criteria 
D 
5.2 & 5.3. 
X 
Additional exclusion criteria 
for third agent (only patients 
moving to Part II) 
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 
Physical examination 
S 
7.2.2.1. 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol No. CLGX818X2109 
 
 
 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
ECOG performance status 
(WHO) 
D 
7.2.2.2. 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3. 
X 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.4. 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
7.2.2.5. 
Hematology 
D 
7.2.2.5.1. 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.5.2. 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
D 
7.2.2.5.3. 
X 
If clinically relevant 
X 
Ophthalmologic 
examination 
D 
7.2.2.5.7. 
X 
X 
X2 
X 
Urinalysis 
D 
7.2.2.5.5. 
X 
If clinically relevant 
Pregnancy test 
D 
7.2.2.5.8. 
X 
X 
X 
X 
X 
Dermatologic evaluation 
D 
7.2.2.5.6. 
X 
X 
HbA1c 
(only patients moving to 
BKM120 arm Part II) 
D 
7.2.2.5.4. 
X 
Fasting plasma glucose 
(only patients moving to 
BKM120 arm Part II) 
D 
7.2.2.5.4. 
X 


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Protocol No. CLGX818X2109 
 
 
 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
Thyroid Function 
(only patients moving to 
LEE011 arm Part II) 
D 
7.2.2.5.9. 
X 
Imaging 
7.2.1. 
Brain CT/MRI with contrast 
(patients assigned to 
LEE011 arm in Part II) 
D 
7.2.1. 
X 
Brain CT/MRI with contrast 
(patients with baseline brain 
metastases) 
D 
7.2.1. 
X 
Every 6 
weeks 
X 
Tumor evaluation (RECIST) 
- CT/MRI 
Color photography if skin 
lesions are present 
D 
7.2.1. 
X 
X 
Every 6 
weeks, 
every 6-12 
weeks after 
≥ 24 months 
of treatment3 
X 
Every 9 
weeks, 
every 9- 
12 
weeks 
after 
≥ 24 
months 
of treat- 
ment4 


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Protocol No. CLGX818X2109 
 
 
 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
ECG5 (triplicate only at Day 
1 Cycle1) 
D 
7.2.2.6.1. 
X 
X 
X 
X 
X 
X C3, C5 
every 2 
Cycles every 
3 cycles 
after ≥ 24 
months of 
treatment 
X 
Cardiac imaging 
D 
7.2.2.6.2. 
X 
X 
C5, C8, C11 
and every 3 
Cycles 
thereafter 
X 
GAD-7 and PHQ-9 
Questionnaires 
(only patients moving to 
BKM120 arm Part II) 
D 
7.2.2.7. 
X 
Additional Ophthalmologic 
exam (only patients moving 
to BGJ398 arm Part II) 
D 
7.2.2.5.7. 
X 
Safety 
7.2.2. 
Adverse events 
D 
X6 
X 
Continuous 


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Protocol No. CLGX818X2109 
 
 
 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
Biomarkers 
7.2.4. 
Collection of archival 
paraffin blocks/slides & 
corresponding pathology 
report 
D 
7.2.4. 
X (if 
needed) 
X-if not collected 
at molecular 
screening 
Collection of newly 
obtained tumor sample 
from biopsy 
D 
7.2.4. 
X (if 
needed) 
X-if not collected 
at molecular 
screening 
At Progression 
Report genetic 
assessments results of 
progression biopsy 
(only patients moving to 
Part II) 
D 
7.2.4. 
X 
CCI 
BRAF 
D 
7.2.4.2. 
X 
X 
X 
X 
Study Drug 
Administration 
LGX818 QD/MEK162 BID 
administration 
D 
6.1.1. 
Continuous 
PK Blood Sampling 
D 
7.2.3. 
X 
X 
X pre- 
dose 
X pre- 
dose 
X Up to C5 
only 
X 
Meal Record 
D 
7.2.3.1. 
X 
Antineoplastic therapies 
since discontinuation of 
study treatment 
D 
7.1.6.2. 
X 
X 
X 


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Protocol No. CLGX818X2109 
 
 
 
Run-in 
Screening Phase 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of Study 
Treatment 1 
Safety Follow-up7 
Disease 
Progression 
Follow-up 
Day of cycle 
-14 to-1 
1 
15 
21 
8 
21 
15 
30 days 
from last 
dose 
1. EOT assessments will take place for patients who discontinue study treatment during Part I and will not move into Part II of the trial, and for patients moving to Part II 
at the time the genetic assessment results are available. EOT for patients permanently discontinuing the study treatment will occur within 14 days of the last dose of 
study treatment or within 14 days of date of decision to discontinue study treatment 
2. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months (Cycle 25 Day 1 onward) without a retinal AE in the past 12 months should 
be evaluated only for visual acuity at each scheduled patient visit and at End of Study Treatment visit. A full ophthalmic examination is required if clinically indicated and 
at End of Study Treatment visit. 
3. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months will have CT/MRI scans every 6-12 weeks (+/- 7 days). 
4. Patients who have been on the LGX818/MEK162 double-agent treatment for ≥ 24 months and then discontinue study treatment for any reason other than disease 
progression will be followed up by CT/MRI scans every 9-12 weeks (+/- 7 days). 
5. All ECGs should be taken before a blood sample or at least 0.5 hours after a blood sample. 
6. To collect only the Pre-screening Procedure Related SAEs. 
7. Following the 30-day follow-up, when clinically appropriate, it is recommended patients be monitored with physical examinations, dermatological examinations, and 
chest CT 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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Protocol No. CLGX818X2109 
 
 
 
Table 7-3 
Part II - Visit evaluation schedule for Part II (21 day cycles for triple combinations with INC280 and BKM120) 
Note: As of Protocol Amendment 06, enrollment to the BKM120- and INC280-containing arms is closed. 
Part II 
(21 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment 1 
Safety Follow-up 2 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 
15 
16 
1 
15 
1 
Molecular pre-screening 
Informed Consent 
D 
7.1.2. 
X 
Study Informed Consent 
D 
X 
Documented BRAF V600 
mutation 
D 
7.1.1. 
X 
Demography 
D 
7.1.2.3. 
X 
Inclusion criteria /exclusion 
criteria 
D 
5.1; 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 
Physical examination 
S 
7.2.2.1. 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
(WHO) 
D 
7.2.2.2. 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3. 
X 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
X 


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Protocol No. CLGX818X2109 
 
 
 
Part II 
(21 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
 
 
Subsequent Cycles 
End of Study 
Treatment 1 
Safety Follow-up 2 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 
15 
16 
1 
15 
1 
Vital signs 
D 
7.2.2.4. 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
7.2.2.5. 
Hematology 
D 
7.2.2.5.1. 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.5.2. 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
D 
7.2.2.5.3. 
X 
If clinically relevant 
X 
HbA1c (BKM120 arm only) 
D 
7.2.2.5.4. 
X 
X 
X 
X 
Every 3 Cycles 
Fasting plasma glucose 
(BKM120 arm only) 
D 
7.2.2.5.4. 
X 
X 
X 
X 
X 
X 
X 
Hepatotoxicity follow up/ 
procedures (BKM120 arm only) 
D 
6.3.2.5. 
As clinically indicated 
Urinalysis (and 24h urine 
collection if applicable) 
D 
7.2.2.5.5. 
X 
X 
if clinically 
indicated 
X 
Pregnancy test 
D 
7.2.2.5.8. 
X 
X 
X 
X 
X 
Dermatologic evaluation 
D 
7.2.2.5.6. 
X 
X 
X 
Every 2 Cycles 
X 
Ophthalmologic examination 
7.2.2.5.7. 
X 
X 
X 
X 
X 
X 
Imaging 
7.2.1. 
Brain CT/MRI with contrast 
(patients with brain metastases) 
D 
7.2.1. 
X 
Every 9 weeks 
X 
X Every 
9 weeks 


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Protocol No. CLGX818X2109 
 
 
 
Part II 
(21 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
 
 
Subsequent Cycles 
End of Study 
Treatment 1 
Safety Follow-up 2 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 
15 
16 
1 
15 
1 
Tumor evaluation (RECIST)- 
CT/MRI 
Color photography if skin 
lesions are present 
D 
7.2.1. 
X 
Every 9 weeks 
X 
X Every 
9 weeks 
ECG (triplicate only at Day1 
Cycle1) 
D 
7.2.2.6.1. 
X 
X 
X 
X 
X 
X 
X 
Every 2 Cycles 
X 
Cardiac imaging 
D 
7.2.2.6.2. 
X4 
X 
4 
X4 
X 
At C3 and every 
3rd cycle 
X 
GAD-7 and PHQ-9 
Questionnaires (for BKM120 
arm only) 
D 
7.2.2.7. 
X 
X 
X 
X 
X 
Safety 
7.2.2. 
Adverse events 
D 
Continuous 
Biomarkers 
7.2.4. 
Report results of progression 
biopsy performed in previous 
studies 
D 
7.2.4. 
X 
Collection of newly obtained 
tumor sample from biopsy, if 
applicable 
D 
7.2.4. 
X, if 
needed 
X, if 
needed 
X 
X at 
progressio 
n 


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Page 173 
Protocol No. CLGX818X2109 
 
 
 
Part II 
(21 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
 
 
Subsequent Cycles 
End of Study 
Treatment 1 
Safety Follow-up 2 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 
15 
16 
1 
15 
1 
Collection of archival paraffin 
blocks/slides & corresponding 
pathology report 
7.2.4. 
X 
CCI 
Study Drug administration 
LGX818 QD + MEK162 BID 
administration 
D 
6.1.1. 
Continuous 
INC280 BID or BKM120 QD 
administration 
D 
6.1.1. 
Continuous 
PK blood sampling 
D 
7.2.3. 
X 
X 
X 
X 
X 
X 
X 
up to Cycle 5 
X 
Meals record 
D 
7.2.3.1. 
X 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
7.1.6.2. 
X 
X 
X 
X 
Survival Follow-up (Contact 
every 3 months) 
D 
7.1.6.3. 
X 


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Page 174 
Protocol No. CLGX818X2109 
 
 
 
Part II 
(21 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
 
 
Subsequent Cycles 
End of Study 
Treatment 1 
Safety Follow-up 2 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 
15 
16 
1 
15 
1 
1. EOT will occur within 14 days of the last dose of study treatment or within 14 days of date of decision to discontinue study treatment 
2. Safety follow-up will occur 30 days after the last dose 
3. For patients in group C, who need to undertake a biopsy at screening and are going to continue treatment with LGX818/MEK162 combination, the screening 
assessments can be started at day -28 (instead of day -14) as described in Section 7.1.2. 
4. Patients coming from Part I will perform the cardiac imaging at Day 1 of Cycle 1, Day 1 of Cycle 3 and every third cycle and at the End of Study Treatment visit. 
Patients coming from other trials will perform the cardiac imaging at Screening/baseline, Day 1 of Cycle 2, Day 1 of Cycle 3 and every third cycle and at the End of 
Study Treatment visit. 


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Protocol No. CLGX818X2109 
 
 
 
Table 7-4 
Part II - Visit evaluation schedule for Part II (28 day cycles for LEE011 and BGJ398) 
Note: As of Protocol Amendment 06, enrollment to the BGJ38-containing arm is closed. As of Amendment 07, enrollment to the 
LEE011 arm is closed. 
 
 
Part II (28 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment1 
Safety follow-up 2,7 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 15 
16 
21 
1 
15 
1 
155 
Molecular pre-screening 
Informed Consent 
D 
X 
Main Study Informed 
Consent 
7.1.2. 
X 
Documented BRAF V600 
mutation 
D 
7.1.1. 
X 
Demography 
D 
7.1.2.3. 
X 
Inclusion/ exclusion criteria 
D 
5.1; 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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Protocol No. CLGX818X2109 
 
 
 
Part II (28 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment1 
Safety follow-up 2,7 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 15 
16 
21 
1 
15 
1 
155 
Physical examination 
S 
7.2.2.1. 
X 
X 
X X 
X 
X 
X 
X 
X5 
X 
ECOG performance status 
(WHO) 
D 
7.2.2.2. 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3. 
X 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.4. 
X 
X 
X X 
X 
X 
X 
X 
X5 
X 
Laboratory assessments 
7.2.2.5. 
Hematology 
D 
7.2.2.5.1. 
X 
X 
X X 
X 
X 
X 
X 
X5 
X 
Chemistry 
D 
7.2.2.5.2. 
X 
X 
X X 
X 
X 
X 
X 
X5 
X 
Coagulation 
D 
7.2.2.5.3. 
X 
If clinically relevant 
X 
Thyroid Function 
(LEE011 arm only) 
D 
7.2.2.5.9. 
X 
X 
X 
X 
Every 2 cycles 
from C3 only if 
clinically indicated 
Hepatotoxicity follow up/ 
procedures 
(LEE011 arm only) 
D 
6.3.2.6. 
As clinically indicated 
Urinalysis 
D 
7.2.2.5.5. 
X 
X 
if clinically 
indicated 
X 
Pregnancy test 
D 
7.2.2.5.8. 
X 
X 
X 
X 
X 
Dermatologic evaluation 
D 
7.2.2.5.6. 
X 
X 
Every 2 
Cycles 
X 


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Part II (28 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment1 
Safety follow-up 2,7 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 15 
16 
21 
1 
15 
1 
155 
Ophthalmologic 
examination 
D 
7.2.2.5.7. 
X 
X 
X 
X 
X6 
X 
Additional Ophthalmologic 
exam for BGJ398 arm only 
D 
7.2.2.5.7. 
X 
X 
X 
X 
X 
X5 
X 
Imaging 
7.2.1. 
Tumor evaluation 
(RECIST)-CT/MRI 
Color photography if skin 
lesions are present 
D 
7.2.1. 
X 
Every 9 weeks 
X 
X 
Every 9 
weeks 
Brain CT/MRI with contrast 
(patients assigned to 
LEE011 arm and patients 
with history of brain 
metastases) 
D 
7.2.1. 
X 
Every 9 weeks 
X 
X Every 
9 weeks 
ECG (triplicate only at 
Day1 Cycle1) 
D 
7.2.2.6.1. 
X 
X 
X X 
X 
X 
X 
X 
X 
Every 2 Cycles, 
then every 3 cycles 
after ≥ 24 months 
of treatment 
Cardiac imaging 
D 
7.2.2.6.2. 
X4 
X4 
X4 
X 
X 
At C3 and every 
3rd cycle 


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Part II (28 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment1 
Safety follow-up 2,7 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 15 
16 
21 
1 
15 
1 
155 
Safety 
7.2.2. 
Adverse events 
D 
X 
X 
Continuous 
Biomarkers 
7.2.4. 
Report results of 
progression biopsy in 
previous studies 
D 
7.2.4 and 
4.1. 
X 
Collection of newly 
obtained tumor sample 
from biopsy, if applicable 
D 
7.2.4 and 
4.1. 
X, if 
neede 
d 
X, if 
needed 
X 
X at 
progression 
Collection of archival 
paraffin blocks/slides or 
corresponding sequencing 
report. 
D 
7.2.4 and 
4.1. 
X 
CCI 
Study Drug 
administration 
LGX818 QD + MEK162 
BID administration 
D 
6.1.1. 
Continuous 
BGJ398 QD or LEE011 
QD administration 
D 
6.1.1. 
3 weeks on 1 week off 
PK blood sampling 
D 
7.2.3. 
X 
X X 
X 
X 
X 
X 
X 
X 
Up to Cycle 5 


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Part II (28 days cycle) 
Screening Phase 
Group C 
Treatment Phase 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Study 
Treatment1 
Safety follow-up 2,7 
Disease 
Progression 
Follow-up 
Survival Follow-up 
Day of cycle 
-14 to-13 
1 
8 15 
16 
21 
1 
15 
1 
155 
Meals record 
D 
7.2.3.1. 
X 
Antineoplastic therapies 
since discontinuation of 
study treatment 
D 
7.1.6.2. 
X 
X 
X 
X 
Survival Follow-up 
(Contact every 3 months) 
D 
7.1.6.3. 
X 
1. EOT will occur within 14 days of the last dose of study treatment or within 14 days of date of decision to discontinue study treatment 
2. Safety follow-up will occur 30 days after the last dose 
3. For patients in group C, who need to undertake a biopsy at screening and are going to continue treatment with LGX818/MEK162 combination, the screening 
assessments can be started at day -28 (instead of day -14) as described in Section 7.1.2. 
4. Patients coming from Part I will perform the cardiac imaging at Day 1 of Cycle 1, Day 1 of Cycle 3 and every third cycle, and at the End of Study Treatment visit. 
Patients coming from other trials will perform the cardiac imaging at Screening/baseline, Day 1 of Cycle 2, and Day 1 of Cycle 3 and every third cycle, and at the End 
of Study Treatment visit. 
5. Day15 visit will be only performed up to Cycle 4. After that, only Day 1 visit will be scheduled at each cycle from Cycle 5. 
6. Patients who have received LGX818/MEK162 for ≥ 24 months (Cycle 25 Day 1 onward) without a retinal AE in the past 12 months should be evaluated only for 
visual acuity at each scheduled patient visit and at End of Study Treatment visit. A full ophthalmic examination is required if clinically indicated and at End of Study 
Treatment visit. 
7. 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 LGX818 dose or until initiation of another antineoplastic 
therapy. 


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Table 7-5 
Part I - LGX818 + MEK162 Visit Evaluation Schedule for patients on treatment ≥ 36 months (Amendment 07) 
Part I Procedure or Assessment1 
(± 3-day window for 
procedures/assessments) 
LGX818 + MEK162 Treatment 
Starting Week 157 
(≥ 36 months on treatment) 
Treatment 
Discontinuation 
Visit 
30-Day Safety 
Follow-up13 
Day of Cycle 
Category 
Protocol 
Section 
Per local 
standard of care 
(Recommended 
every 4 weeks) 
Recommended 
every 
8-12 weeks 
Physical Examination2,13 
D 
7.2.2.1. 
X 
X 
Vital Signs3 
D 
7.2.2.4. 
X 
X 
ECOG PS 
D 
7.2.2.2. 
X 
X 
Single ECG 
D 
7.2.2.6.1. 
X 
X 
Hematology4 
D 
7.2.2.5.1. 
X 
X 
Coagulation5 
D 
7.2.2.5.2. 
X 
X 
Clinical Chemistry6 
D 
7.2.2.5.3. 
X 
X 
Urinalysis 
D 
7.2.2.5.5. 
X7 
X7 
Pregnancy Test8 
D 
7.2.2.5.8. 
X 
X 
Cardiac Ejection Fraction9 
D 
7.2.2.6.2. 
X 
X 
Visual Acuity 
D 
7.2.2.5.7. 
X 
X 
Ophthalmic Examination 
D 
7.2.2.5.7. 
(X)10 
(X)10 
(X)10 
Dermatological Examination13 
D 
7.2.2.5.6. 
X 
LGX818+MEK16211 - Dispense and/or 
Assess Compliance 
D 
6.1.1. 
X12 
Review adverse events 
D 
8.1. 
X 
X 
X 
Review concomitant medications 
D 
7.1.2.3. 
X 
X 
X 
CCI 
BRAF 
D 
7.2.4. 
X 
X 
Tumor Assessments 
D 
7.2.1. 
Per institutional standard of care 


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1 
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. For all visits, there is a general ± 3-day window for assessments to take into account scheduling over public or religious holidays. 
2 
Body weight will be measured as part of the physical examination. 
3 
Including: blood pressure, pulse and temperature, as appropriate. 
4 
Including: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils/ANC, platelets, RBC, WBC. 
5 
Including: aPTT, INR/PT. 
6 
Including: ALT, AST, bilirubin (total and direct), albumin, alkaline phosphatase, BUN/urea, calcium, CK, creatinine, creatinine clearance (calculated), magnesium, 
potassium, sodium, total protein, troponin. For Grade 2 total CK that is also ≥ 3 × ULN or asymptomatic Grade 3 total CK: measure CK, CK isoenzymes and 
myoglobin in blood or urine weekly for 3 weeks and if total CK remains ≤ the grade which triggered increased monitoring, continue to assess CK, CK isoenzymes and 
myoglobin along with regularly scheduled clinical chemistry assessments. 
7 
To be done if clinically indicated. 
8 
Local urine test for women of childbearing potential only. 
9 
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. 
10 Patients who have been on LGX818 + MEK162 treatment without a retinal AE within the past 12 months should be evaluated only for visual acuity at each 
scheduled patient visit and at End of Study Treatment visit. A full ophthalmic examination is required, if clinically indicated. Full ophthalmic examination includes: 
slit lamp examination; best corrected visual acuity for distance testing; automated visual field testing; IOP; and dilated fundoscopy with attention to retinal 
abnormalities, especially RPED, serous detachment of the retina and RVO. Patients with clinical suspicion of retinal abnormalities of any grade (i.e., RPED, serous 
detachment of the retina, RVO, photopsia, metamorphopsia, impairment of visual acuity, etc.) must be seen by an ophthalmologist as soon as possible and additional 
assessments with OCT (spectral domain OCT recommended) of the macula (for non-vascular abnormalities) and color fundus photography of the central 30 degrees 
and/or fluorescein angiography (for vascular abnormalities) are mandatory. 
11 LGX818 + MEK162 dosed PO BID with water irrespective of food, continuously. 
12 After Week 157, LGX818 and MEK162 will be dispensed every 12 weeks 
13 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-cutaneuous secondary malignancies for up to 6 months after the last LGX818 dose or until initiation of another antineoplastic 
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7.1.1 
Molecular pre-screening 
The molecular pre-screening informed consent must be signed prior to any study-related 
molecular pre-screening procedure. 
To enter the screening phase for Part I, Run-in and Part II of this study, patients must complete 
the molecular pre-screening assessment if written documentation of BRAF V600 mutation is 
unavailable, or, there is a new lesion growing for which BRAF status may be of interest. 
Patients, for whom the BRAF mutational status was not already assessed outside of this study, 
must sign the molecular pre-screening informed consent and provide either an archival biopsy 
sample or consent to providing a new tumor biopsy sample, which will be locally analyzed for 
BRAF status (for patients enrolled at US sites, an FDA-approved test must be used). This does 
not apply to patients moving from Part I to Part II after progressing on LGX818/MEK162 
combination. Once the mutation of the BRAF V600 codon (e.g. V600E/K/D/R) is confirmed 
by the designated local laboratory and documented by the site, the patient may begin the 
screening procedures. 
In the case of patients previously treated with any BRAF and/or MEK inhibitors, and therefore 
eligible to be screened for participation into the Run-in or Part II, they should sign the pre- 
screening informed consent and provide an archival tumor sample collected pre-BRAF and/or 
MEK inhibitor treatment and a new, or archival, tumor sample collected at the time of relapse 
from the above treatment(s). The tumor samples will be fully characterized through a 
comprehensive genomic analysis performed at a Sponsor-delegated central laboratory. 
 
7.1.2 
Screening 
Screening will start after the BRAF mutational status is documented. 
For all patients in the study, the main 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, Table 7-2, Table 7-3 and Table 7-4. Part I 
Screening/baseline CT/MRI scans must be completed within 21 days prior to the first dose of 
study treatment. Part II Screening/baseline CT/MRI scans (Only Group C patients) must be 
completed, if not already performed within 28 days from the scan performed at progression. All 
other screening assessments must be completed, if not already performed within 14 days prior 
to the first dose with the exception of pregnancy test, which must be performed within 72 hours 
before the first dose. 
For Groups B and C, patients enrolled from other LGX818/MEK162 combination studies (e.g. 
COLUMBUS, IIT), who had safety and tolerability assessments in the previous study at End of 
Study Treatment visit completed within 14 days prior to the first dose of the triple combination, 
data should be reported in CLGX818X2109 and be used as baseline assessments. Therefore, 


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for Groups B and C patients, safety and tumor assessments performed at last visits in the 
previous clinical trials should not be repeated at Screening, if fitting the above time windows 
to the first triple treatment dose (CT/MRI within 28 days and safety within 14 days of the first 
dose of triple combination). At screening, Group B patients will provide either a pre-BRAF 
and/or MEK inhibitors biopsy, or, a relapse biopsy from previous BRAF and/or MEK 
inhibitors. Group C patients at screening, will either provide a recent progression biopsy from 
previous LGX818/MEK162 trial, or, a new biopsy. Decision to continue receiving 
LGX818/MEK162 medications beyond progression, during the genetic assessment, will be 
taken by the investigator in the best interest of patients. The investigator will need to confirm 
patients’ eligibility to continue receiving LGX818/MEK162 combination (see Section 5.1, 
Section 5.2 and Section 5.3). During this time, patients will be monitored according to Part I 
assessments as described in Table 7-1 (subsequent cycles). For patients in Group C, who need 
to undertake a biopsy at screening and are going to continue treatment with LGX818/MEK162 
combination, the screening assessments can be started at day -28 (instead of day -14). 
Patients in Group A and B who progressed while treated with LGX818/MEK162, will not 
perform the Screening Part II assessments before starting the triple combination treatment 
phase. These patients will perform the safety and tolerability assessments at the End of Study 
Treatment visit Part I (see Table 7-1 and Table 7-2 and Section 7.1.5). 
Assessments which are indicated to be performed at Screening/baseline (Table 7-1, Table 7-2, 
Table 7-3 and Table 7-4), or at End of Treatment Part I (Table 7-1, Table 7-2) for patients 
moving to treatment phase Part II, and on Cycle 1 Day 1, need to be repeated at Cycle 1 Day 1 
only if Screening/baseline assessments, or End of Treatment Part I assessments were performed 
more than 3 days before the first dose administration. 
For all patients, screening examinations and assessments specifically required for triple 
combinations will be performed upon availability of the genetic assessment results from 
Sponsor-delegated central laboratory. All results should be available at site and exclusion 
criteria for the specific triple combination arm must not be met in order to declare a 
patient eligible for receiving the selected triple combination. If a patient does not meet all 
eligibility criteria (e.g. fails a laboratory assessment) a retest within the screening period is 
allowed. The same patient number should be kept. All assessments of initial screening are 
entered in eCRF and any repeat assessments are reported as unscheduled assessments. 
 
7.1.2.1 
Eligibility screening 
When a 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 the various 
treatment arms will be handled by the Sponsor. 
 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign the molecular prescreening informed consent and/or the main study informed 
consent, but fail to be started on study treatment for any reason will be considered a screen 
failure and data will be handled in the same manner. The reason for not being started on 
treatment will be entered on the applicable Screening Log eCRF page. The molecular pre- 


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screening failure or screening failure information will be entered on the Screening Phase 
Disposition Page. The demographic information, informed consent, Dosage Administration 
Record (only for group C patients during the genetic assessment period) and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8.2 for SAE 
reporting details). For molecular pre-screening failures, only SAEs possibly related to a study 
procedure will be reported (i.e., tumor biopsy). 
Patients who have received study drug in Part I, or Run-in, and cannot continue onto Part II, 
because of unmet additional exclusion criteria for the triple combination (Part II), will be 
identified as not eligible for Part II only. Thus, they need to complete the End of Study 
Treatment visit (Part I, or Run-in) 
 
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 
Run-in period (only for Group B) 
Patients who progressed after treatment with single agent BRAF and/or MEK inhibitor or the 
combination of BRAF/MEK inhibitors (excluding LGX818/MEK162 combination) will 
receive LGX818/MEK162 combination in a brief Run-in phase followed by early disease 
assessment (after 3 weeks). Patients achieving at least a PR from this treatment at the first 
CT/MRI scan may continue on LGX818/MEK162 combination until progression. At this time, 
a newly obtained tumor biopsy will be mandatory and patients will be assigned to a triple 
combination arm in Part II on the basis of the tumor sample’s genetic assessment (Table 4-1). 
Patients not deriving clinical benefit from LGX818/MEK162 combination therapy will be 
assigned to a treatment arm in Part II on the basis of the analysis of their most recent tumor 
biopsy. 
Patients who did not progress on their prior BRAF/MEK regimen (including LGX818 and /or 
MEK162), may enter the Run-in (Group B) and continue LGX818/MEK162 combination until 
evidence of disease progression at which point a tumor biopsy will be taken and analyzed to 
guide assignment to a triple combination arm in Part II. 
 
7.1.4 
Treatment period 
Treatment period is divided into two parts: 
Part I: BRAF and MEK inhibitor naïve patients will be dosed continuously with 
LGX818/MEK162 combination on 21-day (3 calendar weeks) cycles beginning on Day 1 of 
Cycle 1. There will be no scheduled break between cycles. Patients will receive 
LGX818/MEK162 combination until initiation of triple combination treatment after 
progression of disease or until unacceptable toxicity occurs, whichever comes first. 


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During the genetic assessment period patients will follow the same schedule of assessments for 
subsequent cycles of Part I or Run-in. However, only specific information will be collected such 
as dosing, AEs, concomitant medications until initiation of triple combination treatment. 
Only patients in group B will go through a run-in period (LGX818/MEK162 combination) 
before entering Part II (see Section 4.1) 
Part II: Patients, who received LGX818/MEK162 combination for at least 3 weeks and 
progressed, will enter in Part II to receive a triple combination treatment of LGX818/MEK162 
+ third agent, based upon the genetic alterations identified in the tumor biopsy at progression. 
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). 
For details of the frequency of the visits and assessments during the treatment period, refer to 
Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 
 
7.1.5 
End of Study Treatment visit including study completion and 
premature withdrawal 
Patients permanently discontinuing the study treatment, as well as patients in Group A and B 
switching from LGX818/MEK162 to the triple combination treatment, must perform the End 
of Study Treatment assessments (Table 7-1, Table 7-2, Table 7-3, and Table 7-4). For patients 
who permanently discontinue study treatment, this visit should take place ≤ 14 days after the 
last dose of study treatment, or after the decision to discontinue study treatment. For patients in 
Group A and B moving to Part II, this visit should take place as soon as the results of the 
progression biopsy genetic assessment are available and the patients can be assigned to a triple 
combination in Part II. However, at End of Study Treatment, CT/MRI scans must be completed, 
if not already performed within 28 days from the last CT/MRI scan, while other screening 
assessments must be completed, if not already performed within 14 days prior to the first dose 
with the exception of pregnancy test, which must be performed within 72 hours before the first 
dose. Moreover, the End of Study Treatment disposition CRF page should be completed, giving 
the date and reason for stopping the study treatment. End of Study Treatment/Premature 
withdrawal visit is not considered as the end of the study. 
At a minimum, all patients who discontinue study treatment will be contacted to return 30 days 
after the last administration of the study treatment for safety follow up evaluations according to 
Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 
Additionally, patients in Part I and Part II who discontinue study treatment for any reason prior 
to disease progression should also return for disease follow-up, but only patients enrolled in 
Part II will be subsequently followed for survival (Section 7.1.5 and Section 7.1.6) 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 follow-up information. 
If a patient discontinues study treatment, but continues study assessments in the Follow-Up 
period, the patient remains on study until such time as he/she completes protocol criteria for 


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ending study assessments. At that time, the reason for study completion should be recorded on 
End of post-treatment evaluation follow-up). 
 
