Conditions: Locally Advanced or Metastatic NRAS Mutant Melanoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 102
Healthy volunteers: no

Brief summary:
In the phase Ib, the primary purpose is to establish the maximum tolerated dose (MTD)(s)/recommended phase ll dose (RP2D) and schedule of LEE011 and MEK162 orally administered combination. Once the MTD(s)/RP2D have been determined for each tested schedule, additional patients will be enrolled in the phase II portion of the study at the RP2D on the chosen schedule in order to assess the anti-tumor activity of the combination in addition to continued evaluation of safety.

Detailed description:

Arms:
arm 1: The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients receiving various dose pairs considering the recommendation from an adaptive BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. If multiple alternate dosing schedules are explored in parallel, the allocation of patients will proceed in an alternating fashion. Approximately 40 patients are expected to be treated during the phase Ib part of the study.

Dosing Schedule 1: MEK162 administered orally twice daily on a continuous dosing schedule. LEE011 administered orally once daily for 21 days followed by a 1 week break (28-day cycle).

Dosing Schedule 2: MEK162 administered orally twice daily and LEE011 administered orally once daily for 3 weeks followed by a 1 week break (28-day cycle).

Dosing Schedule 3: MEK162 administered orally twice daily and LEE011 administered once daily for 2 weeks followed by a 1 week break (21-day cycle). arm 2: The Phase II part will begin once the MTD(s)/RP2D have been determined in the Phase Ib in order to assess antitumor activity of the LEE011and MEK162 combination. Patients enrolled in the Phase II part of the study are required to have measurable disease. Approximately 40 patients will be treated in this part.

Phase II part will begin at the RP2D on the chosen schedule in order to assess antitumor activity of the LEE011 and MEK162 combination.

Interventions: intervention 1: LEE011 intervention 2: MEK162
Intervention descriptions: intervention 1: LEE011 will be administered orally once daily intervention 2: MEK162 will be administered orally twice daily

Protocol document:
Prot_001.pdf: 
 
 
 
Clinical Development 
LEE011/MEK162 
Clinical Trial Protocol CMEK162X2114 
A phase Ib/II, multicenter, open label, study of LEE011 in 
combination with MEK162 in adult patients with NRAS 
mutant melanoma 
Document type 
Amended Protocol Version 
EUDRACT number 
2012-004104-35 
Version number 
03 (Clean) 
Development phase 
Ib/II 
Document status 
Final 
Release date 
26-Aug-2015 
Property of Array BioPharma 
 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of appendices ................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Amendment 3 .................................................................................................................... 12 
Summary of previous amendments ................................................................................... 16 
Glossary of terms ............................................................................................................... 26 
Protocol summary: ............................................................................................................. 27 
1 
Background ........................................................................................................................ 31 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 31 
1.2 
Introduction to investigational treatment(s) and other study treatment(s)............. 32 
1.2.1 
Overview of LEE011 ............................................................................ 32 
1.2.2 
Overview of MEK162 ........................................................................... 35 
2 
Rationale ............................................................................................................................ 41 
2.1 
Study rationale and purpose................................................................................... 41 
2.2 
Rationale for the study design ............................................................................... 41 
2.3 
Rationale for dose and regimen selection .............................................................. 42 
2.4 
Rationale for choice of combination drugs ............................................................ 43 
3 
Objectives and endpoints ................................................................................................... 43 
4 
Study design ...................................................................................................................... 45 
4.1 
Description of study design ................................................................................... 45 
4.2 
Timing of interim analyses and design adaptations ............................................... 47 
4.3 
Definition of end of the study ................................................................................ 47 
4.4 
Early study termination.......................................................................................... 47 
5 
Population .......................................................................................................................... 47 
5.1 
Patient population .................................................................................................. 47 
5.2 
Inclusion criteria .................................................................................................... 48 
5.3 
Exclusion criteria ................................................................................................... 49 
6 
Treatment ........................................................................................................................... 51 
6.1 
Study treatment ...................................................................................................... 51 
6.1.1 
Dosing regimen and treatment administration ...................................... 51 
6.1.2 
Treatment duration ................................................................................ 53 
6.2 
Dose escalation guidelines ..................................................................................... 53 
6.2.1 
Starting dose rationale ........................................................................... 53 


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6.2.2 
Provisional dose levels .......................................................................... 53 
6.2.3 
Criteria for dose escalation and determination of MTD/RP2D ............ 54 
6.2.4 
Definitions of dose limiting toxicities (DLTs) ...................................... 56 
6.3 
Dose modification .................................................................................................. 58 
6.3.1 
Dose modification and dose delays ....................................................... 58 
6.4 
Concomitant medications ...................................................................................... 65 
6.4.1 
Prohibited concomitant therapy ............................................................ 65 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 65 
6.4.3 
Permitted concomitant therapy ............................................................. 66 
6.5 
Subject numbering, treatment assignment or randomization ................................ 67 
6.5.1 
Subject numbering ................................................................................ 67 
6.5.2 
Treatment assignment ........................................................................... 67 
6.5.3 
Treatment blinding ................................................................................ 67 
6.6 
Study drug preparation and dispensation ............................................................... 67 
6.6.1 
Study drug packaging and labeling ....................................................... 68 
6.6.2 
Drug supply and storage ........................................................................ 68 
6.6.3 
Study drug compliance and accountability ........................................... 68 
6.6.4 
Disposal and destruction ....................................................................... 69 
7 
Visit schedule and assessments ......................................................................................... 69 
7.1 
Study flow and visit schedule ................................................................................ 69 
7.1.1 
Pre-screening assessments .................................................................... 76 
7.1.2 
Screening ............................................................................................... 76 
7.1.3 
Treatment period ................................................................................... 77 
7.1.4 
End of treatment visit ............................................................................ 77 
7.1.5 
Follow-up period ................................................................................... 78 
7.2 
Assessment types ................................................................................................... 79 
7.2.1 
Efficacy assessments ............................................................................. 79 
7.2.2 
Safety and tolerability assessments ....................................................... 80 
7.2.3 
Pharmacokinetics .................................................................................. 86 
 
 89 
8 
Safety monitoring and reporting ........................................................................................ 91 
8.1 
Adverse events ....................................................................................................... 91 
8.1.1 
Definitions and reporting ...................................................................... 91 
8.1.2 
Laboratory test abnormalities ................................................................ 92 
8.1.3 
Adverse events of special interest ......................................................... 92 
8.2 
Serious adverse events ........................................................................................... 93 
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8.2.1 
Definitions ............................................................................................. 93 
8.2.2 
Reporting ............................................................................................... 93 
8.3 
Pregnancies ............................................................................................................ 94 
8.4 
Warnings and precautions...................................................................................... 95 
8.5 
Data Safety Monitoring Board............................................................................... 95 
8.6 
Steering Committee ............................................................................................... 95 
9 
Data collection and management ....................................................................................... 96 
9.1 
Data confidentiality ............................................................................................... 96 
9.2 
Site monitoring ...................................................................................................... 96 
9.3 
Data collection ....................................................................................................... 97 
9.4 
Database management and quality control ............................................................ 97 
10 Statistical methods and data analysis ................................................................................ 97 
10.1 
Analysis sets .......................................................................................................... 98 
10.1.1 
Full analysis set ..................................................................................... 98 
10.1.2 
Safety set ............................................................................................... 98 
10.1.3 
Per-Protocol Set .................................................................................... 99 
10.1.4 
Dose-determining analysis set ............................................................... 99 
10.1.5 
Pharmacokinetic analysis set ................................................................. 99 
10.2 
Patient demographics/other baseline characteristics ........................................... 100 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 100 
10.3.1 
Study treatment ................................................................................... 100 
10.3.2 
Concomitant therapies ......................................................................... 100 
10.3.3 
Compliance ......................................................................................... 100 
10.4 
Primary objective ................................................................................................. 100 
10.4.1 
Variable ............................................................................................... 101 
10.4.2 
Statistical hypothesis, model and method of analysis ......................... 101 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 103 
10.4.4 
Supportive analyses ............................................................................. 104 
10.5 
Secondary objectives ........................................................................................... 104 
10.5.1 
Key secondary objectives .................................................................... 104 
10.5.2 
Other secondary efficacy objectives ................................................... 104 
10.5.3 
Safety objectives ................................................................................. 105 
10.5.4 
Pharmacokinetics ................................................................................ 106 
 
 108 
 
 108 
 
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10.7 
Interim analysis .................................................................................................... 110 
10.8 
Sample size calculation........................................................................................ 111 
10.9 
Power for analysis of key secondary variables .................................................... 111 
11 Ethical considerations and administrative procedures .................................................... 111 
11.1 
Regulatory and ethical compliance ...................................................................... 111 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 111 
11.3 
Informed consent procedures ............................................................................... 112 
11.4 
Discontinuation of the study ................................................................................ 112 
11.5 
Publication of study protocol and results............................................................. 112 
11.6 
Study documentation, record keeping and retention of documents ..................... 112 
11.7 
Confidentiality of study documents and patient records ..................................... 113 
11.8 
Audits and inspections ......................................................................................... 113 
11.9 
Financial disclosures ............................................................................................ 113 
12 Protocol adherence .......................................................................................................... 114 
12.1 
Amendments to the protocol ................................................................................ 114 
13 References (available upon request) ................................................................................ 115 
14 Appendices ...................................................................................................................... 117 
14.1 
Appendix 1: ECOG Performance Status ............................................................. 117 
14.2 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ....... 118 
14.2.1 
Introduction ......................................................................................... 118 
14.2.2 
Efficacy assessments ........................................................................... 118 
14.2.3 
Disease measurability .......................................................................... 118 
14.2.4 
Eligibility based on measurable disease .............................................. 119 
14.2.5 
Methods of tumor measurement-general guidelines ........................... 119 
14.2.6 
Baseline documentation of target and non-target lesions ................... 121 
14.2.7 
Follow-up evaluation of target and non-target lesions ........................ 122 
14.2.8 
Follow-up and recording of lesions ..................................................... 122 
14.2.9 
Determination of target lesion response .............................................. 123 
14.2.10 
New lesions ......................................................................................... 126 
14.2.11 
Evaluation of overall lesion response ................................................. 126 
14.2.12 
Efficacy definitions ............................................................................. 127 
14.2.13 
Best overall response........................................................................... 127 
14.2.14 
Time to event variables ....................................................................... 129 
14.2.15 
Progression-free survival .................................................................... 129 
14.2.16 
Overall survival ................................................................................... 129 
14.2.17 
Time to progression............................................................................. 130 


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14.2.18 
Time to treatment failure ..................................................................... 130 
14.2.19 
Duration of response ........................................................................... 130 
14.2.20 
Time to response ................................................................................. 131 
14.2.21 
Definition of start and end dates for time to event variables .............. 132 
14.2.22 
Handling of patients with non-measurable disease only at baseline ... 133 
14.2.23 
Sensitivity analyses ............................................................................. 134 
14.2.24 
Data handling and programming rules ................................................ 135 
14.2.25 
Study/project specific decisions .......................................................... 135 
14.2.26 
End of treatment phase completion ..................................................... 136 
14.2.27 
End of post treatment follow-up (study phase completion) ................ 136 
14.2.28 
Medical validation of programmed overall lesion response ............... 137 
14.2.29 
Programming rules .............................................................................. 137 
14.2.30 
References (available upon request) ................................................... 139 
14.3 
Appendix 3: List of prohibited concomitant therapies and therapies to be used 
with caution ......................................................................................................... 140 
14.4 
Appendix 4: Guidance on medications with a risk of Torsades de Pointes......... 144 
14.5 
Appendix 5: Statistical details for the Phase Ib part: Bayesian logistic 
regression model (BLRM), priors, design properties for hypothetical data 
scenarios and design operating characteristics .................................................... 146 
14.5.1 
Statistical model and prior distributions ............................................. 146 
14.5.2 
Hypothetical dose escalation scenarios ............................................... 151 
14.5.3 
Operating characteristics for Phase Ib ................................................. 152 
14.5.4 
Statistical details for the Phase II part ................................................. 155 
 
List of appendices 
Appendix 1: ECOG Performance Status 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Appendix 3: List of prohibited concomitant therapies and therapies to be used with caution 
Appendix 4: Guidance on medications with a risk of Torsades de Pointes 
Appendix 5: Prior calibration and operating characteristics of the Bayesian logistic regression 
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List of figures 
Figure 4-1 
Study design .......................................................................................... 46 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 44 
Table 6-1 
Provisional dose levels .......................................................................... 53 
Table 6-2 
Criteria for defining dose-limiting toxicities ......................................... 57 
Table 6-3 
Dose modification guidelines after Cycle 1 .......................................... 60 
Table 7-1 
Visit evaluation schedule (28-day cycle) .............................................. 70 
Table 7-2 
Visit evaluation schedule (21-day cycle) .............................................. 73 
Table 7-3 
Clinical laboratory parameters collection plan ..................................... 82 
Table 7-4 
ECG collection plan (28–day cycle) ..................................................... 84 
Table 7-5 
ECG collection plan (21–day cycle) ..................................................... 85 
Table 7-6 
Pharmacokinetic blood collection log (Phase Ib) 28-day cycle ............ 86 
Table 7-7 
Pharmacokinetic blood collection log (Phase Ib) 21-day cycle ............ 87 
Table 7-8 
Pharmacokinetic blood collection log (Phase II) 28-day cycle ............. 87 
Table 7-9 
Pharmacokinetic blood collection log (Phase II) 21-day cycle ............. 88 
 
 90 
Table 10-1 
Non-compartmental pharmacokinetic parameters .............................. 107 
 
 110 
Table 14-1 
ECOG performance scale .................................................................... 117 
Table 14-2 
Response criteria for target lesions ..................................................... 123 
Table 14-3 
Response criteria for non-target lesions .............................................. 125 
Table 14-4 
Overall lesion response at each assessment ........................................ 126 
Table 14-5 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 133 
Table 14-6 
Options for event dates used in PFS, TTP, duration of response ........ 134 
Table 14-7 
List of prohibited medications during LEE011 and MEK162 
treatment .............................................................................................. 140 
Table 14-8 
List 1 of medications to be used with caution during LEE011 and 
MEK162 treatment .............................................................................. 140 
Table 14-9 
Drugs with a conditional risk of Torsades de Pointes ......................... 144 
Table 14-10 
Drugs with a possible risk of Torsades de Pointes .............................. 144 
Table 14-11 
Data from study [LEE011X2101] ....................................................... 147 
Table 14-12 
Data from study [ARRAY-162-111] .................................................. 148 
Table 14-13 
A priori interaction at provisional dose levels .................................... 148 
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Table 14-14 
Prior, posterior and predictive distribution of model parameters ....... 149 
Table 14-15 
Prior summaries (derived from priors in Table 14-14) ....................... 149 
Table 14-16 
Current data from initial combination dosing regimen included as 
historical data for the new regimen ..................................................... 150 
Table 14-17 
On-study decisions for dosing ............................................................. 151 
Table 14-18 
True underlying probabilities of DLT for Scenario 1 ......................... 152 
Table 14-19 
True underlying probabilities of DLT for Scenario 2 ......................... 152 
Table 14-20 
True underlying probabilities of DLT for Scenario 3 ......................... 153 
Table 14-21 
True underlying probabilities of DLT for Scenario 4 ......................... 153 
Table 14-22 
True underlying probabilities of DLT for Scenario 5 ......................... 153 
Table 14-23 
Results ................................................................................................. 154 
 


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List of abbreviations 
λz 
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for terminal 
elimination rate constant (time-1) 
5 FU 
Fluorouracil 
ADME 
Absorption, distribution, metabolism and excretion 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic-Therapeutic-Chemical classification 
AUC0-24h 
Area under the curve from time zero to 24 hours 
AUCinf 
Area under the curve from time zero to infinity 
AUClast 
Area under the curve from time zero to the last measureable concentration time 
BID 
Twice daily 
BLRM 
Bayesian logistic regression model 
BOR 
Best overall response 
BSEP 
Bile salt export pump 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CDK 
Cyclin-Dependent Kinase 
CFR 
Code of federal regulations 
CK 
Creatinine Kinase 
CL/F 
Total body clearance of drug from the plasma 
Cmax 
Maximum plasma concentration after a single dose 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CSR 
Central Serous Retinopathy 
Css 
Plasma concentration during steady state 
CT 
Computed tomography 
CTCAE 
NCI common terminology criteria for adverse events (version 4.0) 
DDS 
Dose-determining set 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribose nucleic acid 
DOR 
Duration of Response 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


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EDC 
Electronic data capture 
EOT 
End of Treatment 
EWOC 
Escalation with overdose control 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
FMO 
Flavin-containing monooxygenase 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyltransferase 
GI 
Gastro intestinal 
GLP 
Good laboratory practice 
GSH 
Glutathione 
HDPE 
High density polyethylene 
HIV 
Human immunodeficiency virus 
IC50 
Concentration resulting in 50% inhibition 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMS 
Integrated medical safety 
IN 
Investigator notification 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LC/MS/MS 
Liquid chromatography-tandem mass spectrometry assay 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LVEF 
Left ventricular ejection fraction 
MCL 
Mantle Cell Lymphoma 
MDRI 
Multidrug-resistant protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple gated acquisition scan 
MXR 
Mitoxantrone resistant protein 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OCRDC 
Oracle clinical research data capture 
OCT 
Ocular coherence tomography 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PFS 
Progression free survival 
Pgp 
P-glycoprotein 
PIB 
Powder in Bottle 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetic/pharmacodynamics 


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PPS 
Per-Protocol Set 
PR 
Partial response 
pRb 
Retinoblastoma protein 
PT 
Prothrombin time 
PVC 
Premature ventricular contraction 
PXR 
Pregnane X receptor 
QD 
Every day 
QTcF 
QT corrected with Fredericia’s formula 
Racc 
Accumulation ratio 
RAP 
Report and Analysis Plan 
Rb 
Retinoblastoma protein 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria for Solid Tumors 
RNA 
Ribonucleic acid 
RPED 
Retinal pigmented epithelial detachment 
SAE 
Serious adverse event 
SD 
Stable disease 
SUSAR 
Suspected, unexpected serious adverse reaction 
SUV 
Standardized uptake value 
T1/2 
Half life 
T1/2,acc 
Effective elimination half-life 
TDI 
Time-dependent inhibition 
Tmax 
Time to reach maximum (peak) plasma concentration 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
Vss/F 
Apparent volume of distribution at steady state 
Vz/F 
The apparent volume of distribution during terminal phase after oral administration 
(associated with λz) 
WBC 
White blood cell 
WCBP 
Women of child bearing potential 
WHO 
World Health Organization 
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Amendment 3 
Amendment rationale 
The main purpose of this amendment is to address recently observed safety findings from 
patients treated with LEE011 (Ribociclib) in other clinical trials. 
1. Recent data suggests a potential risk of hepatic toxicity (drug induced liver injury [DILI] 
indicated by an increase of transaminases, in isolation or with bilirubin increase, in 
patients treated with LEE011. Updates to monitoring and dose adjustment guidelines for 
hepatobiliary toxicities including ALT, AST, and total bilirubin have been added and 
separated from the dose modification guidance for other adverse events. Specific changes 
are as follows: 
a. Updates to dose modification language and the guidelines for the management of 
hepatic toxicity 
b. To specify that for patients meeting biochemical criteria for Hy’s law (AST or ALT > 
3.0 x ULN and total bilirubin > 2.0 x ULN in the absence of cholestasis or 
hemolysis), the study treatment must be permanently discontinued 
2. Updates to monitoring and dose adjustment guidelines for QTcF prolongation in order to 
improve patient safety based on program standard language recommendations have been 
implemented. Specific changes are as follows: 
a. Dose modification guidelines and dose limiting toxicity definitions have been 
changed to more aggressively manage QTcF prolongation 
b. Additional ECG assessments 
c. Follow-up of electrolyte abnormalities until normalization in the event of QTcF 
prolongation 
d. Mandated review of concomitant medications in the event of QTcF prolongation, also 
updated based on recent metabolism data for LEE011 or MEK162 
e. Mandated review of dosing regimen in the event of QTcF prolongation 
f. Addition of continued ECG monitoring for all cycles in the event of a patient QTcF ≥ 
481 ms at any time before Cycle 7 Day 1 
3. A change in study sponsorship was made from Novartis to Array BioPharma. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Changes in the header of this document and in multiple sections to reflect the study 
sponsorship changes from Novartis to Array BioPharma 
• The Protocol Summary is updated to reflect the changes to the inclusion and exclusion 
criteria 
• Section 5.2 Inclusion criteria has been updated with the following: 


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• Clarification of inclusion criteria for serum total bilirubin for patients with Gilbert 
syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x 
ULN 
• Update of AST and ALT <2.5 x ULN, except in patients with tumor involvement of 
the liver who must have AST and ALT < 5 x ULN. 
• Addition of criteria for the following laboratory values within normal limits or 
corrected to within normal limits with supplements before the first dose of study 
medication: Sodium, Potassium, Magnesium, Inorganic phosphate, Calcium 
(corrected for serum albumin) 
• Section 5.3 Exclusion criteria has been updated with the following: 
• Clarification of QTcF interval criteria on the ECG (ie: unreadable or not interpretable) 
or QTcF >450 ms (using Frederica’s correction). All as determined by screening ECG 
(mean of triplicate ECGs). 
• Addition of symptomatic pericarditis within 12 months prior to starting study drug 
• Increase in exclusion window from 3 months to 12 months prior to starting study drug 
for angina pectoris 
• Increase in exclusion window from 3 months to 12 months prior to starting study drug 
for acute myocardial infarction 
• Addition exclusion window of 12 months prior to starting study drug for clinically 
significant resting bradycardia, history or presence of ventricular tachyarrhythmia, 
complete left bundle branch block, right bundle branch block and left anterior hemi 
block (bifasicular block) 
• Addition of exclusion of agents that are known to induce Torsades de Pointes 
• Clarification that patients who are currently receiving agents known to cause QT 
prolongation, induce Torsades de Pointes, or that are metabolized predominantly 
through CYP3A4 and have a narrow therapeutic window, and cannot be discontinued 
7 days prior to Cycle 1 Day 1, are excluded 
• Addition of criteria to exclude patients with history of retinal degenerative disease 
• Increase of time to 30 days after stopping treatment that a male should not father a 
child 
• Section 6.1.1, added grapefruit hybrids, pummels and star-fruit to list of items to be 
avoided due to CYP3A4 mediated interaction 
• Section 6.2.4, clarification of criteria to be followed for DLT 
• Table 6-1 Criteria for defining dose-limiting toxicities, has been updated to: 
• Include grade 2 bilirubin >7 consecutive days 
• Clarification for CTCAE grade 3 ALT > 4 consecutive days 
• Addition of DLT for grade 4 ALT or both ALT and AST(isolated increases in AST 
without concomitant increases in ALT will not be considered dose-limiting, because 
of the non-specific nature of AST) 
• Addition of DLT for CTCAE grade 4 serum alkaline phosphatase > 7 consecutive 
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• Section 6.3.1, clarification that during Cycle 1 the dose should not be reduced or 
interrupted unless the patient has experienced a DLT 
• Section 6.3.1, clarification that if a patient discontinues either study drug, then the patient 
must discontinue the study. 


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• Table 6-3 Dose modification guidelines after Cycle 1, has been updated to: 
• Include new guidelines for the management of hepatic toxicity 
• Include new guidelines for the management of QTcF prolongation. Dose reduction is 
recommended in case of grade 2 QTc prolongation (QTcF 481-500 ms). For patients 
who experience grade 3 QTc prolongation (QTcF  501 ms on at least two separate 
ECGs), local cardiologist consultation is also recommended in addition to dose 
reduction. Patients who experience grade 4 QTc prolongation must discontinue study 
treatment. 
• Section 6.3.1.1 added to outline Additional follow-up for hepatic toxicities 
• Section 6.4.1 updated to include medications that are known to induce Torsades de 
Pointes, as well as addition of grapefruit hybrids, pummelos and star-fruit 
• Section 6.4.2 was updated with list of prohibited concomitant therapy 
• 
 
 
 
 
• Section 7.2.2.5.7 was updated to clarify follow-up guidelines in the event a QTcF value of 
 481 ms is observed prior to cycle 7 
• Table 7-4 and 7-5, ECG collection plan, were updated to reflect the new ECG frequency 
and additional recommendations given with regards to ECG assessment in case of 
abnormalities and cardiologist consultation. 
• 
 
 
• Appendix 3 updated with prohibited concomitant therapies and therapies to be used with 
caution 
• Appendix 4 was added to provide guidance on medications with a risk of Torsades de 
Pointes 
In addition to these changes, inconsistencies and typographical errors have been corrected as 
needed. 
IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
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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Summary of previous amendments 
Amendment 2 
Amendment rationale 
Emerging safety data from this and other studies with LEE011 and MEK162 warrant the 
following changes to the protocol: 
Preliminary evaluation of LEE011 and MEK162 indicates it is an active combination but 
associated with frequent adverse events necessitating dosing interruptions and reductions. In 
order to determine the most tolerable and efficacious dosing schedule for the combination, 
evaluation of alternate dosing schedules are incorporated. 
Evaluation of the 28 day continuous dosing schedule was performed in the phase 1 single 
agent LEE011 study [CLEE011X2101]. Due to hematological toxicity, this schedule will not 
be pursued any longer. Therefore all references to continuous dosing schedule will be 
removed from this protocol. In addition, the eligibility criterion is modified to include only 
patients with ECOG performance score of 0 and 1. 
 
 
 
 
 
While the protocol excludes patients with symptomatic brain metastases, brain imaging prior 
to study entry had not been required and was not performed for this patient. As a 
precautionary measure, this amendment will mandate brain imaging for all patients at 
screening and will exclude patients with brain metastases. Furthermore, coagulation 
assessments will be collected at screening and at C1D1 to exclude patients with abnormal 
coagulation evaluations. 
Emerging safety data from the phase I single agent study [CLEE011X2101] suggest that 
LEE011 has an effect on cardiac repolarization. Therefore additional evaluations have been 
added to the ECG monitoring schedule to better assess the safety and tolerability of LEE011. 
An additional echocardiogram evaluation will be added to the C3D1 visit. The DLT definition 
and dose modification guidelines have been revised to monitor cardiac function more 
thoroughly as many patients have underlying hypertension and other cardiac conditions that 
could be affected by the study drugs. 
Following consultation with a panel of ophthalmologists who have experience in treating 
MEK inhibitor associated visual toxicities, the exclusion criterion has been refined such that 
risk factors for central serous retinopathy (CSR) and current or history of CSR are no longer 
exclusionary. In order to better characterize the visual events related to MEK162 treatment, 
the amendment modifies the terminology used to identify the retinal abnormalities associated 
with MEK162. The term Central Serous Retinopathy-like (CSR-like) will no longer be 
applied generally to characterize the retinal events associated with MEK162. The term retinal 
pigmented epithelial detachment (RPED) will be applied, when appropriate imaging studies, 
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like ocular coherence tomography (OCT) support its diagnosis. The standard DLT criteria and 
dose modification guidelines have been updated to reflect the modified terminology. 
The recommended dose modifications for CTCAE Grade 4 creatine phosphokinase (CPK) 
have been revised based on the growing safety data from this and other ongoing studies with 
MEK162. Blood CPK elevations are mostly asymptomatic and not clinically significant. 
Therefore, it is reasonable to recommend careful evaluation of the patients and consider dose 
modification for Grade 4 CPK elevation based on whether the patient is symptomatic or not. 
The exclusion criteria related to hypertension, creatine phosphokinase (CPK) elevation, and 
prior malignancies have been modified in order to be in alignment with other MEK162 
studies. 
 
 
 
 
MEK162 has been shown to have a potential teratogenic affect in preclinical studies. 
Therefore, additional serum pregnancy tests have been added to align with Novartis’s 
standards. 
To align with the MEK162 program standard language, the contraceptive washout following 
study drug discontinuation has been changed from 15 days to 30 days. 
Results from the MEK162 food effect study and preliminary results from the LEE011 food 
effect study indicate that MEK162 and LEE011 can be administered with or without food. As 
of this amendment, MEK162 and LEE011 may be administered irrespective of food. 
The objectives and endpoints and PK sections were updated to include
 
Finally, changes to correct typographical errors and harmonize protocol text where applicable 
have been made. 
Changes to the protocol 
Changes to the specific sections of the protocol are shown in the track change version of the 
protocol. 
• The Protocol summary section has been updated to include information regarding the 
alternate dosing schedule and to include the updated inclusion/exclusion criteria from 
Section 5. 
• Section 1.2.1.4 Clinical experience, has been updated to include clinical information from 
the most recent LEE011 IB version 5 dated November 7, 2013. 
• Section1.2.1.5 Clinical Pharmacokinetics of LEE011, has been updated to include clinical 
information from the most recent LEE011 IB version 5 dated November 7, 2013. 
• Section 1.2.2.4 Clinical experience of MEK162, has been updated to include FDA 
mandated language regarding a hypertensive crisis that occurred in June 2013. 
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• Section 1.2.2.6 Clinical experience with the combination of LEE011 and MEK162 has 
been updated to include the most recent information available regarding the MEK162 and 
LEE011 combination study 
• Section 2.2 Rationale for the study design has been updated to clarify the definition of 
MTD(s)/RP2D 
• Section 2.3 Rationale for dose and regimen selection, has been updated with the 
following: The MTD/RP2D of LEE011 
1. Deleted information regarding the continuous dosing of LEE011 (28 days) 
Introduction of alternate schedule(s) 
2. Updated language regarding the starting dose of the alternate dosing schedules 
• Table 3-1 Objectives and related endpoints has been updated to include the following: 
 
• Section 4.1 Description of study design has been updated to include the following: 
1. The alternate dosing schedules 
a. 2 weeks on 1 week off of both LEE011 and MEK162 
b. 3 weeks on 1 week off of both LEE011 and MEK162 
2. To allow multiple cohorts to be open in parallel 
3. Updated the number of patient in phase Ib from “18” to “40” and replaced the word 
“will” with “expected” to enroll in phase Ib 
4. Updated the language around the MTD/RP2D declaration and schedule 
5. Added paired biopsy information for the 21 day schedule 
6. Replace the word “fresh” with “newly obtained” tumor biopsies in this section and 
throughout the protocol except for Section 7 
7. 
 
8. Updated total number of patients in phases Ib and II from “90” to “80” 
9. Updated the disease progression assessments (phase II only) from every “two” to 
every “three” months and removed follow up phone calls. 
10. Updated the survival follow up period (phase II only) from “24” to “12” months 
• Figure 4-1 Study design has been updated to include the total of patients in phase Ib from 
“N15” to “N~40” 
• Section 4.3 Definition of end of the study has been updated to include updated Novartis 
standard language 
• Section 5.2 Inclusion criteria has been updated to include the following: 
1. Inclusion criteria #3 has been updated to change the ECOG status from “0-2” to “0-1” 
2. Inclusion criteria #5 has been updated to clarify that “patients with accessible tumors 
that are amenable for biopsy” must undergo a tumor biopsy in phase II 
3. Exclusion criteria #1 has been updated to exclude patients with brain metastases 
4. Exclusion criteria #2 has been updated to clarify GI disease as “active” 
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5. Exclusion criteria #3 has been added to exclude patients with uncontrolled 
hypertension 
6. Exclusion criteria #4 has been updated to include updated standard cardiac 
assessments 
7. Exclusion criteria #6 has been added to exclude patients with neuromuscular disorders 
associated with elevated CK 
8. Exclusion criteria #7 has been updated to include a new coagulation assessment for 
organ function “PT/INR or aPTT ≤ 1.5 ULN” 
9. Exclusion criteria #12 has been updated to include update MEK162 ophthalmologic 
information 
10. Exclusion criteria #15 has been added to exclude patients with other malignancies 
within 3 years prior to enrollment 
11. Exclusion criteria #17 has been updated to change the contraceptive washout 
following drug discontinuation from “15 days” to “30 days” 
12. Certain exclusion criteria were shifted upwards based on priority 
• Section 6.1.1 Dosing regimen and treatment administration has been updated with the new 
fasting guidance for MEK162 and LEE011. Fasting restrictions for both drugs have been 
lifted and drugs may be administered irrespective of food. In addition, this section was re-
arrange to further clarify the different dosing requirements for LEE011 and MEK162 
• Section 6.1.1.1 “Continuous dosing regimen of LEE011” has been deleted and replaced 
with the “Alternate dosing schedule of LEE011 and MEK162” to include the alternate 
schedules 
• Section 6.2.2 Provisional dose levels has been updated and sentence “Only LEE011 can be 
escalated at the time of the dose escalation keeping MEK162 at the same starting dose 
level (e.g. for provisional dose level 2 only LEE011 is escalated from 200 mg to 400 mg 
when compared to dose level 1)” has been deleted. 
• Table 6-1 Provisional dose levels has been updated with the following: 
1. New dosing reduction of MEK162 to “30mg QD” if approved by Novartis 
2. Deleted statement “In particular, LEE011 doses higher than 600mg may be evaluated 
depending on the observed safety, PK and PD data” 
3. Deleted “3weeks on 1 week off” and “continuous” language from the table to 
eliminate confusion 
• Section 6.2.3.2 Dose Cohort Modification has been updated to include the following: 
1. Clarification around the initial dosing schedule 
2. Language around the dosing of the alternate dosing schedules 
3. Clarification that Bayesian models will be run for each alternate dosing schedule 
• Table 6-2 Criteria for defining dose-limiting toxicities has been updated to include the 
most recent standard DLT criteria definition information from other MEK162 and 
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• Section 6.2.4.1 Follow up evaluations for appearance of Retinal Events has been updated 
to include management guidelines of retinal events. The title has also been modified from 
“follow up evaluations for appearance of central serous retinopathy (CRS) to “Follow up 
evaluations for appearance of retinal events” 
• Section 6.3.1 Dose modification and dose delays has been updated to include a second 
dose reduction of MEK162 to “30mg QD or 15 BID” when approved by Novartis 
• Table 6-3 Dose Modification Guidelines has been updated to include updated MEK162 
and LEE011 dose modification guidelines 
• Sections 6.5.1 Subject numbering has been updated to include information regarding the 
use of IRT for drug management in phase II 
• Section 6.5.2 Treatment assignment has been updated to include guidance on the treatment 
assignments using IRT in phase II 
• Section 6.6.1 Study drug packaging and labeling has been update to include drug 
management with IRT 
• 
 
 
 
• Table 7-1 Visit Evaluation Schedule (28-day cycle) has been updated to include the 
following assessments: 
1. Additional ECG’s and cardiac imaging assessments 
2. Hematology and chemistry sections were separated to minimize confusion 
3. A section for cardiac and muscle enzymes was added for additional clarification 
4. A section for coagulation assessments was added 
5. Additional follow up serum/urine pregnancy tests 
6. 
 