7.1.5.1 
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: 
• Adverse event 
• Withdrawal of informed consent 
• Lost to follow-up 
• Progressive disease in the triple combination part of the study 
• New therapy for study indication 
• Any patient who becomes pregnant during study treatment will be immediately 
withdrawn. 
 
7.1.5.2 
Replacement policy 
No patients will be replaced on the study. 
 
7.1.6 
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. 
 
7.1.6.1 
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. For patients who have been on treatment in Part I for 
≥ 36 months, the 30 day follow-up will include a review of concomitant medications and 
assessment of compliance with administration of LGX818 (encorafenib) and MEK162 
(binimetinib). There will also be review of AEs with recording of all Grade 3 or 4 AEs and all SAEs 
(SAEs, follow-up of SAEs to continue as described in Section 8). Other safety evaluations may be 
conducted if clinically indicated. 
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-cutaneuous secondary malignancies for up to 6 months after the last 
LGX818 dose or until initiation of another antineoplastic therapy. 


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7.1.6.2 
Disease progression follow-up period 
Patients enrolled in Part I, Run-in and Part II who discontinue study treatment for any reason 
other than disease progression will be followed up by CT/MRI scans every 9 weeks (+/- 7 days) 
as detailed in Table 7-1, Table 7-2, Table 7-3, Table 7-4, Table 7-5 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. 
Patients enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 
double-agent treatment for ≥ 24 months and then discontinue study treatment for any reason 
other than disease progression will be followed up by CT/MRI scans every 9-12 weeks 
(+/- 7 days) as detailed in Table 7-1, Table 7-2 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. 
 
7.1.6.3 
Survival follow-up period 
After Safety Follow-up, all patients enrolled in Part II of this study will be followed for survival 
every 3 months by contacting the patient (e.g., telephone calls, registered letters, etc.) until they 
have been followed for at least 18 months after the first dose of their treatment, or until death, 
or until End of Study (see Section 4.3), whichever occurs first. Newly started antineoplastic 
therapies during this follow-up period must be recorded on the Antineoplastic therapy since 
discontinuation. 
 
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 (Appendix 8). 
In the LGX818/MEK162 double-agent treatment, Part I, eligible patients will be evaluated for 
all potential sites of tumor lesions at Screening/baseline and every 6 weeks after starting study 
treatment until disease progression. Patients enrolled in Part I who have been on the 
LGX818/MEK162 double-agent treatment for ≥ 24 months will be evaluated for all potential 
sites of tumor lesions every 6-12 weeks (+/- 7 days) until disease progression. 
Patients in Group B, eligible to enter the Run-in will be evaluated for all potential sites of tumor 
lesions after received at least 21 days (after one three-week cycle) of LGX818/MEK162 
combination during the time of biopsy molecular analysis. For patients with PR or CR, the 
following assessments will be then executed every 6 weeks (every two three-week cycles) until 
disease progression. Patients in Group B who have been on the LGX818/MEK162 double-agent 
treatment for ≥ 24 months will be evaluated for all potential sites of tumor lesions every 6-12 
weeks (+/- 7 days) until disease progression. If signs of tumor progression are observed, an 
unscheduled scan to assess progression may be performed upon investigator`s decision. 
In the triple combination treatment part (Part II) of the study, each patient will be evaluated 
every 9 weeks after starting triple combination treatment until disease progression. 


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The Screening/baseline (Part I and Run-in) CT/MRI scan assessments may be performed within 
21 days of treatment start for Part I and Run-in. The Screening/baseline Part II (only patients in 
Group C) and End of Study Treatment Part I and Run-in (only patients moving to Part II) 
CT/MRI scans assessments must be completed, if not already performed within 28 days of the 
previous CT/MRI scan. End of Study Treatment Part I and Run-in (only patients assigned to 
LEE011 arm in Part II) CT/MRI brain scans assessments must be completed, if not already 
performed within 28 days of the previous CT/MRI scan. At screening, patients in Group C, 
enrolled from other LGX818/MEK162 double agent studies (e.g. [CME162X2110], 
[COLUMBUS], IIT), can provide the last visit tumor evaluation data documenting the 
progressive disease as baseline assessment of CLGX818X2109 (Part II), if those tumor 
assessments have been performed within 28 days. 
For patients in Group C assigned to LEE011 arm, the brain CT/MRI scans must be completed 
within 28 days before triple combination first dose. 
On-study tumor assessments have a ± 7 day window, except for the first post-baseline tumor 
assessment. The first post-baseline tumor assessment should be performed 6 weeks (Part I), 3 
weeks (Run-in) (± 3 days) and 9 weeks (Part II) +7 day window permitted after starting 
treatment. Patients enrolled in Part I and the Run-in phase, who have been on the 
LGX818/MEK162 double-agent treatment for ≥ 24 months will be evaluated for all potential 
sites of tumor lesions every 6-12 weeks (+/- 7 days) or per local standard-of-care clinical 
practice until disease progression. There will be a tumor assessment at the End of Study 
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. 
Patients included in Part I, Run-in and Part II of the study (triple combination part), who 
discontinue study treatment due to another reason than disease progression, should be followed 
up and undergo tumor assessments every 9 weeks (± 7 days) until disease progression or 
initiation of subsequent anti-neoplastic therapy, or death, whichever occurs first (Section 7.1.6). 
Patients enrolled in Part I and the Run-in phase, who have been on the LGX818/MEK162 
double-agent treatment for ≥ 24 months and then discontinue study treatment for any reason 
other than disease progression will have CT/MRI scans every 9-12 weeks (+/- 7 days). 
At Screening/baseline (Part I and Part II), the following should be performed: 
• A CT/MRI scan with intravenous (IV) contrast of chest, abdomen and pelvis is required 
for all patients. This is the preferred radiologic technique for the study. However, if CT 
assessments require additional regulatory approval in a country, MRI is allowed for chest, 
abdomen, pelvis. If a patient is known to have a contraindication to CT contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if possible) of 
the abdomen and pelvis should be performed. 
• In patients with a history of brain metastases, a brain MRI or CT scan must be performed. 
• At screening in Part II, Group C patients assigned to LEE011 arm must perform a brain 
MRI or CT scan with contrast. 
• 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 


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method per their local standard of care (e.g., Tc99m bone scan, FDG-PET, 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 and should be evaluated with 
same frequency as chest, abdomen, pelvis CT/MRI/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 and End of Treatment (Part I, Run-in and Part II), 
the following should be performed: 
• All patients are required to undergo chest, abdomen and pelvis CT/MRI scans. 
• Brain MRI or CT scan, if metastases were documented at baseline 
• At End of Treatment (Part I and Run-in), brain MRI or CT scan must be performed if 
patient is assigned to LEE011 arm in Part II. 
• Skeletal lesions identified at baseline should continue to be imaged at subsequent 
scheduled visits using localized CT, MRI or x-ray (the method for any given lesion should 
be kept consistent across visits). 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 imaging evaluations 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. If off-schedule imaging evaluations are performed (e.g. to confirm response or if 
progression is suspected), every effort should be made to perform subsequent imaging 
evaluations in accordance with the original imaging schedule. If evidence of progressive disease 
is not unequivocal, every effort should be made to keep the patient on study medication for at 
least one additional imaging evaluation as long as it is clinically acceptable. 
CT scans should be acquired with IV contrast. If a patient is known to have a medical 
contraindication to CT IV contrast agent or develops a contraindication during the study, a CT 
scan without IV contrast of the chest and MRI with IV contrast, if possible, of the abdomen and 
pelvis may be performed. A CT scan of the brain, preferably with IV 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 


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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 8). 
Each center should have a designated radiologist responsible for the interpretation of scans and 
response evaluations for study patients. Preferably, a single radiologist should perform all 
evaluations for an individual patient. 
 
Table 7-6 
Disease assessment collection plan 
 
Procedure 
Screening/Baseline and EOT 
During Treatment and 
Follow-up 
Part I: C2D21 and every 6 weeks during 
treatment. 
Run-in: First assessment after 3 weeks 
during Run-in, and after 6 weeks thereafter. 
Part I and Run-in: For patients who have 
been on the LGX818/MEK162 double- 
agent treatment for ≥ 24 months, every 6- 
12 weeks. 
CT or MRI 
with contrast 
enhancement 
(Chest, Abdomen, 
Pelvis) 
Mandated in Part I, Run-in and 
Part II 
For patients who have been on the 
LGX818/MEK162 double-agent treatment 
for ≥ 36 months, every 8-12 weeks or per 
local standard-of-care. 
Every 9 weeks during Progressive Disease 
Follow-up. For patients who discontinue the 
LGX818/MEK162 double-agent treatment 
after ≥ 24 months without progressive 
disease, every 9-12 weeks. 
Part II: 
Every 9 weeks during treatment.. 
Every 9 weeks during Progressive Disease 
Follow-up 
Whole bone 
scintigraphy 
If clinically indicated 
If clinically indicated 
Brain CT or MRI 
(e.g. Brain) 
Mandated in Part I for patients 
with a history of asymptomatic 
brain metastases. 
Mandated at EOT (Part I and 
Run-in) only for patients 
assigned to LEE011 arm and 
at Screening (Part II) 
Every 6 weeks in Part I and Run-in 
(patients with history of brain metastasis). 
Every 9 weeks in Part II (patients with 
baseline brain metastasis and patients in 
LEE011 arm). 
Every 9 weeks during the disease follow-up 
period for patients in Part II. 


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7.2.2 
Safety and tolerability assessments 
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. 
For Group C patients enrolled from other LGX818/MEK162 combination studies (e.g. 
COLUMBUS, IIT), who had safety and tolerability assessments at End of Study Treatment visit 
completed within 14 days prior to the first dose of the triple combination, data should be 
reported in CLGX818X2109 and be used as baseline assessments. 
 
7.2.2.1 
Physical examination 
A complete physical examination will be conducted 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, vascular and neurological. 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 occur at all other visits 
indicated below unless the investigator considers a complete physical examination necessary. 
Physical examinations will take place at the following visits irrespective of the time of dosing: 
• Screening/Baseline (Part I, Run-in and Part II) 
• Part I and Run-in Cycle 1: Days 1, 15 
• Run-in Cycle 1: Day 21 
• Part I and Run-in Cycle 2: Days 8, 21 
• Part I and Run-in subsequent cycles: Day 15 
• Part I and Run-in patients on treatment ≥ 36 months: Per local standard of care 
(recommended every 4 weeks) (Table 7-5). 
• Part II (21 days cycle) Cycle 1: Days 1, 8, 15 
• Part II (21 days cycle) Cycle 2: Days 1, 15 
• All other Part II (21 days cycle) subsequent cycles: Day 1 
• Part II (28 days cycle) Cycle 1: Days 1, 8, 15, 21 
• Part II (28 days cycle) Cycle 2: Days 1, 15 
• All other Part II (28 days cycle) subsequent cycles: Cycle 3 and 4 Days 1 and 15, from 
Cycle 5 only Day 1. 
• End of Study Treatment (Part I, Run-in and Part II) 
Significant findings that were present prior to the signing of study informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s eCRF. 


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7.2.2.2 
Performance status 
Assessment of ECOG Performance Status (WHO) will be performed at screening and on Day 
1 of cycle 1 and once per cycle thereafter throughout the whole study period irrespective of the 
time of dosing. End of Study Treatment assessment will be performed. 
Performance status should be obtained on the scheduled day, even if study medication is being 
held. 
 
Table 7-7 
ECOG performance status scale (WHO) 
 
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. 
 
7.2.2.3 
Height and weight 
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, even for patients coming from 
other LGX818/MEK162 double agent studies (e.g. COLUMBUS, IIT). Weight information will 
be collected irrespective of the time of dosing according to the applicable visit evaluation 
schedule. 
 
7.2.2.4 
Vital signs 
Vital signs (respiratory rate, pulse, blood pressure and temperature) will be obtained in the same 
position, either sitting or supine, as appropriate prior to any blood collection and taken pre-dose. 
Vital signs will be measured at screening, at every scheduled visit in Part I, Run-in, Part II 21- 
day cycle and 28-day cycle (with the exception of cycle 1 Day 16 and cycle 2 Day 8) and at 
End of Study Treatment as detailed in Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 
 
7.2.2.5 
Laboratory evaluations 
Sites will use their local laboratories for the analysis of all safety lab samples collected at the 
timepoint s indicated in the Visit Schedule (Table 7-1, Table 7-2, Table 7-3, Table 7-4 and 
Table 7-5). More frequent assessments may be performed if clinically indicated, or at the 
investigator’s discretion; 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. 
 
Table 7-8 
Local clinical laboratory parameters collection plan 
 
Hematology 
RBC 
Monocytes 
WBC 
Eosinophils 
Platelets 
Basophils 
Neutrophils/ANC 
Hemoglobin 
Hemoglobin HbA1c (only for BKM120 arm) 
Lymphocytes 
Hematocrit 
Chemistry 
Albumin 
Sodium, Potassium, Magnesium, Calcium 
Total Protein 
ALT (SGPT), AST (SGOT), 
Phosphate 
Bicarbonate/CO2 
Glucose (non-fasting) 
Fasting plasma glucose (only 
BKM120 arm) 
Gamma-glutamyl-transferase (GGT) 
Lipase, Amylase 
LDH 
TSH (free T4, and free T3) 
Alkaline Phosphatase 
Total Bilirubin (direct and indirect bilirubin 
only need to be measured if total bilirubin is 
grade 2 or higher) 
Urea 
Serum Creatinine 
Uric Acid 
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT), fibrinogen. 
Cardiac/Muscle 
Enzymes 
Creatine Kinase (CK) 
If total CK ≥3 X ULN (≥ CTCAE Grade 2), then measure isoenzymes and 
myoglobin in blood or urine weekly until resolved to ≤ CTCAE Grade 1 
Pregnancy Test 
(for women of 
child-bearing 
potential) 
Serum β-hCG test 
urine pregnancy test to be performed locally 
Viral hepatitis 
serologic tests 
and other tests 
for hepatotoxicity 
follow-up (if 
clinically 
indicated for 
BKM120, INC280 
& LEE011 arms) 
HAAb, HBsAg, HBsAb HBcAb, HCV RNA, HDV RNA, EBV or HSV(where 
needed), 
HEAb, CMVAb, EBcAb, ALP, CPK, LDH, WBC (eosinophilia). 
Urinalysis 
pH, protein, glucose, blood, ketones, and leukocytes 
microscopic evaluations only if clinically indicated 


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7.2.2.5.1 Hematology 
The parameters listed in Table 7-7 will be measured pre-dose at screening, at every scheduled 
visit in Part I, Run-in, Part II 21-day cycle and 28-day cycle (with the exception of cycle 1 Day 
16 and cycle 2 Day 8) and at End of Study Treatment as detailed in Table 7-1, Table 7-2, 
Table 7-3, Table 7-4 and Table 7-5. 
 
7.2.2.5.2 Clinical chemistry 
The parameters listed in Table 7-7, including CK, will be measured pre-dose at screening, at 
every scheduled visit in Part I, Run-in, Part II 21-day cycle and 28-day cycle (with the exception 
of cycle 1 Day 16 and cycle 2 Day 8) and at End of Study Treatment as detailed in Table 7-1, 
Table 7-2, Table 7-3, Table 7-4 and Table 7-5. 
 
7.2.2.5.3 Coagulation 
For Part I, Run-in and Part II, coagulation profiles will be performed pre-dose at: 
• Screening/baseline 
• If clinically relevant during treatment periods 
• End of Study Treatment 
7.2.2.5.4 Fasting glucose and hemoglobin HbA1c monitoring (for combination 
treatment arm with BKM120) 
Fasting plasma glucose (fasting is defined as no caloric intake for at least 8 hrs prior to analysis) 
will be assessed pre-dose at: 
• Part II: Screening/baseline 
• Part II: Cycles 1 Days 1 and 15 and Cycles 2 Days 1 and 15 pre-dose (prior to 
snack/breakfast) 
• Part II subsequent Cycles: Day1 
• End of Study Treatment (in Part I and Run-in, only for patients that will be assigned to 
BKM120 arm, and in Part II, for all patients in BKM120 arm) 
Hemoglobin HbA1c will be assessed pre-dose at: 
• Part II: Screening/baseline 
• Part II: Cycles 2 Day1 
• Part II subsequent cycles: Day 1 of every 3 Cycles 
• End of Study Treatment (in Part I and Run-in, only for patients that will be assigned to 
BKM120 arm, and in Part II, for all patients in BKM120 arm) 
 
7.2.2.5.5 Urinalysis 
Urine color and appearance should be evaluated. 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 


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findings) need only be performed if the urinalysis result is abnormal (except for institutions 
where microscopic urinalysis is not available). 
Urinalysis will be performed pre-dose at: 
• Screening/baseline (Part I, Run-in and Part II) 
• Part I and Run-in: only if clinically indicated 
• Part II 28-day cycle: Cycle 1 Day 21 
• Part II 28-day cycle: All subsequent cycles if clinically indicated 
• Part II 21-day cycle: Cycle 2 Day 1 
• Part II 21-day cycle: All subsequent cycles if clinically indicated 
• End of Study Treatment (Part I, Run-in and Part II) 
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. 
 
7.2.2.5.6 Dermatologic evaluation 
Skin evaluations will be performed by dermatologists at Screening/baseline and End Study of 
treatment for Part I, Run-in and Part II. During Part II (21-day cycle and 28-day cycle), 
evaluations will take place at screening and Day 1 of Cycle 2 and every 2 cycles from Cycle 3 
thereafter (±1 week) and at the End of Study Treatment visit to look for the appearance of 
squamous cell carcinoma of the skin 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. 
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-cutaneuous secondary malignancies for up to 6 months after the last 
LGX818 dose or until initiation of another antineoplastic therapy. 
 
7.2.2.5.7 Ophthalmologic evaluation 
 
Routine testing 
Full ophthalmic examination including slit lamp examination, best recorded visual acuity for 
distance testing, confrontational visual field testing, intraocular pressure (IOP) and dilated 
funduscopy with attention to retinal abnormalities, especially RPED and RVO, will be 
performed at the following timepoints and as clinically indicated: 
• Screening/baseline (Part I, Run-in and Part II) 
• Part I and Run-in: Cycle 2 Day 8 and for all the subsequent Cycles in Days 15* 
• Part II 21-day cycle: Cycle 1 Day 15, Cycle 2 Day 1, Day 15 and for all the subsequent 
Cycles in Days 1 


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• Part II 28-day cycle: Cycle 1 Day 15, Cycle 2 Day 1, Day 15 and for all the subsequent 
Cycles in Days 1* 
• End of Study Treatment (Part I, Run-in and Part II)* 
 
* Patients who have been on LGX818/MEK162 for ≥ 24 months (Table 7-1 and Table 7-2) or 
≥ 36 months (Table 7-5) in Part I and the Run-in phase without a retinal AE within the past 12 
months should be evaluated for visual acuity at each scheduled patient visit and at the End of 
Study Treatment visit. A full ophthalmic examination is required if clinically indicated and at 
the End of Study Treatment visit. 
 
Additional testing 
Patients with clinical suspicion of retinal abnormalities (i.e. photopsia, metamorphopsia, 
impairment of visual acuity, etc.) or RVO, must complete at least one of the following 
additional assessments: 
• For non-vascular abnormalities: optical coherence tomography of the macula (spectral 
domain is preferred) 
• For vascular abnormalities: fluorescein angiography of the central 30 degrees. 
Images of the ophthalmic exams, especially OCT and/or fluorescein angiography should be sent 
to the investigative site along with the results of the exam and be maintained in the patient’s 
source document file. These images may be requested to be sent to the sponsor or designee. 
 
Additional testing for BGJ398 arm only. As of Protocol Amendment 06, 
patients will no longer be enrolled in the LGX818/MEK162 + BGJ398 treatment 
arm. 
Patients enrolled in the BGJ398 triple combination arm will undergo an additional examination 
such as specular microscopy (that enables a magnified, direct view of the corneal endothelium), 
corneal pachymetry that will be performed at screening, Cycle 1 Days 15 and Cycle 2 Days 1, 
15 up to Cycle 4 and for all the subsequent cycles at Day 1, and at End of Study Treatment (in 
Part I and Run-in, only for patients that will be assigned to BGJ398 arm, and in Part II, for all 
patients in BGJ398 arm). 
 
7.2.2.5.8 Pregnancy and assessments of fertility 
All females of childbearing potential will have a serum pregnancy test ≤72 hrs before first dose 
of study drug at Screening/baseline and a urine or serum test performed during each study cycle 
on the first visit day and at the End of Study 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. 


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7.2.2.5.9 Thyroid function assessment only for LEE011 triple combination arm 
TSH (free T4, and free T3 should also be measured only if clinically indicated) will be assessed 
at the following timepoints: 
• Part II: Screening, Cycle 2 Day 1 and every 2 Cycles from Cycle 3 only if clinically 
indicated. 
• End of Study Treatment (in Part I and Run-in, only for patients that will be assigned to 
LEE011 arm, and in Part II, for all patients in LEE011 arm) 
 
7.2.2.6 
Cardiac assessments 
 
7.2.2.6.1 Electrocardiogram (ECG) 
At screening in Part I Run-in and Part II a standard 12 lead ECG (local assessment) will be 
performed to assess eligibility. For all patients, prior to the first administration of the 
LGX818/MEK162 combination and LGX818/MEK162 + third agent combination on Cycle 1 
Day 1 (baseline), 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 timepoints, at EOT and if clinically indicated, as indicated in 
Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5 and listed below. All ECGs 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. 
Interpretation of the screening/baseline tracing must be made by a qualified physician and 
documented on the ECG eCRF page. Each ECG tracing should be labeled with the study 
number, patient initials (where local regulations permit), subject number, date, and kept in the 
source documents at the study site. Clinically significant abnormalities present when the patient 
signed informed consent should be reported on the Medical History eCRF page. Clinically 
significant findings must be discussed with the Sponsor prior to enrolling the patient in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded on the Adverse Events eCRF page. 
12-lead ECGs are to be conducted in Part I, Run-in and Part II at Screening and at pre-dose and 
1.5 hrs (+/- 0.5 hr) post-dose, in addition for LEE011 triple combination arm at 4 hr (+/- 0.5 hr) 
post drug administration at the following timepoint s: 
 
In Part I and Run-in 
• Cycle 1 Days 1and15 
• Cycle 2 Days 8 and 21 
• Cycle 3 Day 15 and Day 15 every 2 cycles for all the subsequent cycles* 
End of Study Treatment 
In Part II 21-day cycle 
• Cycle 1 Days 1, 8 and 15 


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• Cycle 2 Days 1 and 15 
• Cycle 3 Day 1 and Day 1 of subsequent cycles every 2 cycles* 
• End of Study Treatment 
In Part II 28-day cycle 
• Cycle 1 Day 1, 8, 15, 21 
• Cycle 2 Days 1 and 15 
• Cycle 3 Day 1 and Day 1 of subsequent cycles every 2 cycles* 
• End of Study Treatment 
*Patients who have been on study treatment for ≥ 24 months (Cycle 25 Day 1) will have ECGs 
every 3 cycles. 
All ECGs (except the screening/baseline ECG) 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 Lab Manual. Significant findings must be recorded either as Medical 
History (if present before signing consent) or as Adverse Events (if newly occurring or 
worsening since signing consent). All patients treated in the study experiencing a grade 3 QTc 
interval prolongation, hypokalemia, hypomagnesaemia and oxygenation status should be 
monitored. 
 
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
The left ventricular heart function will be evaluated by echocardiography (ECHO) or Multiple 
gated acquisition (MUGA). 
For Part I and Run-in cardiac imaging will be performed at: 
• Screening/baseline 
• Cycle 2 Day 8 
• Cycle 5 Day 15 and every third cycles for the subsequent cycles 
• End of Study Treatment (only patients permanently discontinuing the study drug). 
For Part II (21-day cycles and 28-day cycles) cardiac imaging will be performed: 
• For patients coming from Part I: on Day 1 of Cycle 1, on Day 1 of Cycle 3 and every third 
cycle, and at the End of Study Treatment visit. 
• For patients coming from other trials: at Screening/baseline, on Day 1 of Cycle 2, on Day 
1 of Cycle 3 and every third cycle, and at the End of Study Treatment visit. 


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7.2.2.7 
LGX818/MEK162 + BKM120 combination: Patient self-reported Mood 
Questionnaires 
 
7.2.2.7.1 GAD-7 and PHQ-9 Questionnaires (for combination treatment arm with 
BKM120 – Part II) 
The Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) will be 
collected to screen patients for the study Part II and to aid in the identification and severity 
assessment of potential mood alterations. The PHQ-9 and GAD-7 are validated (Kroenke 2001, 
Spitzer 2006, Spitzer 1999), patient self-administered questionnaires developed for use in 
clinical practices. 
The PHQ-9 (Appendix 6) consists of 9 questions that assess anhedonia, depressed mood, sleep, 
energy, appetite, guilt and worthlessness, concentration, feeling slowed down or restlessness, 
and suicidal thoughts. For each of these questions, patients are asked to rate how much over the 
past 2 weeks they have been bothered by the symptom. Scoring of the PHQ-9 is based on a 
Likert-type scale from 0 to 3 (0 indicates not at all; 1, several days; 2, more than half the days; 
3, nearly every day). The sum of all nine questions is used to determine a total PHQ-9 score 
ranging from 0 to 27. 
The GAD-7 (Appendix 6) is a one-dimensional questionnaire consisting of 7 questions. 
Similarly to the PHQ-9, in the GAD-7, patients are asked to indicate how often, over the past 2 
weeks, they have been bothered by each of the seven core symptoms of generalized anxiety 
disorder as referenced in the DSM IV. Response options are ‘‘not at all,’’ ‘‘several days,’’ 
‘‘more than half the days,’’ and ‘‘nearly every day,’’ scored as 0, 1, 2, and 3, respectively. The 
sum of all seven questions calculates the total GAD-7 score. Therefore, GAD-7 scores range 
from 0 to 21. 
The patient must complete two different mood questionnaires, (PHQ-9 and GAD-7) before the 
first dose (at EOT visit in Part I for patients that will be assigned to Part II in BKM120 arm and 
at Screening in Part II for Group C patients only), at cycle 1 day 15, day 1 of each subsequent 
cycle in addition to the EOT visit in Part II (See Table 7-3). Additional assessments may be 
done according to the clinical judgment of the investigator. 
All questionnaires should be given by the site to the patient in the patient’s local language and 
reviewed for completeness and possible adverse events. 
On visits sites should instruct patients to complete the mood questionnaires after all other patient 
questionnaires and prior to administration of any study-related treatment or clinical assessments 
or procedures. 


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Table 7-9 
PHQ-9/GAD-7 patient self-reported questionnaire collection plan 
(BKM120 triple combination arm only) 
 
Patient 
Questionnaires 
Cycle (Part II) 
Day 
Time 
PHQ-9 
GAD-7 
Screening (Part II) 
Day -14 to Day -1 
Prior to any clinical 
assessments, study drug 
dosing, or diagnostic testing. 
Cycle 1 (Part II) 
Day 15 
Cycle 2 (Part II) 
Day 1 
Every subsequent cycle (Part 
II) 
Day 1 
End of treatment (Part II) 
Day of end of 
treatment 
assessment 
End of treatment (Part I or 
Run-in) 
Day -14 to Day -1 
(only for patients 
moving to Part II in 
BKM120 arm) 
 
Management of mood alterations 
Patient self-rating mood questionnaires PHQ-9 (depression) and GAD-7 (anxiety) will be used: 
• To support assessment of eligibility at Screening 
• To monitor for and report as adverse events newly occurring or worsening mood 
alterations during the study 
The severity classification table described in Table 7-10 for the PHQ-9 and GAD-7 will be used 
in this study to increase the sensitivity of identifying potential anxiety and/or depression 
disorders. During the study, questionnaire scores and corresponding severity classification can 
be used to aid the investigator in identifying new or worsening of events. However, grading 
must be based on the clinical interpretation of severity according to the NCI- CTCAE (v 4.03). 
 
Table 7-10 
Classification of severity based on depression and/or anxiety 
questionnaire scores 
PHQ-9 (depression) 
GAD-7 (anxiety) 
Score 
Severity 
Score 
Severity 
0-4 
None 
0-4 
None 
5-9 
Mild 
5-9 
Mild 
10-19 
Moderate 
10-14 
Moderate 
20-27 
Severe 
≥ 15 
Severe 
At Screening of Part II (Group C patients) or at End of Treatment (Part I or Run-in, only patients 
in Group A and B moving to Part II), a patient may be judged by the investigator or a psychiatrist 
to be ineligible based on medical mental health history as listed in the exclusion. Alternatively, 
patients who score ≥ 12 on the PHQ-9 or ≥ 15 on the GAD-7 mood scale, respectively, or select 
a positive response of ‘1, 2, or 3’ to question number 9 regarding suicidal thoughts or ideation 
will be excluded from the study. 


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During the treatment phase, patients who indicate a positive response by selecting ‘1, 2, or 3’ 
to question number 9 in the PHQ-9 must omit treatment with study drug BKM120 and must be 
referred for psychiatric consultation for optimal management regardless of the total 
questionnaire score or CTCAE grading to confirm if study drug should be interrupted or 
permanently discontinued. In this specific case, the psychiatric advice can overrule the patient 
PHQ-9 self-assessment. 
Patients with symptoms of a mood disorder (anxiety or depression) ≥ grade 1 must be monitored 
on a weekly basis as long as the patient is receiving treatment with study drug. Investigators 
must not encourage the patients to change responses reported in questionnaires. Guidelines on 
how to instruct the patient to complete the questionnaires as well as how to determine the scores 
will be provided with each instrument. Guidance on scoring questionnaires are also provided in 
Appendix 6. Dosing modification guidelines for BKM120 are provided in Table 6-7. For 
additional information on AE reporting, please refer to Section 8.1. 
 