7. Additional guidance around tumor assessments 
8. Mandatory brain images was added 
9. Clarification of MEK162 and LEE011 dosing 
10. Removed disease progression monthly phone calls 
11. Merged disease progression and survival follow up rows and columns 
12. Additional footnotes were added for further clarification 
• Table 7-2 Visit Evaluation Schedule (21-day cycle) has been inserted to include the 
schedule of assessments for the alternate dosing schedules of 21 days 
• Section 7.1.4 End of treatment visit has been updated to include the current “end of 
treatment visit” language 
• Section 7.1.5 Follow-up period has been updated to include current “follow-up period” 
language 
• Section 7.1.5.1 30-day safety follow-up period has been updated to include current “30-
day safety follow-up period” 
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• Section 7.1.5.2 Disease progression follow-up assessments (Phase II only) has been 
updated to change the disease progression follow up tumor assessments from “every two 
months” to “every three months” 
• Section 7.1.5.3 Survival follow-up period (Phase II only) has been updated to change the 
survival follow-up period from “24 months” to “12 months” 
• Section 7.2.1 Efficacy assessments has been updated to include the following: 
1. Mandatory baseline brain imaging to access CNS disease was added. 
2. Follow-up tumor assessments for the alternate dosing schedules 
3. Screening window has been extended from “14” to “28” days 
4. Clarification of evaluable sites (Chest, Abdomen and pelvis) for all follow up 
assessments 
5. Include central collection of radiological and photographic assessments in both 
“phases Ib and II” from “phase II” only 
• Table 7-3 Clinical Laboratory Parameters Collection Plan has been updated to include 
additional cardiac, coagulation and serum/urine pregnancy assessments 
• Section 7.2.2.5.5 Pregnancy Assessments has been updated to include new follow up 
serum pregnancy testing “every other month” 
• Section7.2.2.5.6 Ophthalmic Examination has been updated to include additional guidance 
on ophthalmic examinations 
• Table 7-4 ECG Collection Plan (28–day cycle) has been updated to include additional 
ECG assessments for the 28 day cycle 
• Table 7-5 ECG Collection Plan (21–day cycle) has been added to include ECG 
assessments for the alternate dosing schedules (21 days) 
• Section 7.2.2.5.7 Cardiac imaging - MUGA (multiple gated acquisition) scan or bilateral 
echocardiogram has been updated to include an additional assessment on “C3D1” 
• Section 7.2.2.5.8 Cardiac Markers [Enzymes] has been updated to include additional 
cardiac marker assessments 
• Section 7.2.3.1 PK blood sample collection and handling has been updated collection and 
handling instructions for blood PK 
• Table 7-5 Pharmacokinetic blood collection log (Phase Ib) 28-day cycle has been updated 
to include “28-day cycle” on the header 
• Table 7-6 Pharmacokinetic blood collection log (Phase Ib) 21-day cycle have been added 
to include collection and handling instructions for blood PK for the alternate dosing 
schedules 
• Table 7-7 Pharmacokinetic blood collection log (Phase II) 28-day cycle has been updated 
to include “28-day cycle” on the header 
• Table 7-8 Pharmacokinetic blood collection log (Phase II) 21-day cycle have been added 
to include collection and handling instructions for blood PK for the alternate dosing 
schedules 
• Section 7.2.3.1.1 LEE011 has been updated to include updated LEE011 analytical 
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• Section 7.2.3.1.2 MEK162 has been updated to include updated LEE011 analytical 
methods 
• 
 
 
 
 
 
 
 
 
 
 
 
• Section 9.4 Database management and quality control has been updated to include 
information regarding the management of data by IRT 
• Sections 10.1.4 Dose-determining analysis set has be updated to clarify the DLT 
evaluation period as cycle 1. 
• Section 10.4.2 Statistical hypothesis, model and method of analysis, has been updated to 
include information around the use of historical data for the new dosing schedule 
• Section 10.5.4 Pharmacokinetics, has been updated to include clarification regarding the 
LEE011 and MEK162 analysis 
• 
• Section 10.8 Sample size calculation has been updated to include information regarding 
the alternate dosing schedules 
• Section 14.6 Appendix 6: Statistical details for the Phase Ib Part: Bayesian logistic 
regression model (BLRM), priors, design properties for hypothetical data scenarios and 
design operating characteristics has been updated with the following: 
1. Addition of “3 weeks on and 1 week off” in Table 14-15 through Table 14-26 
2. Section 14.6.1 Statistical model and prior distributions has been updated to include 
the sentence “of LEE011 administered on 3 weeks on/1 week off schedule “ under 
LEE011 and “of MEK162 administered on BID continuous over 28 days schedule” in 
the MEK162 section 
3. Tables 14-14, 14-15, 14-16, 14-17, 14-21 through 14-26 have been updated to clarify 
the MEK162 dosing is BID and is continuous over 28 days 
4. Two sections were added “Alternative regimen: LEE011 QD and MEK162 BID, both 
3 weeks on and 1 week off” and “Alternative regimen: LEE011 QD and MEK162 
BID, both 2 weeks on and 1 week off” along with Table 14-20 to further clarify the 
alternate dosing schedules. 
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IRB/IEC/REB Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol. 


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Amendment 1 
Amendment rationale 
The purpose of this amendment is to implement health authority mandated changes. In 
addition, editorial changes have been made to sections where previous language was deemed 
inaccurate or ambiguous by site staff and study investigators, to ensure better protocol 
compliance. 
• The statement, “there was no evidence of cardio vascular toxicity in the 4 week toxicology 
studies, and” “rare and isolated” have been removed from Section 1.2.1.3 to be consistent 
with language that will be included in an updated [LEE011 Investigator’s Brochure]. 
• Section 1.2.2.4.1 has been updated to include information on cardiac toxicity that has been 
observed in patients who have received MEK162 post the release of the version 8 
[Investigator’s Brochure]. 
• Section 6.2.3.2 has been updated to include “If two or more patients experience CTCAE 
grade 2 or greater treatment-related toxicities at a dose level in any cohort, all future dose 
escalations of LEE011 will be ≤ 50%. Only toxicities that occur during the first cycle will 
necessarily be considered for decisions”. 
• Hepato-biliary related DLT criterion (Table 6-2) has been updated to “CTCAE grade 2 
total bilirubin concurrent with grade 2 ALT is a DLT except for patients with known liver 
metastatic disease. The corresponding changes to the dose modification table have been 
made. Table 6-3 has been updated to “in the event of this DLT hold LEE011 and MEK162 
until the toxicity resolves to ≤ Grade 1 and restart at one dose level below for both agents. 
If toxicity recurs at the lower dose, then discontinue from study”. 
• Investigations-related DLT criterion (Table 6-2) has been updated to “Serum CK/CPK 
CTCAE Grade 3 if symptomatic and Serum CK/CPK CTCAE Grade 4” will now be 
considered a DLT. The corresponding changes to the dose modification table have been 
made. Table 6-3 has been updated to “discontinue MEK162 if Serum CK/CPK CTCAE is 
Grade 4”. 
• Blood chemistry panel (Table 7-2) has been updated to include brain natriuretic peptide 
(BNP) and troponin measurements at each cycle of treatment for additional cardiac 
monitoring in patients. 
• As patients are required to submit an FFPE sample from diagnosis or relapse at screening 
in this study, the statement “unless otherwise agreed upon by Novartis and the 
investigator” has been removed from Section 4.1 and Section 7.2.4 to comply with 
inclusion criteria. 
• Patients with an LVEF less than 50% will be excluded from this study. There was a 
typographic error which has been corrected. Therefore exclusion criteria # 3 (first bullet) 
in Section 5.3 and corresponding criteria (#2a) in the protocol summary have been 
updated to: 
• Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated 
acquisition scan (MUGA) or echocardiogram (ECHO). 


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• Exclusion criteria # 12 has been updated to be consistent with new standard language for 
MEK162 in regards to male/female contraception during and post study. 
• Section 7.2.4 has been updated to provide clarity around tumor sample collections. Per 
investigator’s request, the option of providing an on-treatment biopsy during the dose 
escalation part (Ph1b) of the study has been added. This is to more thoroughly evaluate the 
pharmacodynamic effect of the LEE011 and MEK162 combination. 
• Section 7.2.1 has been updated for clarification to reflect that “photographic assessments” 
in addition to radiologic assessments will be collected and held by an imaging CRO for 
those patients enrolled in the phase II. 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g. 21 or 28 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 
Medication number 
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study 
Subject Number 
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
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 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body 
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 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium. 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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Protocol summary: 
Protocol number 
CMEK162X2114 
Title 
A Phase Ib/II, multicenter, open label, study of LEE011 in combination with MEK162 
in adult patients with NRAS mutant melanoma 
Brief title 
Study of safety and efficacy in adult melanoma patients with NRAS mutant tumors 
Sponsor and 
Clinical Phase 
Array BioPharma 
Phase 1b/II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits 
highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cyclinD3 
complexes, with concentration resulting in 50% inhibition (IC50) values of 10 nM and 
39 nM, respectively, in isolated enzyme assays. It is inactive against the majority of 
other kinases. MEK162 is an oral, ATP non-competitive, highly selective inhibitor of 
MEK1/2. The compound has nanomolar activity against purified MEK enzyme (IC50= 
12 nM) and inhibits both basal and induced levels of ERK phosphorylation in 
numerous cancer cell lines with IC50 values as low as 5 nM. Based on pathway 
biology and preclinical data, the combination of LEE011 and MEK162 has the 
potential to be effective in patients with NRAS mutant melanoma. 
 
In the phase Ib, the primary purpose is to establish the MTD(s)/RP2D of the LEE011 
and MEK162 combination. Once the MTD(s)/RP2D have been determined, the phase 
II part will begin in order to assess antitumor activity of LEE011and MEK162 
combination. 
Primary Objective 
Phase Ib 
Determine the Maximum Tolerated Dose(s) (MTD(s)) and/or Recommended Phase II 
Dose (RP2D) of LEE011 and MEK162 in combination 
 
Phase II 
Assess the anti-tumor activity of the LEE011 and MEK162 combination at the RP2D 
 
Secondary Objectives 
Phase Ib 
Characterize the safety and tolerability of the LEE011 and MEK162 combination. 
Characterize the pharmacokinetics of the LEE011 and MEK162 combination and any 
clinically significant metabolites that may be identified. 
To assess clinical efficacy of the LEE011 and MEK162 combinations. 
 
Phase II 
Characterize the safety and tolerability of the LEE011 and MEK162 combination. 
To assess the clinical efficacy of the LEE011 and MEK162 combination. 
 
Study design 
This is a multi-center, open label, two part study, with a dose escalation followed by a 
phase II part. Both parts of the study are limited to patients aged 18 or older with 
metastatic or locally advanced NRAS mutant melanoma. The phase II part will start 
after the MTD/RP2D has been determined in the phase Ib part. LEE011 will be 
administered orally, once daily for 21 days followed by a 1 week break in combination 
with MEK162 administered twice daily in a continuous dosing schedule (28 day 
cycle). In addition, the combination of LEE011 and MEK162 may be administered 
together for 14 days followed by a 1 week break in both drugs (21 day cycle) and/or 
together for 21 days followed by a 1 week break in both drugs (28 day cycle). For the 
purpose of establishing the MTD(s)/RP2D, the DLT evaluation period is 1 cycle. 
 
Population 
Patients, ≥ 18 years, with metastatic or locally advanced NRAS mutant melanoma 
 


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Inclusion criteria 
1. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 – 1. 
2. Patients enrolled into phase Ib may be enrolled with evaluable disease only. 
Patients enrolled into the phase II expansion must have at least one measurable 
lesion as defined by RECIST 1.1 criteria. 
3. Patients must have adequate organ function, as defined by the following 
parameters: 
● 
Bone marrow: 
a. 
Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L 
b. 
Hemoglobin (Hgb) ≥ 9 g/dL 
c. 
Platelets ≥ 75 x 109/L without transfusions within 21 days before 1st 
treatment 
d. 
PT/INR and aPTT ≤ 1.5 ULN. 
● 
Serum creatinine ≤1.5 ULN 
● 
Hepatic function: 
a. 
Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for 
patients with known Gilbert syndrome, who are excluded if total bilirubin > 
3.0 x ULN or direct bilirubin > 1.5 x ULN 
b. 
Aspartate Aminotransferase (AST) (serum glutamic oxaloacetic 
transaminase (SGOT) and ALT (SGPT) ≤ 2.5 x ULN, except in patients with 
tumor involvement of the liver who must have AST and ALT < 5 x ULN 
● 
Laboratory values within normal limits or corrected to within normal limits 
with supplements before the first dose of study medication: 
a. 
Sodium 
b. 
Potassium 
c. 
Magnesium 
d. 
Inorganic phosphate 
e. 
Calcium (corrected for serum albumin) 
Exclusion criteria 
1. Presence of any brain metastases detected by MRI or CT with i.v. contrast of the 
brain at screening. 
2. Uncontrolled arterial hypertension despite medical treatment 
3. Impaired cardiac function, clinically significant cardiac diseases, and/or recent 
cardiac events, including any of the following: 
a. 
Left ventricular ejection fraction (LVEF) < 50% as determined by multiple 
gated acquisition scan (MUGA) or echocardiogram (ECHO) 
b.  
Congenital long QT syndrome or family history of unexpected sudden 
cardiac death.  
c. 
On screening, inability to determine QTcF interval on the ECG (i.e.: 
unreadable or not interpretable) or QTcF >450 ms (using Frederica’s correction). 
All as determined by screening ECG (mean of triplicate ECGs). 
d. 
Angina pectoris or symptomatic pericarditis within 12 months prior to starting 
study drug 
e. 
Acute myocardial infarction within 12 months prior to starting study drug 
f. 
Clinically significant resting bradycardia within 12 months prior to starting 
study drug 
g. 
History or presence of ventricular tachyarrhythmia within 12 months prior to 
starting study drug 
h. 
Unstable atrial fibrillation (ventricular response >100 bpm) 
i. 
Complete left bundle branch block within 12 months prior to starting study 
drug 
j. 
Right bundle branch block and left anterior hemi block (bifascicular block) 
within 12 months prior to starting study drug 
k. 
Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator  
l. 
Any other clinically significant heart disease (e.g. documented congestive 


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heart failure, documented cardiomyopathy) 
4. Patients who are currently receiving treatment with agents that are known to 
cause QT prolongation or induce Torsades de Pointes in humans and cannot be 
discontinued 7 days prior to Cycle 1 Day 1 
5. Patients who are currently receiving treatment with agents that are metabolized 
predominantly through CYP3A4 and that have a narrow therapeutic window and 
cannot be discontinued 7 days prior to Cycle 1 Day 1. Agents that are known strong 
inducers or inhibitors CYP3A4 are prohibited. 
6. Patients with concurrent severe and/or uncontrolled concurrent medical conditions 
that could compromise participation in the study (e.g. uncontrolled diabetes mellitus, 
clinically significant pulmonary disease, clinically significant neurological disorder, 
active or uncontrolled infection) 
7. 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) 
 
Investigational and 
reference therapy 
LEE011 + MEK162 
Efficacy assessments 
Phase Ib 
Best Overall Response (BOR) and Overall response rate (ORR), Duration of 
response (DOR), Time to progression (TTP), Progression Free Survival (PFS), and 
Overall Survival (OS) as per RECIST 1.1. 
 
Phase II 
Best Overall Response (BOR) and Overall Response Rate (ORR), Duration of 
response (DOR), Time to progression (TTP), Progression Free Survival (PFS) and 
Overall Survival (OS) as per RECIST 1.1. 
 
Safety assessments 
Incidence rate of Dose Limiting Toxicities (DLT) during the first cycle of LEE011 and 
MEK162 combination treatment 
 
Adverse events and serious adverse events, changes in laboratory values, 
assessments of physical examinations, vital signs, electrocardiograms, and dose 
interruptions, dose reduction and dose intensity. 
 
Other assessments 
Plasma concentration-time profiles of LEE011 and MEK162, PK parameters, 
including but not limited to AUCtau, AUCtau,ss, Cmin,ss, Cmax, Cmax,ss, Tmax, 
Tmax,ss, accumulation ratio (Racc), and T1/2,acc, CL/F(phase Ib). 
 
 
 
 
 
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Data analysis 
The primary purpose of the study is to estimate the MTD(s) and/or identify the RP2D 
and schedule of LEE011 and MEK162 combination in adult patients with NRAS 
mutant melanoma. The corresponding primary endpoint is the incidence of DLTs in 
cycle 1. 
 
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 DDS (see definition below), using an 
adaptive BLRM guided by the EWOC principle. 
 
Unless otherwise specified, the Full Analysis Set (FAS) will be the default analysis set 
used for all analyses. It includes all patients who received at least one dose of 
LEE011 or MEK162. 
 
For all safety analyses, the safety set will be used. It includes all patients who 
received at least one dose of LEE011 or MEK162, and have at least one valid post-
baseline safety assessment. 
 
The dose-determining set (DDS) will be used for the estimation of MTD. It consists of 
all patients from the safety set who meet a minimum exposure criterion as outlined in 
Section 10 and have sufficient safety evaluations, or discontinue earlier due to DLT. 
 
All the data will be summarized with respect to demographic, baseline characteristics 
and safety observations using descriptive statistics (quantitative data) and 
contingency tables (qualitative data). 
 
Pharmacokinetic parameters will be determined using either non-compartmental 
method(s) or fitting of the actual values to a population PK model. 
 
Anti-tumor activity will be summarized in terms of ORR, DOR, TTP, PFS and OS as 
per RECIST 1.1. 
 
 
 
 
 
 
 
 
 
 
The study data will be analyzed and reported based on all patients’ data from the 
dose escalation and expansion parts. Details of the statistical analysis and data 
reporting will be provided in the Report and Analysis Plan (RAP) document finalized 
prior to database lock. 
 
Key words 
Phase Ib/II, adult, open-label, NRAS mutant melanoma 
 
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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Approximately 160,000 new cases of melanoma are diagnosed and 48,000 melanoma-related 
deaths occur worldwide each year (World cancer report 2008, International Agency for 
Research on Cancer 2008). Among cancers in patients under 40 years of age, the incidence of 
melanoma is second only to that of breast cancer for women and leukemia for men  
(Siegel 2012). 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 metastases 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 2010). 
There is a high frequency of activating mutations in proteins of the RAS/RAF/MEK/ERK 
pathway in melanoma. The NRAS gene is mutated in 15-20% of melanomas. The most 
common mutations in NRAS occur at codons 12, 61 and less frequently at 13  
(van Elsas 1995). The presence of NRAS mutations in melanoma causes a switch in MAPK 
signaling from BRAF to CRAF, initiating dysregulated cAMP signaling that allows CRAF to 
signal to MEK (Dumaz 2006). Mutations in NRAS are exclusive of alterations in PTEN, 
implying that mutations in NRAS alone may activate signaling through both the MAPK and 
PI3K pathways (Goel 2006, Davies 2009). Compared to other melanoma subtypes, 
melanomas with NRAS mutations are associated with a worse prognosis (Devitt 2011). 
Selective pharmacological inhibition of NRAS remains technically challenging because its 
GTPase activity has so far eluded the successful design of specific small-molecule 
antagonists. A number of clinical trials are underway to evaluate alternative strategies which 
combine inhibitors of molecules downstream of NRAS, such as BRAF and MEK inhibitor 
combinations and the combination of PI3K pathway inhibitors with drugs that inhibit the ERK 
pathway (Kelleher 2012). The efficacy of these various approaches is not yet established and 
there remains a need for effective therapy for NRAS mutated melanoma. 
Deregulation of cell cycle check points have been well described in melanoma (Wang 1996). 
The loss of expression of the p16 (also known as INK4A) tumor suppressor, by mutation, 
deletion or transcriptional silencing of the CDKN2A locus, is a frequent event in melanoma 
(Yang 2005). Activating mutations in CDK4 have been described in familial melanoma, as 
well as in sporadic cases of melanoma, as has CDK4 amplification (Walker 1998). Intact p16 
inhibits CDK4 activity, so genetic inactivation of p16 is thought to result in aberrant CDK4 
activity. Amplification of cyclin D, which cooperates with CDK4 to drive cell cycle 
progression, is observed in a subset of melanoma and provides further genetic evidence that 
CDK4 activity is a fundamental element in melanoma transformation (Hodis 2012, Curtin 
2005, Smalley 2008). Therefore, targeting the CCND1/CDK4 axis may provide therapeutic 
benefit to melanoma patients. 
In addition to this genetic deregulation of the cell cycle, mutant NRAS itself plays a known 
central role in proliferation (Eskandarpour 2009). In an inducible mouse model of NRAS-


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mutant melanoma, NRASQ61K expression can be shut off genetically. This produces a near-
complete cessation of mitotic activity after four days, accompanied by enhanced apoptosis 
(Kwong 2012). Importantly, this occurs despite the permanent deletion of p16INK4A by genetic 
engineering, indicating that this cell cycle arrest is independent of – and not rescued by – the 
loss of p16. When NRAS signaling is only partially inhibited, either by partial NRAS 
extinction at two days post-shutoff or by pharmacological MEK inhibitor treatment, apoptosis 
is induced but not cell cycle arrest. Therefore, while NRAS signaling cross-talks with the cell 
cycle machinery via the CDK4-Rb axis, NRAS signaling is not an all-or-nothing process: its 
outputs such as apoptosis can be decoupled from the cell cycle along a gradient of NRAS 
activity. Together, these data on the importance of the cell cycle in melanoma suggests that it 
may be a separate and therefore complementary target to MAPK pathway inhibition. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of LEE011 
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits 
highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cyclinD3 complexes, 
with concentration resulting in 50% inhibition (IC50) values of 10 nM and 39 nM, 
respectively, in isolated enzyme assays. It is inactive against the majority of other kinases. It 
is currently being tested in a clinical trial in adult cancer patients [CLEE011X2101]. 
1.2.1.1 
Preclinical pharmacology 
LEE011 inhibits the growth of many tumor cell types in vitro and in vivo, including mantle 
cell lymphoma, liposarcoma, rhabdoid tumors, neuroblastoma, and carcinomas of the 
esophagus, breast, lung and pancreas. Regardless of the various genetic aberrations that may 
be present in the cancer cells, the anti-tumor activity of LEE011 requires the presence of 
functional retinoblastoma protein (Rb). 
LEE011 has demonstrated tumor growth suppression in multiple melanoma xenograft models 
as a single agent. Tumor regression was achieved in two models, while tumor stasis was 
observed in five models. In addition, LEE011 has also demonstrated anti-tumor activity as a 
single agent in two NRAS-mutant melanoma models. In these models, LEE011 in 
combination with MEK162 resulted in tumor regression. 
1.2.1.2 
Non-clinical pharmacokinetics and metabolism 
The PK of LEE011 was investigated in four different species: mouse, rat, dog and monkey. 
After oral administration to rats, LEE011 was moderately absorbed (48 to 84%) with 
bioavailability ranging from 10% to 65% across animal species. Maximum serum drug 
concentration (Cmax) was between 2 and 4 hours. The terminal half-life (T1/2) of LEE011 
was moderate in rodents and monkeys (2 to 7 h), and was comparatively longer (18 h) in 
dogs. 
The binding of LEE011 to plasma proteins was moderate (unbound fraction in plasma for 
human is 30 ± 2%). 3H-LEE011 and its metabolites were extensively distributed into the 
organs and tissues of rats including choroid, ciliary body, and meninges with the exception of 


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the brain. The highest radioactivity concentrations were found in tissues such as pituitary 
gland, pineal gland, spleen, kidney, and adrenal medulla, with remarkably high exposure in 
the thyroid gland. Distribution of LEE011 and/or its metabolites into melanin-containing 
structures was seen in pigmented rats. 
Oxidative metabolism of LEE011 was dominated by CYP3A4 with a minor contribution by 
flavin-containing monooxygenase 3 (FMO3). LEE011 is a moderate substrate of P-
glycoprotein (Pgp). LEE011 is a time-dependent CYP3A4 inhibitor and a reversible inhibitor 
of CYP1A2. LEE011 was found to inhibit the mitoxantrone-resistant protein (MXR), and 
human bile salt export pump (BSEP) but not the rat or dog BSEP. LEQ803 (N-demethylation) 
is a major metabolite in the rat and monkey, the main metabolite in humans and the only 
metabolite in dogs. This metabolite was found to interact with hERG channels in vitro. 
In rat ADME studies, LEE011 was predominantly excreted with bile. The elimination of 
unchanged drug was limited. A minor proportion of the administered dose is excreted in urine. 
The bulk of the administered dose (87.3%) was excreted within 24 h. 
Overall, the elimination of LEE011 may potentially be affected by co-administered drugs that 
inhibit or induce CYP3A4. LEE011 may inhibit CYP3A4, CYP1A2 and BSEP depending on 
the dose administered. 
1.2.1.3 
Safety pharmacology and toxicology 
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 premature ventricular contractions (PVCs) at higher exposure levels. LEE011 and 
LEQ803 likely contributed to the QT prolonging effects seen in vivo. 
In rats and dogs, LEE011 induced bone marrow hypocellularity, lymphoid depletion, atrophy 
of the skin and intestinal mucosa, decreased bone formation and testicular atrophy. These are 
consistent with the mechanism of action of LEE011. In addition, an increased number of 
ovarian corpora lutea was observed in a single female dog at the highest dose tested. The 
liver, bile system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder 
calculi, and inspissated bile) were identified as additional target organs of toxicity which are 
not likely related to the primary pharmacology of LEE011. Correlating hematological and/or 
biochemistry changes were seen for the effects described in the bone marrow, lymphoid 
system and liver. All the described changes were fully reversible in rats and dogs. 
Based on its mechanism of action and preclinical toxicology studies, the major potential 
toxicities for LEE011 include myelosuppression, hepatic toxicity, and prolongation of the QT 
interval. The risk of these toxicities may be amplified by concomitant administration of strong 
inhibitors of CYP3A4. 
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1.2.1.4 
Clinical experience 
Safety and PK reported in this document are from the first-in-human (FIH) study, 
[CLEE011X2101] – “A phase I, multicenter, open label, dose escalation study of oral LEE011 
in patients with advanced solid tumors and lymphomas”. 
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) in [CLEE011X2101]. 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 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 most frequently reported AEs (>15%) 
regardless of study treatment relationship include neutropenia (44%), nausea (42%), anemia 
(41%), leukopenia (37%), fatigue (35%), diarrhea (31%), thrombocytopenia (28%), vomiting 
(28%), lymphopenia (27%), decreased appetite (24%), asthenia (23%), constipation (19%), 
hyperglycemia (17%), and hypoalbuminemia (17%). 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 in the above referenced study. 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.1.5 
Clinical pharmacokinetics of LEE011 
Following oral dosing, LEE011 is rapidly absorbed with median time to reach maximum 
plasma concentrations (Tmax) ranging from 1 to 4 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 
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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.Following oral dosing, LEE011 is 
rapidly absorbed with median time to reach maximum plasma concentrations (Tmax) ranging 
from 1 to 4 hours. 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). Steady-state is generally reached by Day 8 and the arithmetic mean effective 
T1/2 based on accumulation ratio ranges from 15.9 to 43.1, hours. The accumulation ratio 
based on AUC (Racc) ranged from 1.55- to 3.13-fold. The MTD of LEE011 is 900 mg QD 
with a 3 weeks on/1 week off schedule. The R2PD for future development is 600 mg QD with 
a 3 weeks on/1 week off schedule which has an acceptable safety profile, lower risk for QT 
prolongation, adequate exposures, and preliminary evidence of clinical activity. 
For further information regarding clinical experience with LEE011, refer to the [Investigator’s 
Brochure]. 
1.2.2 
Overview of MEK162 
MEK162, previously named ARRY-438162, is an oral, ATP non-competitive, highly 
selective inhibitor of MEK1/2. The compound has nanomolar activity against purified MEK 
enzyme (IC50 = 12 nM) and inhibits both basal and induced levels of ERK phosphorylation in 
numerous cancer cell lines with IC50 values as low as 5 nM. MEK162 is undergoing clinical 
evaluation for the treatment of a range of BRAFV600E and RAS-mutated solid-tumor 
indications including melanoma, colorectal and biliary cancers. 
1.2.2.1 
Preclinical pharmacology 
MEK162 potentially inhibits the cell proliferation of mutant BRAF and RAS human cancer 
cell lines in vitro. NRAS mutation is a predictor of sensitivity to MEK inhibitors with a 
positive predictive value of 56% in a panel of 272 WT and mutant lines. MEK162 has 
demonstrated tumor regression in BRAF mutant melanoma xenograft models with clear 
evidence of pathway inhibition. MEK162 has demonstrated in vitro and in vivo antitumor 
activity in other cancer models driven by the MAPK pathway (colorectal, pancreatic, non-
small cell lung) with tumor regressions in some. Tumor growth inhibition correlated with 
decreased phospho-ERK levels in all tumor xenografts. MEK162 has also shown significant 
anti-tumor activity in xenograft models in combination with targeted agents like LGX818, 
RAF265, and LEE011, and standard-of-care agents such as cisplatin, 5 FU, and taxanes. 
1.2.2.2 
Non-clinical pharmacokinetics and metabolism of MEK162 
In animals, exposure (AUC) and Cmax generally increases in a dose proportional manner. 
The plasma clearance is low (range: ~2 to 8 mL/min/kg) and the mean plasma T1/2 ranges 
from 2 to 9 hours. MEK162 has moderate membrane permeability and is a substrate of P-gP 
and BCRP. MEK162 exhibits high plasma protein binding in vitro (> 96%, except dog 84%) 
and is predicted to have good stability with respect to hepatic metabolism. Nonclinical in vitro 
and in vivo data indicate that MEK162 is metabolized by multiple routes but primarily by 


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glucuronidation pathways (mainly via UGT1A1, 1A3 and 1A9) and to a lesser extent by 
oxidation pathways (mainly via CYP1A2 and 2C19). The formation of active metabolite 
AR00426032 is mediated primarily by CYP1A2 with minor contributions from other CYPs. 
MEK162 potently inhibits CYP2B6 and weakly inhibits CYP1A2 and 2C9. It is not 
considered a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 and CYP3A. In vitro 
evidence also suggests that MEK162 could induce CYP3A. 
1.2.2.3 
Safety pharmacology and toxicology 
Nonclinical toxicological studies indicated that MEK162 was well tolerated. The most 
prominent in-life findings were dose-related, reversible hair loss and/or scabbing in rats and 
dose-related, reversible loose or watery stools in monkeys. Administration of MEK162 to rats 
was associated with microscopic findings of soft tissue mineralization, skin effects and 
minimal to mild clinical pathology changes. Gastric mucosal lesions were associated with 
MEK162 administration to rats at 100 mg/kg. In cynomolgus monkeys, administration of 
MEK162 was associated with soft stools, moderate clinical pathology changes in some 
animals and reversible histopathologic changes in the gastrointestinal tract. 
There was no evidence of genotoxicity. Embryo-fetal development studies showed evidence 
of teratogenicity in rabbits (ventricular septal defects and outflow tract defects) and decreased 
ossification that is considered to be secondary to decreased fetal body weights at maternally 
toxic doses in rats. 
For detailed information refer to the [MEK162 Investigator’s Brochure]. 
1.2.2.4 
Clinical experience 
MEK162 has been tested in multiple clinical studies including healthy subjects, patients with 
rheumatoid arthritis, and patients with various advanced solid tumors. Some studies are 
complete and several are on-going. As of 29 Feb 2012, a total of 450 subjects/patients have 
received at least 1 dose of MEK162 and been evaluated for safety, including 70 healthy 
subjects, 164 patients with rheumatoid arthritis and 216 patients with advanced cancer. For 
detailed information regarding these clinical studies with MEK162, refer to the [Investigator’s 
Brochure]. 
The 216 patients with advanced solid tumors have received or are currently receiving 
MEK162 (either as a single agent or in combination) at doses of 30 to 80 mg BID. MEK162 
has target-related PD activity in skin at multiple-dose levels at and below the MTD of 60 mg 
BID. 
As of the data-cutoff date of 29 February 2012, the most frequent treatment-related AEs in 
patients receiving MEK162 for advanced cancer were rash, dermatitis acneiform, nausea, 
diarrhea, peripheral edema, vomiting, fatigue and increase in blood creatine phosphokinase 
(CPK/CK). 
130/171 patients treated with MEK162 as a single agent developed an AE of rash. Of those, 
78% were assessed as related to MEK162. Most were Grade 1-2 in severity and improved or 
resolved with treatment (topical or oral antibiotics, topical or oral steroids). In most cases, 
MEK162 was continued throughout treatment of the rash, however a small number of patients 
required a dose hold and/or dose reduction. Grade 3/4 events of rash occurred in eight 