7.2.3 
Pharmacokinetics 
Note: Enrollment to the BKM120- (Amendment 03), BGJ398-, INC280- (Amendment 06) 
and LEE011 (Amendment 07)-containing arms is closed. 
During Part I and Run-in of the study, PK blood samples of LGX818 and MEK162 will be 
collected and the sampling schedules are listed in Table 7-11. During Part II of the study, the 
pharmacokinetics of LGX818, MEK162 (including its primary active metabolite 
AR00426032), LEE011 (including its active metabolite LEQ803), BGJ398 (including its active 
metabolite BHS697 and CQM157), BKM120, and INC280 will be assessed and the sampling 
schedules are listed in Table 7-12 to Table 7-17, respectively. PK samples will be collected and 
evaluated on all patients enrolled in both parts of the study for the first 5 cycles or until they 
withdraw consent. 
In addition to the analysis mentioned above, metabolite profiling analyses on remaining plasma 
material may be performed using a non-validated, semi-quantitative or qualitative LC-MS/MS 
method, if deemed appropriate. 
Plasma samples remaining from the analysis may be retained by the Sponsor for additional 
investigations (i.e. long term stability, reproducibility). 
A detailed description of the planned pharmacokinetic analyses is given in Section 10.5.4. 
 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
 
7.2.3.1.1 Blood collection plan 
During Part I and Run-in, PK blood samples for LGX818 and MEK162 will be collected from 
all patients up to Cycle 5 according to the timepoints listed in Table 7-11. An end of study 
treatment sample will be collected if a patient withdraws from the study during Part I/Run-in 
and if a patient moves from Part I/Run-in treatment phase to Part II treatment phase. 
During Part II (28-days cycle), PK blood samples for LGX818, MEK162 (including its primary 
active metabolite AR00426032), LEE011 (including its active metabolite LEQ803), BGJ398 


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(including its active metabolite BHS697 and CQM157), will be collected from all patients 
according to the timepoints listed in Table 7-12, Table 7-15 and Table 7-17. An end of study 
treatment sample will be collected as soon as possible after a patient withdraws from the study 
during Part II. 
During Part II (21-days cycle), PK blood samples for LGX818, MEK162 (including its primary 
active metabolite AR00426032), INC280 and BKM120 will be collected from all patients up 
to Cycle 5 according to the timepoints listed in Table 7-13, Table 7-14 and Table 7-16. An end 
of study treatment sample will be collected as soon as possible after a patient withdraws from 
the study during Part II. 
For all patients from whom PK samples are collected, exact dates and clock times of drug 
administration (first dose of LGX818/MEK162 and the first dose of the third agent) 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 before dose administration 
should be recorded on PK sampling days for first cycles on Day 15 during both parts on the 
appropriate eCRF. 
PK collection windows (+/- min/hr timepoint for the PK timepoints) are: 
0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 
4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2h 
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 for each 
compound will be provided in the [Laboratory Manual] 


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Table 7-11 
Pharmacokinetic blood collection log for LGX818 and MEK162 during 
Part I/ Run-In (LGX818/MEK162 combination) 
 
Treatment 
Period or 
Day 
Scheduled Time 
Point 
Dose 
Reference 
PK 
Sample 
Dose 
Reference 
PK 
sample 
Sample 
Volume 
Cycle 
ID LGX818 
No 
ID MEK162 
No 
(ml) 
LGX818 
MEK162 
1 
1 
1.5 hr post dose 
100 
100 
700 
700 
3 
1 
15 
Pre-dose* 
101 
101 
701 
701 
3 
1 
15 
1.5 hr post dose 
101 
102 
701 
702 
3 
2 
8 
Pre-dose* 
102 
103 
702 
703 
3 
2 
21 
Pre-dose* 
103 
104 
703 
704 
3 
3 
15 
Pre-dose* 
104 
105 
704 
705 
3 
4 
15 
Pre-dose* 
105 
106 
705 
706 
3 
5** 
15 
Pre-dose* 
106 
107 
706 
707 
3 
EOT 
NA 
EOT 
107 
108 
707 
708 
3 
NA 
NA 
Unscheduled*** 
NA 
1001+ 
NA 
7001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Pre-dose PK samples will be collected up to Cycle 5 only. 
***Applies only to samples collected before effective date of Protocol Amendment 06. Unscheduled PK 
samples will be uniquely, sequentially numbered 


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Table 7-12 
Pharmacokinetic blood collection log for LGX818 and MEK162 during 
Part II (triple combination, 28 days cycle with LEE011 and BGJ398) 
 
Combination 
Treatment 
Day 
Scheduled Time 
Point 
Dose 
Reference 
PK 
Sample 
Dose 
Reference 
PK 
sample 
Sample 
Volume 
Cycle 
ID 
LGX818 
No 
LGX818 
ID 
MEK162 
No 
MEK162 
(ml) 
1 
1 
1.5 hr post dose 
200 
200 
800 
800 
3 
1 
1 
4 hr post dose$ 
200 
217 
800 
817 
3 
1 
8 
Pre-dose* 
201 
201 
801 
801 
3 
1 
15** 
Pre-dose* 
202 
202 
802 
802 
3 
1 
15 
0.5 hr post dose 
202 
203 
802 
803 
3 
1 
15 
1.5 hr post dose 
202 
204 
802 
804 
3 
1 
15 
2.5 hr post dose 
202 
205 
802 
805 
3 
1 
15 
4 hr post dose 
202 
206 
802 
806 
3 
1 
15 
6 hr post dose 
202 
207 
802 
807 
3 
1 
15 
8 hr post dose 
202 
208 
802 
808 
3 
1 
16 
24 hr post dose 
immediately prior 
to dosing on 
C1D16 
202/203 
209 
802/803 
809 
3 
1 
21 
Pre-dose* 
204 
210 
804 
810 
3 
2 
1 
Pre-dose* 
205 
211 
805 
811 
3 
2 
15 
Pre-dose* 
206 
212 
806 
812 
3 
3 
1 
Pre-dose* 
207 
213 
807 
813 
3 
4 
1 
Pre-dose* 
208 
214 
808 
814 
3 
5*** 
1 
Pre-dose* 
209 
215 
809 
815 
3 
EOT 
NA 
EOT 
210 
216 
810 
816 
3 
NA 
NA 
Unscheduled**** 
2001+ 
NA 
8001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy is collected 
*** Pre-dose PK samples will be collected up to Cycle 5 only 
****Applies only to samples collected before effective date of Protocol Amendment 06. Unscheduled 
PK samples will be uniquely, sequentially numbered. 
$ This sample will only be collected for the LGX818 and LEE011 combination 


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Table 7-13 
Pharmacokinetic blood collection log for LGX818 and MEK162 during 
Part II (triple combination, 21 days cycle with BKM120 and INC280) 
 
Combination 
Treatment 
Day 
Scheduled Time 
Point 
Dose 
Reference 
PK 
Sample 
Dose 
Reference 
PK 
sample 
Sample 
Volume 
Cycle 
ID 
LGX818 
No 
LGX818 
ID 
MEK162 
No 
MEK162 
(ml) 
1 
1 
1.5 hr post dose 
200 
200 
800 
800 
3 
1 
8 
Pre-dose* 
201 
201 
801 
801 
3 
1 
15** 
Pre-dose* 
202 
202 
802 
802 
3 
1 
15 
0.5 hr post dose 
202 
203 
802 
803 
3 
1 
15 
1.5 hr post dose 
202 
204 
802 
804 
3 
1 
15 
2.5 hr post dose 
202 
205 
802 
805 
3 
1 
15 
4 hr post dose 
202 
206 
802 
806 
3 
1 
15 
6 hr post dose 
202 
207 
802 
807 
3 
1 
15 
8 hr post dose 
202 
208 
802 
808 
3 
1 
16 
24 hr post dose 
immediately prior 
to dosing on 
C1D16 
202/203 
209 
802/803 
809 
3 
2 
1 
Pre-dose* 
204 
210 
804 
810 
3 
2 
15 
Pre-dose* 
205 
211 
805 
811 
3 
3 
1 
Pre-dose* 
206 
212 
806 
812 
3 
4 
1 
Pre-dose* 
207 
213 
807 
813 
3 
5*** 
1 
Pre-dose* 
208 
214 
808 
814 
3 
EOT 
NA 
EOT 
209 
215 
809 
815 
3 
NA 
NA 
Unscheduled**** 
2001+ 
NA 
8001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy is collected 
*** Pre-dose PK samples will be collected up to Cycle 5 only 
****Unscheduled PK samples will be uniquely, sequentially numbered. 


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Table 7-14 
Pharmacokinetic blood collection log for BKM120 during Part II (triple 
combination) (21 days cycle) 
 
Combination 
Treatment 
Cycle 
Day 
Scheduled 
Time Point 
Dose 
Reference ID 
BKM120 
PK Sample 
No BKM120 
Sample Volume 
(ml) 
1 
1 
1.5 hr post dose 
300 
300 
3 
1 
8 
Pre-dose* 
301 
301 
3 
1 
15** 
Pre-dose* 
302 
302 
3 
1 
15 
0.5 hr post dose 
302 
303 
3 
1 
15 
1.5 hr post dose 
302 
304 
3 
1 
15 
2.5 hr post dose 
302 
305 
3 
1 
15 
4 hr post dose 
302 
306 
3 
1 
15 
6 hr post dose 
302 
307 
3 
1 
15 
8 hr post dose 
302 
308 
3 
1 
16 
24 hr post dose 
immediately 
prior to dosing 
on C1D16 
302/303 
309 
3 
2 
1 
Pre-dose* 
304 
310 
3 
2 
15 
Pre-dose* 
305 
311 
3 
3 
1 
Pre-dose* 
306 
312 
3 
4 
1 
Pre-dose* 
307 
313 
3 
5*** 
1 
Pre-dose* 
308 
314 
3 
EOT 
NA 
309 
315 
3 
NA 
NA 
Unscheduled**** 
NA 
3001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy is collected. 
*** Pre-dose PK samples will be collected up to Cycle 5 only. 
****Unscheduled PK samples will be uniquely, sequentially numbered. 


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Table 7-15 
Pharmacokinetic blood collection log for BGJ398 during Part II (triple 
combination) (28 days cycle) 
 
Combination 
Treatment 
Cycle 
Day 
Scheduled 
Time Point 
Dose 
Reference ID 
BGJ938 
PK Sample 
No BGJ398 
Sample Volume 
(ml) 
1 
1 
1.5 hr post dose 
400 
400 
3 
1 
8 
Pre-dose* 
401 
401 
3 
1 
15** 
Pre-dose* 
402 
402 
3 
1 
15 
0.5 hr post dose 
402 
403 
3 
1 
15 
1.5 hr post dose 
402 
404 
3 
1 
15 
2.5 hr post dose 
402 
405 
3 
1 
15 
4 hr post dose 
402 
406 
3 
1 
15 
6 hr post dose 
402 
407 
3 
1 
15 
8 hr post dose 
402 
408 
3 
1 
16 
24 hr post dose 
immediately 
prior to dosing 
on C1D16 
402/403 
409 
3 
1 
21 
Pre-dose* 
404 
410 
3 
2 
1 
Pre-dose* 
405 
411 
3 
2 
15 
Pre-dose* 
406 
412 
3 
3 
1 
Pre-dose* 
407 
413 
3 
4 
1 
Pre-dose* 
408 
414 
3 
5*** 
1 
Pre-dose* 
409 
415 
3 
EOT 
NA 
EOT 
410 
416 
3 
NA 
NA 
Unscheduled**** 
NA 
4001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy and skin biopsy 
is collected. 
*** Pre-dose PK samples will be collected up to Cycle 5 only. 
****Unscheduled PK samples will be uniquely, sequentially numbered. 


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Table 7-16 
Pharmacokinetic blood collection log for INC280 during Part II (triple 
combination) (21 days cycle) 
 
Combination 
Treatment 
Cycle 
Day 
Scheduled 
Time Point 
Dose 
Reference ID 
INC280 
PK Sample 
No INC280 
Sample Volume 
(ml) 
1 
1 
1.5 hr post dose 
500 
500 
3 
1 
8 
Pre-dose* 
501 
501 
3 
1 
15** 
Pre-dose* 
502 
502 
3 
1 
15 
0.5 hr post dose 
502 
503 
3 
1 
15 
1.5 hr post dose 
502 
504 
3 
1 
15 
2.5 hr post dose 
502 
505 
3 
1 
15 
4 hr post dose 
502 
506 
3 
1 
15 
6 hr post dose 
502 
507 
3 
1 
15 
8 hr post dose 
502 
508 
3 
1 
16 
24 hr post dose 
immediately 
prior to dosing 
on C1D16 
502/503 
509 
3 
2 
1 
Pre-dose* 
504 
510 
3 
2 
15 
Pre-dose* 
505 
511 
3 
3 
1 
Pre-dose* 
506 
512 
3 
4 
1 
Pre-dose* 
507 
513 
3 
5*** 
1 
Pre-dose* 
508 
514 
3 
EOT 
NA 
EOT 
509 
515 
3 
NA 
NA 
Unscheduled**** 
NA 
5001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy is collected. 
*** Pre-dose PK samples will be collected up to Cycle 5 only. 
****Unscheduled PK samples will be uniquely, sequentially numbered. 


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Table 7-17 
Pharmacokinetic blood collection log for LEE011 during Part II (triple 
combination) (28 days cycle) 
 
Combination 
Treatment Cycle 
Day 
Scheduled 
Time Point 
Dose 
Reference ID 
LEE011 
PK Sample No 
LEE011 
Sample Volume 
(ml) 
1 
1 
1.5 hr post dose 
600 
600 
3 
1 
1 
4 hr post dose 
600 
617 
3 
1 
8 
Pre-dose* 
601 
601 
3 
1 
15** 
Pre-dose* 
602 
602 
3 
1 
15 
0.5 hr post dose 
602 
603 
3 
1 
15 
1.5 hr post dose 
602 
604 
3 
1 
15 
2.5 hr post dose 
602 
605 
3 
1 
15 
4 hr post dose 
602 
606 
3 
1 
15 
6 hr post dose 
602 
607 
3 
1 
15 
8 hr post dose 
602 
608 
3 
1 
16 
24 hr post dose 
immediately 
prior to dosing 
on C1D16 
602/603 
609 
3 
1 
21 
Pre-dose* 
604 
610 
3 
2 
1 
Pre-dose* 
605 
611 
3 
2 
15 
Pre-dose* 
606 
612 
3 
3 
1 
Pre-dose* 
607 
613 
3 
4 
1 
Pre-dose* 
608 
614 
3 
5*** 
1 
Pre-dose* 
609 
615 
3 
EOT 
NA 
EOT 
610 
616 
3 
NA 
NA 
Unscheduled**** 
NA 
6001+ 
3 
Total 
*Collect PK sample immediately prior to the start of oral study drug(s) administration. 
** Schedule PK collection together with collection fresh tumor biopsy (if applicable). If it is not possible 
to collect the tumor biopsy on D15 of first triple-agent combination cycle, then an additional 
unscheduled pre-dose PK sample should be collected on the day fresh tumor biopsy is collected. 
*** Pre-dose PK samples will be collected up to Cycle 5 only. 
****Applies only to samples collected before effective date of Protocol Amendment 06. Unscheduled 
PK samples will be uniquely, sequentially numbered. 
 
7.2.3.2 
Analytical method 
 
LGX818 
Plasma LGX818 concentrations will be measured at the Sponsor or a designated CRO using a 
validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay. The lower 
limit of quantitation (LLOQ) is currently 1.0 ng/mL. 


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MEK162 
Plasma concentrations of MEK162 and its metabolite, AR00426032, will be measured at the 
Sponsor or a designated CRO using a validated LC/MS/MS assay. The lower limit of 
quantitation (LLOQ) is currently 1.0 ng/mL. 
 
INC280 
Plasma Concentrations of INC280 will be measured in plasma at the Sponsor or a designated 
CRO using a valid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The 
lower limit of quantitation (LLOQ) is currently 1.0 ng/mL. 
 
BGJ398 
Plasma concentrations for BGJ398 and its known pharmacologically active metabolites (i.e. 
BHS697 and CQM157) will be assayed at the Sponsor or a designated CRO using a validated 
liquid chromatography-tandem mass spectrometry method (LC-MS/MS). The lower limit of 
quantitation (LLOQ) is currently 1.0 ng/mL. 
 
BKM120 
BKM120 will be analyzed by liquid chromatography-tandem mass spectrometry, LC/MS/MS, 
for parent drug in plasma at the Sponsor or a designated CRO. The limit of quantitation is 
currently 0.25 ng/mL. 
 
LEE011 
The plasma samples from all patients will be assayed for concentrations of LEE011, LEQ803 
and if needed any other clinically significant identified metabolites using a validated liquid 
chromatography-tandem mass spectrometry assay (LC/MS/MS). The lower limit of 
quantitation (LLOQ) is currently 5.0 ng/mL. 
 
7.2.4 
Biomarkers 
As of Amendment 07, patients in Part I who have been on the combination treatment with 
LGX818/MEK162 for ≥ 36 months will no longer be required to provide a new tumor biopsy 
at disease progression. 
Tumor samples will be collected pre-LGX818/MEK162 combination and at progression with 
both LGX818/MEK162 combination and triple combinations in order to fully characterize the 
tumor through a comprehensive genomic analysis (using technologies such as next generation 
sequencing). This will help to better understand the genomic profile of the patients' tumors and 
will allow assigning the drug to be given in combination with LGX818/MEK162 in Part II of 
the study. 
In particular, biopsies will be performed for each patient groups as follows: 
Patients in Group A will provide either an archival or a newly obtained tumor sample before 
entering Part I and receive LGX818/MEK162 combination therapy until disease progression. 


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At that time, patients will provide a new tumor biopsy sample to allow for assessment of genetic 
alterations as outlined in Table 4-1 and be assigned to a triple combination arm in Part II. 
Patients in Group B will provide a biopsy sample at screening obtained either at progression 
from last treatment (i.e. BRAFi and/or MEKi), or, if they have not progressed yet, they will 
provide the most recent pre-BRAFi and/or MEKi biopsy sample. If not available, a new tumor 
sample must be obtained prior to entering the Run-in phase with LGX818/MEK162 
combination. During Run-in, the first scan will be performed after 3 weeks treatment to assess 
patients’ response. Patients achieving at least a PR from this treatment at the time of the first 
CT/MRI scan during the Run-in phase will continue on LGX818/MEK162 combination until 
progression. At this time, collection of a newly obtained tumor sample will be mandatory and 
patients will be assigned to a triple combination arm in Part II. Patients not deriving clinical 
benefit from LGX818/MEK162 combination therapy will be assigned to a treatment arm in Part 
II on the basis of the analysis of their most recent tumor biopsy. 
Patients who did not progress on their prior BRAF and/or MEK inhibitor regimen (including 
LGX818 and/or MEK162 inhibitor), may enter the Run-in (Group B) and continue 
LGX818/MEK162 combination until evidence of disease progression at which point a tumor 
biopsy sample will be taken and analyzed to guide assignment to a triple combination arm in 
Part II. 


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Figure 7-1 
Biopsy flow chart for patients in Group B 
 
 
Patients in Group C should provide an archival biopsy sample collected pre-LGX818/MEK162 
combination, or, the related DNA sequencing report produced by a Sponsor-designated Central 
Laboratory. Moreover, Group C patients entering this trial from other LGX818/MEK162 
combination studies (e.g. [COLUMBUS], [CMEK162X2110] [CLGX818X2102] or IITs) will 
either provide a progression biopsy sample for genetic assessment, or, the related DNA 
sequencing report produced by a Sponsor-designated Central Laboratory. The molecular 
alteration identified will determine the assignment to one of the triple combination treatments 
in Part II (see Table 4-1). If a progression biopsy is not available, patients will be requested to 
provide a tumor biopsy at screening/baseline of Part II. 
The newly obtained paired tumor samples collected before and during study treatments (Part 1 
and Part II) will be used to investigate the pharmacodynamic effects of the triple drug 
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For all biomarker samples, the collection information must be captured on the Biomarker 
Assessment eCRF page(s) and Central Lab Requisition form(s). 
CCI 


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Table 7-18 
Biomarker sample collection plan and biomarker assessments 
 
Sample Type 
CCI 
Visit 
Time 
point 
Markers to be assessed 
Tumor samples 
Archival tumor 
sample & 
Corresponding 
Pathology 
Report 
CCI 
CCI 
Requested from all patients if 
available 
Collected at molecular pre- 
screening (if needed) or at the 
screening/baseline visit 
otherwise 
Anytime 
Part I, 
Run-in, 
Part II3 
Archival and/or Newly 
Obtained Tumor: 
Molecular status 
(mutation/ amplification/ 
expression) of markers 
related to RAF/MEK/ERK 
pathway, PI3K/AKT 
Newly 
obtained 
tumor sample 
Baseline - required 
Collected at molecular pre- 
screening (if needed) or at the 
screening/baseline visit 
otherwise 
Prior to 
first 
dose 
Part I 
and 
Run-in 
Part II4 
pathway or cancer CCI 
CCI 
At time of progression under 
LGX818/MEK162 combination - 
required1 
At time of progression under 
LGX818/MEK162 + third agent 
combination 
To be collected preferably from 
a growing or new lesion 
Pre- 
dose 
Part I 
And 
Part II 
CCI 
CCI 
CCI 
3. Archival tumor sample is collected in Part II only from patients in Group C. 
4. Newly obtained tumor biopsy is collected at molecular pre-screening or at the screening/baseline 
visit from patients in Group C, who cannot provide the progression biopsy from the previous study. 


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8 
Safety monitoring and reporting 
As of Amendment 07, for patients who have been on LGX818 + MEK162 for ≥ 36 months, 
only Grade 3 or 4 AEs and all SAEs will be recorded on the AE eCRF. Any AEs that meet 
these criteria until 30 days after the last dose of study drug must be recorded. 
All SAEs are to be reported to the Sponsor or designee using the SAE form. 
CCI 


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8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
For patients whose BRAF status is unknown and who sign the molecular pre-screening ICF, 
AEs which occur after signature of this consent will only be captured if they meet the definition 
of serious as outlined in Section 8.2 and are reported to be causally related with study 
procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is signed, all 
AEs per the descriptions below will be captured in the Adverse Event CRF. 
Patients whose BRAF status is known will sign the main study ICF. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g. hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Except for screening failures, adverse events that begin or worsen after informed consent should 
be recorded in the Adverse Events CRF. Conditions that were already present at the time of 
informed consent should be recorded in the Relevant Medical History/Current Medical 
Conditions CRF page of the patient’s CRF. Adverse event monitoring should be continued for 
at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03, unless otherwise noted. 
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 through a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(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: 
• The severity grade (CTCAE Grade 1-4) 
• Its duration (Start and end dates) or Ongoing after the 30 day Safety Follow-up. 
• Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 


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• Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
• Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
• Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
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 CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 


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8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
For patients with unknown BRAF status and who sign the molecular pre-screening ICF, SAE 
collection will start upon signing the molecular pre-screening ICF. SAEs will only be reported 
if the event is suspected to be causally related to a study procedure as assessed by the 
investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure. 
For patients with known BRAF status who sign the main study ICF, SAE collection starts at 
time of main study informed consent whether the patient is a screen failure or not. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to the Sponsor within 24 hours of learning of its 
occurrence. 
Any SAEs experienced after this 30 days period (or 5 half-lives, whichever is longer) should 
only be reported to the Sponsor if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the follow-up 


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information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the Sponsor or 
designee. 
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder provided to 
each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Sponsor study treatment, the Sponsor or designee 
may urgently require further information from the investigator for Health Authority reporting. 
The Sponsor or designee may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to the Sponsor or designee within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the Sponsor or designee. Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatments, and 


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any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
8.5 
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. 
 
8.6 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be in place for this trial. 
Instead, the Sponsor or designee will convene joint teleconferences with the participating 
Investigators of this study. Updated safety data on ongoing patients, including data in later 
cycles, will be discussed. 
Inter-patient as well as intra- patient 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 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/RP2D 
of the combinations, escalate the dose any further, or whether to de-escalate and/or expand 
recruitment. The Sponsor or designee will prepare minutes from these meetings and circulate 
them to all concerned. 
 
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 


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


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The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK and biomarker (blood and tumor tissue, except the pre-screening BRAF status assessment) 
samples drawn during the course of the study will be collected by investigational sites and 
analyzed by a Sponsor-delegated Central Laboratory. 
All ECGs (except the screening/baseline ECG performed locally) collected during the study 
will be independently reviewed by a central laboratory. 
 
9.4 
Database management and quality control 
For studies using eCRFs, 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 and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
PK and biomarkers samples and ECG data (except screening baseline) will be processed 
centrally and the results will be sent electronically to the Sponsor (or a designated CRO). 
For EDC studies, 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 
The data will be analyzed by the Sponsor and/or designated CRO. 
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. The data will be summarized with 
respect to demographic and baseline characteristics, efficacy observations and measurements, 
safety observations and measurements, and all relevant PK and PD measurements 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, minimum, and maximum will be presented. 
In all cases, data will be analyzed and/or presented separately for Part I and Part II. In Part II 
all outputs will be provided by triple combination arm unless otherwise stated. 
Unless otherwise specified, baseline measurements/observations will be identified for each 
study part. The baseline for a study part is defined as the last available/valid assessment prior 
to the start of the study treatment for that study part. Consequently, the day of the 1st dose of 
the study treatment for a study part will be used as the reference date for all derivation of 
durations. 


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The study data will be analyzed and reported following end of study (see Section 4.3 for 
definition). 
 
10.1 
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. 
The following analysis sets will be used. 
 
10.1.1 
Full Analysis Set 
For Part I, the Full Analysis Set (FAS) consists of all patients who received at least one dose 
(partial or full) of LGX818 or MEK162. 
For Part II, the FAS consists of all patients who have received at least one dose of LGX818 or 
MEK162 or the assigned third agent following the assignment of the triple combination 
treatment. 
Note that patients who were screened and/or are eligible but never started treatment for a study 
part will not be included in the FAS for that study part. This is considered as an acceptable 
deviation from the ITT principle in the context of a non-randomized exploratory study. 
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 treatment 
they have been assigned to. 
 
10.1.2 
Safety Set 
The safety set for a study part consists of all patients from the FAS who had at least one valid 
post-baseline safety assessment. Please note that the statement that a patient had no adverse 
event on the Adverse Events eCRF constitutes a valid safety assessment. 
For each study part, patients will be classified according to treatment received, where treatment 
received is defined as the following: 
1. The treatment assigned if it was received at least once in the first cycle, or 
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
The safety set will be the primary analysis set for all safety related endpoints except in 
summaries of DLTs and for the determination of the dose-DLT relationship where the dose- 
determining set will be used (Section 10.1.4). 
 
10.1.3 
Per-Protocol Set 
The per-protocol set (PPS) consists of all Part II patients in the FAS who are compliant with the 
protocol in the following ways: 
1. Diagnosis corresponds to that defined in inclusion criteria #5: histologically confirmed 
diagnosis of locally advanced or metastatic melanoma. 


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2. Stage of disease corresponds to that defined in inclusion criteria #5: stage IIIC to IV per 
American Joint Committee on Cancer [AJCC]. 
3. Prior treatment corresponds to that defined in exclusion criteria #13: Progressive disease 
following prior treatment with LGX818/MEK162 combination. 
4. The patient was evaluated at least once for the primary efficacy variable or discontinued 
due to adverse event, unacceptable toxicity, Investigator’s decision, patient’s refusal, 
disease progression, or died prior to the first evaluation of the primary efficacy variable. 
5. Patients will be evaluable for efficacy if they have at least one response assessed 
differently from ‘unknown’ or ‘not assessed’ under RECIST v1.1. 
The Per-protocol set will be used in Part II in order to define the patients used in the sensitivity 
analysis of the primary endpoint. 
 
10.1.4 
Dose-determining analysis set 
The dose-determining analysis set (DDS) consists of all patients from the Safety Set for Part II 
who have met the requirements for minimum safety evaluation and minimum exposure or 
experienced DLT during the first cycle of the assigned triple combination treatment. 
To complete the minimum safety evaluations a patient must be observed for at least 1 cycle (21 
days following the first dose of the combination treatment with BKM120, or INC280; 28 days 
for the combination with LEE011 or BGJ398) and considered to have sufficient safety data by 
both the Sponsor and Investigators to conclude that a DLT did not occur during this 1st cycle. 
Patients meet the minimum exposure requirements if they have received at least 16 out of the 
21 planned daily doses of the defined triple combinations. 
 
10.1.5 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable pharmacokinetic (PK) data. The PAS will be used for summaries 
of PK data (tables and figures) as well as for listings of derived parameters. 
Note: Patients will be removed from the estimation of certain PK parameters on an individual 
basis, depending on, for example, the number of available blood samples and whether the PK 
parameter can be reliably estimated based on the available blood samples. These patients will 
be identified at the time of the analyses along with their reason for removal. 
 
10.1.6 
Other analysis sets 
Not applicable 
 
10.1.6.1 Efficacy/evaluable set 
Not applicable 


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10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including age, gender, height, weight, medical condition, 
disease characteristics, etc. will be summarized descriptively for all patients in the FAS. The 
summaries will be based on the assessments from the screening. 
 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
The actual dose and duration in days of LGX818, MEK162 (Part I and II) and the third assigned 
agent (Part II) 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) of each drug, will be listed and 
summarized by means of descriptive statistics in the clinical study report. The summary data 
will be presented for each treatment cycle individually, as well as for all study days as a single 
category. 
 