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patients, one of which was a DLT at the 80 mg BID dose level. In the combination studies of 
MEK162 with other PI3K or RAF inhibitors, rash was also one of the most commonly 
reported AEs. 
Retinal events have occurred in 17 out of 90 patients tested in the [ARRAY-162-111] study at 
dose levels of 45 mg BID or higher and include 5 patients with Grade 1, 11 patients with 
Grade 2, and 1 patient with Grade 3 events. Approximately 71% of these patients reported 
visual symptoms associated with the retinal abnormalities. Symptoms have included “flashing 
lights/floaters, color variations, blurred vision, and seeing shapes upon opening the eye”. 
Retinal events have been described as “leaky” type detachment with collections of sub-
neurosensory fluid which is best visualized on optical coherence tomography. No “tear” type 
detachments have been reported. The retinal events have included central serous retinopathy 
(CSR), retinal deposits, retinopathy, chorioretinopathy and venous stasis retinopathy. To date, 
these retinal events have been reversible in all patients upon discontinuation or dose reduction 
of MEK162. In most patients, MEK162 was held until resolution of all signs and symptoms. 
In two patients in the 45 mg BID cohort, the dose was reduced without holding treatment and 
there was no reoccurrence of the event. Low grade (Grade 1/2) CSR-like events were also 
reported by 17/81 patients in the single agent [MEK162X2201] study and 3/3 patients in the 
Japanese single agent [MEK162X1101] study. Low grade (Grade 1/2) CSR-like events were 
also reported in all combination studies of MEK162 with PI3K or RAF inhibitors. 
Diarrhea has been reported in 45/90 patients in the [ARRAY-162-111] study and in 36/81 
patients in the [MEK162X2201] study. Of those, 41% and 30%, respectively, were assessed 
as related to MEK162. In addition, 2/3 Japanese patients in the [MEK162X1101] study 
reported treatment-related diarrhea. The majority of these events were Grade 1 or 2 and 
responded well to standard anti-diarrheal agents. Treatment-related diarrhea has also been 
reported in all trials where MEK162 has been used as a combination treatment. 
Peripheral edema has been observed in 42/90 patients in the [ARRAY-162-111] study and in 
34/81 patients in the [MEK162X2201] study. Of those, 34% and 27%, respectively, were 
assessed as related to MEK162. Events were reported in the 45, 60, and 80 mg BID cohorts, 
though none were reported in the 30 mg BID cohort. Most of the events were Grade 1 or 2 
and responded well to diuretic agents. Two out of 81 patients reported Grade 3/4 peripheral 
edema in the [CMEK162X2201] study. 
Adverse events of reversible elevations of CK were reported in 12/90 (13%) patients in the 
[ARRAY-162-111] study. Additionally, clinical laboratory results have shown that 64/90 
(71%) patients had an elevated CK after starting study therapy. Most elevations were of Grade 
1-2. 
Eight patients had Grade 3 elevations and one patient had a Grade 4 elevation. Most of the CK 
elevations were asymptomatic and reversible. In the [CMEK162X2201] study, increase of the 
blood CK has been reported in 24/81 (30%) patients, including Grade 3/4 events reported by 
16/81 patients. Of those, the event was reported as related to MEK162 treatment in 28% of 
patients. Adverse events of reversible elevations of CK have also been reported in the 
combination studies of MEK162 with PI3K or RAF inhibitors. 
As of the data-cutoff date 32, (15%) out of 216 patients with advanced cancer treated with 
MEK162 (as a single agent or in combination with PI3K or RAF inhibitors) experienced liver-


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related adverse events (19 patients Grade 1 or 2, 12 patients Grade 3, 1 patient Grade 4). 
Twenty three of 32 patients had liver metastases at baseline. The reported adverse events 
included elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyltransferase (GGT), alkaline phosphatase (AP), bilirubin, hepatic pain, 
ascites, cytolytic hepatitis, bile duct obstruction, cholangitis, jaundice and cholestatic 
jaundice. One case of acute liver failure with fatal outcome at a dose of 60 mg BID, possibly 
related to MEK162 has been reported after the data-cutoff date. In this case, the investigator 
considered the liver failure was related to study drug; however, other diagnoses, such as 
muscular toxicity and/or thrombotic/vascular/hepatic events, may be considered. This is the 
only case of fatal liver failure reported in more than 450 subjects/patients that have received at 
least one dose of MEK162 to date. 
One case of cardiac failure, possibly related to MEK162 has been reported after the data 
cutoff date. A second case of a non-serious decrease in cardiac ejection fraction was reported 
in a patient receiving MEK162 at a starting dose of 60 mg BID. This patient had, however, a 
number of confounding factors, including significant hypothyroidism and hypertension. 
Elevated CK was associated with the administration of MEK162, as described above. It 
cannot be excluded that in a small percentage of patients with advanced cancer MEK162 is 
associated with liver transaminase elevations. No other apparent trends in clinical laboratory 
parameters, vital signs or electrocardiograms (ECGs) were associated with the administration 
of MEK162. 
Additionally, post the [MEK162 Investigator’s Brochure] cut-off date of 29 February 2012 
and 10 December 2012, Novartis received five serious adverse event (SAE) reports of 
cardiotoxicity that are considered possibly related to MEK162; patients received doses of 45 
mg BID or 60 mg BID. In three cases MEK162 was used in combination with a RAF 
inhibitor. 
The five cardiotoxicity cases were: reduced left ventricular ejection fraction (LVEF) (2 cases); 
cardiac failure with decreased LVEF (1 case); bradycardia with decreased LVEF (1 case) and 
atrial fibrillation with left and right ventricular dysfunction (1 case) The events were 
considered related to the study drug(s) by the investigators; however, four of the five patients 
had risk factors for cardiovascular disease, confounding a conclusive association with the 
study drug(s). Three of the five cardiac toxicities resolved to baseline levels following study 
drug discontinuation; one patient recovered with sequalae, and one patient’s symptoms were 
ongoing (reduced LVEF and increased troponin) as of the 10 December 2012 cutoff. 
There has been no evidence of phototoxicity or photosensitivity in humans treated with 
MEK162 for cancer or for rheumatoid arthritis. Given the embryo-lethal effects seen in rats 
and rabbits and the teratogenic effects seen in rabbits, MEK162 should not be used in 
pregnant women and women of child-bearing potential must be advised to use highly 
effective contraception methods. 
In June 2013, one case of hypertensive crisis in a patient receiving MEK162 prompted a 
review of blood pressure data across all MEK162 studies. These data showed that 
hypertension could be an early onset adverse event isolated to a limited group of patients with 
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For further information regarding clinical experience with MEK162 refer to the  
[MEK162 Investigator’s Brochure]. 
1.2.2.5 
Clinical pharmacokinetics of MEK162 
In healthy subjects, MEK162 exposure (as quantified by Cmax and AUC) tended to increase 
in a dose-proportional manner following single and multiple doses over a dose range of 5 to 
80 mg QD for single dose and 5 to 60 mg QD for multiple doses. One additional cohort 
received 20 mg BID for 14 consecutive days. The mean T1/2 was 7 to 8 hours, and the mean 
(Tmax) was 1.18 hrs. The AR00426032 metabolite represented < 13% of the parent drug in 
plasma and < 5% of the parent drug was excreted renally. Accumulation of MEK162 was < 
40% following QD dosing and < 75% following BID dosing. 
The initial evaluation of the PK of MEK162 in patients with advanced cancer ([ARRAY-162-
111] and [CMEK162X2201]) at the doses evaluated to date (30 to 80 mg BID) indicated that 
both the plasma concentration-time profiles and PK parameters were similar to those in 
healthy subjects, as well as in patients with rheumatoid arthritis. The inter-subject variability 
for AUC and Cmax was ~40%. The mean active metabolite-to-parent ratio was less than 25% 
across all study days and dose levels tested. Steady-state is reached by Day 15 and 
accumulation of MEK162, as estimated using non-compartmental methods, is around 50% (or 
1.5 fold). 
To integrate all the available PK information, a preliminary population PK model describing 
the PK of MEK162 was built using data from 68 subjects from the Array and Novartis 
studies. The model suggests that the PK can be adequately described using linear kinetics (2 
compartmental open model with first order absorption and a lag time). Clearance of MEK162 
estimated as 17 L/h. For the typical individual, steady-state is reached by Day 15 and 
accumulation of MEK162 is around 70% (or 1.7 fold). 
For further information regarding clinical experience with MEK162, refer to the 
[Investigator’s Brochure]. 
1.2.2.6 
Clinical experience with the combination of LEE011 and MEK162 
As of 17 February 2014, 22 patients have been treated with the combination of LEE011 
administered orally once daily for 21 consecutive days followed by a 1 week break (3 weeks 
on /1 week off) in combination with MEK162 administered orally twice daily in a continuous 
dosing schedule on a 28-day cycle [CMEK162X2114]. Four dose levels were explored; 
Cohort 1: LEE011 200mg QD + MEK162 45mg BID (9 patients), Cohort 2: LEE011 300mg 
+ MEK162 45mg BID (6 patients), Cohort 3A: LEE011 300mg + MEK162 30mg BID (4 
patients) and Cohort 3B: LEE011 250mg + MEK162 45mg BID (3 patients). 
One DLT of grade 3 acute renal injury occurred in Cohort 1 (n=1) and two DLTs of grade 4 
CPK elevation (n=1) and of grade 4 atrial fibrillation (AF) and grade 3 edema (n=1) occurred 
in Cohort 2. 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim safety summary from 17 patients (as of 17-Feb-2014) is listed below. Treatment-
related AEs occurring in 2 or more patients (10%) included blood creatine phosphokinase 
increased (41%), acneiform dermatitis (41%), diarrhea (24%), fatigue (24%), nausea (24%), 
peripheral edema (24%), anemia (18%), aspartate aminotransferase (AST) elevation (12%), 
increased creatinine (12%), decreased appetite (12%), hyperphosphatemia (12%), 
hypoalbuminemia (12%), mucosal inflammation (12%), neutropenia (12%), acute renal 
failure (12%), retinopathy (12%), vomiting (12%), leukopenia (12%), and decreased white 
blood cell count (12%). Treatment-related CTCAE Grade 3-4 AE occurring in one or more 
patients included blood creatine phosphokinase increased (18%), acute renal failure (12%), 
atrial fibrillation (6%), hypertension (6%), hypokalemia (6%), hypophosphatemia (6%), 
neutropenia (6%), decreased neutrophil count (6%), and rash (6%). 
 
 
 
 
 
 
 
 
 
 
Preliminary PK data are consistent with that of the respective single agents and there appears 
to be no evidence of drug-drug interaction. Of the 14 patients who have had at least one post-
baseline scan, 1 confirmed partial response (PR), 5 unconfirmed PR, and 6 patients with 
stable disease (4 with >20% tumor shrinkage) have been reported. Of the 21 patients, 14 
remain on treatment. A majority of patients have required multiple dose interruptions for 
management of toxicities, and 7 patients have required dose reductions for one or both drugs. 
PPD
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2 
Rationale 
2.1 
Study rationale and purpose 
There are no established therapies for patients with NRAS mutant melanoma and their 
prognosis is poor. Targeting the RAS/RAF/MEK/ERK pathway and the CCND1/CDK 
pathway downstream may be an effective strategy for treatment. MEK inhibitors act 
downstream of RAS and RAF and can potentially block signal transduction that results from 
either mutations or activation through cell surface receptors. In an inducible mouse model of 
NRAS-mutant melanoma, pharmacological MEK inhibition activated apoptosis but failed to 
trigger cell cycle arrest. This is in contrast to complete mutant NRAS extinction by genetic 
means, which induced both apoptosis and cell cycle arrest. Systems biology analyses of 
comparative microarray data demonstrated that the lack of cell cycle arrest with MEK 
inhibition centered on a CDK4-Rb axis. Accordingly, the combined pharmacological 
inhibition of MEK and CDK4 in vivo led to apoptosis, cell cycle arrest and tumor regression. 
This was validated in two independent NRAS-mutant human melanoma cell line xenograft 
models, one each of mucosal and cutaneous origin. The mechanism was also validated in an 
ex vivo model using a fresh patient biopsy. (Kwong 2012). Simultaneous inhibition of MEK 
and CDK4/6 could ensure complete inhibition of activated pathways and lead to enhanced 
anti-tumor activity. 
In clinical studies, MEK162 has demonstrated single agent anti-tumor activity in patients with 
NRAS cutaneous melanoma [CMEK162X2201]. As of the data cutoff date May 31, 2012 
thirty one patients with NRAS mutant status were evaluable for efficacy. 7 patients (23%) had 
a partial response (4 confirmed), 13 patients had stable disease (42%), and the disease control 
rate was 63%. The median PFS was 3.65 months (95 % CI: 2.53 - 5.36) [Ascierto PA. 
Abstract 8511. ASCO 2012]. LEE011 is a highly selective inhibitor of CDK4/6, which has 
shown in vitro and in vivo activity in models of NRAS melanoma both as single agent and in 
combination with MEK162. Based on pathway biology and preclinical data, the combination 
of LEE011 and MEK162 has the potential to be effective in patients with NRAS mutant 
melanoma. The purpose of this study is to evaluate the safety of the combination of these 
agents, evaluate ORR and PFS in comparison to the single agent activity of MEK162 in the 
ongoing studies in the same patient population. This study will be used to inform future 
development of the combination in NRAS mutant melanoma. 
2.2 
Rationale for the study design 
The study will follow a phase Ib/II design. As outlined in Section 1.1, NRAS mutations are 
well known oncogenic drivers in melanoma and play a prognostic role in outcome. While 
deregulation of cell cycle check points occur frequently in melanoma, their role as oncogenic 
molecular drivers is less clear. Therefore, in this study patients will be pre-selected based on 
NRAS mutant status, but no pre-selection will be made based on aberrations in the 
CCND1/CDK4 axis. Only patients with a documented mutation in NRAS (e.g, substitutions at 
positions 60 and 61; Q61 R/K/L) will be included in both phases of the study. Intact Rb is 
present in >90% of NRAS melanoma tumors (Hodis 2012); therefore, no pre-screening for the 
presence of Rb will be required, but the analysis will be performed retrospectively. 


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The primary purpose of the phase Ib portion is to estimate the MTD(s) and/or the RP2D of the 
LEE011 and MEK162 combination. The dose escalation will be guided by an adaptive 
Bayesian logistic regression model (BLRM) with overdose control (EWOC) principle. 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 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. 
Once the MTD(s)/RP2D have been determined for each tested schedule, additional patients 
will be enrolled in the phase II portion of the study at the RP2D on the chosen schedule in 
order to assess the anti-tumor activity of the combination in addition to continued evaluation 
of safety. In the Phase II part of the study, a Bayesian design will be used in order to estimate 
the true overall response rate (ORR) in the phase II arm. No interim analysis will be 
performed due to the expectation that all patients will be recruited prior to any analysis time 
point. 
2.3 
Rationale for dose and regimen selection 
The MTD for MEK162 single agent is 60 mg BID dosed continuously. The RP2D of 45 mg 
BID is the single agent dose used in ongoing studies in patients with melanoma. This dose has 
been shown to be very well tolerated and has demonstrated anti-tumor activity in patients with 
NRAS melanoma. Since the dose is safe and effective and the risk for drug-drug interaction is 
minimal, this study will use MEK162 at 45 mg BID from the first dose cohort without any 
planned escalation. If at the time of the dose escalation, the available safety, tolerability, PK, 
PD and efficacy data, as well as the recommendations from the BLRM do not support 
treatment of the next cohort of patients with any LEE011 doses in combination with MEK162 
45 mg BID, then LEE011 doses in combination with MEK162 30 mg BID may be evaluated 
if they satisfy the EWOC criterion. 
The MTD and RP2D for LEE011 are 900 mg QD and 600 mg QD, respectively, on a 3 weeks 
on/1 week off schedule. The starting dose of LEE011 in this study will be 200 mg QD based 
upon review of the safety, tolerability, and PK observed at different dose levels tested in 
[CLEE011X2101] study, as well as the BLRM recommendations based on EWOC criterion 
(see Section 10.4.2 and Appendix 5 for details). The dose of LEE011 will be escalated during 
the study to establish a MTD(s)/RP2D of the combination. At the 200 mg QD dose in adults, 
LEE011 was well tolerated with an acceptable safety profile. The phase Ib part of the study 
will begin with LEE011 administered orally once daily for 21 consecutive days followed by a 
7-day planned break (3 weeks on /1 week off) in combination with MEK162 administered 
orally twice daily in a continuous dosing schedule on a 28-day cycle. In addition, should 
safety and PK data from the dose escalation part of this study and/or other MEK162/LEE011 
study(s) indicate that alternate dosing schedules of MEK162 and LEE011 are more 
appropriate, alternate dosing schedules may be explored (see Section 4.1). All available safety 
and PK data collected from the initial dosing schedule will be considered and reviewed prior 
to exploring new alternate dosing schedule(s). 


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MTD(s) will be established for all tested dosing schedules. Based on their safety, tolerability, 
and efficacy, a single RP2D and schedule will be selected for the phase II part of the study in 
order to assess antitumor activity of the LEE011and MEK162 combination. 
The starting dose decision for the initial dosing schedule (LEE011 QD on a 3 weeks on/1 
week off and MEK BID on a continuous schedule) took into consideration all information 
currently available about the dose-DLT relationships of MEK162 and LEE011 as single 
agents and the uncertainty about the toxicity of the combination. The prior distribution of 
DLT rates derived from the BLRM presented in Appendix 5 indicates that the proposed 
starting dose combination meets the EWOC criterion (less than 25% chance that true DLT 
rate > 35%). There is minimal overlap of toxicities between LEE011 and MEK162. Special 
attention will be paid to GI toxicities, edema, cardiac function, liver function, and ECGs in 
evaluating the combination. Based on CYP3A4 interaction, the risk for drug-drug interaction 
(DDI) is minimal. PK of both agents will be obtained to monitor for DDI. 
The starting dose decision for any alternate dosing schedule will take into consideration all 
available safety and PK data collected from the initial dosing schedule and must satisfy the 
EWOC criterion at the time of the decision to switch to the new combination schedule (see 
Appendix 5 for details). 
2.4 
Rationale for choice of combination drugs 
Please refer to Section 2.1 for the rationale for choice of combination drugs. 
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 
 
Refer to Section 10.4. 
Phase Ib: To estimate the MTD(s)and/or to identify the 
RP2D and schedule of LEE011 and MEK162 in 
combination 
Incidence of dose limiting toxicities in cycle 1 
 
Phase II: To describe the anti-tumor activity of the 
LEE011 and MEK162 in combination at the RP2D 
ORR (CR and PR) according to RECIST 1.1 
 
Secondary 
 
Refer to Section 10.5. 
Phase Ib: To characterize the PK profiles of LEE011 and 
MEK162 as well as any other clinically significant 
metabolites that may be identified. 
Plasma concentration-time profiles of LEE011 and MEK162, PK parameters, 
including but not limited to AUCtau, AUCtau,ss, Cmin,ss, Cmax, 
Cmax,ss,Tmax, Tmax,ss, accumulation ratio (Racc), and T1/2,acc, CL/F 
 
Phases Ib and II: To characterize the safety and 
tolerability of LEE011 and MEK162. 
Incidence and severity of adverse drug reactions and serious adverse drug 
reactions. Changes in hematology and chemistry values, vital signs, ECGs, 
and dose interruptions, dose reduction and dose intensity. 
 
Phases Ib and II: To assess clinical efficacy of the 
LEE011 and MEK162 combination 
Duration of response (DOR), Time to progression (TTP), Progression Free 
Survival (PFS) and Overall Survival (OS) as per RECIST 1.1. Best Overall 
Response (BOR) according to RECIST 1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
Study design 
4.1 
Description of study design 
This is a multi-center, open-label Phase Ib/II study in patients with locally advanced or 
metastatic NRAS mutant melanoma. The study has 2 parts – phases Ib and II. 
MEK162 will be administered orally at 45 mg twice daily (BID) on a continuous dosing 
schedule (28-day cycle). There is no planned escalation of MEK162, although a lower dose of 
30 mg BID may be explored if the combination is not tolerated. Oral LEE011 will be 
administered once daily for 21 days followed by a 1 week break (28-day cycle) at a starting 
dose of 200 mg QD. 
Should safety and PK data from the dose escalation part of this study and/or other 
MEK162/LEE011 study(s) indicate that alternate dosing schedules of MEK162 and 
LEE011may be more appropriate, the following schedules will be considered: 
• LEE011 QD and MEK162 BID, both administered for 3 weeks followed by a 1 week 
planned break (28-day cycle) 
• LEE011 QD and MEK162 BID, both administered for 2 weeks followed by a 1 week 
planned break (21-day cycle) 
The phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled 
patients receiving various dose pairs considering the recommendation from an adaptive 
BLRM incorporating the EWOC principle until MTD(s)/RP2D is defined. Patients with either 
measurable or evaluable disease will be eligible. If multiple alternate dosing schedules are 
explored in parallel, the allocation of patients will proceed in an alternating fashion  
(see Section 4.1). Approximately 40 patients are expected to be treated during the phase Ib 
part of the study. 
Once the MTD(s)/RP2D have been determined for each tested schedule, the phase II part will 
begin at the RP2D on the chosen schedule in order to assess antitumor activity of the 
LEE011and MEK162 combination. Data from enrolled patients will also be used to better 
characterize the safety, tolerability and PK profile of the two agents. Patients enrolled in the 
phase II part of the study are required to have measurable disease. Approximately 40 patients 
will be treated in phase II. 
All patients will be required to provide a representative tumor specimen upon study entry. 
This can either be an archival tumor biopsy with the corresponding pathology report or a 
newly obtained tumor biopsy. Tumor biopsies obtained at the time of diagnosis or any other 
time after that will be accepted. Most recent tumor biopsies are preferred. If a new tumor 
biopsy is collected at screening, patients in phase Ib have the option of providing an on-
treatment biopsy. 
In the phase II part of the study, all patients with accessible tumors that are amenable for 
biopsy must supply a newly obtained tumor sample at screening and at on-treatment to assess 
the pharmacodynamic effects of the combination. 


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Patients may enroll on an optional companion protocol to study the mechanisms of resistance 
to therapy with LEE011 and MEK162. Patients who agree to participate in the companion 
study will provide samples for analysis of their cancer at study entry and again upon disease 
progression 
Patients will continue to receive treatment until disease progression, occurrence of 
unacceptable toxicity that precludes any further treatment, or if treatment is discontinued at 
the discretion of the investigator or by patient’s withdrawal of consent. Analysis of the study 
data will occur after all patients have had the opportunity to complete at least six cycles of 
treatment. 
Patients in phase Ib who discontinue study treatment for any reason will not be followed long 
term in this study. Patients in phase II who have not progressed at the time of discontinuation 
of study treatment will be followed via phone call by site study staff until progression, death 
or until a new cancer therapy is initiated (Section 7.1.5). 
Approximately 80 patients will be treated in the entire study. 
Figure 4-1 
Study design 
 
Screening period 
Upon signing the Study Informed Consent Form, patients will be evaluated against study 
inclusion and exclusion criteria. Eligible patients will be enrolled in the study within 14 days 
of the commencement of the screening assessments and evaluations (Table 7-1 or Table 7-2 
and Section 7.1.2). 
Follow-up assessments 
After study drug discontinuation, all patients must complete End of Treatment assessments 
within 14 days and the safety follow up assessments within 30 days after the last dose of the 
study treatment (see Section 7.1.4 and Section 7.1.5). 
Disease progression assessments (Phase II only) 
Patients enrolled in the Phase II part of the study who discontinue study treatment for any 
reason other than disease progression will be followed up with CT/MRI scans every three 
months as detailed in Table 7-1 or Table 7-2 and Section 7.1.5.2, until disease progression, the 
initiation of subsequent anticancer therapies, death, or until patients have been followed for at 
least 12 months after their first dose of study treatment, have been lost to follow-up or 
withdrew consent, whichever occurs first. Newly started antineoplastic therapies during this 
follow up period must be recorded on the Antineoplastic therapy since discontinuation eCRF. 


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Survival follow-up period (Phase II only) 
All patients enrolled in the Phase II part of the study will be followed for survival every three 
months via phone call until death, or until all patients have been followed for at least 12 
months after their first dose of study treatment, or have been lost to follow up or withdrew 
consent, whichever occurs first. One additional phone call per quarter may be allowed. 
Possible newly started antineoplastic therapies during this follow up period must be recorded 
on the Antineoplastic therapy since discontinuation eCRF. 
4.2 
Timing of interim analyses and design adaptations 
At the end of phase Ib the RP2D will be selected based on available safety, tolerability, PK, 
PD and efficacy data, as well as the recommendations from the BLRM using EWOC. The 
phase II will then begin with a new group of 40 patients recruited. Patients from the Phase Ib 
and Phase II parts will not be pooled for the primary ORR analysis. 
4.3 
Definition of end of the study 
Phases Ib and II of the study will end when the treatment period, safety follow-up, disease 
follow-up and survival follow-up (only for phase II) have ended for all patients as described 
in, Section 7.1.5 or when the study is terminated early. A primary CSR will be written after all 
patients have completed at least six cycles of treatment or discontinued treatment, and a final 
CSR will be written at the end of the study. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by the Sponsor. Should this be 
necessary, the patients should be contacted within 24 hours, informed to stop taking the study 
drug and be seen as soon as possible. The same assessments should be performed as described 
in Section 7.1.4 for a prematurely withdrawn patient. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The investigator will be responsible for informing 
IRBs and/or ECs of the early termination of the trial. 
5 
Population 
5.1 
Patient population 
This study is limited to patients with histologically or cytologically confirmed locally 
advanced or metastatic NRAS mutant melanoma. 
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. 


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5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures. 
2. Patients aged ≥18 years with a histologically or cytologically confirmed diagnosis of 
locally advanced or metastatic NRAS mutant melanoma. Written documentation of NRAS 
mutation is required prior to enrollment in this study. 
3. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 – 1. 
4. Patients enrolled into phase Ib may be enrolled with evaluable disease only. Patients 
enrolled into the phase II expansion must have at least one measurable lesion as defined 
by RECIST 1.1 criteria for solid tumors. 
5. All patients must agree to submit an archival or a newly obtained tumor biopsy specimen 
(performed at diagnosis or relapse) upon study entry in Phase Ib. If an archival specimen 
is submitted a corresponding pathology report must also be provided. In the phase II 
portion of the study, patients with accessible tumors that are amenable for biopsy must 
agree to undergo a tumor biopsy at the time of study entry and on-treatment. 
6. A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy 
(including cytotoxic and biological therapies ) and enrollment in this study, to allow the 
effects of prior therapy to have been reduced: 
• Systemic antineoplastic therapy or any experimental therapy within 2 weeks before 
the first dose of study drugs (6 weeks for nitrosoureas and mitomycin-C). 
• Biologic therapy (e.g., antibodies): ≥ 4 weeks. 
7. Patients must have adequate organ function, as defined by the following parameters: 
a. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L. 
b. Hemoglobin (Hgb) ≥ 9 g/dL. 
c. Platelets ≥ 75 x 109/L without transfusions within 21 days before 1st treatment. 
d. PT/INR and aPTT ≤ 1.5 ULN. 
e. Serum creatinine ≤1.5 ULN. 
f. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with 
known Gilbert syndrome, who are excluded if total bilirubin > 3.0 x ULN or direct 
bilirubin > 1.5 x ULN 
g. AST and ALT <2.5 x ULN, except in patients with tumor involvement of the liver 
who must have AST and ALT < 5 x ULN. 
h. Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements before the first dose of study medication: 
• Sodium 
• Potassium 
• Magnesium 
• Inorganic phosphate 
• Calcium (corrected for serum albumin) 


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8. A negative serum βHCG test ≤ 72 hours before starting study treatment for pre-
menopausal women and for women < 1 year after the onset of menopause. 
9. Patients must give written informed consent to participate in this study prior to undergoing 
any study procedure. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Presence of any brain metastases detected by MRI or CT with i.v. contrast of the brain at 
screening. 
2. Impairment of gastro-intestinal (GI) function or active GI disease that may significantly 
alter the absorption of LEE011 or MEK162 such as ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection. 
3. Uncontrolled arterial hypertension despite medical treatment 
4. Impaired cardiac function, clinically significant cardiac diseases and/or recent cardiac 
events, including any of the following: 
a. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated 
acquisition scan (MUGA) or echocardiogram (ECHO). 
b. Congenital long QT syndrome or family history of unexpected sudden cardiac death. 
c. On screening, inability to determine QTcF interval on the ECG (i.e.: unreadable or 
not interpretable) or QTcF >450 ms (using Frederica’s correction). All as determined 
by screening ECG (mean of triplicate ECGs). 
d. Angina pectoris or symptomatic pericarditis within 12 months prior to starting study 
drug 
e. Acute myocardial infarction within 12 months prior to starting study drug 
f. Clinically significant resting bradycardia within 12 months prior to starting study drug 
g. History or presence of ventricular tachyarrhythmia within 12 months prior to starting 
study drug 
h. Unstable atrial fibrillation (ventricular response >100 bpm) 
i. Complete left bundle branch block within 12 months prior to starting study drug 
j. Right bundle branch block and left anterior hemi block (bifascicular block) within 12 
months prior to starting study drug 
k. Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator 
l. Any other clinically significant heart disease (e.g. documented congestive heart 
failure, documented cardiomyopathy) 
5. Patients who are currently receiving treatment with agents that are known to cause QT 
prolongation or induce Torsades de Pointes in humans and cannot be discontinued 7 days 
prior to Cycle 1 Day 1.  
6. Patients who have neuromuscular disorders that are associated with elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy) or elevated baseline CK levels (≥ Grade 2) 
7. Patients who are currently receiving treatment with agents that are metabolized 
predominantly through CYP3A4 and that have a narrow therapeutic window and cannot 


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be discontinued 7 days prior to Cycle 1 Day 1. Agents that are known strong inducers or 
inhibitors CYP3A4 are prohibited. (Refer to Appendix 3). Patients are not permitted to 
receive enzyme inducing anti-epileptic drugs. 
8. Patients with concurrent severe and/or uncontrolled concurrent medical conditions that 
could compromise participation in the study (i.e. uncontrolled diabetes mellitus, clinically 
significant pulmonary disease, clinically significant neurological disorder, active or 
uncontrolled infection). 
9. Major surgery <2 weeks before starting study treatment. 
10. Patients unwilling or unable to comply with the protocol. 
11. Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not 
mandatory). 
12. 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). 
13. In the phase II, prior exposure to CDK4/6 inhibitor (e.g., PD 0332991). 
14. In the phase II, prior exposure to MEK inhibitor unless approved by the Sponsor. 
15. Another malignancy within three years prior to enrollment, with the exception of 
adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell 
carcinoma of the skin, or other indolent malignancies that have not required therapy 
within the past 3 years. 
16. 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 βHCG 
laboratory test 
17. 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 30 days after study 
drug discontinuation. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject. 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 


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b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of 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 have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
18. Sexually active males, unless they use a condom during intercourse while taking the drug 
and for 30 days after stopping treatment and should not father a child in this period. A 
condom is also required to be used by vasectomized men in order to prevent delivery of 
the drug via seminal fluid. 
6 
Treatment 
6.1 
Study treatment 
The investigational drugs to be used in this trial are: 
• LEE011, supplied as capsules for oral use. 
• MEK162, supplied as film-coated tablets for oral use. 
The study drugs will be administered as a flat-fixed dose, and not by body weight or body 
surface area. 
6.1.1 
Dosing regimen and treatment administration 
LEE011 will be taken orally, once a day for 21 consecutive days followed by a 7 day planned 
break. MEK162 will be taken orally twice daily on a continuous dosing schedule. Both drugs 
are given as part of a 28-day cycle of treatment. 
Detailed instructions regarding administration of LEE011 capsules as well as MEK162 tablets 
will be supplied to Investigator sites in a separate document [CMEK162X2114 Pharmacy 
Manual] from this protocol. 
LEE011 and MEK162 should be taken as follows: 
• Patients should be instructed to take the study drug combination of one or more tablets of 
MEK162 and one or more capsules of LEE011 together with a large glass of water (~250 
ml) daily in the morning at approximately the same time every day. 
• On all dose administration days, tablets of MEK162 and capsules of LEE011 should be 
administered with a glass of water, irrespective of food. 


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• The second dose of MEK162 should be administered with a glass of water 12 ± 2 hours 
after the first dose. On days when blood collection is scheduled at the clinic, patients will 
take LEE011 and MEK162 in the clinic under the supervision of the Investigator or 
designee. On all other days patients will take the LEE011 and MEK162 combination at 
home. 
• Patients should be instructed to swallow the capsules and tablets whole and not to chew, 
crush or open them. 
• If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increase stool frequency) during a treatment cycle must be noted in the 
adverse events section of the eCRF. In addition, on the days of full pharmacokinetic 
sampling, the exact time of any episodes of vomiting and diarrhea (or increase stool 
frequency) within the first 4 hours post-dosing on that day must be noted in a separate 
section of the eCRF. 
• Any doses that are missed should be skipped and should not be replaced or made up 
during the evening dosing or on a subsequent day, whichever applies. 
• Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, or 
Seville (sour) oranges during the entire study and preferably 7 days before the first dose of 
study medications, due to potential CYP3A4 mediated interaction with the study 
medications. Orange juice is allowed. 
The investigator or responsible site personnel should instruct the patient to take the study 
drugs as per protocol (promote compliance). All dosages prescribed and dispensed to the 
patient and all dose changes and all missed doses during the study must be recorded on the 
Dosage Administration Record eCRF. Drug accountability must be performed on a regular 
basis. Patients will be instructed to return used/unused study drugs to the site at the end of 
each cycle. The site personnel will ensure that the appropriate dose of each study drug is 
administered at each visit and will provide the patient with the correct amount of drugs for 
subsequent dosing. 
6.1.1.1 
Alternate dosing schedule of LEE011 and MEK162 
Should safety and PK data from the dose escalation part of this study and/or other 
MEK162/LEE011 study(s) indicate that alternate dosing schedules of MEK162 and 
LEE011may be more appropriate, the following schedules will be considered: 
• LEE011 QD and MEK162 BID, both administered for 3 weeks followed by a 1 week 
planned break (28-day cycle) 
• LEE011 QD and MEK162 BID, both administered for 2 weeks followed by a 1 week 
planned break (21-day cycle) 
Please refer to Section 4.1 for additional information. 