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 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 
The primary objective of this study is to assess during Part II of the study the anti-tumor activity 
of LGX818 and MEK162 in combination with third targeted agents after progression on 
LGX818/MEK162 combination. Specific focus is placed on the LEE011 arm where it is 
expected that 30% of patients will be treated (see Section 10.4.2 and Section 10.8) 
 
10.4.1 
Variable 
Best Overall Response (BOR) assessed per RECIST v1.1 during Part II will be used to evaluate 
the tumor response in terms of Overall Response Rate (ORR) for combinations of LGX818, 
MEK162 and the third agents. This will be based on investigator-assessed tumor evaluations 
per RECIST v1.1. 


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10.4.2 
Statistical hypothesis, model, and method of analysis 
BOR for all patients in the FAS (Part II) will be listed and summarized for each treatment 
combination. All patients from a combination arm will be pooled together irrespective of their 
initial planned combination treatment. 
The ORR will be provided with a corresponding 95% confidence interval. Hence the summaries 
obtained will indicate whether progression can be reversed upon addition of a third targeted 
agent for which the initial dose may be titrated up when the triple combination treatment is 
tolerated. Consequently given that some patients will be treated below the MTD/RP2D prior to 
intra-patient dose-escalation, it is expected that the observed ORR will provide a conservative 
estimate of the true ORR for the final selected MTD/RP2D for each triple combination. 
Additional summaries by planned treatment may be generated if appropriate and if sample size 
allows. 
In addition, since the LGX818+MEK162+LEE011 is expected to be the most used triple 
combination on study, and should be received by about 40 patients, a Bayesian inference will 
be performed to estimate the true ORR of this combination. 
A minimally informative unimodal Beta prior distribution of the true ORR is derived as follows. 
A priori it is assumed that the true mean of the ORR equals 20%. A true ORR of 20% is the 
midpoint between limited and clinical relevant 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 clinically relevant efficacy. The parameter of the minimally 
informative Beta prior distribution of the ORR are then derived as a = 1/4 and b = 1. 
At completion of the study, this prior distribution will be updated with all of the data available 
in the LGX818+MEK162+LEE011 combination arm. Once updated, the probabilities that the 
true ORR lies in the following categories will be reported: 
• [0, 10%) unacceptable efficacy 
• [10%, 20%) limited efficacy 
• [20%, 30%) clinically relevant efficacy 
• [30%, 100%] highly clinically significant efficacy 
If the observed ORR is equal to or greater than 20%, then this will be considered as preliminary 
evidence of clinically relevant efficacy of the combination. If the observed ORR is less than 
20% (i.e. ≤ 7 CR or PR out of 40), then insufficient efficacy will be concluded. 
Note that for a sample size of n = 40 (see Section 10.8), if the observed ORR is greater than or 
equal to 20% (i.e. ≥ 8 CR or PR), then the true ORR has a posterior risk of less than 5% of being 
in the insufficient efficacy category. 
If the number of patients recruited to any other triple-agent combination within Part 2 exceeds 
30 patients this analysis will be performed for that combination in the same way as defined for 
the LGX818+MEK162+LEE011 combination. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
As of the date of data-cutoff for the primary CSR for the purposes of reporting: 


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• Patients continuing to receive treatment will have time-to-event data (e.g. progression-free 
survival) censored at the date of last radiological disease assessment prior to the cut-off 
date. 
• Continuing events (e.g. adverse events, concomitant therapies, 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 paragraph. 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study treatment, duration of exposure to study treatment 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 
The efficacy analysis for the LGX818/MEK162+LEE011 combination arm will also be 
performed using the PPS. Summaries in this arm by molecular alteration (see Table 4-1) will 
also be produced. In addition summaries for all patients enrolled in Part II pooled together will 
 
10.5 
Secondary objectives 
Please refer to Section 3 for the secondary objectives. 
 
10.5.1 
Key secondary efficacy objective(s) 
Not applicable 
 
10.5.2 
Secondary efficacy objectives 
As per the analysis of the primary efficacy endpoint, all patients from the same triple 
combination arm will be pooled together irrespective of their initial planned combination 
treatment dose level. 
BOR will be listed and summarized for Part I, and then by combination arm for Part II. Exact 
95% confidence intervals for ORR and DCR will also be derived 
For each study part, Kaplan-Meier plots will be used to depict the progression-free survival for 
LGX818/MEK162 and their combination with third targeted agent (by combination arm). The 
corresponding median PFS as well as PFS rates at selected timepoints (e.g. 3 and 6 months) 
will be provided along with a 95% confidence interval when appropriate. OS, TTR and DOR 
will be summarized in a similar way by the triple combination treatment arm if appropriate. 
be provided. CCI 
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10.5.3 
Safety objectives 
Safety and tolerability of LGX818/MEK162 and their combination with third target agents will 
be assessed for incidence and severity of adverse drug reactions and serious adverse drug 
reactions (as assessed by CTCAE Version 4.03), changes in hematology and chemistry values, 
physical examinations, vital signs, electrocardiogram, cardiac monitoring, ophthalmological 
and dermatological examinations. 
 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
study part and by initial received treatment group. The DDS will be used for all analyses of 
DLTs. The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group and study arm. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and combination arm. 
 
Bayesian Logistic Regression Model 
An adaptive BLRM guided by the EWOC principle will guide the dose-escalation of each of 
the study drugs (BKM120, BGJ398, INC280, or LEE011) combined with LGX818 and 
MEK162 to its respective 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 and by 
(Rogatko et al 2007) and is one of the key elements of the FDA’s Critical Path Initiative. 
The definition of the BLRM, the prior distributions for the model parameters (based on 
currently available information about the targeted agents) and the associated prior distributions 
of DLT rates are provided in the appendix Section 14.1. 
Note that any additional information on the dose-DLT relationship generated by on-going 
studies used to define the prior distribution will be incorporated before the first dose escalation 
is made within this study in order to reflect all relevant information at that time. 


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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. 
For each triple combination, a 10-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 on a q.d. schedule at 
dose d1 mg, and π2(d2) the probability of a DLT if MEK162 is given as a single agent on a 
b.i.d. schedule at dose d2 mg, and π3(d3) be the probability of a DLT if the third assigned agent 
is given as a single agent on its schedule at dose d3 mg (as described in Section 6.1.1). 
The marginal dose-response relationships are then modeled as: 
LGX818: logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
MEK162:  logit(π2(d2)) = log(α2) + β2log(d2/d2*) 
3rd agent:   logit(π3(d3)) = log(α3) + β3log(d3/d3*) 
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d.* is the reference dose of each compound, and α1, 
α2, α3, β1, β2, β3 > 0. 
The dose-response relationship of the dual combinations is subsequently modeled as: 
LGX818+MEK162: 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))), 
LGX818+3rd agent: 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))), 
MEK162+3rd agent: Odds(π23(d2,d3))) = π23(d2,d3)/(2- π23(d2,d3)) 
= exp(η23(d2/d2*)(d3/d3*))(π2(d2)+ π3(d3) – π2(d2)π3(d3))/((1- π2(d2))(1- π3(d3))), 
where -∞ < η12, η13, η23 < ∞ is a scalar. 
The dose-response relationship of the triple combinations is then modeled as: 
LGX818+MEK162+3rd agent: 
Odds(π123(d1,d2,d3))) = π123(d1,d2,d3)/(1- π123(d1,d2,d3)) 
= exp(η123(d1/d1*)(d2/d2*)(d3/d3*) + η12(d1/d1*)(d2/d2*) + η13 (d1/d1*)(d3/d3*) + 
η23(d2/d2*)(d3/d3*))(π1(d1)+ π2(d2) + π3(d3) – π1(d1)π2(d2) – π1(d1)π3(d3) – π2(d2)π3(d3) 
+ π1(d1)π2(d2)π3(d3))/((1- π1(d1))(1- π2(d2)) (1- π3(d3))), 
where -∞ < η123 < ∞ is a scalar. 
For further details on the statistical model, prior specification and operating characteristics, 
please refer to Section 14.1 Appendix 1. 
 
Dose recommendation 
Dose recommendation for the third target agent is conditional to the dose of LGX818 and 
MEK162 which may differ between patients entering Part II. This recommendation will be 


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based on posterior summaries of the DLT rate 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 recommended dose 
combination 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. The dose escalation for the triple combination is limited to 100%. A clinical 
synthesis of the available toxicity information (including AEs that are not DLTs), PK, PD, and 
efficacy information as well as the recommendations from the Bayesian model will be used to 
determine the dose combination for the next patients at a dose-escalation teleconference (see 
Section 6.2.3.2). The Investigators and Sponsor trial personnel will be involved in the decision 
making. 
The final recommended MTD/RP2D for each combination will be based on considerations of 
the recommendation from the BLRM, and on an overall assessment of safety taking into 
consideration tolerability data from subsequent cycles at all different dose combinations tested. 
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. DLTs will be listed and their incidence summarized by primary system organ 
class, worst grade based on the CTCAE version 4.03, type of AE, and by treatment. The DDS 
will be used for these summaries. 
For further details of the BLRM model and results under a variety of scenarios, please refer to 
Section 14.1.1 and Section 14.1.2 of Appendix 1. 
 
10.5.3.3 Laboratory abnormalities 
All laboratory values will be converted into SI units, as appropriate, 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 treatment group. The frequency of notable lab 
abnormalities (i.e. newly occurring CTCAE grade 3 or 4 laboratory toxicities), will be reported 
by parameter, cycle and treatment group. Similarly, the frequency of all laboratory 
abnormalities will be tabulated by parameter, worst CTCAE v4.03 grade experienced, and 
treatment group. Laboratory data will be summarized by presenting grade shift tables for those 
parameters that can be classified using CTCAE version 4.03. All remaining data will be 
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10.5.3.4 Other safety data 
Data from other tests (e.g., electrocardiogram, ophthalmological assessments and vital signs) 
will be listed and summarized by treatment group, notable values will be flagged, and any other 
information collected will be listed and summarized as appropriate. Any statistical tests 
performed to explore the data will be used only to highlight any interesting comparisons that 
may warrant further consideration. 
 
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 
Definitions of notably abnormal results have to part of the CDP, MAP, CSP and RAP. 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline timepoint s and 
change from baseline to this/these post-baseline timepoint s. 
 
10.5.3.5 Supportive analyses for secondary objectives 
Any supportive analyses undertaken for estimation of the MTD/RP2D will be defined within 
the study RAP. 
 
10.5.3.6 Tolerability 
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions. Reasons for dose interruption and dose reductions will be 
listed and summarized. 
 
10.5.4 
Pharmacokinetics 
All patients who have at least one blood sample providing evaluable PK data for study treatment 
will be included in the PK data analysis. The PAS will be used. Missing/not collected values 
will be denoted as such in summary. 
 
Pharmacokinetic variables and data analysis 
Pharmacokinetic parameters for LGX818, MEK162 (including its primary active metabolite 
AR00426032), LEE011, BGJ398 (including its active metabolite BHS697 and CQM157), 
BKM120, and INC280 will be determined for all PK-evaluable patients using either non- 
compartmental method(s), using Phoenix WinNonlin® (Pharsight, Mountain View, CA), and/or 
compartmental method(s). The PK parameters listed in Table 10-1, but not limited to, will be 
estimated and reported, as appropriate. 


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The plasma concentration/time data will be summarized by treatment group and graphically 
presented. Descriptive graphical plots of individual and median plasma concentration (per 
treatment) along with its time course will be generated. 
 
Table 10-1    Non compartmental pharmacokinetic parameters 
 
Term 
Definition 
AUCtau, ss 
Area under the concentration-time curve from time zero to time tau at steady-state 
[mass x time x volume-1] 
Cmax 
Maximum observed plasma concentration after drug administration (ng/mL) 
Cmax, ss 
The maximum (peak) observed plasma concentration after drug administration at 
steady state [mass x volume-1] 
Tmax 
Time to reach maximum (peak) plasma drug concentration (h) 
Tmax, ss 
The time to reach Cmax at steady state [time] 
Ctrough 
Measured concentration at the end of a dosing interval at steady-state ( taken 
directly before next administration) (ng/mL) 
Clast, ss 
Last measurable plasma concentration at steady state [mass x volume-1] 
T1/2, ss 
The elimination half-life associated with the terminal slope (λz) 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 
The apparent volume of distribution at the terminal elimination phase at steady state 
(volume) 
Note: it is assumed that C1D15 is at steady state. 
 
10.5.4.1 Data handling principles 
All concentrations of LGX818, MEK162, AR00426032, LEE011, BGJ398, BHS697, 
CQM157, BKM120 and INC280 below their respective LLOQs (lower limits of quantification) 
or missing data will be labeled as such in the concentration data listings. Concentrations below 
the LLOQ will be treated as zero in summary statistics and for the calculation of PK parameters. 
Patients may be removed from the estimation of certain PK parameters on an individual basis 
when the PK parameters cannot be reliably estimated based on the available blood samples. 
These patients will be identified prior to the time of the data analysis. Only PK blood sample 
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 hours 
of dosing will be excluded from the analysis. 
 
10.5.5 
Biomarkers 
 
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Part I 
Molecular 
status 
(mutation/amplification/expression) 
of 
markers 
relevant 
to 
the 
RAF/MEK/ERK and PI3K/AKT pathways 
at 
screening/baseline and at progression with LGX818/MEK162 combination will be listed and 
summarized. 
 
 
10.7 
Interim analysis 
No formal interim analyses are planned. However, the dose-escalations planned for Part II 
foresee that decisions based on the current data are taken before the end of the study. More 
precisely, in each combination arm, the next combination of LGX818, MEK162 and the third 
targeted agent has to be chosen depending on the observed data. Details of this procedure and 
the process for communication with Investigators are provided in Section 6.2. 
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10.8 
Sample size calculation 
Part II LGX818/MEK162+LEE011 arm 
About 140 patients are expected to enroll in Part II of the study to address the primary objective 
of the study. From these 140 patients, it is anticipated that about 30% of patients progressing 
on LGX818+MEK162 would be eligible to the LGX818+MEK162+LEE011 arm. With 140 
patients recruited it would give 89% probability that the number of patients assigned to the LEE 
arm will be at least 36. 
Based on the ORR (per RECIST 1.1) intervals described in Section 10.4.2, it was assessed how 
likely it is to wrongly declare activity as defined by observing at least “clinical relevant 
efficacy” (i.e. seeing at least 8 responses out of 40 patients) given the true ORR = 10%, and 
how likely it is to correctly declare activity given the true ORR = 30% when 40 patients are 
evaluated. 
• If the true ORR = 10%, the probability to wrongly declare activity is 4.2%. 
• If the true ORR = 30%, the probability to correctly declare activity is 94.5%. 
Given a sample size of 40, if 8 responses are seen, the observed ORR is 20% with a 90% credible 
interval of (10.8%, 30.9%). This will be considered as preliminary evidence of antitumor 
activity of the treatment at the MTD/RDE within this arm. 
 
Part II other arms 
Note: Enrollment to the BKM120- (Amendment 03), BGJ398-, INC280- (Amendment 06), 
and LEE011 (Amendment 07)-containing arms is closed. 
Dose escalation in Part II will proceed with groups of at least 3 evaluable patients receiving 
triple combination therapy at the current dose levels according to Table 6-2 and Table 6-3. At 
least six patients must be included at the MTD/RP2D level for each triple combination. 
Additional patients may be enrolled at any dose level below the current dose if this dose has not 
been tested before and if there are already 3 evaluable patients enrolled. Any dose level below 
the estimated MTD/RP2D may be expanded for further elaboration of safety and 
pharmacokinetic parameters as required. Approximately 100 patients are expected to be treated 
in total in the BKM120, BGJ398 and INC280 triple combination arms. The number of patients 
treated within each triple combination will depend upon the prevalence of the corresponding 
molecular alterations. 
 
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. 


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11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the Sponsor or designee monitors, 
auditors, 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 CRFs. 
The Sponsor or designee will provide to investigators, in a separate document, a proposed 
informed consent form (ICF) that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to this ICF suggested by the 
investigator must be agreed to by the Sponsor before submission to the IRB/IEC/REB, and a 
copy of the approved version must be provided to the Sponsor or designee’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. 
 
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 4.3 and Section 4.4. 


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


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11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to the Sponsor. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by the Sponsor or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact 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. 
 
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 at the study site 
should be informed according to local regulations (e.g. UK requires the notification of urgent 
safety measures within 3 days) but not later than 10 working days. 


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13 
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14 
Appendices 
14.1 
Appendix 1 - Operating characteristics of the Bayesian logistic 
regression mode and hypothetical dose escalation scenarios 
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used to guide the dose escalation of each of the 
study drugs (BGJ398, BKM120, INC280, or LEE011) combined with LGX818 and MEK162 
to their respective MTD(s)/RP2D(s) during Part II of the study. The use of Bayesian response 
adaptive models for Phase I studies has been advocated by the EMEA guideline on small 
populations (2006) and by Rogatko (2007) and is one of the key elements of the FDA’s Critical 
Path Initiative. 
This section provides details of the statistical model, the derivation of prior distributions for the 
model parameters, and the properties of the adaptive design (dosing recommendations for 
hypothetical data scenarios). 
 
14.1.1 
Statistical model and prior distributions 
This section is organized in the following way: 
• A short motivation is provided. 
• The single-agent prior distribution for each of the compound is derived. 
• The prior distribution for each of the interaction parameters (eta) is derived. 
• Numerical values and summary statistics at different dose levels are shown. 
Motivation 
For each combination, a 10-parameter BLRM (refer to the protocol Section 10.5.3.2 for detail) 
will be used to model the dose-limiting toxicity rate in the first cycle to assess the dose-toxicity 
relationship of BGJ398, BKM120, INC280 or LEE011 given in combination with LGX818 and 
MEK162. 
Details regarding dose recommendation are described in Section 10.5.3.2 of the protocol. The 
Bayesian approach requires the specification of prior distributions for all model parameters, 
which comprise the single-agent parameters for LGX818, MEK162, BKM120, BGJ398, 
INC280 and LEE011, and for all the interaction parameters (See model definition in 
Section 10.5.3.2). Derivation of these is provided in the following subsections. 
Intermediate and final parameter values are given in Table 14-2 and the data used to derive the 
informative priors are presented in Table 14-1. For some of the provisional dose levels, 
Table 14-3 summarizes the associated prior distribution of DLT rates corresponding to the 
priors. 
 
LGX818 
An informative bivariate normal prior for the model parameters (log(α1), log(β1)) is obtained as 
follows: 


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Patients involved in the dose escalation of a triple combination in Study Part II will have 
tolerated LGX818+MEK162 well. For this reason, the DLT rate is assumed to be very low: 
• Assume that at 200 mg QD, the median probability of a DLT is 0.025 with 5th and 95th 
percentiles 0.0005 and 0.05 respectively. 
• Assume that at 450 mg QD, the median probability of a DLT is 0.05 with 5th and 95th 
percentiles 0.001 and 0.10 respectively. 
Based on the above specified medians and percentiles for the DLT rate at each dose, the optimal 
parameters of the bivariate normal distribution can be obtained following the procedure 
described by Neuenschwander et al (2008). 
 
MEK162 
An informative bivariate normal prior for the model parameters (log(α2), log(β2)) is obtained as 
follows: 
Patients involved in the dose escalation of a triple combination in Study Part II will have 
tolerated LGX818+MEK162 well. For this reason, the DLT rate is assumed to be very low: 
• Assume that at 30 mg QD, the median probability of a DLT is 0.025 with 5th and 95th 
percentiles 0.0005 and 0.05 respectively. 
• Assume that at 45 mg QD, the median probability of a DLT is 0.05 with 5th and 95th 
percentiles 0.001 and 0.10 respectively. 
Based on the above specified medians and percentiles for the DLT rate at each dose, the optimal 
parameters of the bivariate normal distribution can be obtained following the procedure 
described by Neuenschwander et al (2008). 
The single-agent priors for BGJ398, BKM120, INC280 and LEE011 are derived from available 
historical data in a stepwise fashion. The details are listed below. 
 
BGJ398 
Currently available historical data from study [CBGJ398X2101] are used in order to derive the 
prior for the BLRM parameters. The bivariate normal prior for the model parameters is obtained 
as follows: 
Step 1 The following non-informative prior for (log(αBGJ), log(βBGJ)) was used: 
• The median DLT rate at the reference dose (75 mg QD) was assumed to be 0.15, i.e. 
mean(log(αBGJ)) = log(0.176). 
• A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(βBGJ)) = 0. 
• The standard deviation of log(αBGJ) was set to 2, and the standard deviation of log(βBGJ) 
was set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile. 
• The correlation between log(αBGJ) and log(βBGJ) was set to 0. 
Step 2 Data from 34 
patients eligible for 
the dose-determining set of the 
study 
[CBGJ398X2101] were used to update the dose-toxicity profile (See Table 14-1). 


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Step 3 Heterogeneity between the historical and current study was incorporated by between- 
trial standard deviations τ1 and τ2 for log(αBGJ) and log(βBGJ). Both were set to follow a normal 
distribution. Mean log(0.25) and log(0.125) were chosen for τ1 and τ2 respectively, and stand 
deviation 0.01 were chosen for both τ1 and τ2, which correspond to moderate between-trial 
variability. 
 
BKM120 
Currently available historical data from study [CBKM120X2101] are used in order to derive 
the prior for the BLRM parameters. The bivariate normal prior for the model parameters is 
obtained as follows: 
Step 1 The following non-informative prior for (log(αBKM), log(βBKM)) was used: 
• The median DLT rate at the reference dose (50 mg QD) was assumed to be 0.15, i.e. 
mean(log(αBKM)) = log(0.176). 
• A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(βBKM)) = 0. 
• The standard deviation of log(αBKM) was set to 2, and the standard deviation of log(βBKM) 
was set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile. 
• The correlation between log(αBKM) and log(βBKM) was set to 0. 
Step 2 Data from 40 patients eligible for the dose-determining set of the study 
[CBKM120X2101] were used to update the dose-toxicity profile (See Table 14-1). 
Step 3 Heterogeneity between the historical and current study was incorporated by between- 
trial standard deviations τ1 and τ2 for log(αBKM) and log(βBKM). Both were set to follow a normal 
distribution. Mean log(0.25) and log(0.125) were chosen for τ1 and τ2 respectively, and stand 
deviation 0.01 were chosen for both τ1 and τ2, which correspond to moderate between-trial 
variability. 
 
INC280 
Currently available historical data from study [CINC398X2101], [CINC398X1101], and 
[CINC398X2102] are used in order to derive the prior for the BLRM parameters. The bivariate 
normal prior for the model parameters is obtained as follows: 
Step 1 The following non-informative prior for (log(αINC), log(βINC)) was used: 
• The median DLT rate at the reference dose (200 mg BID) was assumed to be 0.15, i.e. 
mean(log(αINC)) = log(0.176). 
• A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(βINC)) = 0. 
• The standard deviation of log(αINC) was set to 2, and the standard deviation of log(βINC) 
was set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile. 
• The correlation between log(αINC) and log(βINC) was set to 0. 
• Since two schedules have been investigated for INC280, the difference in schedule is 
expressed by a covariate assumed to be normally distributed with mean 0.693 and 
standard deviation 0.541. This is based on the assumptions that at the reference dose 


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changing schedule from QD to BID lead to a 2-fold (median) and a 4-fold (90th 
percentile) increase in the odds of DLT. 
Step 2 Data from 40 patients eligible for the dose-determining set of the study 
[CINC398X2101], 30 patients from [CINC398X1101], and 30 patients from [CINC398X2102] 
were used to update the dose-toxicity profile (See Table 14-1). 
Step 3 Heterogeneity between the historical and current study was incorporated by between- 
trial standard deviations τ1 and τ2 for log(αINC) and log(βINC). Both were set to follow a normal 
distribution. Mean log(0.25) and log(0.125) were chosen for τ1 and τ2 respectively, and stand 
deviation 0.01 were chosen for both τ1 and τ2, which correspond to moderate between-trial 
variability. 
 
LEE011 
Currently available historical data from study [CLEE011X2101] are used in order to derive the 
prior for the BLRM parameters. The bivariate normal prior for the model parameters is obtained 
as follows: 
Step 1 The following non-informative prior for (log(αLEE), log(βLEE)) was used: 
• The median DLT rate at the reference dose (400 mg QD) was assumed to be 0.15, i.e. 
mean(log(αLEE)) = log(0.176). 
• A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(βLEE)) = 0. 
• The standard deviation of log(αLEE) was set to 2, and the standard deviation of log(βLEE) 
was set to 1, which allows for considerable prior uncertainty for the dose-toxicity profile. 
• The correlation between log(αLEE) and log(βLEE) was set to 0. 
Step 2 Data from 53 patients eligible for the dose-determining set of the study 
[CLEE011X2101] were used to update the dose-toxicity profile (See Table 14-1). 
Step 3 Heterogeneity between the historical and current study was incorporated by between- 
trial standard deviations τ1 and τ2 for log(αLEE) and log(βLEE). Both were set to follow a normal 
distribution. Mean log(0.25) and log(0.125) were chosen for τ1 and τ2 respectively, and stand 
deviation 0.01 were chosen for both τ1 and τ2, which correspond to moderate between-trial 
variability. 
 
Table 14-1 
Data from single-agent trials used to derive priors for BGJ398, 
BKM120, INC280 and LEE011 
 
Study 
Schedule 
Dose (mg/day) 
No. of DLTs/No. of evaluable patients 
[BGJ378X2101] 
QD 
5 
0/3 
QD 
10 
0/2 
QD 
20 
0/4 
QD 
40 
0/5 
QD 
60 
0/3 
QD 
100 
1/6 
QD 
125 
1/10 
QD 
150 
2/4 


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Study 
Schedule 
Dose (mg/day) 
No. of DLTs/No. of evaluable patients 
[BKM120X2101] 
QD 
12.5 
0/1 
QD 
25 
0/1 
QD 
50 
0/3 
QD 
80 
1/9 
QD 
100 
4/23 
QD 
150 
2/3 
[INC280X2101] 
QD 
10 
0/3 
QD 
20 
0/3 
QD 
50 
1/6 
QD 
70 
0/3 
BID 
100 
0/3 
QD 
150 
0/3 
QD 
200 
0/3 
QD 
300 
0/4 
QD 
400 
0/4 
BID 
400 
0/4 
BID 
600 
0/4 
[INC280X1101] 
QD 
100 
0/3 
QD 
200 
0/3 
QD 
400 
0/3 
QD 
500 
0/3 
QD 
600 
0/4 
QD 
800 
0/4 
BID 
800 
0/3 
BID 
1200 
1/3 
[INC280X2102] 
BID 
200 
0/4 
BID 
400 
1/4 
BID 
500 
1/4 
BID 
700 
0/3 
BID 
900 
1/8 
BID 
1200 
0/7 
[LEE011X2101] 
QD 
50 
1/4 
QD 
70 
0/2 
QD 
140 
0/3 
QD 
260 
0/4 
QD 
280 
1/4 
QD 
350 
0/5 
QD 
400 
1/4 
QD 
600 
1/12 
QD 
750 
2/10 
QD 
900 
1/13 
QD 
1200 
2/3 
 
Interaction parameter 
The prior reflecting the current uncertainty about the toxicity of the combination treatment is 
used for the parameter modeling the interactions. Based on the PK drug-drug interaction 
assessment (Section 6.2.1), the following assumptions are made for the interaction parameters. 


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LGX818 and MEK162: 
• The parameter η is normally distributed and centered at 0, i.e. no increase in odds of DLT 
over independence at the combination starting dose. 
• 97.5th percentile is log(2), i.e. 2 fold increase in odds of DLT over independence at the 
combination starting dose. 
This assumes, a priori, that there will be a small interaction, but also allows for the potential of 
both synergism and antagonism of the safety profiles. 
 
LGX818 and BGJ398, MEK162 and BGJ398, LGX818 and BKM120, MEK162 and 
BKM120, MEK162 and INC280, MEK162 and LEE011: 
• The parameter η is normally distributed and centered at 0, i.e. no increase in odds of DLT 
over independence at the combination starting dose. 
• 97.5th percentile is log(3), i.e. 3 fold increase in odds of DLT over independence at the 
combination starting dose. 
This assumes, a priori, that there will be a small interaction, but also allows for the potential of 
both synergism and antagonism of the safety profiles. 
 
LGX818 and INC280: 
• The parameter η is normally distributed and centered at log(1.2), i.e. 20% increase in odds 
of DLT over independence at the combination starting dose. 
• 97.5th percentile is log(3), i.e. 3 fold increase in odds of DLT over independence at the 
combination starting dose. 
This assumes, a priori, that there will be a slight synergistic interaction, but also allows for the 
potential of both significant synergism and antagonism of the safety profiles. 
 
LGX818 and LEE011: 
• The parameter η is normally distributed and centered at log(1.1), i.e. 10% increase in odds 
of DLT over independence at the combination starting dose. 
• 97.5th percentile is log(3), i.e. 3 fold increase in odds of DLT over independence at the 
combination starting dose. 
This assumes, a priori, that there will be a slight synergistic interaction, but also allows for the 
potential of both significant synergism and antagonism of the safety profiles. 
 
All three-way interactions: 
• The parameter η is normally distributed and centered at 0, i.e. no increase in odds of DLT 
over independence at the combination starting dose. 
• 97.5th percentile is log(2), i.e. 2 fold increase in odds of DLT over independence at the 
combination starting dose. 
This assumes, a priori, that there will be a small interaction, but also allows for the potential of 
both synergism and antagonism of the safety profiles. 


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Numerical values and summary statistics 
Table 14-2 summarizes the information for all model parameters: distributions for the single- 
agent parameters (weakly-informative prior, posterior from historical data, and discounted prior 
due to between-trial heterogeneity), and the prior for the interaction parameter. Table 14-3 
summarizes the prior distribution of DLT rates corresponding to the prior. The doses not 
meeting the overdose criteria are bold in the table, i.e. doses not eligible at the start of the study 
(under the prior). 