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6.1.2 
Treatment duration 
Patients may continue treatment with LEE011 and MEK162 combination until disease 
progression, unacceptable toxicity occurs that precludes any further treatment and/or 
treatment is discontinued at the discretion of the investigator or by patient refusal (withdrawal 
of consent), as well as in the event of patients death. Patients who have documented 
progressive disease but continue to receive clinical benefit may be allowed to continue 
treatment with either or both drugs (depending on treatment status at time of consideration) 
after discussion between the Sponsor and the investigator. 
6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
Please refer to Section 2.3 for starting dose rationale. 
6.2.2 
Provisional dose levels 
Provisional dose levels are listed in Table 6-1. With the exception of starting dose level 1 for 
the initial schedule (LEE011 3 weeks on/ 1 week off and MEK162 BID continuously), actual 
dose levels will be determined following a discussion with participating Investigators during 
dose escalation teleconferences and may differ from those presented within Table 6-1. Dose 
escalation will continue until MTD(s)/RP2D is/are reached. 
Table 6-1 
Provisional dose levels 
Dose level 
LEE011 mg QD 
MEK162 mg BID 
-1b 
200 mg 
30 mg 
-1a 
100 mg 
45 mg 
1 
200 mg 
45 mg 
2 
400 mg 
45 mg 
3 
600 mg 
45 mg 
a. It is possible for additional and/or intermediate dose combinations to be investigated during the course of the 
study based on available data. 
 
b. Doses -1a and -1b are applicable to those patients requiring a dose reduction from the starting dose of any 
dosing schedule. Dose reductions for MEK162 will be from 45 mg BID to 30 mg BID and from 30 mg BID to 15 mg 
BID or 30 mg QD. All dose reductions beyond 30 mg BID require prior approval by the Sponsor. 
 
c. Cohorts may be added at any dose level below the estimated MTD(s)/RP2D in order to better understand 
safety, PK or PD. 
At all decision timepoints, the adaptive BLRM permits alterations in the dose increments 
based on the observed DLTs. If the starting dose level does not satisfy the EWOC, MEK162 
can be de-escalated below its single agent MTD. 


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6.2.3 
Criteria for dose escalation and determination of MTD/RP2D 
6.2.3.1 
MTD definition 
The MTD is defined as the highest combination drug dosage not causing medically 
unacceptable DLT in more than 35% of the treated patients in the first cycle of treatment. 
Since the initial MEK162 45 mg BID tested with different LEE011 dose levels may be de-
escalated to 30 mg BID and, additionally, different LEE011 and MEK162 dosing schedules 
may be investigated, several combinations may correspond to this definition and more than 
one MTD may be identified with different doses/schedules of the study drugs. 
The applied adaptive Bayesian methodology provides an estimate of the combinations of 
MEK162 and LEE011 not exceeding the MTD. Typically the MTD is a tested dose with 
maximum probability of targeted toxicity (DLT rate between 16% to 35%). The use of 
EWOC principle limits the risk that a potential next dose will exceed the MTD  
(Section 10.4.2) 
6.2.3.2 
Dose cohort modification 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly 
enrolled patients who will be treated at the specified combination dose levels. The first cohort 
will be treated with the starting combination dose at the initial schedule (LEE011 3 weeks 
on/1 week off and MEK162 BID continuously) as shown in Table 6-1. The starting dose for 
any alternate dosing schedule will be at a dose combination deemed to be safe in a previously 
tested schedule. Patients must complete a minimum of 1 cycle of treatment with the minimum 
safety evaluation and drug exposure to have had a DLT within the first cycle of treatment to 
be considered evaluable for dose escalation decisions. Dose escalation decisions will occur 
when the cohort of patients has met these criteria. Dose escalation decisions will be made by 
Investigators and Sponsor study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1, PK, and PD data from evaluable patients. 
The recommended dose for the next cohort of patients will be guided by the Bayesian logistic 
regression model (BLRM) with EWOC principle (please refer to Section 10.4.1 and  
Appendix 5). The adaptive Bayesian methodology provides an estimate of all combination 
dose levels of MEK162 and LEE011 within a dosing schedule that do not exceed the MTD 
and incorporates all DLT information at all dose levels for this estimation. In general, the next 
combination dose will have the highest chance that the DLT rate will fall in the target interval 
(16 to <35%) and will always satisfy the EWOC principle. (Note: If at any time on study, no 
dose pair satisfies the overdose criteria for a specific combination schedule, then the 
combination of MEK162 and LEE011 at that schedule will be terminated). In all cases, the 
combination dose for the next cohort will not exceed a 100% increase from the previous 
combination dose (e.g. up to 100% and 0% increase for LEE011 and MEK162 respectively). 
If two or more patients experience CTCAE grade 2 or greater treatment-related toxicities at a 
dose level in any cohort, all future dose escalations of LEE011 will be ≤ 50%. Only toxicities 
that occur during the first cycle will necessarily be considered for decisions. Smaller increases 


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in combination dose may be recommended by the Investigators and the Sponsor upon 
consideration of all of the available clinical data. If needed to better define the dose-toxicity 
relationship additional patients may be enrolled to the current combination dose level, to a 
preceding combination dose level, or to an intermediate combination dose level before 
proceeding with further dose escalation. 
If the first 2 patients in a previously untested dose level experience a DLT, the next cohort 
will be opened at the next lower dose level or an intermediate dose level (see Table 14-15, 
Appendix 5). However, if the first 2 patients in a new cohort at a previously tested dose 
combination experience a DLT, further enrollment to that cohort will stop and the BLRM will 
be updated with this new information. Re-evaluation of the available safety, PK, and PD data 
will occur. By incorporating information gained at the preceding dose levels, additional 
patients may be enrolled at this dose cohort only if the combination still meets the overdose 
criteria and as agreed by Investigators and Sponsor personnel. Alternatively, if recruitment to 
the same cohort may not resume, a new cohort of patients may be recruited to a lower dose 
level as agreed by Investigators and Sponsor personnel and if the BLRM predicts that the risk 
for this dose to exceed the MTD remains below 25% (EWOC). 
Dose escalation will continue until identification of the MTD(s) or a suitable lower 
combination dose for phase II. This will occur when the following conditions are met: 
1. At least 6 patients have been treated at this combination dose 
2. This combination dose satisfies one of the following conditions: 
• the posterior probability of targeted toxicity at this combination dose exceeds 50% 
and is the highest among potential doses, or 
• a minimum of 15 patients have already been treated on the trial. 
3. It is the dose recommended for the next cohort of patients, either per the model or by 
review of all clinical data by the Sponsor and Investigators in a dose-escalation 
teleconference. 
To better understand the safety, tolerability and PK of MEK162 in combination with LEE011 
additional cohorts of patients may be enrolled at preceding dose levels, or to intermediate 
dose levels before or while proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BRLM will be updated with this new information before any additional patients are 
enrolled at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels. 
6.2.3.3 
Implementation of dose escalation decisions 
At each decision time point, the adaptive BLRM provides the upper boundary for the 
combinations that meet the EWOC criterion. The available safety, tolerability, PK, PD and 
efficacy data, as well as the recommendations from the BLRM, will be used to determine the 
dose combination for the next cohort(s) at a dose escalation teleconference. Provisional dose 
levels are given in Table 6-1. 


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When enrollment of the cohort is complete, further enrollment will only resume after the 
Investigators and the Sponsor have jointly decided on the next dose escalation step of the 
combination. Refer to Section 6.2.3 for the requirements to declare MTD(s)/RP2D. 
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 investigator receives written confirmation from the Sponsor indicating that 
the results of the previous dose level were evaluated and that it is permissible to proceed to a 
higher dose level. 
6.2.3.4 
Intra-patient dose escalation 
Intra-patient dose escalation prior to declaration of MTD(s)/RP2D is not permitted at any time 
during this study. However once the MTD(s)/RP2D is declared, individual patients may be 
considered for escalation/switching to treatment at the RP2D of the combination from the 
dose and schedule to which they were initially assigned. In order for a patient to be treated at 
the RP2D of the combination, he or she must have tolerated the lower dose pair for at least 
two cycles of therapy, i.e., he or she must not have experienced at the lower dose pair 
originally assigned a toxicity of CTCAE Grade ≥ 2 for which relationship to study drug 
cannot be ruled out. 
Consultation with the Sponsor must occur prior to intra-patient dose escalation occurring. 
These changes must be recorded on the Dosage Administration Record eCRF. 
6.2.4 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event or clinically significant 
abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current 
illness, or concomitant medications that occurs within the first cycle of treatment with 
LEE011 and MEK162 and meets any of the criteria included in Table 6-3. National Cancer 
Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will 
be used for all grading. 
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the 
study drug combination will be interrupted and the toxicity will be followed up as described 
in Section 6.3.1. For the purpose of dose-escalation decisions, DLTs will be considered and 
included in the BLRM. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level. 


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Table 6-2 
Criteria for defining dose-limiting toxicities 
TOXICITY 
DLT CRITERIA 
Hematology 
CTCAE grade 4 neutropenia lasting more than 7 consecutive days 
CTCAE grade 4 thrombocytopenia 
CTCAE Grade 3 or 4 neutropenia with fever (temperature ≥ 38.5°C) 
Skin and subcutaneous 
tissue disorders 
Rash or photosensitivity CTCAE Grade 3 > 7 consecutive days despite skin toxicity 
treatment (as per local practice) 
Rash or photosensitivity CTCAE Grade 4 
Eye disorders: retinal 
events 
Retinal events CTCAE grade 3 for > 14 consecutive days, confirmed by 
ophthalmologic examination 
Retinal events CTCAE grade 4, confirmed by ophthalmologic examination 
Eye disorders: Retinal Vein 
Occlusion 
CTCAE grade ≥ 1 confirmed by ophthalmologic evaluation 
Eye disorders: Other 
Any eye disorder CTCAE grade 3 >14 consecutive days 
Any eye disorder CTCAE Grade 4 
Gastrointestinal 
CTCAE grade ≥3 nausea or vomiting ≥ 48 hrs despite optimal anti-emetic therapy 
CTCAE grade ≥3 diarrhea ≥ 48 hrs despite optimal anti-diarrhea treatment 
Hepatobiliary 
CTCAE grade 2 bilirubin > 7 consecutive days 
CTCAE ≥ grade 3 total bilirubin 
CTCAE grade 2 total bilirubin concurrent with grade 2 ALT with the exception of 
known liver metastatic disease 
CTCAE grade 3 ALT > 4 consecutive days 
CTCAE grade 4 ALT or AST (isolated increases in AST without concomitant 
increases in ALT will not be considered dose-limiting, because of the non-specific 
nature of AST) 
CTCAE grade 4 serum alkaline phosphatase > 7 consecutive days 
Cardiac disorders 
Left ventricular systolic dysfunction ≥ Grade 3 
Asymptomatic decrease of >10% in LVF from baseline (and is below the LLN) 
Other cardiac disorders CTCAE Grade ≥ 3 
Investigations 
Serum CK/CPK CTCAE Grade 3 if clinically significant (symptomatic) 
Serum CK/CPK CTCAE Grade 4 
ECG QT Interval 
QTc interval ≥ 501 ms on at least two separate ECGs 
Renal 
Serum creatinine CTCAE Grade ≥ 3 
Non-hematologic events 
≥ CTCAE grade 3, except for the exclusions noted below 
Exceptions to DLT criteria 
Grade 3 alopecia 
< 7 days of CTCAE grade 3 fatigue 
< 7 days of CTCAE grade 3 edema 
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant 
CTCAE version 4.03 will be used for all grading. 
Optimal therapy for vomiting, diarrhea, or skin disorders will be based on institutional guidelines, with 
consideration of the prohibited medications listed in this protocol. 
Follow-up for dose limiting 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 


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subsequently at approximately 4 weeks 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 the 
specific study drug combination induced toxicities are provided in Table 6-3. 
6.2.4.1 
Follow up evaluations for appearance of retinal events 
Patients on the study will be examined regularly to monitor for the possible development of 
retinal events, as the appearance of retinal events has been associated with MEK162 
treatment. Ophthalmologic examinations will be performed periodically as outlined in Table 
7-1 or Table 7-2. For patients developing retinal events of any grade it is recommended to 
follow up the retinal events with an ophthalmological exam every two weeks for 8 weeks, and 
subsequently at approximately a 4week’s interval. Dose modification guidelines are outlined 
in Table 6-3. 
6.3 
Dose modification 
6.3.1 
Dose modification and dose delays 
If a patient experiences a DLT, then treatment with both drugs must be interrupted. For all 
toxicity grades, if the toxicity resolves to grade 1 or baseline within 1 week of onset, treatment 
may be resumed at the same or a lower dose level at the investigator’s discretion and 
following discussion with the Sponsor. 
The dose during Cycle 1 should not be reduced or interrupted unless the patient has 
experienced a DLT. 
For toxicities that result in treatment delays of more than 7 but not more than 21 days, 
treatment may be resumed at a lower dose level. If a patient requires a dose interruption of > 
21 days from the intended day of the next scheduled dose, then the patient must be 
discontinued from the study. In this event, more frequent follow up as outlined in cycle 1 to 
monitor this toxicity may be appropriate. Changes to the dose or schedule must be recorded 
on the Dosage Administration Record eCRF. All patients will be followed for AEs and for 
SAEs for 30 days following the last dose of study drug. 
Each patient is allowed a maximum of two dose reductions for LEE011 and two dose 
reductions for MEK162. After this, the patient will be discontinued from the study treatment. 
For each patient, once a dose level reduction has occurred, the dose level may not be re-
escalated during subsequent treatment cycles. 


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Dose reductions for MEK162 will be from 45 mg BID to 30 mg BID and from 30 mg BID to 
15 mg BID or 30 mg QD. All dose reductions beyond 30 mg BID require prior approval by 
the Sponsor. Dose reductions for LEE011 will be to the previously tested acceptable dose 
level. Specific dose modification guidelines are provided in Table 6-3. 
If a patient discontinues either study drug, then the patient must discontinue the study. 


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Table 6-3 
Dose modification guidelines after Cycle 1 
Toxicity category 
Severity 
Action on study drug 
Hematology 
ANC <1.0 x 109/L and/or platelets < 
75 x 109/L and/or 
Febrile neutropenia 
Hold LEE011 and MEK162 until ANC is ≥1.0 x 109/L and the platelet count is ≥75 x 109/L. 
If treatment delay is ≤ 7 days, restart at same dose for both 
If treatment delay is >7 days but ≤ 21 days, restart one dose level down for both If treatment 
delay >21 days, discontinue treatment of both. 
Nausea, emesis, and/or 
diarrhea with maximal 
prophylaxis 
Grade 2 
Hold MEK162 until it resolves to ≤ Grade 1 and restart at same dose. 
Grade 3 
Hold LEE011 and MEK162 until it resolves to ≤ Grade 1 and restart one dose level down for both. 
Grade 4 
Discontinue treatment of both. 
Hepatobiliary 
Total Bilirubin without ALT/AST increase above baseline value 
Grade 1 total bilirubin (without 
ALT/AST increase) (confirmed 48-
72h later) 
Maintain dose level with LFTs monitored bi-weekly 
Grade 2 total bilirubin (without 
ALT/AST increase)  
Dose interruption of LEE011  
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose level 
If toxicity recurs and is resolved to ≤ grade 1 in ≤ 21 days, then reduce LEE011 1 dose level 
If toxicity recurs after two dose reductions, discontinue treatment of both 
Grade 3 total bilirubin (without 
ALT/AST increase) 
Dose interruption of LEE011 and MEK162 
If resolved to ≤ grade 1 in ≤ 21 days, lower 1 dose level of LEE011 and MEK162 
If toxicity recurs, discontinue treatment of both 
Grade 4 total bilirubin (without 
ALT/AST increase) 
Discontinue LEE011 and MEK162 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose interruption/reduction. They 
include but are not limited to: evidence of obstruction, such as elevated ALP and GGT typical of gall bladder or bile duct disease, 
hyperbilirubinemia due to the indirect component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert Syndrome, 
pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only. 
Bilirubin will be fractionated if elevated. 
AST or ALT without bilirubin elevation >2 xULN 
AST or ALT same grade as baseline 
or increase from baseline grade 0 to 
grade 1 (confirmed 48-72h later) 
No dose adjustment required with LFTs monitored per protocol if same grade as baseline or bi-
weekly in case of increase from baseline grade 0 to 1 


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Toxicity category 
Severity 
Action on study drug 
AST or ALT Increase from baseline 
grade 0 or 1 to grade 2 (> 3.0 – 5.0 x 
ULN) 
or 
from baseline grade 2 to grade 3 (> 
5.0 – 20.0 x ULN) 
 
Dose interruption of LEE011 and MEK162 
If resolved to ≤ baseline value in ≤ 21 days, then maintain dose level 
If toxicity recurs and is resolved to ≤ baseline in ≤ 21 days, then reduce LEE011 1 dose level 
 
If toxicity recurs after two dose reductions or recovery to ≤ baseline value is > 21 days, discontinue 
treatment of both 
AST or ALT Increase from baseline 
grade 0 or 1 to grade 3 (> 5.0 – 20.0 
x ULN) 
 
Dose interruption of LEE011 and MEK162 until resolved to ≤ baseline value ≤ 21 days, then lower 1 
dose level of LEE011 and MEK162 
If toxicity recurs, discontinue LEE011 and MEK162 
If recovery to ≤ baseline value is > 21 days, discontinue treatment of both 
AST or ALT Grade 4 (> 20.0 x ULN) 
Discontinue LEE011 and MEK162 
AST or ALT and concurrent Bilirubin 
AST or ALT ≥ grade 2 (> 3 x ULN) in 
patients with normal values at 
baseline and total bilirubin > 2 x ULN
or 
AST or ALT ≥ grade 3 (> 5 x ULN) in 
patients with grade 1 or 2 at baseline, 
and total bilirubin > 2 x ULN 
Discontinue LEE011 and MEK162 
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose interruption/reduction. They 
include but are not limited to: concomitant medications, herbal preparations or dietary supplements, infection, hepato-biliary disorder or 
obstruction, new or progressive liver metastasis, and alcohol intake. 
 