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Table 14-2 
Prior distributions of model parameters 
 
Parameter 
Means 
Standard deviations 
Correlation 
Priors for LGX818 and MEK162 
log(α1), log(β1) 
-3.200, 0.007 
0.660, 0.060 
0.582 
log(α2), log(β2) 
-1.859, 0.802 
1.077, 1.307 
0.963 
Non-informative priors for BGJ398, BKM120, INC280 and LEE011 (Step 1) 
log(αBGJ), log(βBGJ) 
-1.737, 0 
2, 1 
0 
log(αBKM), log(βBKM) 
-1.737, 0 
2, 1 
0 
log(αINC), log(βINC) 
-1.737, 0 
2, 1 
0 
log(αLEE), log(βLEE) 
-1.737, 0 
2, 1 
0 
γ 
0.693 
0.541 
NA 
Posterior for BGJ398, BKM120, INC280 and LEE011 given available data (Step 2) 
log(αBGJ), log(βBGJ) 
-2.600, 0.483 
0.768, 0.745 
-0.578 
log(αBKM), log(βBKM) 
-2.763, 0.382 
0.932, 0.795 
-0.794 
log(αINC, X2101), log(βINC, X2101) 
-3.273, -0.922 
0.903, 0.702 
-0.083 
log(αINC, X1101), log(βINC, X1101) 
-3.603, -0.355 
1.135, 0.761 
-0.536 
log(αINC, X2102), log(βINC, X2102) 
-2.921, -0.803 
0.747, 0.709 
-0.544 
log(αLEE), log(βLEE) 
-1.986, -0.789 
0.382, 0.653 
-0.266 
Prior used for BGJ398, BKM120, INC280 and LEE011 (incorporating between-trial 
heterogeneity, Step 3) 
log(αBGJ), log(βBGJ) 
-2.605, 0.494 
0.851, 0.762 
-0.508 
log(αBKM), log(βBKM) 
-2.772, 0.396 
1.010, 0.824 
-0.731 
log(αINC), log(βINC) 
-3.138, -0.709 
0.573, 0.429 
-0.351 
log(αLEE), log(βLEE) 
-1.987, -0.782 
0.523, 0.684 
-0.189 
Priors for interaction terms 
ηLGX, MEK (for BGJ398 or 
BKM120 arm) 
0 
0.472 
NA 
ηLGX, MEK (for INC280 or 
LEE011 arm) 
0 
1.061 
NA 
ηLGX, BGJ 
0 
0.561 
NA 
ηMEK, BGJ 
0 
0.747 
NA 
ηLGX, BKM 
0 
0.467 
NA 
ηMEK, BKM 
0 
0.623 
NA 
ηLGX, INC 
0.205 
0.526 
NA 
ηMEK, INC 
0 
0.374 
NA 
ηLGX, LEE 
0.858 
4.607 
NA 
ηMEK, LEE 
0 
2.989 
NA 
ηLGX, MEK, BGJ 
0 
0.472 
NA 
ηLGX, MEK, BKM 
0 
0.393 
NA 
ηLGX, MEK, INC 
0 
0.530 
NA 
ηLGX, MEK, LEE 
0 
4.244 
NA 


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Table 14-3   Summary of prior distribution of DLT rates for LGX818 = 450 mg (QD, 
for BGJ398 or BKM120 arm) / 200 mg (QD, for INC280 or LEE011 arm) 
and MEK162 = 45 mg (BID) 
 
Dose of 
combination 
treatment 
(mg/day) 
Prior probabilities that Pr(DLT) 
is in interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.35) 
[0.35, 1] 
2.50% 
50.00% 
97.50% 
BGJ398 
75 
0.470 
0.354 
0.176 
0.212 
0.158 
0.026 
0.170 
0.624 
100 
0.378 
0.312 
0.310 
0.277 
0.213 
0.022 
0.218 
0.795 
125 
0.329 
0.257 
0.414 
0.344 
0.267 
0.017 
0.276 
0.920 
BKM120 
60 
0.433 
0.363 
0.203 
0.228 
0.167 
0.028 
0.184 
0.661 
80 
0.350 
0.310 
0.339 
0.296 
0.224 
0.024 
0.237 
0.830 
100 
0.311 
0.254 
0.436 
0.360 
0.274 
0.019 
0.292 
0.939 
INC280 
400 
0.518 
0.358 
0.124 
0.189 
0.136 
0.028 
0.155 
0.545 
800 
0.420 
0.235 
0.344 
0.292 
0.254 
0.010 
0.209 
0.883 
1200 
0.393 
0.169 
0.439 
0.372 
0.330 
0.003 
0.266 
0.980 
LEE011 
100 
0.536 
0.336 
0.128 
0.186 
0.140 
0.023 
0.149 
0.553 
200 
0.459 
0.228 
0.313 
0.273 
0.251 
0.008 
0.186 
0. 877 
300 
0.436 
0.158 
0.405 
0.344 
0.326 
0.002 
0.223 
0.977 
400 
0.428 
0.121 
0.451 
0.393 
0.371 
0.001 
0.259 
0.996 
Note: bold values indicate doses not meeting the overdose criterion (more than 25% chance of 
excessive toxicity) with the prior information only. For INC280, BID dosing is used, therefore, total 
daily doses shown in this table are twice the BID dose. 
Details regarding dose recommendation are described in Section 10.5.2 of the protocol. 
 
14.1.2 
Hypothetical dose escalation scenarios 
In order to show how well the BLRM model performs, different hypothetical dose escalation 
scenarios were investigated. The model should make reasonable dose recommendations during 
the study based on the observed DLTs. During the study, the decision to escalate dose 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. Details regarding dose recommendation using this model are 
described in Section 10.5.3 of the CSP. 
Some scenarios to illustrate both inter-patient and intra-patient dose escalation up to the fourth 
dose cohort for each triple combination are listed in Table 14-4 to Table 14-7. It is assumed for 
most scenarios that each cohort has 3-6 evaluable patients. The maximum dose increment 
allowed in the scenarios did not exceed 100% for inter-patient dose escalation or 50% for intra- 


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patient dose escalation as per escalation rules defined in Section 6.2.3 of the CSP. The 
recommended next dose level satisfied the EWOC principle. 
Note that the next dose level for the 3rd agent is selected in concordance with the provisional 
dose levels specified in Section 6.2.2 of the protocol wherever it is allowed, to mimic possible 
on-study escalation steps. However, for better examination of the performance of the model, 
several additional provisional dose levels are added. 
 
Table 14-4 
Hypothetical scenarios for on-study decisions with LGX818 = 450mg 
QD and MEK162 = 45mg BID in combination with BGJ398 (cohort size: 
3) 
 
Scenario 
Dose of 
Npat 
Ntox 
P(Over) 
Next Dose 
P(Over) 
Next Dose 
BGJ398 
NDC 
Combination 
NDC 
Combination 
(mg/day) 
(inter- 
(inter-patient 
(intra- 
(intra-patient 
patient DE) 
DE) 
patient 
DE) 
DE) 
1 
75 
3 
0 
0.238 
125 
0.137 
100 
2 
75 
3 
1 
0.214 
75 
0.391 
100 
3 
75 
3 
2 
0.243 
50 
0.243 
50 
4 
 
5 
 
6 
 
7 
 
8 
0.201 
50 
0.201 
50 
75 
3 
2 
75 
3 
0 
9 
125 
3 
1 
0.152 
125 
0.264 
150 
100 
3 
0 
75 
3 
0 
10 
125 
3 
2 
0.059 
75 
0.270 
100 
75 
3 
0 
75 
3 
1 
11 
75 
3 
0 
0.245 
150 
0.245 
150 
100 
3 
0 
75 
3 
1 
12 
75 
3 
1 
0.099 
75 
0.287 
100 
75 
3 
0 
75 
3 
0 
125 
3 
1 
75 
3 
0 
125 
3 
2 
75 
3 
1 
75 
3 
0 
75 
3 
1 
75 
3 
1 
75 
3 
1 
0.127 
100 
0.282 
125 
0.147 
75 
0.147 
75 
0.213 
100 
0.213 
100 
0.235 
75 
0.235 
75 


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Table 14-5 
Hypothetical scenarios for on-study decisions with LGX818 = 450mg 
QD and MEK162 = 45mg BID in combination with BKM120 (cohort 
size: 3) 
 
Scenario 
Dose of 
Npat 
Ntox 
P(Over) 
Next Dose 
P(Over) 
Next Dose 
BKM120 
NDC 
Combination 
NDC 
Combination 
(mg/day) 
(inter- 
(inter-patient 
(intra- 
(intra-patient 
patient 
DE) 
patient 
DE) 
DE) 
DE) 
1 
60 
3 
0 
0.217 
90 
0.217 
90 
2 
60 
3 
1 
0.235 
60 
0.330 
70 
3 
60 
3 
2 
0.186 
30 
0.298 
40 
4 
 
5 
 
6 
 
7 
 
8 
0.224 
40 
0.362 
50 
60 
3 
2 
60 
3 
0 
9 
80 
3 
1 
0.182 
100 
0.280 
120 
80 
3 
0 
60 
3 
0 
10 
80 
3 
2 
0.203 
70 
0.363 
80 
60 
3 
0 
60 
3 
1 
11 
60 
3 
0 
0.247 
120 
0.247 
120 
80 
3 
0 
60 
3 
1 
12 
60 
3 
1 
0.240 
70 
0.335 
80 
50 
3 
0 
60 
3 
0 
80 
3 
1 
60 
3 
0 
80 
3 
2 
60 
3 
1 
60 
3 
0 
60 
3 
1 
60 
3 
1 
60 
3 
1 
0.203 
80 
0.346 
100 
0.201 
60 
0.352 
70 
0.230 
80 
0.301 
90 
0.156 
50 
0.369 
70 


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Table 14-6 
Hypothetical scenarios for on-study decisions with LGX818 = 200mg 
QD and MEK162 = 45mg BID in combination with INC280 (cohort size: 
3) 
 
Scenario 
Dose of 
Npat 
Ntox 
P(Over) 
Next Dose 
P(Over) 
Next Dose 
INC280 
NDC 
Combination 
NDC 
Combination 
(mg/day) 
(inter- 
(inter-patient 
(intra- 
(intra-patient 
patient 
DE) 
patient 
DE) 
DE) 
DE) 
1 
400 
3 
0 
0.187 
800 
0.117 
600 
2 
400 
3 
1 
0.157 
400 
0.338 
600 
3 
400 
3 
2 
0.241 
300 
0.241 
300 
4 
 
5 
 
6 
 
7 
 
8 
0.206 
300 
0.206 
300 
400 
3 
2 
400 
3 
0 
9 
800 
3 
1 
0.249 
1400 
0.202 
1200 
800 
3 
0 
400 
3 
0 
10 
800 
3 
2 
0.154 
500 
0.284 
600 
400 
3 
0 
400 
3 
1 
11 
400 
3 
0 
0.226 
1400 
0.149 
1000 
700 
3 
0 
400 
3 
1 
12 
400 
3 
1 
0.248 
600 
0.248 
600 
400 
3 
0 
400 
3 
0 
800 
3 
1 
400 
3 
0 
800 
3 
2 
400 
3 
1 
400 
3 
0 
400 
3 
1 
400 
3 
1 
400 
3 
1 
0.244 
800 
0.346 
1000 
0.125 
400 
0.272 
500 
0.241 
700 
0.186 
600 
0.179 
400 
0.299 
500 


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Table 14-7 
Hypothetical scenarios for on-study decisions with LGX818 = 200mg 
QD and MEK162 = 45mg BID in combination with LEE011 (cohort size: 
3) 
 
Scenario 
Dose of 
Npat 
Ntox 
P(Over) 
Next Dose 
P(Over) 
Next Dose 
LEE011 
NDC 
Combination 
NDC 
Combination 
(mg/day) 
(inter- 
(inter-patient 
(intra- 
(intra-patient 
patient 
DE) 
patient 
DE) 
DE) 
DE) 
1 
100 
3 
0 
0.157 
200 
0.094 
150 
2 
100 
3 
1 
0.166 
100 
0.319 
150 
3 
100 
3 
2 
0.129 
50 
0.129 
50 
4 
 
5 
 
6 
 
7 
 
8 
0.092 
50 
0.092 
50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within Table 14-4 to Table 14-7 “P(Over) NDC” represents the probability that the true DLT 
rate for the next recommended dose combination exceeds or equals to 35%. Note, the actual 
number of evaluable patients per cohort is variable (see Section 6.2.3) and the recommendations 
during the study will depend on the number of evaluable patients at each dose combination and 
the observed number of DLT. 
In summary, the models are showing appropriate behaviors, leading to decisions that are in 
agreement with clinical sense: progressive increase of the 3rd compound doses if no DLT is 
observed, enrolling of a new cohort at the same dose combination when 1 DLT out of 3 patients 
is reported and decrease when more than 1 DLT out of 3 patients is reported in a cohort. 
Recommended dose levels for intra-patient dose escalation are usually higher compared to 
inter-patient dose escalation, when the increase is within 50%. 
100 
3 
2 
100 
3 
0 
9 
200 
3 
1 
0.184 
300 
0.184 
300 
200 
3 
0 
100 
3 
0 
10 
200 
3 
2 
0.066 
100 
0.265 
150 
100 
3 
0 
100 
3 
1 
11 
100 
3 
0 
0.203 
300 
0.109 
200 
150 
3 
0 
100 
3 
1 
12 
100 
3 
1 
0.228 
150 
0.228 
150 
100 
3 
0 
100 
3 
0 
200 
3 
1 
100 
3 
0 
200 
3 
2 
100 
3 
1 
100 
3 
0 
100 
3 
1 
100 
3 
1 
100 
3 
1 
0.225 
200 
0.387 
300 
0.146 
100 
0.146 
100 
0.163 
150 
0.163 
150 
0.198 
100 
0.391 
150 


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14.2 
Appendix 2 - Guidelines for the treatment of study drug 
combination induced hyperglycemia 
Figure 14-1 
Algorithm for the treatment of study drug combination induced 
hyperglycemia 
 


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Management of (A) grade 2 hyperglycemia (161 to 250 mg/dL), (B) asymptomatic grade 3 
hyperglycemia (250 to 500 mg/dL), (C) symptomatic grade 3 hyperglycemia (250 to 
500 mg/dL) or grade 4 hyperglycemia (> 500 mg/dL), and (D) hyperglycemia in previously 
diagnosed diabetics. 
NOTE. Recommendations based on experience and expertise of the panel. Some patients are 
able to stop insulin or sulfonylureas later with therapeutic lifestyle changes (TLC), after acute 
lowering of blood glucose or after discontinuation of phosphoinositide 3-kinase–Akt– 
mammalian target of rapamycin (PAM) pathway inhibitors. AC, before meals; DLT, dose- 
limiting toxicity; IVF, intravenous fluids; QHS, before every bedtime. (*) Do not use metformin 
if creatine > 1.3 mg/dL (women) or > 1.4 mg/dL (men) or if any state of decreased tissue 
perfusion or hemodynamic instability is present (eg, heart failure); hold metformin for 
computed tomography scans; GI symptoms may occur with initiation but usually subside after 
first week (Busaidy et al 2012). 


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14.3 
Appendix 3 - Guidelines for the treatment of study drug 
combination induced diarrhea 
Anti-diarrhea therapy 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, patient education as well as proper management of diarrhea is mandatory. The 
following section outlines the recommended algorithm for management and treatment of study 
drug-induced diarrhea (Figure 14-2) (Benson 2004, Kornblau 2000, Wadler 1998). 
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose 
stools or overt diarrhea. It is recommended that the anti-diarrhea treatment algorithm detailed 
in this document will be applied. All concomitant therapies used for treatment of diarrhea must 
be recorded on the Concomitant Medications/Non-drug Therapies eCRF. It is recommended 
that patients be provided loperamide tablets. It is mandatory that patients are instructed on the 
use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea at home. Patients 
should be instructed to start oral loperamide (initial administration of 4mg, then 2mg every 4 
hrs (maximum of 16 mg/day) at the first sign of loose stool or symptoms of abdominal pain. 
These instructions should be provided at each cycle and the site should ensure that the patient 
understood the instructions. At the beginning of each cycle, each patient should be specifically 
questioned regarding any experience of diarrhea or diarrhea related symptoms. 
Refer to detailed guidelines for the treatment of persisting diarrhea grade 1 or 2 and severe 
diarrhea grade 3 or 4 below: 


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Figure 14-2 
Algorithm for management and treatment of study drug-induced 
diarrhea 
 
 
 
Patient history of diarrhea 
At screening, the patient’s history of diarrhea should be reviewed and the patient should be 
appropriately informed of drug-induced diarrhea and its management: 
• Review previous medical history of diarrhea within the last 12 months; laxative use, colon 
surgery, abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative colitis and 
other diarrhea-inducing diseases/conditions; 
• Stop all diarrheogenic agents at screening if possible, otherwise exclude from trial; 
• Instruct patients regarding risk of developing diarrhea; 
• Perform baseline clinical/laboratory studies according to the trial protocol (e.g. one could 
rule out carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., 
Giardia, Entamoeba, Cryptosporidium which can lead to opportunistic infections in 
immunosuppressed patients); 
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading (Table 14-8) 


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Table 14-8 
NCI CTCAE v4.0 grading of diarrhea for patients without 
ileostomy/colostomy 
 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Diarrhea 
increase of < 4 
increase of 4-6 
increase of ≥ 7 
Life 
death 
stools per day 
stools per day 
stools per day 
threatening 
over baseline; 
over baseline; 
over baseline; 
consequences; 
mild increase in 
moderate 
hospitalization 
urgent 
ostomy output 
increase in 
indicated; severe 
intervention 
compared to 
ostomy output 
increase in 
indicated 
baseline 
compared to 
ostomy output 
baseline 
compared to 
baseline; limiting 
self-care ADL 
 
Preemptive management of diarrhea 
Proactively investigate for occurrence of diarrhea 
Educate patient 
1. Remind patients at each visit to contact the site immediately upon the first sign of loose 
stool or symptoms of abdominal pain. Additionally, at the beginning of each cycle, each 
patient should be specifically questioned regarding any experience of diarrhea or diarrhea- 
related symptoms. If symptoms were experienced by the patient, then the site should 
question the patient regarding the actions taken for these symptoms and re-instruct as 
necessary. 
2. In addition to dietary modification, the patients should be instructed on early warning 
signs (e.g. severe cramping → severe diarrhea, fever with diarrhea → infection). Patients 
should be instructed on what to report to the investigator if possible (i.e. number of stools, 
stool composition, stool volume) and how to report symptoms of life-threatening sequelae 
(eg, fever or dizziness on standing). 
3. Contact the patient 2 times a week after the start of study treatments to detect diarrhea 
early during at least the first 2 cycles. If no problems occur, instruct the patient to call 
when a problem does arise. 
 
Loperamide supply 
• It is recommended that patients are provided a sufficient supply of loperamide tablets with 
the administration of study treatments at the start of each cycle in case the patient 
experiences diarrhea. When loperamide is provided to patients, it is mandatory that 
patients are instructed at each cycle in detail on the use of loperamide in order to manage 
signs or symptoms of diarrhea at home. The site should ensure that the patient understood 
the instructions. 
• Patients should be instructed to start oral loperamide at the first sign of loose stool or 
symptoms of abdominal pain. 


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Multiple events of diarrhea may occur throughout the duration of treatment. When each 
occurrence of diarrhea is first reported, the following steps to manage the event are 
recommended: 
 
Evaluate condition of patient 
• Obtain history of onset and duration of diarrhea including a description of the number of 
stools and stool composition (e.g. watery, blood or mucus in stool); 
• Assess patient for fever, abdominal pain/cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration); 
Determine if diarrhea is complicated vs. uncomplicated (Table 14-9); 
• Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary profile 
(i.e., to identify diarrhea-enhancing foods). 
For study treatment dose adjustment refer to Section 6.3.1. 
 
Table 14-9 
Uncomplicated vs. complicated diarrhea- defining symptoms 
 
Uncomplicated 
Complicated 
• 
CTCAE Grade 1-2 diarrhea with no 
complicating signs and symptoms 
• 
CTCAE Grade 3-4 diarrhea 
• 
CTCAE Grade 1-2 with the following complicating 
signs or symptoms: 
• 
Moderate to severe cramping 
• 
Grade ≥ 2 nausea/vomiting 
• 
Decreased performance status 
• 
Fever 
• 
Sepsis 
• 
Neutropenia 
• 
Frank bleeding 
• 
Dehydration 
• 
Unresolved diarrhea after 48 hrs of treatment 
with loperamide (including high dose 
administration) and initiation of second-line 
treatment 
 
Instruct on the supportive management of diarrhea (diet and other related 
concomitant medications) 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (like Metamucil®), and stool softeners (i.e, docusate sodium; 
Colace®) 
• Stop high-osmolar food supplements such as i.e, Ensure® Plus and i.e, Jevity® Plus (with 
fiber) 
• Drink 8 to 10 large glasses of clear liquids per day (like i.e, water, Pedialyte®, Gatorade®, 
broth) 
• Eat frequent small meals (i.e, bananas, rice, applesauce, toast) 


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Treatment with anti-diarrhea therapy 
Intensive management of diarrhea must be instituted at the first sign of abdominal cramping, 
loose stools or overt diarrhea. It is strongly recommended that the following anti-diarrhea 
treatment algorithm outlined in Table 14-10 and Table 14-11 be used. Note: all concomitant 
therapies used for treatment of diarrhea must be recorded on the Concomitant Medications/Non- 
drug Therapies eCRF. 
Loperamide is the first-line treatment of diarrhea (any Grade) in this recommended algorithm. 
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based on 
severity and duration of diarrhea and related signs/symptoms. Upon treatment with any anti- 
diarrhea agents, the patient’s response to treatment should be observed and appropriately 
documented in the source document and eCRF. 
• Table 14-10 outlines the recommended treatment for diarrhea Grade 1 and 2. 
• Table 14-11 outlines the recommended treatment for diarrhea Grade 3 and 4. 
NOTE: Although the use of the Novartis product Sandostatin® (octreotide acetate) is included 
in the diarrhea management algorithm outlined in this protocol, please be advised it is not 
approved by the FDA or other health authorities for the treatment of chemotherapy-induced 
diarrhea (CID). The use of Sandostatin® or any other drug for the treatment of CID is at the 
discretion of the physician investigator. Please review the Sandostatin® full prescribing 
information for important safety information. 
 
Diarrhea workup 
If applicable and as necessary, perform appropriate tests (i.e., CBC and electrolytes, stool work- 
up, abdominal exam) for patients with persisting (> 48 hrs) CTCAE Grade 1-2 diarrhea not 
requiring hospitalization (AGA Technical Review on the Evaluation and Management of 
Chronic Diarrhea 1999). Patients with CTCAE Grade 3-4 diarrhea should have CBC, 
electrolytes and stool work-up completed with hospitalization. 
1. Spot stool analysis [This may be obtained under discretion of the physician] 
• Collect stool and separate it from the urine (use special containers, analysis 
immediately, freeze samples for future analysis); 
2. Analyze the following: 
• Blood from stool; 
• Fecal leukocytes (Wright's staining and microscopy); 
• C. difficile toxin; 
• Fecal cultures including the tests mentioned in section Patient history of diarrhea plus 
Shigella and pathogenic E.coli-enterotoxigenic, enterohemorrhagic etc., possibly 
Aeromonas, Pleisiomonas (if suspected exposure to contaminated water), infectious 
colitis. 
3. Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures. 


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Table 14-10 
Treatment of diarrhea Grade 1-2 (uncomplicated) 
 
Timeline 
Treatment 
Initial Treatment 
Treat with standard dose of loperamide: initial administration 4 mg, 
then 2 mg every 4 hrs (maximum of 16 mg/day) or after each 
unformed stool. 
12-24 hrs after 
initial onset of 
diarrhea 
Diarrhea 
resolved 
Continue instructions for dietary modification and gradually add solid 
foods to diet; 
Discontinue loperamide after 12-hrs diarrhea-free (Grade 0) interval. 
Diarrhea 
unresolved 
If diarrhea Grade 1-2 (uncomplicated) 
Escalate to high dose loperamide: 2 mg every 2 hrs (max. of 16 
mg/day) or after each unformed stool; 
Monitor patients’ condition (to rule out dehydration, sepsis, ileus); 
Observe patient for response to anti-diarrhea treatment and reassess 
12 to 24 hrs later. 
If patient progresses to complicated CTCAE Grade 1-2 (i.e. presence 
of fever, dehydration, neutropenia) or CTCAE Grade 3-4 with or 
without symptoms - refer to Table 14-4 for treatment guidance. 
Note: Oral antibiotics may be started as prophylaxis for infections 
under the discretion of the physician. 
24-28 hrs after 
the initial 
onset of 
diarrhea 
Diarrhea 
resolved 
Continue instructions for dietary modification and gradually add solid 
foods to diet; 
Discontinue loperamide and/or other treatment after 12-hrs diarrhea- 
free (Grade 0) interval. 
Note: Use of high-dose loperamide can result in paralytic ileus if 
administered in the absence of diarrhea 
Diarrhea 
unresolved 
If diarrhea Grade 1-2 is still unresolved after 24 hrs high-dose 
loperamide (48 hrs total treatment with loperamide): 
Evaluated patient in an office/outpatient center for a medical/laboratory 
check and selected workup (see ‘Diarrhea workup’ within this section 
for additional recommended tests); Hospitalization may need to be 
considered. 
Replace fluids and electrolytes as appropriate. 
Discontinue loperamide and begin a second-line agent which can be 
an opiate or octreotide acetate: 
Opiates (choose a or b) 
Opium tincture (deodorized tincture of opium or opium 10% tincture) 
contains the equivalent of 10 mg/mL of morphine with a recommended 
dose of 0.6 mL up to four times a day. Treatment with opium tincture 
should be stopped 24 hrs after resolution of diarrhea to Grade 0. 
Paregoric (Camphorated Tincture of Opium®) contains the equivalent 
of 0.4 mg/mL morphine with a recommended dose of 5 mL in water up 
to four times a day. Treatment with Paregoric should be stopped 24 
hrs after resolution of diarrhea to Grade 0. 
Important Note: Due to the differences in morphine content, special 
care must be taken to avoid potential overdose. Opium tincture is 25 
times more concentrated (at 10 mg/mL of morphine) than Paregoric (at 
0.4 mg/mL). 


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Timeline 
Treatment 
If opium tincture is not available administration of codeine phosphate 
can be considered as an alternative. The recommendations below are 
provided as a general guidance however, physician discretion is 
advised. 
The use of codeine phosphate is not mentioned in the recommended 
guidelines for the treatment of CID published by Benson et al (2004), 
or by Wadler et al (1998), however, the WHO Model Formulary 2004 
provides recommendations for codeine phosphate in the treatment of 
acute diarrhea. 
The recommended dose of codeine phosphate for the treatment of 
acute diarrhea is: 
Starting dose: 1 mg/kg every 6 hrs (may be increased up to 1.5 mg/kg 
every 6 hrs in the absence of a clinical improvement within 12 to 24 
hrs). 
Maximum dose: 6mg/kg per 24 hrs. 
The doses and administration schedules above are recommended for 
the treatment of acute pain with codeine phosphate and may differ 
according to country. The WHO Model Formulary 2004 recommends 
30 mg PO every 3-4 times daily. 
Treatment with codeine phosphate should be stopped 24 hrs after 
resolution of diarrhea to Grade 0. 
Octreotide acetate 
Recommended dose of octreotide acetate is 100-150 μg TID (every 8 
hrs) with dose escalation up to 500 µg TID. Treatment should be 
administered until patient has experienced 24-hr diarrhea-free (Grade 
0) interval. This recommendation is based upon published data 
supporting its use for CID (see Benson 2004). 
Important Note: Caution should be paid to a potential very quick 
decrease of water and electrolyte loss after the onset of treatment with 
octreotide acetate. It is advised to monitor the stool volume every 4 to 
6 hrs and to adapt the administration of fluids and electrolytes 
accordingly. 
If diarrhea persists with the second-line agent (complicated CTCAE 
Grade 1-2 diarrhea) or has progressed to NCI CTCAE Grades 3-4, 
admit to hospital and employ measures described in Table 14-4. 


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Table 14-11 
Treatment of diarrhea CTCAE Grade 3-4 or complicated diarrhea 
CTCAE Grade 1-2 
 
Diarrhea Grade 3 or 4 
Admit to hospital. 
Stop loperamide and opiates if not already stopped. 
Administer IV fluids and electrolytes as needed. 
Administer SC octreotide acetate (100-150 µg TID - every 8 hrs) 
NOTE: Caution should be paid to a potential very quick decrease of water and electrolyte loss after the 
onset of treatment with octreotide acetate. It is advised to monitor the stool volume every 4 to 6 hrs 
and to adapt the administration of fluids and electrolytes accordingly. 
If there is no improvement in the diarrhea after 24 hrs, dose escalate octreotide acetate up to 500 µg 
TID SC until diarrhea is controlled. 
Medical/laboratory check and selected workup if patient does not need hospitalization (see ‘Diarrhea 
workup’ within this section for additional recommended tests) 
Monitor/Continue IV fluids and antibiotics as needed. Treatment should be discontinued within 24 hrs 
after the resolution of diarrhea. 
For study drug dose adjustment see Criteria for dose modifications in the study protocol. 


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14.4 
Appendix 4 - Guidelines for the treatment of study drug 
combination induced skin toxicity 
14.4.1 
Rash 
Skin disorder/rash has been observed in the ongoing studies of single-agent LGX818, BKM120 
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/MEK162 or LGX818/MEK162 + BKM120 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/ MEK162 should be maintained at the current dose, and the rash 
should be closely monitored for change in severity. 
• Treatment with LGX818/MEK162 + BKM120 should be omitted, or reduced whether this 
is first occurrence, or second occurrence 
• Doxycycline or minocycline are not recommended due to phototoxicity and could 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, etc.). 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/MEK162 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. If skin toxicity CTCAE Grade 3 is not resolved within 7 days, 
discontinue patient from study drug treatment. 
• Treatment with LGX818/MEK162 + BKM120 should be omitted until resolved to 
CTCAE Grade ≤ 1, and then reduced, if this is the first occurrence, or omitted and patients 
discontinued from study drug treatment if this is the second occurrence. 
• 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). 
 
CTCAE Grade 4 
• If skin toxicity CTCAE Grade 4 occurs the dose of LGX818/MEK162 or 
LGX818/MEK162 + BKM120 should be omitted and patients discontinued from study 
drug treatment. 
 
Table 14-12 
Recommended 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). 


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14.4.2 
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 14-13. 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. 
 
Table 14-13   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 regularly 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 (Von Moos et al 2008). 


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14.5 
Appendix 5 - Phosphate-lowering therapy 
Since the administration of BGJ398 may be associated with hyperphosphatemia and given the 
potential role of phosphorus and calcium in vascular calcifications, accepted limits of serum 
phosphorus and tCa x Pi have been predefined. 
The in-vivo-solubility product of tCa x Pi is about 58mg2/dLl2 and higher values involve a 
significant risk of calcium phosphate precipitation. Phosphorus retention of serum Pi > 6.5 
mg/dL is associated with a significantly increased mortality rate of ESRD patients and several 
studies in this population have reported that tCa x Pi values > 55-60mg2/dL2 significantly 
increase the risk of cardiovascular calcification, suggesting that these levels should be the upper 
limit of acceptability. 
The management of hyperphosphatemia includes reduction of phosphorus intake in sufficiently 
alimented cancer patients and increasing doses of the aluminum- and calcium-free phosphorus 
binder sevelamer and the phosphaturic agent acetazolamid, as described below. 
If serum Pi > 5.5 mg/dL has been demonstrated, this parameter along with serum concentrations 
of ionized and total calcium as well as serum creatinine levels will continue to be monitored at 
least weekly. Serum 1,25-(OH)2Vit D3 and iPTH levels as well as urinary phosphate and 
calcium have to be determined as medically indicated. Serum phosphorus lowering therapy 
consisting dietary phosphate intake restriction, oral phosphate binders and phosphaturic agents 
should be applied as follows: 
Serum Pi > 5.5 - 7.5 mg/dL: 
• Restriction of dietary phosphate intake to 600 - 800 mg/day, if BMI ≥ 21kg/m2. 
• Sevelamer 1 tablet (800mg) per meal; i.e. 3 x 800 mg/day. 
Serum Pi > 7.5 - 9.0mg/dL : 
• Restriction of dietary phosphate intake to 600 - 800 mg/day, if BMI ≥ 21kg/m2. 
• Sevelamer 1- 2 tablets per meal; i.e. 3 x 1200 mg/day. 
Serum Pi > 9.0 mg/dL : 
• Restriction of dietary phosphate intake to 600 - 800 mg/day, if BMI ≥ 21kg/m2. 
• Sevelamer 2 tablets per meal; i.e. 3 x 1600mg/day. 
• Acetazolamide 2- 3x 250mg/day. 
If serum phosphorus increases > 7.0mg/dL despite phosphorus lowering therapy over at least 
14 days the BGJ398 dose must be reduced and eventually permanently discontinued if not 
decreased to ≤ 5.5 mg/dL within 7 days after suspending BGJ398. All patients will continue to 
be followed-up until resolution to serum phosphorus ≤ 5.5 mg/dL or baseline or stabilization 


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14.6 
Appendix 6 - Guidelines for the treatment of study drug induced 
psychiatric disorders 
Psychiatric adverse events will be closely monitored and evaluated at each planned visit until 
recovery to Grade ≤ 1 or baseline status. The grading of psychiatric adverse events/mood 
alterations must be based on the clinical interpretation of severity according to the NCI- CTCAE 
(v 4.03) guidelines. 
For patients who experience new or worsening of existing psychiatric AEs of Grade ≥1, 
psychiatric consultation should be considered as described in Table 6-9. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for screening and 
during the study treatment phase to aid the investigator in identifying new or worsening of 
events. For additional information regarding safety assessments based on patient self-reported 
mood questionnaires, please refer to Section 7.2.2.7. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", or "3"), 
omit treatment with study drug and refer the patient for psychiatric consultation for optimal 
management regardless of the total questionnaire score or CTCAE grading to confirm if study 
drug should be interrupted or permanently discontinued. In this specific case, the psychiatric 
advice can overrule the patient’s PHQ-9 self-assessment. During the study, subjects will be 
monitored at regular scheduled visits (e.g. Day 15 of Cycle 1, Day 1 and Day 15 of Cycles 2 
and 3, Day 1 of each subsequent cycle, and at the End of Study Treatment visit) by the 
investigator/site staff through personal interaction and the two self-reported questionnaires. 
Additional assessments may be done according to the clinical judgment of the investigator if 
desired 


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Table 14-14 
PHQ-9 Depression Scale 
 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
(Use “” to indicate your answer”) 
Not at 
all 
Several 
days 
More 
than 
half the 
days 
Nearly 
every 
day 
1. Little interest or pleasure in doing things 
0 
1 
2 
3 
2. Feeling down, depressed, or hopeless. 
0 
1 
2 
3 
3. Trouble falling or staying asleep, or sleeping 
too much 
0 
1 
2 
3 
4. Feeling tired or having little energy. 
0 
1 
2 
3 
5. Poor appetite or overeating 
0 
1 
2 
3 
6. Feeling bad about yourself - or that you are a 
failure or have let yourself or your family down 
0 
1 
2 
3 
7. Trouble concentrating on things, such as 
reading the newspaper or watching television. 
0 
1 
2 
3 
8. Moving or speaking so slowly that other people 
could have noticed? Or the opposite - being so 
fidgety or restless that you have been moving 
around a lot more than usual 
0 
1 
2 
3 
9. Thoughts that you would be better off dead or 
of hurting yourself in some way 
0 
1 
2 
3 
For Office Coding 
  0 
 
+ 
  
 
+ 
  
 
+ 
  
 
= Total Score:  
 
If you checked off any problems, how difficult have these problems made it for you to do your work, 
take care of things at home, or get along with other people? 
Not difficult 
at all 
Somewhat 
difficult 
Very 
difficult 
Extremely 
difficult 
 
Note: The questionnaire provided here is a sample for information purposes only. Paper 
questionnaires for patient completion in the study will be provided by the Sponsor to be used 
as source documents. 


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Table 14-15   GAD-7 Anxiety Scale 
 
Over the last 2 weeks, how often have you 
been bothered by the following problems? 
(Use “” to indicate your answer”) 
Not 
at all 
Several 
days 
More than 
half the 
days 
Nearly 
every 
day 
1. Feeling nervous, anxious or on edge 
0 
1 
2 
3 
2. Not being able to stop or control worrying 
0 
1 
2 
3 
3. Worrying too much about different things 
0 
1 
2 
3 
4. Trouble relaxing 
0 
1 
2 
3 
5. Being so restless that it is hard to sit still 
0 
1 
2 
3 
6. Becoming easily annoyed or irritable 
0 
1 
2 
3 
7. Feeling afraid as if something awful 
might happen 
0 
1 
2 
3 
(For office coding: Total Score T 
  
 
= 
  
 
+ 
  
 
+ 
 
) 
Note: The questionnaire provided here is a sample for information purposes only. Paper 
questionnaires for patient completion in the study will be provided by the Sponsor to be used 
as source documents. 
 
14.7 
Appendix 7 - List of prohibited and concomitant medications to 
be used with caution 
The substrates in Table 14-16 through Table 14-28 do not represent exhaustive lists of 
substrates, inducers or inhibitors. 
 
Table 14-16   Prohibited concomitant therapy for LGX818/MEK162 combination 
 
CYP2C9 substrates with narrow therapeutic index 
See Table 14-21. 
Strong CYP3A4 inhibitors 
See Table 14-22. 
Enzyme inducing anti-epileptic drugs (EIAEDs) 
carbamazepine 
ethotoin 
felbamate 
fosphenytoin 
phenytoin 
primidone 
topiramate 
phenobarbital 
 
Table 14-17 
Additional prohibited concomitant therapy for LGX818/MEK162 + 
BKM120 
 
Strong and Moderate CYP3A4/5 inhibitors 
See Table 14-22. 
Strong & Moderate CYP3A4/5 inducers 
See Table 14-22. 
Drugs with known risk for to QT interval prolongation or Torsades de Pointes (TdP) as well as 
sensitive CYP3A substrates with a possible or conditional risk for TdP 
See Table 14-26. 


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Table 14-18 
Additional prohibited concomitant therapy for LGX818/MEK162 + 
LEE011 
 
Strong CYP3A4 inducers or inhibitors 
See Table 14-22. 
Substrates of CYP3A4/5 with a narrow therapeutic index (NTI) 
See Table 14-22. 
Medications with known QTc prolongation effect 
See Table 14-26. 
Drugs with known risk for Torsades de Pointes (TdP) 
See Table 14-26. 
Herbal preparations 
St. John’s wort 
Kava 
Ephedra (ma huang), 
Gingko biloba 
Dehydroepiandrosterone 
(DHEA) 
Yohimbe 
Saw palmetto 
Ginseng 
Black cohosh 
 
Table 14-19 
Additional prohibited concomitant therapy for LGX818/MEK162 + 
BGJ398 
 
Strong CYP3A4 inducers and inhibitors 
See Table 14-22. 
Medications with known QTc prolongation effect 
See Table 14-26. 
Drugs with known risk for Torsades de Pointes (TdP) 
See Table 14-26. 
 
Table 14-20 
Additional prohibited concomitant therapy for LGX818/MEK162 + 
INC280 
 
CYP3A4, CYP1A2, CYP2C8 or CYP2C19 substrates with narrow therapeutic index 
See Table 14-21. 
Strong CYP43A4 inhibitors and inducers 
See Table 14-23, Table 14-24 
Long acting proton pump inhibitors 
See Table 14-28. 


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Table 14-21 
Narrow therapeutic index substrates and substrates of CYP3A4, 
CYP2B6, CYP2C8 and CYP2C9, CYPC19 and CYP1A2 
This list of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the 
University of Washington’s Drug Interaction Database. This might not be an exhaustive list. 
 
 
Category 
Drug Names 
Narrow Therapeutic 
index substrates of 
CYP1A2 
theophylline, tizanidine (also sensitive) 
Sensitive Substrates of 
CYP1A2 
alosetron, caffeine, duloxetine, melatonin, ramelteon, selegiline, tacrine, 
tizanidine 
Other Substrates of 
CYP1A2 
clozapine, melatonin, ropivacaine 
Narrow Therapeutic 
index substrates of 
CYP2B6 
None reported to date 
Sensitive Substrates of 
CYP2B6 
bupropion, efavirenz 
Other Substrates of 
CYP2B6 
methadone, nevirapine, sibutramine 
Narrow Therapeutic 
index substrates of 
CYP2C8 
paclitaxel 
Sensitive substrates of 
CYP2C8 
repaglinide 
Other Substrates of 
CYP2C8 
amodiaquine, atorvastatin, buprenorphine, carbamazepine, enzalutamide, 
loperamide, montelukast, pioglitazone, rosiglitazone 
Narrow Therapeutic 
index substrates of 
CYP2C9 
phenytoin, warfarin (also sensitive) 
Sensitive substrates of 
CYP2C9 
celecoxib 
Other Substrates of 
CYP2C9 
diclofenac, losartan, tolbutamide 
Narrow Therapeutic 
index substrates of 
CYP2C19 
(S)-mephenytoin (also sensitive) 
Sensitive substrates of 
CYP2C19 
clobazam, dexlansoprazole, diazepam, gliclazide, lansoprazole, (R)- 
lansoprazole, (S)-lansoprazole, (R)-mephobarbital, omeprazole, (R)- 
omeprazole, pantoprazole, (+) pantoprazole, rabeprazole, tilidine 
Other Substrates of 
CYP2C19 
antipyrine, bosentan, dapasone, dexloxiglumide, diclofenac, esomeprazole, 
flurbiprofen, glyburide, losartan, moclobemide, ospemifene, phenytoin, 
pitavastatin, proguanil, quinidine, rabeprazolerosuvastatin, sildenafil, 
tolbutamide, voriconazole 


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Category 
Drug Names 
Narrow Therapeutic 
index substrates of 
CYP2D6 
pimozide, thioridazine 
Sensitive substrates of 
CYP2D6 
atomoxetine, desipramine, dextromethorphan, doxepin, encainide, 
enclomiphene, methoxyphenamine, metoprolol, nebivolol, nefazodone, 
perhexiline,perphenazine, repinotan, resperidone, tolterodine, traxoprodil, 
trimipramine, tropisetronnicergoline, vernakalant 
Other Substrates of 
CYP2D6 
aripiprazole, brofaromine, buprenorphine, delavirdine, duloxetine, 
iloperidone, imipramine, methadone, nortriptyline, oxycodone, paroxetine, 
pimozide, propranolol, ramosetron, risperidone, tamsulosin, trazodone, 
venlafaxine 
Narrow Therapeutic 
index substrates of 
CYP3A 
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, astemizole, cisapride, 
cyclosporine, diergotamine (dihydroergotamine), ergotamine, fentanyl, 
lomitapide, lovastatin, nicardipine, nisoldipine, pimozide, quinidine, 
rivaroxaban, simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine 
Sensitive substrates of 
CYP3A 
alpha-dihydroergocryptine, alfentanil, alisoporivir, almorexant, apixaban 
(doses < 2.5 mg only),aplaviroc, aprepitant, atazanavir, atorvastatin, 
avanafil, bosutinib, brecanavir, brotizolam, budesonide, buspirone, 
capravirine, casopitant, conivaptan, danoprevir, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, elvitegravir, eplerenone, 
everolimus, felodipine, fluticasone, ibrutinib, indinavir, ivacaftor, 
levomethadyl, lomitapide, lopinavir, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, midostaurin, naloxegol, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, saquinavir, sildenafil, simeprevir, 
simvastatin, ticagrelor, terfenadine, ticagrelor, tilidine,tipranavir, tolvaptan, 
triazolam, ulipristal, vardenafil, vicriviroc, voclosporin. 
Other substrates of 
CYP3A 
alprazolam, ambrisentan, amlodipine, antipyrine, aripiprazole, artemether, 
avosentan, boceprevir, bosentan, buprenorphine, carbamazepine, 
dexloxiglumide, dextromethorphan, diazepam, docetaxel, enzalutamide, 
gemigliptin, halofantrine, imipramine, lansoprazole, lidocaine, linagliptin, 
loperamide, loratadine, losartan, lurasidone, macitentan, 
methadone,mirodenafil, montelukast, morphine, nelfinavir, netupitant, 
nevirapine, nifedipine, nilotinib, nitrendipine, omeprazole, ospemifene, 
oxycodone, paclitaxel, pazopanib, pioglitazone, quinine, ranolazine, 
repaglinide, rifabutin, ritonavir, roflumilast, saxagliptin, selegiline, sertraline, 
sibutramine, sotrastaurine, telaprevir, theophylline, tirilazad, tolterodine, 
udenafil, ulipristal, vincristine, voriconazole 
1 Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a known 
potent inhibitor. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure 
levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
3 Other substrates are these that have shown an in vivo ≥2-fold increase in AUC with co-administration of an inhibitor based 
on the University of Washington DDI database. 


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Table 14-22   List of inhibitors and inducers of UGT1A1 to be used with caution 
The knowledge of UGTs is much more limited compared to that of CYP450s; hence, substrates 
are not classified as sensitive and inhibitors/inducers are not yet classified as 
strong/moderate/weak. This list might not be exhaustive. 
 
 
Category 
Drug Names 
UGT1A1 inhibitors 
atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, 
ketoconazole, nilotinib, pazopanib, propofol, regorafenib, sorafenib, 
silybum marianum (herbal also known as milk thistle), valeriana 
officinalis (herbal) 
UGT1A1 inducers 
carbamazepine, rifampicin, testosterone propiate, cigarette smoke 
 
Table 14-23 
List of CYP inhibitors 
The information presented on inhibitors is a compilation of the University of Washington DDI 
database and FDA DDI guidance. This list might not be exhaustive. 
 
 
Category 
Drug Names 
Strong inhibitors1 of 
CYP1A2 
ciprofloxacin, clinafloxacin, enoxacin, fluvoxamine8, oltipraz, rofecoxib, 
zafirlukast 
Moderate inhibitors2 of 
CYP1A2 
etintidine, idrocilamide,methoxsalen, mexiletine, oral contraceptives 
(drospirenone, norgestimate, ethinyl estradiol), pipemidic acid, 
phenylpropanolamine, propafenone, propranolol, thiabendazole, zileuton 
Weak inhibitors3 of 
CYP1A2 
acyclovir, allopurinol,antofloxacin, artemisinin, caffeine, cimetidine, 
curcumin5, daidzein5, disulfiram, echinacea4, famotidine, grapefruit juice5, 
grepafloxacin, hormone replacement therapy (estradiol+levonogestrel), 
interferon alpha/beta, norfloxacin, pefloxacin, peginterferon alpha, 
simeprivir,terbinafine, thiabendazole, ticlopidine9, verapamil, viloxazine, 
zileuton 
Strong inhibitors of 
CYP2C19 
fluconazole7, fluvoxamine8, fluoxetine, ticlopidine9 
Moderate inhibitors of 
CYP2C19 
Efavirenz, esomeprazole, fluoxetine, moclobemide, omeprazole, 
voriconazole 
Weak inhibitors of 
CYP2C19 
allicin (garlic derivative)5, armodafinil, carbamazepine, cimetidine, etravirine, 
human growth hormone (rhGH), felbamate, ketoconazole, oral 
contraceptives10, tipranavir/ritonavir, simeprivir, clopidogrel 
Strong inhibitors of 
CYP3A 
Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, idelasib, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, VIEKIRA PAK2, voriconazole 


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Category 
Drug Names 
Moderate inhibitors of 
CYP3A 
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir,, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporin, duranavir, 
darunavir/ritonavir, diltiazem, dronedarone, erythromycin, faldaprevir, 
fluconazole7, fosamprenavir, grapefruit juice11, imatinib, lomitapide, 
netupitant,nilotinib, schisandra sphenanthera4, tofisopam, verapamil 
Weak inhibitors of 
CYP3A 
almorexant, alprazolam, amiodarone, amlodipine, atorvastatin, azithromycin, 
berberine4, bicalutamide, blueberry juice5, cilostazol, cimetidine, clotrimazole, 
clozoxazone, cranberry juice5, cyclosporine, delavirdine, evrolimus, 
fluoxetine, fluvoxamine8, fosaprepritantranolaxine, ginkgo4, goldenseal4, 
isoniazid, ivacaftor, lacipidine, linagliptin, nilotinib, oral contraceptives, 
pazopanib, peppermint oil5, propiverine, ranitidine, ranolazine, resveratrol5, 
roxithromycin, Seville orange5, simeprevir, tabimorelin, tacrolimus, ticagrelor, 
tolvaptan, sitaxentan, teriflunomide, tipranavir/ritonavir, zileuton□ 
1. 
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that 
CYP by equal or more than 5-fold. 
2. 
A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 5-fold but equal to or more than 2-fold. 
3. 
A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that 
CYP by less than 2-foldbut equal to or more than 1.25-fold. 
4. 
Herbal product. 
5. 
Food product. 
6. 
Gemfibrozil also inhibits OATP1B1. 
7. 
Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also metabolized 
by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
8. 
Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A; 
9. 
Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2. 
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., 
high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, 
single strength). 
 
 
Table 14-24 
List of CYP inducers 
The information presented on inducers is a compilation of the University of Washington DDI 
database and FDA DDI guidance. This list might not be exhaustive. 
 
 
Category 
Drug Names 
Strong inducers1 
of CYP1A2 
None reported to date 
Moderate 
inducers2 of 
CYP1A2 
montelukast, phenytoin, smokers versus non-smokers, rifampin, ritonavir, 
teriflunomide 
Weak inducers3 
of CYP1A2 
moricizine, nelfinavir, omeprazole, phenobarbital, tipranivir/ritonavir 
Weak inducers 
of CYP2C9 
aprepitant, bosentan, eslicarbazepine, lopinavir/ritonavir, phenobarbital, 
secobarbital, St. John’s Wort5 


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Category 
Drug Names 
Strong inducers 
of CYP2C19 
None reported to date 
Moderate 
inducers of 
CYP2C19 
enzalutamide, rifampin, tipranavir/ritonavir 
Weak inducers 
of CYP2C19 
artemisinin, carbamazepine, efavirenz, ginko5, glycyrrhizin5 St. John’s Wort5 
Strong inducers 
of CYP3A 
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, rifampin, St. 
John’s wort5, rifabutin, phenobarbital 
Moderate 
inducers of 
CYP3A 
bosentan, efavirenz, etravirine, genistein6, lersivirine, lopinavir, modafinil, 
nafcillin, ritonavir, semagacestat4, talviraline4, thioridazine, tipranavir 
Weak inducers 
of CYP3A 
amprenavir, aprepitant, armodafinil, bexarotene, boceprevir, brivacetam, 
clobazam, danshen5, dexamethasone, echinacea5, eslicarbazepine, garlic5, 
gingko (ginkgo biloba)5, ginseng5, glycyrrhizin5, methylprednisolone, nevirapine, 
oxcarbazepine, pioglitazone, prednisone, pleconaril4, primidone, quercetin6, 
raltegravir, ritonavir, rufinamide, sorafenib, Stribild (combo of elvitegravir, 
cobicistat, emtricitabine, and tenofovir), sulfinpyrazone, telaprevir, terbinafine, 
ticagleror, ticlopidine, topiramate, troglitazone4, vinblastine, vemurafenib, 
vicriviroc/ritonavir 
1. 
A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for that 
CYP by equal or more than 80%. 
2. 
A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP 
by 50-80%. 
3. 
A weak inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP by 
20-50%. 
4. 
Drugs not available in the US Market. 
5. 
Herbal product. 
6. 
Food product. 


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Table 14-25 
List of BSEP inhibitors, P-gp inhibitors/inducers and P-gp, BCRP, 
MATE1, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3 substrates 
Substrate and inhibitor information presented on drug transporter substrates and inhibitors is 
from a compilation of the University of Washington DDI database, the FDA DDI guidance, and 
the UCSF-FDA Transportal database. This list might not be exhaustive. 
 
 
Category 
Drug Names 
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 
Pgp (≥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 
Pgp 
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 
P-gp 
Inducers 
avasimibe, carbamazepine, efavirenz, genistein2, phenytoin, quercetin2, rifampin, 
St. Johns wort extract5 
BCRP 
Substrates 
atorvastatin daunorubicin, doxorubicin, ethinyl estradiol, hematoporphyrin, 
imatinib, methotrexate6, mitoxantrone, pitavastatin6, rosuvastatin6, SN-38 
(irinotecan), simvastatin, sulfasalazine, sofosbuvir1, topotecan1, sulfasalazine1 


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Category 
Drug Names 
MATE1 and 
OCT2 
substrates3 
Acyclovir, amantadine, amiloride, apricitabine, carboplatin, cisplatin, cephalexin, 
cephradine, cimetidine, dofetilde, famotidine, fexofenadine, furamidine, 
ganciclovir, glycopyrronium, Ipratropium, lamivudine, linagliptin, memantine, 
metformin (also a substrate for OCT1, MATE1, and MATE2K), oxyplatin, pindolol, 
plisicainide, pramsorafenib, ranitidine, topotecan, tropisetron, trospium, 
umeclidinium, varenicline and zidovudine. 
OAT1/3 
substrates 
adefovir, anagliptin, bumetanide, captopril, chlorothiazide, cidofovir, dapagliflozin, 
furosemide, ganciclovir, ibuprofen, beta-lactam antibiotics, methotrexate, 
olmesartan, pemetrexed, pravastatin, quinaprilat, ranitidine, rosuvastatin, 
tetracycline, topotecan-hydroxyl acid, valacyclovir, zidovudine, zonampanel, 
tenofovir 
OCT1/2 
substrates 
6-beta-hydroxycortisol, amantadine, carboplatin, cisplatin, histamine, lamivudine, 
linagliptin, metformin, oxyp[latin, oxybutynin, phenformin, picoplatin, 
pramsorafenib, tropisetron, trospium, varenicline, umeclidinium 
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 
1These drugs have both a narrow therapeutic index and an in vivo DDI outcome ascribed at least in part ascribed to Pgp 
(inhibition or induction) that exceeds a 20% change in AUC. 
2These drugs have in vivo DDI outcomes (inhibition) which are ≥2x increase in AUC and are at least in part ascribed to Pgp. 
3The US labels for these drugs have specific language on in vivo Pgp substrate status. 
4Dual P-gp and CYP3A4 inhibitor 
5Herbal medication. 
6Have been shown to have DDI in vivo, others are reported as substrates in vitro. 


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Table 14-26 
List of QT prolonging drugs 
 
TdP Risk 
Generic Name 
Known1 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, cocaine, disopyramide, dofetilide, domperidone, donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, fluconazole, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl, mesoridazine, 
methadone, moxifloxacin, ondansetron (i.v. only), oxaliplatin, papaverine HCl, 
pentamidine, pimozide, probucol, procainamide, propofol, quinidine, 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). 
(Check website https://www.crediblemeds.org/healthcare-providers/drug-list for the most updated list) 
 
 
Table 14-27 
List of prohibited enzyme-inducing anti-epileptic drugs 
 
enzyme-inducing anti-epileptic drugs 
carbamazepine, ethotoin, felbamate, fosphenytoin, Phenobarbital, phenytoin, primidone, topiramate 
 
Table 14-28 
List of long acting proton pump inhibitors 
 
Long acting proton pump inhibitors 
omeprazole, pantoprazole, lansoprazole 


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14.8 
Appendix 8 - Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) 
Harmonization of Efficacy Analysis of Solid Tumor Studies 
Guidelines for Response, Duration of Overall Response, TTF, TTP, 
Progression-Free Survival and Overall Survival (based on RECIST 1.1) 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.1: 29-Nov-2011 
Version 3:0: 19-Oct-2009 
Version 2:0: 18-Jan-2007 
Version 1:0: 13-Dec-2002 
 
Release date: 
29-Nov-2011 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
Authors (Version 2): 
 
Authors (Version 1): 
PPD 
PPD 
PPD 
PPD 


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


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14.1.1 Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.28 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming. 
 
14.1.2 Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 
 
14.1.3 Definitions 
 
14.1.4 Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 14.1.26. 
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, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 


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baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 
• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
14.1.5 Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.1.26. 
 
14.1.6 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow- 
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 


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develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a 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. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 


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


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lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
 
14.1.8 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions. 
 
14.1.9 Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
 
14.1.10 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
 
14.1.11 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 


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should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
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 mm.2 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different 
method than baseline.3 
 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. 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 timepoint 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 


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determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions. 


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• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters. 
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): 
 
Progressive Disease 
(PD): 
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) 
Unequivocal progression of existing non-target lesions.1 
 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different 
method than 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. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non- 
CR/Non-PD’ 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. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
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14.1.14 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.6. 
 
14.1.15 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 14-3. 
 
Table 14-3 
Overall lesion response at each assessment 
 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
SD 
UNK 
Non-PD and not UNK 
Non-PD and not UNK 
Non-PD or UNK 
No 
No 
No 
PR1 
SD1, 2 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 14.1.8. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
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 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• -For non-randomized trials where response is the primary endpoint, confirmation is 
needed. 
• -For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
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• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• 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 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 


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• 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. 
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 timepoint 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 timepoint and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease 
control, patients with a best overall response assessment of unknown (UNK) will not be 
regarded as “responders” but may be included in the denominator for ORR and DCR calculation 
depending on the analysis population (e.g. populations based on an ITT approach). 
 
14.1.18 
Time to event variables 
The protocol should state which of the following variables is used in that study. 
 
14.1.19 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 


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14.1.20 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
 
14.1.21 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
 
14.1.22 
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 
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 of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do 
respond. Potent agents induce a response in both good risk and poor risk patients. Less potent 
agents induce a response mainly in good risk patients only. This is described in more detail by 
Morgan (1988). 


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It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
 
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 
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 event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 


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assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
14.1.25 
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 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post- 
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.26). 


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Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
 
14.1.26 
Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with 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 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 14.1.8. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 


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For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
 
14.1.27 
Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP 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: 


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Table 14-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified 
differently in the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of 
treatment3 
Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
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 
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 


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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: 
• 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). 


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14.1.30 
End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow- 
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
 
14.1.31 
End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 


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• Study terminated by the sponsor 
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 external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If the Sponsor elects to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
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 known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
 
14.1.37 
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) 
• Initiation of new anti-cancer therapy 
*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=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 


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


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14.1.40 
References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791. 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47. 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465. 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16. 


 
LGX818, MEK162, BKM120, BGJ398, INC280, LEE011 
Array BioPharma Inc. 
Clinical Study CLGX818X2109 
 
 
SIGNATURE PAGE (SPONSOR) 
 
I have read and understand the contents of the clinical protocol for Clinical Study 
CLGX818X2109 dated 16 December 2019 and agree to meet all obligations of Array BioPharma 
Inc. as detailed in all applicable regulations and guidelines. In addition, I will ensure that the 
Principal Investigators are informed of all relevant information that becomes available during the 
conduct of this study. 
 
 
 
_ 
PPD 
MD 
17th December 2019 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 7 
1 
Confidential 
16 December 2019 
PPD 
PPD 

SAP_001.pdf: 
Clinical Development
CLGX818X2109
The LOGIC 2 trial
A phase II, multi-center, open-label study of sequential 
encorafenib/binimetinib combination followed by a rational combination 
with targeted agents after progression, to overcome resistance in adult 
patients with locally advanced or metastatic BRAF V600 melanoma
SAP – Statistical Analysis Plan 
Version 3.0


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Table of contents
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Objectives and endpoints.........................................................................................8
2
Data Analysis.......................................................................................................................9
2.3
Handling of Incomplete Dates...............................................................................11
AE date imputation................................................................................................11
Concomitant medication date imputation..............................................................11
3
Analysis Sets .....................................................................................................................12
4
Patient demographics and other baseline characteristics...................................................14
4.1
Basic demographic and background data ..............................................................14
4.2
Medical History .....................................................................................................14
4.3
Prior antineoplastic therapy...................................................................................14
4.4
Disease History......................................................................................................15
5
Patient disposition .............................................................................................................15
6
Protocol deviations ............................................................................................................15
7
COVID-19 and Related Events .........................................................................................16
8
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance) .......................................................................................................................16
8.1
Treatment Exposure and Compliance ...................................................................17
8.2
Concomitant therapies ...........................................................................................18
9
Efficacy Evaluation ...........................................................................................................18
9.1
Analysis of the primary endpoint ..........................................................................18
9.2
Analysis of the secondary endpoint(s)...................................................................20
10 Safety and tolerability evaluation......................................................................................26
10.1
Adverse event ........................................................................................................26
10.2
Laboratory data......................................................................................................28
10.2.1
Urinalysis ..............................................................................................30
10.3
Vital signs..............................................................................................................30
10.4
Electrocardiograms................................................................................................30
10.4.1
ECG data descriptive statistics..............................................................30
10.5
Other safety analyses .............................................................................................31
10.5.1
Left Ventricular Ejection Fraction (LVEF)...........................................31
10.6
Pharmacokinetic data.............................................................................................31
10.6.1
Plasma Concentrations..........................................................................31
10.6.2
PK Parameter Analysis .........................................................................32
10.6.3
Pharmacokinetic Data Handling ...........................................................33
10.7
Biomarkers.............................................................................................................34
10.7.1
Biomarker data......................................................................................34
10.7.2
Reporting (summary) and analyses of Biomarker data.........................35
11 Sample size calculation .....................................................................................................36


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12 References .........................................................................................................................37


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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
AUCtau, ss
Area under the concentration-time curve from time zero to time tau at 
steady-state 
BCRP
Breast Cancer Resistance Protein
BID
Bis In Diem/ twice daily
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 concentration
Cmax, ss
The maximum (peak) observed plasma concentration after drug 
administration at steady state 
CK/ CPK
Creatine kinase / Creatine phosphokinase
CL,ss/F
Apparent total plasma clearance of drug 
Clast, ss
Last measurable plasma concentration at steady state 
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
Ctrough, ss
Measured concentration at the end of a dosing interval at steady-state 
(taken directly before next administration) 
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
DV
Protocol Deviation
ECG
Electrocardiogram
eCRF
Electronic case report/record form
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency


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EOT
End Of Treatment
EPT
Early Program Team
ERK
Extracellular signal Regulated Kinase
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
FDA
Food and Drug Administration
FU
Follow Up
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
MA
Left ventricular ejection fraction
Molecular alteration
mCRC
Metastatic colorectal cancer
MedDRA
Medical Dictionary for Regulatory Activities
MEK
Mitogen-activated protein kinase
MR
Metabolite ratio
MRI
Magnetic Resonance Imaging
MTD 
Maximum Tolerated Dose
NRAS
Neuroblastoma RAS viral oncogene homolog
OAT
Organic anion transporter
ORR
Overall 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
PPS
Per-Protocol Set
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
RA
Accumulation ratio
RAF
V-raf murine sarcoma viral oncogene
SAP
Statistical Analysis Plan


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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
T1/2, ss
Terminal elimination half-life at steady state.
Tmax, ss
Time to reach maximum plasma concentration at steady state 
TSH
Thyroid-stimulating hormone
TTR
Time To (overall) Response
TA
Tumor Assessment
VAP
Validation and Analysis Planning
Vz,ss/F
The apparent volume of distribution at steady state 
WBC
White Blood Cell
WHO
World Health Organization


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1
Introduction
This document provides detailed statistical methodology for the analysis of Part I (patients naive 
to selective BRAF and MEK inhibitors), Run-in (non-naive patients for BRAF and/or MEK 
inhibitor treatment who are relapsing and who are receiving a brief run-in with encorafenib
(LGX818)/binimetinib (MEK162) combination), and Part II (patients who are receiving a 
tailored triple combination treatment in one of the four arms: encorafenib/ binimetinib + 
infigratinib (BKM120), buparlisib (BGJ398), capmatinib (INC280) or ribociclib (LEE011)
based on the genetic assessment of a tumor biopsy obtained at progression of disease (PD) on 
Part I/Run-in) data from study CLGX818X2109 that will be presented in the Clinical Study 
Report (CSR). The statistical analysis plan (SAP) specification provides the programming 
specifications for derived variables, datasets, and outputs.  
All changes to the planned analysis described in SAP shell and specifications required before 
or after database lock will be made through an amendment or addendum, respectively. Note 
that obvious corrections will be made at the time of analysis to address minor formatting or 
spelling mistakes present in SAP shell without the need to amend these modules.
The SAP shell and specifications may also serve as a reference for the creation of any outputs 
required outside of the CSR, e.g., maximum tolerated dose (MTD)/recommended Phase 2 dose 
(RP2D) declaration, Investigator’s Brochure (IB) updates, abstracts, posters, presentations, 
manuscripts, and management updates, unless otherwise specified.
1.1
This SAP was created based on final protocol amendment 
version 07 released on 16-Dec-2019.Study design
Figure 1-1
Study design
*Single agents: i.e., vemurafenib, dabrafenib, encorafenib , trametinib, binimetinib; Combos: i.e.,
dabrafenib/trametinib, encorafenib/binimetinib combination


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**Patients who progressed on a previous BRAFi and/or MEKi regimen will continue on 
encorafenib/binimetinib if PR is observed, followed by new Biopsy at progression. Patients who did not 
progress on their prior BRAFi/MEKi regimen may continue encorafenib/binimetinib combination until 
evidence of disease progression at which point a tumor biopsy will be taken and analyzed to guide 
assignment to a triple combination arm in Part II.
*** ribociclib cohort might start directly at the RP2D established in CMEK162X2110, if available.
Note: As of 10 July 2015, the triple combination of encorafenib/binimetinib+ infigratinib is no longer being 
explored
1.2
Objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and endpoints
Objective
Endpoints
Primary
To assess the anti-tumor activity of 
encorafenib/binimetinib in combination with third 
targeted agents after progression on 
encorafenib/binimetinib combination therapy.
Overall response rate (ORR)
Secondary
To estimate the MTD/RP2D of triple combinations after 
progression on encorafenib/binimetinib therapy
To characterize the safety and tolerability of 
encorafenib/binimetinib in combination with targeted 
agents
Incidence of Dose Limiting Toxicities (DLTs) in Cycle 
1 of Combination Part (Part II)
Adverse Events (AEs), serious AEs (SAEs), 
changes in hematology and chemistry values, vital 
signs, electrocardiograms (ECGs), dose 
interruptions, reductions and dose intensity.
To further assess anti-tumor activity of 
encorafenib/binimetinib combination, and in 
combination with targeted agents after progression on 
encorafenib/binimetinib combination
To characterize genomic alterations in tumor tissue at 
baseline and at tumor progression.
To determine the PK profiles of encorafenib,
binimetinib and the third agents when given in 
combination and to assess drug-drug interaction
PFS, DOR, TTR, DCR, and OS (Part II only)
Genomic alteration status (e.g., mutation, 
amplification, deletion, overexpression, ligand 
activation and splice variants) of pre-defined 
markers
Plasma concentration and derived parameters of 
encorafenib/binimetinib, and targeted agents
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2
Data Analysis
The data will be analyzed by PPD using SAS version 9.2 or higher.  For Bayesian modeling, 
SAS version 9.2 or higher will be used.  PK parameters will be calculated using non-
compartmental methods available in Phoenix WinNonlin version 8.3 or higher.
An interim analysis CSR was prepared based on all data collected from the Part I/Run-in 
patients enrolled up to the data cutoff date of 28Jun2022.  A primary CSR will be prepared 
based on all data collected from Part I/Run-in and Part II once all Part II patients have either 
completed at least six cycles of treatment or have discontinued the study.  
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. 
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant PK and biomarker measurements. Quantitative data will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) and 
categorical data will be summarized using contingency tables (frequencies and percentages).
The following rules will be followed for reporting results unless stated otherwise:
All data including efficacy, safety, and biomarker summaries will be provided by part and 
treatment group. Unless specified otherwise, Part I/Run-in and Part II will be presented 
separately and the outputs for Part II will be combined across all dose levels within each 
combination arm. The order of the arms for part II patients will be reported in the descending 
order based on the number of patients (N) receiving the combination treatment. All patients 
from a combination arm will be pooled together irrespective of their initial planned combination 
treatment dose level.
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Patients will be grouped for Part I/Run-in as follows:
Group A: Patients naive to selective BRAF and binimetinib inhibitors
Group B: Patients who progressed after treatment with single-agent BRAF or MEK inhibitor or 
the combination of BRAF/
binimetinib inhibitors (excluding encorafenib/binimetinib
combination)
Group C: Patients who progressed after treatment with encorafenib/binimetinib combination in 
other Sponsor studies
The treatment groups for reporting Part I/Run-in will be:

encorafenib 450mg + binimetinib 45mg (naive)

encorafenib 450mg + binimetinib 45mg (non-naive)

All patients (naive and non-naive)
The non-naive treatment group will summarize the period of dual combination treatment during 
the run-in for Group B patients and the screening phase for Group C patients.
The treatment groups for reporting Part II will be:

encorafenib+ binimetinib + ribociclib

encorafenib+ binimetinib + infigratinib

encorafenib+ binimetinib + buparlisib

encorafenib+ binimetinib + capmatinib 
2.1
Baseline
Baseline is the last available and valid assessment performed or value measured within 14 days 
before the first administration of study drug in each part (Part I/Run-in and Part II), unless 
otherwise stated (e.g., within 21[for Part I/Run-in]/28 [for Part II] days for baseline imaging 
assessment) under the related visit schedules and assessments section of the CSP (Section 7). 
For patients entering from Part I/Run-in to Part II or directly to Part II, the most recent of the 
end of study treatment assessments (Part I or Run-in or other studies e.g, Columbus, 
CMEK162X2110) or of the assessments done on Cycle 1 Day 1 before the start of study drug 
of any combination will be considered baseline for Part II. The summaries and listings for Part 
I/Run-in will be based on the assessments from the corresponding screening/baseline visits.
Baseline can be the day before first study drug 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). For certain assessments including triplicate ECG’s, multiple supine BP readings 
etc., an average of the multiple measurements will be considered as baseline.
If more than 1 baseline assessment is performed for any parameter, then the latest assessment 
prior to the first dose administration of the study treatment will be considered as the baseline.
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.
For biomarkers, the baseline will be considered for the following samples:  


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
Tumor samples: when archival and fresh samples are available at baseline only the fresh 
sample will be used as baseline. Only fresh samples analyzed at baseline and on-treatment 
should be considered for any PD markers. 

Blood samples: only one sample is foreseen for the /screening baseline, however, if it is 
the case that more than one assessment/value is available; the last valid pre-treatment 
assessments will be used as baseline. 
Patients with no data on a particular parameter before the first treatment administration will
have a missing baseline for this parameter.
2.2
Scheduled study visits and window for the analysis
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.  
2.3
Handling of Incomplete Dates
As of the date of data-cutoff for the purposes of reporting in a CSR:
Continuing events (e.g., adverse events, concomitant therapies, etc.) will be listed as continuing.
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event.
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study treatment, duration of exposure to study treatment and date of 
discontinuation for each patient.
Other missing data will simply be noted as missing on appropriate tables/listings.
For patients not known to have died prior to the cut-off date other than primary CSR:
All events (e.g., AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. 
For patients known to have died prior to or on the cut-off date:
If imputation of an end date is required for a specific analysis (e.g., a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed as the cut-off date or death date, whichever is earlier, to calculate e.g., the duration 
of exposure to study treatment. The imputed date will be displayed and flagged in the listings.
AE date imputation
The imputation of missing and partial dates for AE will be handled according to Section 10.1.
Concomitant medication date imputation
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. 


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Prior therapy date imputation
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.
Subsequent therapy date imputation
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.
3
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.  
The following analysis sets will be used.
3.1
Full Analysis Set
For Part I, the Full Analysis Set (FAS) consists of all patients who received at least one dose 
(partial or full) of encorafenib or binimetinib
For Part II, the FAS consists of all patients who received at least one dose of encorafenib or 
binimetinib or the assigned third agent following the assignment of the triple combination 
treatment.
Note that patients who were screened and/or are eligible but never started treatment for a study 
part will not be included in the FAS for that study part. This is considered as an acceptable 
deviation from the ITT principle in the context of a non-randomized exploratory study.


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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 treatment 
they have been assigned to.
3.2
Safety Set
The Safety Set includes all patients who received at least one dose of encorafenib or binimetinib
for Part I/Run-in or 3rd combination agent for Part II patients and have at least one valid post-
baseline safety assessment.
For each part (Part I/Run-in and Part II), patients will be classified according to treatment 
received, where treatment received is defined as:
1. The treatment assigned as a combination if it was received at least once in the first cycle, 
or
2. The first treatment received as a combination when starting therapy with study treatment if 
the assigned treatment was never received.
The Safety Set will be the primary analysis set for all safety related endpoints except DLT
related outputs.
3.3
Per-Protocol Set
The per-protocol set (PPS) consists of all Part II patients in the FAS who are compliant with the 
protocol in the following ways:
1. Diagnosis: histologically confirmed diagnosis of locally advanced or metastatic 
melanoma.
2. Stage of disease: stage IIIC to IV per American Joint Committee on Cancer [AJCC].
3. Prior treatment: Progressive disease following prior treatment with 
encorafenib/binimetinib combination.
4. The patient was evaluated at least once for the primary efficacy variable or discontinued 
due to adverse event, unacceptable toxicity, Investigator’s decision, patient’s refusal, 
disease progression, or died prior to the first evaluation of the primary efficacy variable.
5. Patients will be evaluable for efficacy if they have at least one response assessed 
differently from ‘unknown’ or ‘not assessed’ under RECIST v1.1.
The per-protocol set will be used in Part II to define the patients used in the sensitivity analysis 
of the primary endpoint.
3.4
Dose-Determining Set
The dose-determining analysis set (DDS) consists of all patients from the Safety Set for Part II 
who have met the minimum requirements for safety evaluation and minimum exposure or 
experienced DLT during the first cycle of the assigned triple combination treatment.
To complete the minimum safety evaluations a patient must be observed for at least 1 cycle (21 
days following the first dose of the combination treatment with infigratinib, or capmatinib ; 28 
days for the combination with ribociclib or buparlisib) and considered to have sufficient safety 
data by both the Sponsor and Investigators to conclude that a DLT did not occur during this 1st 
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Patients meet the minimum exposure requirements if they have received at least 16 out of the 
21 planned daily doses of the defined triple combinations.
Note: Patients treated in the ribociclib or buparlisib will meet the minimum exposure 
requirements if they receive at least 16 planned doses of the triple combination out of the first 
21 days of the cycle 1 (28 days).  All DLT related outputs will be based on the DDS.
3.5
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable pharmacokinetic (PK) data. The PAS will be used for summaries 
of PK data (tables and figures) as well as for listings of derived parameters.
4
Patient demographics and other baseline characteristics
Unless specified otherwise, summaries described in this section will be based on the FAS and 
presented by Part I/Run-in and Part II separately.
4.1
Basic demographic and background data
Demographic data including age, sex, race, ethnicity, height, weight, and ECOG performance 
status will be listed and summarized. In addition, age (<65, ≥65 years) and weight (<55, 55-75, 
≥75 kg) categories will be summarized. 
The summaries and listings for each part will be based on the assessments from the screening 
visit/baseline. Where screening/baseline variables are not collected for patients transitioning
from Part I/Run-in to Part II, the corresponding screening/baseline variables collected at the 
time of entering Part I/Run-in will be utilized.
4.2
Medical History
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be summarized and listed. Separate summaries will be presented for current 
and historical medical conditions by primary system organ class and preferred term. Medical 
history and current medical conditions are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology.
4.3
Prior antineoplastic therapy
Prior anti-neoplastic therapy will be summarized for three distinct subtypes (medication, 
radiotherapy, and surgery) in a single output.
The number (%) of patients who received, separately, any prior anti-neoplastic medication, 
radiotherapy or surgery will be summarized.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting and best response at last 
medication, time (in days) between end of last medication to start of study treatment. The last 
medication is defined based on the last end date of all prior regimen components. Prior 


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antineoplastic medications will also be summarized by Anatomical Therapeutic Chemical 
(ATC) class, and preferred term. 
The summary of prior anti-neoplastic radiotherapy will include the patients who had 
radiotherapy and the time (in months) between the last radiotherapy end date to start of study 
treatment. 
The summary of prior anti-neoplastic surgery will include the patients who had surgery and the 
time (in months) between the last surgery date (non-biopsy procedure) to start of study treatment.
4.4
Disease History
The summary of diagnosis and extent of cancer will include primary site of cancer, details of 
tumor histology/cytology, histological grade, stage at initial diagnosis, stage at time of study 
entry, time from initial diagnosis of primary site to start of study treatment (months), time from
initial diagnosis to first recurrence/relapse or progression (months), time since most recent 
recurrence/relapse or progression to start of study treatment (months), number of organs 
involved at baseline, current extent of disease (metastatic sites).
5
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who are still on-treatment presented by Part I/Run-in and Part II
(based on non-completion of the ‘End of Treatment’ page),

Number (%) of patients who discontinued treatment presented by Part I/Run-in and Part II
(based on completion of the ‘End of Treatment’ page with discontinuation date and reason 
entered),

Primary reasons for study treatment discontinuation presented by Part I/Run-in and Part II
(based on discontinuation reason entered in the ‘End of Treatment’ page),

Number (%) of patients who discontinued from study presented by Part I/Run-in and Part 
II (based on completion of the ‘End of post treatment phase disposition’ page with 
discontinuation date and reason entered)

Primary reasons for study evaluation completion presented by Part I/Run-in and Part II
(based on discontinuation reason entered in the ‘End of post treatment phase disposition’ 
page).
6
Protocol deviations
The number and percentage of patients with any protocol or non-protocol deviation will be 
tabulated by the deviation category (entry criteria not satisfied; wrong treatment or incorrect 
dose; developed withdrawal criteria, but not withdrawn; took an excluded concomitant 
medication; others) and will be listed.  Protocol deviations will be presented separately for Part
I/Run-in and Part II. 


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7
COVID-19 and Related Events
Study disruption due to COVID-19 will be reported in a summary table and a listing.
8
Treatments (study treatment, rescue medication, other 
concomitant therapies, compliance)
Unless otherwise noted, the Safety Set will be used for all medication data summaries.
Study drug and study treatment
Study drugs refer to encorafenib, binimetinib, ribociclib, capmatinib, infigratinib, or buparlisib. 
Study treatment refers to any combination of doses of either encorafenib+ binimetinib or 
encorafenib
+ binimetinib + third combination (ribociclib, capmatinib, infigratinib, or 
buparlisib).
Combination arm
This refers to the dual combination (encorafenib+ binimetinib) or triple combination, where 
third agent (ribociclib, capmatinib, infigratinib, or buparlisib) is added to the encorafenib+ 
binimetinib combination in Part II.
Date of first/last administration of study drug and study treatment
The date of first/last administration of study treatment is derived as the first/last date when a 
non-zero dose of any of the study drugs of the study treatment was administered and recorded 
on the Dosage Administration (ZQ) of the eCRF. For the sake of simplicity, the date of first/last 
administration of study treatment will also be referred as start/last date of study treatment.
Last date of exposure to study drug and study treatment
Last date of exposure to study treatment is derived as the last date among the study drugs 
received in a study treatment.
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. Part I/Run-in study day is defined as the event date from the first dose 
of dual combination treatment.  Part II study day is defined as the event date from the first dose 
of triple combination treatment.  For assessments/events occurring on or after the start date of 
study treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1.
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment.
Study day will be displayed in the data listings.
On-treatment assessments/events


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An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment + 30 days 
inclusive. 
Note: Assessment/events that occur to patients moving from Part I/Run-in to Part II before 30 
days of last study drug will be counted in the relevant combination arm of Part II.
8.1
Treatment Exposure and Compliance
Definitions of duration of exposure, cumulative dose, actual dose intensity (DI), planned dose 
intensity (PDI), relative dose intensity (RDI), percentage of days dosed, percentage of days the 
planned/intended dose was received, as well as intermediate calculations for each study drug of 
treatment groups include: 

Duration of exposure (days): last date of exposure to study treatment − first date of study 
treatment + 1 (periods of interruption are not excluded)

Duration of dose interruptions (days): Sum of all dose interruptions

Cumulative dose (mg): sum of all doses of study drug taken by a patient

Cumulative planned dose (mg): sum of all doses of study drug that was intended to have 
been taken during the treated period by a patient

DI (mg/day): cumulative dose (mg) ⁄ duration of exposure (days) 

PDI (mg/day): cumulative planned dose (mg) ⁄ duration of exposure (days) 

RDI (%): DI (mg/day) ⁄ PDI (mg/day)
Planned dose in Part I is 450 mg QD for encorafenib and 45 mg BID for binimetinib. Planned 
dose in Run-in and Part II with non-naïve treatment is the first non-zero dose in the respective 
period, given it is not a dosing error. Planned dose in Part II with triple combination of ribociclib
or capmatinib and actual treatment of encorafenib then considering the minimum of 200 mg 
QD or first dose per patient per actual dose, given it is not a dosing error. Planned dose in Part 
II with triple combination of ribociclib or capmatinib and actual treatment of binimetinib, 
capmatinib, or ribociclib is the first non-zero dose in the respective period, given it is not a 
dosing error. If actual dose is ribociclib and the subject only on the PER PROTOCOL OFF 
WEEKS (i.e., Reason for Dose Adjustment="AS PER PROTOCOL" and Total Daily Dose is 
zero) then the planned dose is zero for those subjects. If actual dose is infigratinib in Part II and 
Dose per Administration is greater than 60 mg QD then the Planned dose is equal to Dose per 
Administration, else planned dose is 60 mg QD. If actual dose is buparlisib in Part II and Dose 
per Administration is greater than 75 mg QD then the Planned dose is equal to Dose per 
Administration. Else if Dose per Administration is zero and Reason for Dose Adjustment="AS 
PER PROTOCOL", then the planned dose is zero, else Planned dose is 75 mg QD. Duration of 
exposure (in weeks) will be summarized for each combination, including the categories: <4, 4-
8, 8-12, 12-24, and >= 24 weeks. Additional categories may be evaluated depending on the 
distribution of the data. The DI and RDI (including categories: <0.5, 0.5-<0.75, 0.75- <0.9, 0.9-
<1.1, ≥1.1) will be summarized for each study drug. Number (n) and percentage (%) of patients 
who have dose reductions and interruptions, and the corresponding reasons, will be summarized. 
All doses of the study treatment along with reasons for any dose change will be listed.


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Dose interruption: An actual dose equal to zero (where the planned dose is not zero) between 
the first and last non-zero doses, following a non-zero actual dose and for which the reason is 
other than “as per protocol”.
Dose reduction: A decrease in dose from the protocol planned dose or a decrease from the 
previous non-zero dose, even if this decrease has been directly preceded by an interruption. For 
example, in the sequence of total daily dose 90 mg – 0 mg – 45 mg, the 45 mg dose will be 
counted as a reduction. 
8.2
Concomitant therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Concomitant therapies will be summarized by ATC class and preferred term. These summaries 
will include 1) medications starting on or after the start of study treatment but starting no later 
than 30 days after last dose of study drug and 2) medications starting prior to the start of study 
drug and continuing after the start of study treatment.
All therapies will be listed. Any therapies starting and ending prior to the start of study drug or 
starting more than 30 days after the last date of study treatment will be flagged in the listing. 
Note: Patients transitioning to Part II who receive concomitant therapies during their transition
to Part II prior to 30 days after last Part I/Run-in study drug will be counted in the relevant 
combination arm of Part II.
Anti-neoplastic therapies since discontinuation of study treatment will be listed and tabulated 
by ATC class and preferred term.
9
Efficacy Evaluation
9.1
Analysis of the primary endpoint
Evaluation of anti-tumor activity will be based on investigator assessment of overall lesion 
response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (see 
Protocol Appendix 14.8) by Part I/Run-in and Part II, separately. The FAS will be used to 
analyze the endpoints that evaluate anti-tumor activity.
Best Overall Response
Best Overall Response (BOR) is the best response recorded from the start of the treatment until 
disease/clinical progression or death or early study discontinuation, whichever happens earlier. 
However, any radiological assessments taken more than 30 days after the last dose of study 
therapy or after antineoplastic agents other than study treatments taken by the patients will be 
excluded from the best overall response derivation. 


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The follow-up periods required to classify overall response as SD should be at least 6 weeks 
after treatment start date. Confirmation of CR or PR should be at least 4 weeks apart from the 
previous radiological assessment. BOR will be considered missing if the patient does not have 
both baseline and at least one post-baseline RECIST assessment by the investigator.  
Number and percentage of patients with CR and PR (confirmed), SD, PD and unknown 
categories will be summarized. Any unconfirmed CR or PR as the best response will be counted 
in the SD category. Both ORR and Disease control rate (DCR) and their corresponding 95% 
confidence intervals (CIs) based on the exact binomial distribution will also be presented in the 
BOR table. Note: DCR is the proportion of patients with a best overall response of CR or PR 
or SD. The ORR and DCR will be calculated separately for confirmed and unconfirmed 
responses. A waterfall plot for best percent change from baseline (for sum of the longest 
diameters) will also be presented. 
BOR will be used to evaluate the tumor response in terms of Overall Response Rate (ORR) for 
combinations of encorafenib, binimetinib and the third agents. This will be based on 
investigator-assessed tumor evaluations per RECIST v1.1.
The ORR will be provided with a corresponding 95% confidence interval based on Clopper and 
Pearson’s method for all patients.  
In addition, since the encorafenib+ binimetinib+ ribociclib is expected to be the triple 
combination with the largest number of patients on study (approximately 40 patients), a 
Bayesian inference will be performed to estimate the true ORR of this combination to provide 
inferential summaries (e.g., mean, median, interval probabilities). The analysis will be 
performed when all patients in the respective group have completed at least 6 cycles of 
treatment or discontinued prior to that time for any reason.
A minimally informative unimodal Beta prior distribution of the true ORR is derived as follows. 
A priori it is assumed that the true mean of the ORR equals 20%. A true ORR of 20% is the 
midpoint between limited and clinically relevant 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 clinically relevant efficacy. The parameters of the minimally 
informative Beta prior distribution of the ORR are then derived as a = 1/4 and b = 1.
At completion of the study, this prior distribution will be updated with all of the data available 
in the encorafenib+ binimetinib+ ribociclib combination arm. Once updated, the probabilities 
that the true ORR lies in the following categories will be reported:

[0, 10%) unacceptable efficacy

[10%, 20%) limited efficacy

[20%, 30%) clinically relevant efficacy

[30%, 100%] highly clinically significant efficacy
If the observed ORR is equal to or greater than 20%, then this will be considered as preliminary 
evidence of clinically relevant efficacy of the combination. If the observed ORR is less than 20% 
(i.e. ≤ 7 CR or PR out of 40), then insufficient efficacy will be concluded.
Bayesian estimates (mean and 95% credible intervals) of the ORR will be provided.


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If the number of patients recruited to any other triple-agent combination within Part II exceeds 
30 patients, the ORR analysis will be performed for that combination in the same way as defined 
for the encorafenib+ binimetinib+ ribociclib combination.
The efficacy analysis for the encorafenib/ binimetinib+ ribociclib combination arm or other 
triple combination arms which exceed 30 patients will also be performed using the PPS. 
9.2
Analysis of the secondary endpoint(s)
Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from the start date of study drug (or study 
treatment for Part II) until documented disease progression or death due to any cause. All 
patients who have not progressed or died at the time of the data cut-off will be censored at the 
date of last tumor assessment (TA) other than those who are unknown or missing. 
Disease progression per RECIST 1.1 and death (from any cause) will be considered as events. 
If a patient has not had a documented event by the date of analysis cut-off or before (s)he 
initiates treatment with further anticancer therapy, the PFS will be censored at the date of last 
adequate tumor assessment (i.e. at the date of last tumor assessment of CR, PR or SD) prior to 
cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. In this case the 
last tumor evaluation date at that assessment is used. 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 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.
Censoring rules to be applied to the PFS endpoint are described in Table 8-1.
Table 9-1 Options for PFS analysis
Situation
Event Date
Outcome
A
No baseline assessment 
(1) Date of start of treatment*
Censored 
B 
No post-baseline assessment
(1) Date of start of treatment*
Censored 
C1 
Progression or death at or before 
next scheduled assessment 
(1) Date of progression (or death)
Progressed 
C2 
Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
Progressed 
D 
Progression or death after two or 
more missed assessments 
(1) Date of last adequate tumor 
assessment** 
Censored
E
No progression or death
(1) Date of last adequate tumor 
assessment**
Censored 
F
New anti-neoplastic therapy given
(1) Date of last adequate tumor 
assessment** 
Censored
* 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. 


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** tumor assessment with non-missing and non-unknown overall lesion response
An exact rule to determine whether there is none, one, or two missing tumor assessments is 
needed.  This rule will be based on the distance between the last adequate tumor assessment 
date and the event date.  If the distance is larger than the threshold D1 or D2 then the analysis 
will assume one or two missing tumor assessments, respectively.  The threshold D1 will be 
defined as the protocol specified interval between the TAs plus the protocol allowed window 
around the assessments. Similarly, the threshold D2 is defined as two times the protocol 
specified interval between the TAs plus the protocol allowed window around the assessments.  
As per protocol, tumor assessments are expected as follows:

Part I (Group A)
o
Evaluated for all potential sites of tumor lesions at screening/baseline. 
o
First post-baseline tumor assessment should be performed 6 weeks ±3 days 
after starting treatment.
o
Subsequent tumor assessments should be performed every 6 weeks ±7 days 
thereafter until disease progression.
o
Once patients have completed ≥ 24 months of study treatment, the frequency of 
tumor assessments can be reduced to every 6-12 weeks ±7 days based on 
Investigator discretion.
o
Patients who discontinue study treatment due to a reason other than disease 
progression should undergo tumor assessments every 9 weeks ± 7 days until 
disease progression or initiation of subsequent anti-neoplastic therapy, or 
death, whichever occurs first.
o
Patients who have completed ≥ 24 months of study treatment and then 
discontinue study treatment due to a reason other than disease progression 
should undergo tumor assessments every 9-12 weeks ± 7 days until disease 
progression or initiation of subsequent anti-neoplastic therapy, or death, 
whichever occurs first.

Run-in (Group B)
o
Evaluated for all potential sites of tumor lesions after receiving ≥21 days of 
study treatment. 
o
First post-baseline tumor assessment should be performed 3 weeks ±3 days 
after starting treatment.
o
Subsequent tumor assessments should be performed every 6 weeks ±7 days 
thereafter until disease progression.
o
Once patients have completed ≥ 24 months of study treatment, the frequency of 
tumor assessments can be reduced to every 6-12 weeks ±7 days based on 
Investigator discretion.
o
Patients who discontinue study treatment due to a reason other than disease 
progression should undergo tumor assessments every 9 weeks ± 7 days until 
disease progression or initiation of subsequent anti-neoplastic therapy, or 
death, whichever occurs first.


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o
Patients who have completed ≥ 24 months of study treatment and then 
discontinue study treatment due to a reason other than disease progression 
should undergo tumor assessments every 9-12 weeks ± 7 days until disease 
progression or initiation of subsequent anti-neoplastic therapy, or death, 
whichever occurs first.

Part II
o
Baseline assessments must be completed within 28 days of the previous 
assessment performed in Part I/Run-in. For patients in Group C assigned to 
ribociclib, the assessment must be completed within 28 days before triple 
combination first dose.
o
First post-baseline tumor assessment and subsequent tumor assessments should 
be performed 9 weeks ± 7 days after starting treatment until disease 
progression.
o
Patients who discontinue study treatment due to a reason other than disease 
progression should undergo tumor assessments every 9 weeks ± 7 days until 
disease progression or initiation of subsequent anti-neoplastic therapy, or 
death, whichever occurs first.
Therefore, for Group A:

if the last adequate tumor assessment is performed between study day 1 and 
study day 21 (inclusive) 
1. and the patient has not discontinued treatment as of 45 days after the 
last assessment for D1 and 91 days after the last assessment for D2, 
then D1=6*7+3=45 days and D2=2*6*7+7=91 days.
2. and the patient has discontinued treatment as of 45 days after the last 
assessment, then D1=9*7+3=66 days and D2=2*9*7+7=133 days.
3. and the patient has discontinued treatment between 45 days and 91 days 
(exclusive) after the last assessment, then D2=6*7+9*7+7=112 days.

if the last adequate tumor assessment is performed between study day 22 and 
study day 42 (inclusive) 
1. and the patient has not discontinued treatment as of 52 days after the 
last assessment for D1 and 94 days after the last assessment for D2, 
then D1=6*7+3+7=52 days and D2=2*6*7+3+7=94 days.
2. and the patient has discontinued treatment as of 52 days after the last 
assessment, then D1=9*7+3+7=73 days and D2=2*9*7+3+7=136 days.
3. and the patient has discontinued treatment between 52 days and 94 days 
(exclusive) after the last assessment, then D2=6*7+9*7+3+7=115 days.

if the last adequate tumor assessment is performed between study day 43 and 
study day 652 (inclusive) 
1. and the patient has not discontinued treatment as of 56 days after the 
last assessment for D1 and 98 days after the last assessment for D2,
then D1=6*7+2*7=56 days and D2=2*6*7+2*7=98 days.


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2. and the patient has discontinued treatment as of 56 days after the last 
assessment then D1=9*7+7=77 days and D2=2*9*7+2*7=140 days.
3. and the patient has discontinued treatment between 56 days and 98 days 
(exclusive) after the last assessment, then D2=6*7+9*7+2*7=119 days.

if the last adequate tumor assessment is performed between study day 653 and 
study day 694 (inclusive), then D1=6*7+2*7=56 days and D2 = 
(6+12)*7+2*7=140 days;

otherwise, when the last adequate tumor assessment is performed after study 
day 694, then D1 = 12*7+2*7=98 days and D2 =2*12*7+2*7=182 days.
For Group B:

if the last adequate tumor assessment is performed between study day 1 and 
study day 21 (inclusive) 
1. and the patient has not discontinued treatment as of 24 days after the 
last assessment for D1 and 91 days after the last assessment for D2, 
then D1=3*7+3=24 days and D2=3*7+6*7+7=73 days.
2. and the patient has discontinued treatment as of 24 days after the last 
assessment, then D1=9*7+7=70 days and D2=2*9*7+7+ 7=140 days.
3. and the patient has discontinued treatment between 24 days and 73 days 
(exclusive) after the last assessment, then D2=3*7+9*3+7=91 days.

if the last adequate tumor assessment is performed between study day 22 and 
study day 652 (inclusive) 
1. and the patient has not discontinued treatment as of 56 days after the 
last assessment for D1 and 98 days after the last assessment for D2, 
then D1=6*7+7+7=56 days and D2=2*6*7+2*7=98 days.
2. and the patient has discontinued treatment as of 56 days after the last 
assessment, then D1 =9*7+7=77 days and D2=2*9*7+2*7=140 days.
3. and the patient has discontinued treatment between 56 days and 98 days 
(exclusive) after the last assessment, then D2=6*7+9*7+2*7=119 days.

if the last adequate tumor assessment is performed between study day 653 and 
study day 694 (inclusive), then D1=6*7+2*7=56 days and D2 = 
(6+12)*7+2*7=140 days;

otherwise, when the last adequate tumor assessment is performed after study 
day 694, then D1 = 12*7+2*7=98 days and D2 =2*12*7+2*7=182 days.
For Part II

if the last adequate tumor assessment is performed between study day 1 and 
study day 21 (inclusive) for encorafenib/ binimetinib + infigratinib, capmatinib


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patients, or between study day 1 and study 28 (inclusive) for encorafenib/
binimetinib + ribociclib, buparlisib patients then D1=9*7+7=70 days and 
D2=2*9*7+7=133 days.

if the last adequate tumor assessment is performed after study day 21 for 
encorafenib/ binimetinib+ infigratinib,  capmatinib patients, or after study day 
28 for encorafenib/ binimetinib+ ribociclib, buparlisib patients then 
D1=9*7+7+7=77 days and D2=2*9*7+7+7=140 days.
Therefore, using the D2 definition above, the censoring of an event occurring after ≥2 missing 
TAs (in primary PFS analysis) can be refined as follows: if the distance between the last 
adequate tumor assessment date and the PFS event date is larger than D2 then the patient will 
be censored, and the censoring reason will be 'Event after >= 2 or more missing assessments'.
A Kaplan-Meier plot for PFS will be presented limited to the groups where at least 10 events 
occur in each of the combination arms. Median PFS (in months) with corresponding 95% CI, 
25th and 75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% 
CIs (Brookmeyer and Crowley, 1982) at several time points (including at least 6, 12, 18, and 
24 months) will be presented. Censored reasons will also be summarized.
Note: 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.
Overall Survival (OS) (Part II only)
Overall survival is defined as the time from the start date of study treatment (3rd agent combined 
with encorafenib and binimetinib) until the date of death due to any reason. A patient who is 
still alive at the time of last known contact will be censored at the time of last known contact.
OS will be presented graphically using Kaplan Meier plots by combination arm. In addition, 
the OS will be listed and will be summarized by presenting the median OS time with 
accompanying 95% CI along with the Kaplan-Meier estimates for the OS rate with 
corresponding 95% CI at 6, 12, 18 and 24 months.
Duration of response 
Duration of response (DOR) will be calculated for “responders” (confirmed) only and is defined 
as 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 tumor 
assessment other than unknown. A listing and a K-M plot with median and 95% CIs will be 
reported.
Time to response
Time to response (TTR) will be calculated for “responders” (confirmed) only and is defined as 
the time between the start date of study drug and first documented response (CR or PR). A 
listing and K-M plot with median and 95% CIs will be reported.


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Construction of waterfall graphs
The waterfall graph will be used to depict anti-tumor activity. This graph displays the best 
percentage change from baseline in the sum of diameter of all target lesions for each patient. 
Patient with unknown/missing best percentage change from baseline will be excluded from this 
graph.
The waterfall graph will use the response based on investigator assessment evaluated by 
RECIST 1.1.
The best overall response (BOR) will be shown above each of the displayed bars in the graph.
The following display will be used (from left to right) in the descending order:
1. Bars above the horizontal axis representing tumor growth
2. Bars below the horizontal axis representing tumor shrinkage
Patients from Part I, Run-in, and Part II will be presented in separate plots.  


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10
Safety and tolerability evaluation
The safety and tolerability of encorafenib/ binimetinib and their combination with a third 
targeted agent will be assessed for incidence and severity of adverse drug reactions and serious 
adverse drug reactions (as assessed by CTCAE Version 4.03), changes in hematology and 
chemistry values, physical examinations, vital signs, electrocardiogram, cardiac monitoring, 
ophthalmological and dermatological examinations. Tolerability assessments include exposure 
and dose reductions/interruptions.
The Safety Set will be used for summaries and listings of safety data.
The safety summary tables (except deaths) will only include 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.
Note: AE’s that occur in patients moving to Part II prior to 30 days after last Part I/Run-in study 
drug will be counted in the relevant combination arm of Part II.
10.1
Adverse event
AEs will be coded using the latest version of MedDRA available prior to clinical database lock 
and will be graded using CTCAE version 4.03. CTCAE grade 5 (death) will not be used in this 
study. Death information will be collected on the “End of Treatment” or “Survival Information” 
eCRF pages.
All treatment-emergent AEs (new or worsening from baseline) will be summarized (counts (n) 
and percentage (%)) by system organ class and preferred term and severity grades (split by ‘All 
grades’ and ‘Grade 3/4’), or only by preferred term, except where otherwise noted. Patients 
with a Grade 5 AE will be included in the “All grades” category but will not be included in the 
“Grade 3/4" category. Listings of adverse events of special interest will be based on the case 
retrieval strategy.
The following AE summaries will be produced:

Overall summary of AEs

AEs regardless of study drug relationship 

AEs of special interest (encorafenib) only for Part I/Run-in

AEs of special interest (binimetinib) only for Part I/Run-in

AEs suspected to be study drug related 

AEs leading to discontinuation of study drug

AEs requiring dose adjustment or study drug interruption

SAEs regardless of study drug relationship

Deaths by primary system organ class and preferred term
The following AE listings will be produced:

AEs

SAEs

AEs leading to study drug discontinuation


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
AEs of special interest (encorafenib) (separate listings for all AESI and grade 3/4)

AEs of special interest (binimetinib) (separate listings for all AESI and grade 3/4)

All deaths
A patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. A patient with multiple occurrences of an AE is counted only once 
in the AE category (system organ class, preferred term etc.).
Missing and partial date for AE will be handled according to rules specified below. 
Completely missing AE start dates will not be imputed. Partial AE start dates missing the year 
will be imputed to the earlier of the non-imputed AE end date – 1 day or the treatment start date 
– 1 day. Treatment start date for Part I/Run-in is defined as the date of the first dose of dual 
combination treatment.  Treatment start date for Part II is defined as the first dose of triple 
combination treatment.  
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-up date.
A missing AE start date will be imputed using the following logic matrix described in Table 
10-1
Table 10-1
AE start date imputation example scenarios
Partial
AE start date
Treatment
start date*
Temporal 
relationship 
compared to 
treatment start 
Imputed Date
Missing
20OCT2001
Uncertain
Missing start date will not be imputed. 
AE treatment emergent flag for both 
Parts I & II will be set to “Y”
ddmmm2000
20OCT2001
Before
01JUL2000
ddmmm2002
20OCT2001
After
01JAN2002
ddmmm2001
20OCT2001
Uncertain
21OCT2001
ddSEP2001
20OCT2001
Before
15SEP2001
ddOCT2001
20OCT2001
Uncertain
21OCT2001
ddNOV2001
20OCT2001
After
01NOV2001
*AE start date will be imputed based upon Part I/Run-in first dose date and Part II first dose date, respectively. The treatment emergent AE 
flag for Part I/Run-in and Part II will be defined correspondingly.   AEs with Part II imputed start date that occur before 30 days of last study 
drug of Part I/Run-in and after treatment start date of Part II will be counted only in the relevant combination arm of Part II.
Table 10-2 provides examples of the different considered imputations for AE end date.


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Table 10-2
AE end date imputation example scenarios
Partial
AE end date
Minimum (Last 
contact date, 30-
day FU date)
Ongoing 
Imputed Date
Missing
20OCT2001
Yes
20OCT2001
ddmmm2000
20OCT2001
No
31DEC2000
ddmmm2002
20OCT2001
No
31DEC2002
ddmmm2001
20OCT2001
No
      20OCT2001
ddmmm2001
20OCT2001
Yes
      31DEC2001
ddSEP2001
20OCT2001
No
30SEP2001
ddOCT2001
20OCT2001
No
20OCT2001
ddOCT2001
20OCT2001
Yes
31OCT2001
10.2
Laboratory data
Laboratory data will be converted into SI units and classified into CTCAE grades according to 
CTCAE v4.03 as applicable. Grade 5 will not be used.
Values entered as “<x”, with x a numerical value, will be considered as x for the analysis.
For cases when the CTCAE grade definition includes change from baseline criteria (e.g., 
creatinine, ejection fraction, fibrinogen, hemoglobin, international normalized ratio [INR]): 
When a lab value is of Grade X based on threshold/ranges, but Grade X+1 when considering 
change from baseline, the final grade is set to X+1. For other cases, a Grade 0 CTCAE grade 
will be set when laboratory value is:

Within LLN and ULN and grading in both directions,

Below ULN and grading in hyper direction,

Above LLN and grading in hypo direction.
Laboratory data for which a CTCAE grading does not exist will be classified into low, normal, 
or high based on local laboratory normal ranges as applicable.
The following summaries will be produced by laboratory parameter:

For lab parameters with CTCAE grades: Shifts from baseline to the worst post-baseline 
CTCAE grade

For laboratory parameters with no CTCAE grades defined: Shifts from baseline to the 
worst post-baseline using low/normal/high classifications

Hy’s law (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 3 x 
ULN with total bilirubin > 2 x ULN and alkaline phosphatase [ALP] < 2 x ULN) to assess
drug-induced liver injury
The following listings will be produced:

Listing of patients with laboratory abnormalities of CTCAE Grade 3 and 4,

Listing of laboratory normal ranges by laboratory identification number and laboratory 
group


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
Listing of all laboratory data with values flagged to show corresponding CTCAE grades 
and the classifications relative to the laboratory reference ranges (i.e., High [H] or Low 
[L])
Table 10-3 and Table 10-4 list all laboratory parameters that will be summarized.
Table 10-3
Laboratory parameters (and directions) for which CTCAE grades are 
defined
Hematology and coagulation
Biochemistry
Urinalysis
White blood cells (WBC)
↑↓
Creatinine
↑
Protein              ↑
Hemoglobin
↑↓
Sodium
↑↓
Platelets counts
↓
Potassium 
↑↓
Absolute neutrophils
↓
Glucose
↑↓
Absolute lymphocytes
↑↓
Calcium
↑↓
INR
↑
Magnesium 
↑↓
Albumin
↓
AST (SGOT)
↑
ALT (SGPT)
↑
Total bilirubin
↑
Inorganic phosphorus
↓
Amylase
↑
Lipase
↑
GGT
↑
Creatine kinase/CPK
↑
Alkaline phosphatase
↑
Uric acid
↑↓
↑ Indicates that CTCAE grade increases as the parameter increases.
↓ Indicates that CTCAE grade increases as the parameter decreases.


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Table 10-4
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined
Hematology and coagulation
Biochemistry
Prothrombin time (PT)
Urea or BUN
Hematocrit
Total protein
Basophils
Eosinophils
Monocytes
Fibrinogen
Bicarbonate
Fasting plasma glucose, and HbA1c
A shift table from worst post-baseline value will be produced based on CTC grade for FPG.
10.2.1
Urinalysis
Urinalysis including, pH, ketones, leukocytes, protein, glucose, and blood will be listed. A 
microscopic urinalysis of RBC and WBC will also be listed. 
10.3
Vital signs
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), respiratory rate (breaths per minute), body temperature (°C), and weight 
(kg). Vital sign values considered notably abnormal are defined in Table 10-5.
Table 10-5
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values
Systolic blood pressure 
[mmHg]
≥160 mmHg/≤90 mmHg with increase/decrease from baseline of 
≥20 mmHg
Diastolic blood pressure 
[mmHg]
≥100 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
Body temperature [°C]
37.5; ≤ 36
Weight [kg]
≥20% decrease/increase from baseline
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced.
10.4
Electrocardiograms
10.4.1
ECG data descriptive statistics
Baseline for electrocardiogram (ECG) analysis is defined as the average of all available ECG 
measurements associated with the baseline assessment. Scheduled study Day 1 pre-dose ECGs 
will be considered to have been obtained prior to study drug administration if dosing time is 


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missing. If a scheduled pre-dose measurement occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
The following summaries will be provided for each applicable ECG parameter:

For each QT interval (QT, QTcF), shift tables based on notable QT interval categories
(≤450, >450 - ≤480, >480 - ≤500, >500 ms) at baseline to the worst post-baseline value
observed,
10.5
Other safety analyses
10.5.1
Left Ventricular Ejection Fraction (LVEF)
A table summarizing the worst change from baseline and worst absolute change from baseline 
LVEF will be provided. The worst value is defined as lowest post-baseline value and the worst 
absolute value is the difference between the worst value and the baseline value. 
10.6
Pharmacokinetic data
All PK analyses will use the FAS. PK analyses will be performed for all subjects in the FAS, 
where possible; however, only subjects included in the PAS will be presented in PK data 
summaries (tables and mean/median plots).
10.6.1
Plasma Concentrations
For Part II of the protocol, blood samples will be collected for the assessment of encorafenib, 
binimetinib (including its primary active metabolite AR00426032), ribociclib (and its 
metabolite LEQ803), buparlisib (including its active metabolites BHS697 and CQM157), 
infigratinib, and capmatinib at the following times:
28-day Cycles
Cycle 1
Day 1 (1.5 and 4 hours), Day 8 (pre-dose), Day 15 (pre-dose, 0.5, 1.5, 2.5, 4, 6, 
8, and 24 hours), and Day 21 (pre-dose).
Cycle 2
Days 1 and 15 (pre-dose).
Cycles 3-5
Day 1 (pre-dose).
21-day Cycles
Cycle 1
Day 1 (1.5 hours), Day 8 (pre-dose), and Day 15 (pre-dose, 0.5, 1.5, 2.5, 4, 6, 8, 
and 24 hours).
Cycle 2
Days 1 and 15 (pre-dose).
Cycles 3-5
Day 1 (pre-dose).
Additional end of treatment (EOT) samples will be collected for each regimen, and unscheduled 
samples may also be collected, where deemed necessary.
The plasma concentration/time data will be summarized by treatment group, dose and 
formulation (when applicable) and listed on a per patient basis; concentration summaries will 
include the number of observations (n), number of non-missing observations (n*), mean, 
standard deviation (SD), CV% mean, geometric mean, CV% geo-mean, median, minimum, 
and maximum. Arithmetic mean concentration-time profiles will be presented by treatment 


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group for Cycle 1 Day 15, and separate individual concentration-time course with median 
overlaid will also be presented by treatment group.
10.6.2
PK Parameter Analysis
Non-compartmental PK analysis will be performed using Phoenix WinNonlin®, Version 8.3 or 
higher (Certara USA, Inc., Princeton, NJ, USA). PK parameters for encorafenib, binimetinib 
(including its primary active metabolite AR00426032), ribociclib (including its metabolite 
LEQ803), buparlisib (including its active metabolites BHS697 and CQM157), infigratinib, and 
capmatinib will be determined for all PK-evaluable patients.
The PK parameters listed in Table 10-6, but not limited to, will be estimated and reported for 
all subjects in Cycle 1 (Day 15 only), as appropriate.
Table 10-6
Non compartmental pharmacokinetic parameters
Term
Definition
AUCtau, ss
Area under the concentration-time curve from time zero to time tau at steady-state 
AUCtau, ss/D
Area under the concentration-time curve from time zero to time tau at steady-state normalized 
by actual dose administered
Cmax, ss
The maximum (peak) observed plasma concentration (Cmax) after drug administration at 
steady state 
Cmax, ss/D
The maximum (peak) observed plasma concentration (Cmax) after drug administration at 
steady state normalized by actual dose given
Tmax, ss
The time to reach Cmax at steady state 
Ctrough, ss
Measured concentration at the end of a dosing interval at steady-state (taken directly before 
next administration) 
Clast, ss
Last measurable plasma concentration at steady state 
T1/2, ss
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve at steady state.
CL,ss/F
Apparent total plasma clearance of drug after oral administration at steady state (for parent 
drugs only) 
Vz,ss/F
The apparent volume of distribution at the terminal elimination phase at steady state (for 
parent drugs only)
MR_Cmax
The metabolite ratio of Cmax, estimated as: Cmax,ss (Metabolite) / Cmax,ss (Parent), 
corrected for molecular weight [estimated for AR00426032, LEQ803, BHS697 and CQM157 
only]
MR_AUC
The metabolite ratio of AUC, estimated as: AUCtau,ss (Metabolite) / AUCtau,ss (Parent), 
corrected for molecular weight [estimated for AR00426032, LEQ803, BHS697 and CQM157 
only]
Note: it is assumed that C1D15 is at steady state. Cmax,ss/D and AUC,ss/D will be reported separately for
treatments where a formulation switch had occurred.
PK parameters will be summarized by treatment group, dose and formulation (when applicable)
using the following descriptive statistics according to Table 10-7. 


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Table 10-7
PK parameters – descriptive statistics
Parameters
Descriptive statistics
AUCtau,ss, AUCtau,ss/D, 
Cmax,ss, Cmax,ss/D, Ctrough,ss, 
Clast,ss, Cl,ss, T1/2,ss, CL,ss/F, 
Vz,ss/F, , MR_Cmax, MR_AUC
Number of observations (n), mean, standard deviation
(SD), CV% mean, geometric mean, CV% geo-mean, 
median, minimum, and maximum.
Tmax,ss
Median, minimum, and maximum.
ss – steady state (assumed on C1D15)
CV% = coefficient of variation (%) = sd/mean*100
CV% geo-mean = sqrt (exp (variance for log transformed data)-1)*100
10.6.3
Pharmacokinetic Data Handling
All concentrations of encorafenib, binimetinib, AR00426032, ribociclib, LEQ803, buparlisib, 
BHS697, CQM157, infigratinib and capmatinib below their respective lower limits of quantification 
(LLOQ) or missing data will be labeled as such where applicable. Concentrations below the LLOQ 
will be treated as zero in summary statistics and for the calculation of PK parameters. 
Patients may be removed from the estimation of certain PK parameters on an individual basis when 
the PK parameters cannot be reliably estimated based on the available blood samples. These patients 
will be identified prior to the time of the data analysis. Only PK blood sample with date and time 
and for which the last prior dose dates and times are adequately recorded will be included in the PK 
analyses. For test articles administered in BID regimens, the 24 h time point on Day 15 will have 
the actual time since dose (in hours) on Day 15 subtracted by 12 to estimate AUCtau,ss over an 
appropriate dosing interval. 
Plasma concentrations and PK parameters will be flagged in concentration and PK parameter 
data listings and excluded from all summary tables, mean figures, and statistical analyses of PK 
data if the following occur:

Patient experienced vomiting or diarrhea within 4 hours of dosing. 

The planned dose was not administered (i.e., a change in dose occurred before the 
sampling occasion).

Steady state was not deemed to have been achieved (i.e. dosing is required for a 
minimum 2 consecutive days prior to the collection of steady state samples).

PK blood samples were collected outside the following time windows:
Scheduled time point
Window
Pre-dose
Before dosing
- 2 h
Post-dose
0.5 hours
± 10 min
1.5 hours
± 15 min
2.5 hours
± 15 min
4 hours
± 30 min
6 hours
± 30 min
8 hours
± 1 h
24 hours
± 2 h


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10.7
Biomarkers
There may be circumstances when a decision is made to stop sample collection, or not perform 
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 perform a rigorous data analysis and the available data will be 
limited to listings. 
The data analysis and reporting required to support the writing of the CSR will be included in 
this analysis plan. Additional or complementary analyses of biomarker and imaging data may 
be described in a stand-alone biomarker and imaging analysis plan document (BIAP).
The following table provides the details of the biomarker data collection and any planned 
statistical analyses:
Table 10-8 Biomarkers and assessments 
Biomarker
Visit/Time point
Method
Datatype
Molecular status (mutation/ 
amplification/ expression) of 
markers related to 
RAF/MEK/ERK pathway, 
PI3K/AKT pathway or cancer 
(e.g. BRAF, RAF1[, KRAS, 
NRAS, PTEN, PIK3CA, 
MAP2K1, MAP2K2, MET, 
FGFR1, FGFR2, FGFR3, 
FGFR4, CCND1, CDK4, 
ERBB2, IGF-1R, EGFR) in 
archived/fresh tumor
Archived: Anytime during 
Part I, Run-in, Part II
Fresh tumor sample: 
Screening/Baseline - Prior to first 
dose Part I and Run-in Part II 
15 days after start of triple 
combination (part II)
At the time of progression (Part I, 
Run-in, Part II)
Somatic 
mutation, Next 
generation 
sequencing 
Categorical
PD markers (such as pERK, 
pAKT, p-pRB) from fresh 
biopsy tumors
Fresh tumor sample: 
Screening/Baseline - Prior to first 
dose Part II 
15 days after start of triple 
combination (part II)
Immunohisto-
chemistry
Continuous
1. Archival tumor sample is collected in Part II only from patients in Group C.
2. Newly obtained tumor biopsy is collected at molecular pre-screening or at the screening/baseline visit from patients in 
Group C, who cannot provide the progression biopsy from the previous study.
CCI


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10.7.1
Biomarker data
Biomarker analysis data set
The Full Analysis Set will be used for all biomarker analysis. Unless otherwise specified, all 
statistical analyses of biomarker data will be performed on patients with biomarker data.
Baseline
The samples analysed before the start of study treatment (Cycle 1 Day 1) would be considered 
as the baseline value for any PD markers. Where replicate measurements are available at any 
other timepoint other than baseline, the average of the measurements will be used for statistical 
summary and analyses.
Molecular Alteration
Molecular Alteration is defined at the baseline for Part II (EOT for RUNIN/ EOT for Part I/ 
SCREENING for Part II) for each tumor biomarkers (BRAF, KRAS, NRAS, HRAS, CDKN2A, 
CDK4, MAP2K1).  Molecular Alteration is used to identify the individual patient’s tumor 
sample upon progression. The triple combination to be evaluated in an individual patient will 
be based on the molecular alteration(s) detected at progression after BRAF/MEK inhibitor 
combination treatment and, alterations identified by amino acid change(Y), amplification (A)
and/or loss (L). For each tumor biomarkers (KRAS, NRAS, HRAS, CDKN2A, CDK4, 
MAP2K1), the Molecular Alteration is Y when subcategory for lab test is “SHORT VARIANT”,
and the examination name is “AMINO ACID CHANGE” with a non-missing value. Molecular 
Alteration is A when subcategory for lab test is “COPY NUMBER VARIANT” and the 
examination name is “COPY NUMBER RATIO” with value is greater than 1. Molecular 
Alteration is L when subcategory for lab test is “COPY NUMBER VARIANT” and the 
examination name is “COPY NUMBER RATIO” with value less than 1.  For tumor biomarkers 
BRAF, the Molecular Alteration is Y when subcategory for lab test is “SHORT VARIANT”,
and the examination name is “AMINO ACID CHANGE” and the value is not missing or not in 
(“V600E” and “V600K”). Molecular Alteration is A when subcategory for lab test is “COPY 
NUMBER VARIANT” and the examination name “COPY NUMBER RATIO” with value 
greater than 1.  Molecular Alteration is L when subcategory for lab test is “COPY NUMBER 
VARIANT” and PFTEST is “COPY NUMBER RATIO” with value less than 1. There is no 
molecular alteration if any of the criteria are met. Apply imputation if we have missing date for 
checking baseline, The imputation of the start date of Molecular Alteration will follow the same 
conventions as for AE start date. 
10.7.2
Reporting (summary) and analyses of Biomarker data 
Genomic biomarkers with tests such as Copy Number Ratio, Genomic Position and Amino Acid 
Change for each Tumor biomarkers (BRAF, RAF1CRAF, KRAS, NRAS, PTEN, PIK3CA, 
MAP2K1, MAP2K2, c-MET, FGFR1, FGFR2, FGFR3, FGFR4FGFRs, CCND1, CDK4, 
ERBB2HER2, IGF-1R, EGFR) will be summarized.
Overall summary for triple combination of
Ribociclib using Kaplan Meier method by
Molecular alteration for each tumor biomarker (BRAF, KRAS, NRAS, HRAS, CDKN2A, 
CDK4, MAP2K1) will be calculated.


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Change from baseline at 15 days after start of triple combination (part II) and at the time of 
Cycle 1 Day 15 in the PD markers (such as pERK, pAKT, PTEN) will be summarized.  
11
Sample size calculation 
Part II encorafenib/binimetinib+ ribociclib arm
About 140 patients are expected to enroll in Part II of the study to address the primary objective 
of the study. From these 140 patients, it is anticipated that about 30% of patients progressing 
on encorafenib+ binimetinib would be eligible to the encorafenib+ binimetinib+ ribociclib arm. 
With 140 patients recruited it would give 89% probability that the number of patients assigned 
to the ribociclib arm will be at least 36.
Based on the ORR (per RECIST 1.1) intervals described in Section 8.1, it was assessed how 
likely it is to wrongly declare activity as defined by observing at least “clinical relevant efficacy” 
(i.e. seeing at least 8 responses out of 40 patients) given the true ORR = 10%, and how likely it 
is to correctly declare activity given the true ORR = 30% when 40 patients are evaluated.

If the true ORR = 10%, the probability to wrongly declare activity is 4.2%.

If the true ORR = 30%, the probability to correctly declare activity is 94.5%.
Given a sample size of 40, if 8 responses are seen, the observed ORR is 20% with a 90% credible 
interval of (10.8%, 30.9%). This will be considered as preliminary evidence of antitumor 
activity of the treatment at the MTD/RP2D within this arm.
Part II other arms
Dose escalation in Part II will proceed with groups of at least 3 evaluable patients receiving 
triple combination therapy at the current dose levels. At least six patients must be included at 
the MTD/RP2D level for each triple combination. Additional patients may be enrolled at any 
dose level below the current dose if this dose has not been tested before and if there are already 
3 evaluable patients enrolled. Any dose level below the estimated MTD/RP2D may be expanded 
for further elaboration of safety and pharmacokinetic parameters as required. 


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12
References 
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat.Med.; 17 (10):1103-1120.
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat.Med.; 27 (13):2420-2439.
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin.Trials; 7 (1):5-18.