 
 
 


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Toxicity category 
Severity 
Action on study drug 
Eye Disorders 
Grade 2 retinal events 
Continue MEK162 and LEE011 but refer the patient to a retinal specialist for further evaluation and 
close follow-up. 
If resolved to Grade ≤ 1 in ≤ 21 days, then continue at same dose of MEK162. 
If resolved to Grade ≤ 1 in > 21 days, lower MEK162 dose by one level. 
Grade 3 retinal events and any other 
Grade 3 eye disorders 
Hold MEK162 and refer the patient to a retinal specialist for further evaluation and close follow-up 
until resolved to grade ≤ 1. 
If resolved in ≤ 21 days, then restart at lower dose. 
If resolved in > 21 days, discontinue treatment of both. 
Grade ≥ 1 retinal vein occlusion, 
grade 4 retinal events, and grade 4 
other eye disorders 
Discontinue LEE011 and MEK162. 
Rash/ HFSR/ 
photosensitivity despite 
maximal therapy 
Grade 3 not responsive to treatment 
Hold MEK162 until resolved to grade ≤ 1. 
If resolved in ≤ 7 days despite appropriate skin toxicity therapy (or ≤14 days for acneiform rash), 
then restart at lower dose. 
If resolved in > 7 days despite appropriate skin toxicity therapy (or >14 days for acneiform rash), 
discontinue treatment of both. 
Grade 4 
Discontinue LEE011 and MEK162. 
Cardiac 
Asymptomatic decrease of >10% in 
LVEF compared to baseline and the 
LVEF is above the institution’s lower 
limit of normal 
Continue MEK162 and LEE011 and repeat evaluation of LVEF every 14 days until LVEF recovers. 
Subsequent follow ups as per protocol. 
Asymptomatic decrease of >10% in 
LVEF compared to baseline and the 
LVEF is below the institution’s lower 
limit of normal 
Hold MEK162 and LEE011 and repeat evaluation of LVEF within 14 days 
If the LVEF recovers (defined as ≥ LLN and decrease ≤ 10% compared to baseline) ≤ 14 days, then 
restart at lower dose of both. Monitor LVEF 14 days after restarting on MEK162, every 4 weeks for 
12 weeks and subsequently as per protocol 
If LVEF recovers in > 14 days, discontinue MEK162 and LEE011 
Grade 3-4 
Discontinue MEK162 and LEE011. 


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Toxicity category 
Severity 
Action on study drug 
QTc prolongation 
Grade 1 (QTc 450-480 ms) 
No dose adjustment required 
Grade 2 (QTc 481-500 ms) 
Hold LEE011 and MEK162 
Perform a repeat ECG within one hour of the first QTcF of ≥ 481 ms. 
If QTcF < 481 ms, restart LEE011 and MEK162 at the same dose. No dose adjustment required for 
first occurrence. 
If QTcF remains ≥ 481 ms, repeat ECG as clinically indicated until the QTcF returns to < 481 ms. 
restart LEE011 and MEK162 at the same dose. No dose adjustment required for first occurrence. 
If QTcF ≥ 481 ms recurs, LEE011 should be reduced by 1 dose level. Refer to Table 6-1 for dose 
levels. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) for any 
patients who had therapy interrupted due to QTcF ≥ 481 ms 
Grade 3 (QTc ≥ 501 ms on at least 
two separate ECGs) 
Hold LEE011 and MEK162. Transmit ECG immediately and confirm prolongation/abnormalities with 
central assessment. 
Perform a repeat ECG within one hour of the first QTcF of > 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat cardiac 
monitoring as clinically indicated until the QTcF returns to < 481 ms. 
If QTcF returns to < 481 ms, LEE011 will be reduced by 1 dose level. Refer to Table 6-1 for dose 
levels. 
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 treatment of both  
Grade 4 (QT/QTc ≥ 501 or > 60 ms 
change from baseline 
and 
Torsades de pointes or polymorphic 
ventricular tachycardia, or 
signs/symptoms of serious 
arrhythmia) 
Discontinue LEE011 and MEK162. 
• 
Obtain local cardiologist consultation. 
• 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
• 
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least once a day until the 
QTcF returns to < 501 ms. 
 
For all grades: 
• 
Check the quality of the ECG. 
• 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If outside of the normal range, interrupt LEE011 and MEK162 
administration, correct with supplements or appropriate therapy as soon as possible, and repeat electrolytes until documented as 
normal. 
• 
Review concomitant medication usage for the potential to inhibit CYP3A4 and/or to prolong the QT interval. 
• 
Check compliance with correct dose and administration of LEE011 and MEK162. 
Serum creatinine 
Grade 3 
Hold LEE011 and MEK162 until it resolves to ≤ Grade 1 and restart one dose level down for both. 


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Toxicity category 
Severity 
Action on study drug 
CK/CPK 
Grade 3 
If asymptomatic: Maintain dose of MEK162 and monitor closely. 
If symptomatic, hold MEK162 until resolved to grade ≤ 1. 
• 
If resolved in ≤ 14 days, then restart at lower dose. 
• 
If resolved in > 14 days, discontinue treatment of both. 
Grade 4 
If asymptomatic: hold MEK162 until resolved to grade ≤ 1. 
• 
If resolved in ≤ 14 days, then restart at lower dose 
• 
If resolved in > 14 days, discontinue MEK162 
If symptomatic, discontinue treatment of both 
All other toxicities 
≥Grade 3 
Determine attribution of toxicity. Hold appropriate therapy until resolved to ≤ Grade 1 or baseline. If 
treatment delay is >7 days but ≤ 21 days, restart at lower dose. If treatment delay >21 days, 
discontinue treatment. 


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6.3.1.1 
Additional follow-up for hepatic toxicities 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT. For patients with Gilbert Syndrome: total and 
direct bilirubin must be monitored, intensified monitoring applies to changes in direct 
bilirubin only. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values. 
• Obtaining a more detailed history of current symptoms. 
• Obtaining a more detailed history of prior and/or concurrent diseases. 
• 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. 
6.4 
Concomitant medications 
6.4.1 
Prohibited concomitant therapy 
The following therapies are prohibited: 
• Strong inducers or inhibitors of CYP3A4 (Refer to Appendix 3). 
• Substrates of CYP3A4 with narrow therapeutic windows (Refer to Appendix 3). 
• Medications with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes. 
• Grapefruit, grapefruit hybrids, pummelos, star-fruit and Seville oranges. 
• Concurrent anti-neoplastic therapy, including radiotherapy for therapeutic purposes. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
The following medications are permitted in this study; however, they should be used with 
caution. Patients receiving such medication must be carefully monitored for potentiation of 


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toxicity due to any individual concomitant medication, and may require dose titration of the 
drug substance. 
The solubility of MEK162 is pH dependent and a 10-fold decrease in solubility is observed 
between pH 1 and 2. Patients receiving concomitant treatments that could potentially modify 
the gastric pH (i.e. PPI) should be instructed to take them at least two hours after the 
administration of MEK162. 
• Moderate inhibitors or inducers of CYP3A4/5. 
• Known BSEP inhibitors. 
• Sensitive substrates of CYP3A4/5 that do not have a narrow therapeutic index. 
• Inhibitors of P-gp. 
• Inhibitors of BCRP. 
• Sensitive substrates of BCRP 
• Sensitive substrates of the renal transporters, MATE1 and OCT2 
• Substrates of CYP2B6. 
• Medications that carry a possible risk for QT prolongation. 
• Known inhibitors and inducers of UGT1A1. 
Refer to Appendix 3 through Appendix 4. 
6.4.3 
Permitted concomitant therapy 
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents, such as PRBCs, pain medications, anti-emetics, short courses of 
steroids, and antidiarrheals are allowed. Oral contraceptive pills are permitted. The use of any 
other potential new concomitant medications may be discussed between the investigator and 
the sponsor on a case by case basis. 
Transfusions or growth factor support for white cell counts or platelets are not permitted 
during Cycle 1, unless the patient has already experienced a DLT. Transfusions and growth 
factor support should not be used prophylactically during Cycle 1. 
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 and blood transfusions) administered during 
the study must be listed on the Concomitant Medications or Significant Non-Drug Therapies 
eCRF, respectively. 
Patients taking concomitant medication chronically should be maintained on the same dose 
and dose schedule throughout the study period, as medically feasible. 
The investigator should instruct the patient to notify the study site about any new medications 
including vitamins, supplements and herbal supplements he/she takes after the start of the 
study drug. All medications (other than study drug) including vitamins, supplements and 
herbal supplements and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug must be listed on 
the relevant pages of the eCRF. 


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Refer to the [LEE011 Investigator’s Brochure] and [MEK162 Investigator’s Brochure] for 
information on possible interactions with other drugs. 
6.5 
Subject numbering, treatment assignment or randomization 
6.5.1 
Subject numbering 
Each patient is identified in the study by a Subject Number, 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 Subject Number (Subject No.) consists 
of the Center Number (Center No.) as assigned by the Sponsor or designee to the investigative 
site with a sequential patient number suffixed to it, so that each patient is numbered uniquely 
across the OCRDC database. Upon signing the informed consent form, the patient is assigned 
to the next sequential Subject Number available to the investigator in OCRDC. 
In the Phase II part, the Investigator or designated staff will contact the Interactive Response 
Technology (IRT) and provide the requested identifying information for the patient to register 
them into the IRT. Once assigned, the Subject No. must not be reused for any other patient 
and the Subject No. for that individual must not be changed. If the patient fails to start 
treatment for any reason, the reason will be entered into the Screening Disposition eCRF. 
IRT must be notified within 2 days that the patient was not enrolled on the study. 
6.5.2 
Treatment assignment 
In phase Ib, the assignment of patients to a particular cohort will be coordinated by the 
Sponsor or designee. 
In phase II, the assignment of patients will coordinated by IRT. Prior to dosing, all patients 
who fulfill all inclusion/exclusion criteria will be enrolled via IRT. The Investigator or his/her 
delegate will call or log on to the IRT and confirm that the patient fulfills all the 
inclusion/exclusion criteria. The IRT will then assign a Subject No. to each patient that fulfills 
all inclusion/exclusion criteria. 
6.5.3 
Treatment blinding 
Treatment is not blinded for this study. 
6.6 
Study drug preparation and dispensation 
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. 
The investigational drugs to be used in this trial are: 
• LEE011, supplied as hard gelatin capsules for oral use of dosage strengths of 50 and 200 
mg. 
• MEK162, supplied as film-coated tablets for oral use of dosage strength 15 mg. 
Other strengths might be made available during development of the study drugs if deemed 
necessary. 


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All dosages prescribed to the patient and all dose changes during the study must be recorded 
on the Dosage Administration Record CRF. 
6.6.1 
Study drug packaging and labeling 
LEE011 capsules and MEK162 tablets are packaged in HDPE bottles with child resistant 
closures. 
For the phase II part where IRT is involved for medication management, the labels will have a 
unique medication number for tracking purposes. 
Study drug two-part open labels will be in the local language and comply with the legal 
requirements of each country. They will include storage conditions for the drug but no 
information about the patient. 
6.6.2 
Drug supply and storage 
Study drugs will be centrally supplied by the Sponsor or designated CRO, and must be 
received by a designated person at the study site, handled and stored safely and properly, and 
kept in a secured location to which only the investigator and designated assistants have 
access. Upon receipt, the study drugs should be stored according to the instructions specified 
on the drug labels and in the [Investigator’s Brochure]. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
At the day of a scheduled visit to the clinic, the patient will take the study drugs under 
supervision of the Investigator or designee. The time of dose administration must be recorded 
in the Dose Administration Record eCRF. For all other study days, the patient will take the 
study drugs at home. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
Patients will be instructed to write down the date and time of administration in a patient diary 
provided by the sponsor. The investigator or designee must check compliance and note any 
drug interruptions in the Dose Administration record page of the eCRFs. 
6.6.3.2 
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 


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completed drug accountability log to the Sponsor or designee’s monitor or to the Sponsor 
address provided in the investigator folder at each site. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Sponsor facility, Drug Supply group or 
third party, as appropriate. Drug supply is to be destroyed at the site only if permitted by local 
regulations and authorized by the Sponsor in a prior agreement. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 or Table 7-2 lists all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. 
For all visits, there is a ± 3 days window on assessments to take into account scheduling over 
public or religious holidays except for assessments that are dose administration dependent 
such as ECG’s and PK. All data obtained from these assessments must be supported in the 
patient’s source documentation. Assessments that were completed within 72 hours of Cycle 1, 
Day 1 (C1D1) do not need to be repeated. For efficacy assessments refer to Section 7.2.1. 


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Table 7-1 
Visit evaluation schedule (28-day cycle) 
Day of cycle 
Protocol 
Section 
Screening
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 
day 
f/u 
Disease 
Progression 
and Survival 
f/u 
-14 to -1 
1 
2 
8 
15 
21
22 
1 
15 
22 
1 
1 
22 
Within 14 
days of last 
dose 
Phase II only 
Demography/Informed 
Consent 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 5.2 / 5.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Antineoplastic Therapy 7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
7.2.2.1. 
X 
X 
 
 
X 
 
 
X
X 
 
X 
X 
 
X 
 
 
Weight 
7.2.2.3. 
X 
X 
 
 
 
 
 
X
 
 
X 
X 
 
X 
 
 
Height 
7.2.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
7.2.2.2. 
X 
X 
 
X 
X 
X 
 
X
X 
 
X 
X 
 
X 
 
 
Ophthalmic Examination 
7.2.2.5.6. 
X 
X 
 
X 
 
X 
 
X
 
 
X 
X 
 
X 
 
 
ECOG Performance Status 
7.2.2.4. 
X 
X 
 
 
 
 
 
X
 
 
X 
X 
 
X 
 
 
ECG 
7.2.2.5.7. 
X 
X 
 
X 
X 
X 
 
X
X 
 
X 
X1 
 
X 
 
 
Cardiac MUGA/ECHO 
7.2.2.5.8. 
X 
 
 
 
 
 
 
X
 
 
X 
X2 
 
X 
 
 
Hematology 
7.2.2.5.1. 
X 
X 
 
X 
X 
X 
 
X
X 
 
X 
X 
 
X 
 
 
Biochemistry including BNP, 
Troponin I and/or Troponin T 
7.2.2.5.9. 
X 
X 
 
X 
X 
X 
 
X
X 
 
X 
X 
 
X 
 
 
Coagulation12 
7.2.2.5.3. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total CPK/CK (If CK ≥3x 
ULN, follow isoenzymes and 
myoglobin in blood or urine 
weekly) 
7.2.2.5.2. 
X 
X 
 
X 
X 
X 
 
X
X 
 
X 
X 
 
X 
 
 


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Day of cycle 
Protocol 
Section 
Screening
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 
day 
f/u 
Disease 
Progression 
and Survival 
f/u 
-14 to -1 
1 
2 
8 
15 
21
22 
1 
15 
22 
1 
1 
22 
Within 14 
days of last 
dose 
Phase II only 
Thyroid Function Tests (TSH 
only. If TSH abnormal, total 
T3 and free T4 should be 
performed) 
7.2.2.5.4. 
X 
 
 
 
 
 
 
X
 
 
 
X3 
 
X 
 
 
Pregnancy Test 
7.2.2.5.5. 
X 
X 
 
 
 
 
 
 
 
 
X10 
X10 
 
X 
 
 
PK Sampling (phase Ib) 
7.2.3. 
 
X 
X 
X 
X 
X 
X 
X
 
 
X 
X4 
 
 
 
 
PK Sampling (phase II) 
7.2.3. 
 
X 
 
X 
X 
X 
 
X
 
 
X 
X4 
 
 
 
 
Archival or Newly Obtained 
Tumor Biopsy (Phase Ib) 
7.2.4. 
X5 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Paired Tumor Biopsy (Phase 
II) 
7.2.4. 
X5 
 
 
 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard MRI / CT Tumor 
Assessment 
7.2.1. 
X7 
 
 
 
 
 
 
 
 
X 
 
 
X8 
X 
 
X9 
Brain MRI/CT 
7.2.1. 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEK162 Dosing 
 
 
Continuous or alternate (Days 1-21) in a 28-day cycle 
 
 
 
LEE011 Dosing 
 
 
Days 1-21 in a 28-day cycle 
 
 
 
Antineoplastic therapies 
since discontinuation of 
study medication 
 
X 
X 
X 
Phone calls for survival and 
CT/MRI scans for disease 
progression f/u (every 3 
months if applicable) 
 
 
 
 
 
X 


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Day of cycle 
Protocol 
Section 
Screening
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 
day 
f/u 
Disease 
Progression 
and Survival 
f/u 
-14 to -1 
1 
2 
8 
15 
21
22 
1 
15 
22 
1 
1 
22 
Within 14 
days of last 
dose 
Phase II only 
Prior/concomitant 
medications 
 
X 
CONTINUOUS 
X 
 
Adverse Events 
 
X 
CONTINUOUS 
X 
X 
 
1. 
ECGs will be performed at screening and up to cycle 6 or as clinically indicated. If a QTcF value of ≥ 481 ms is observed at any time prior to cycle 7, the patient will 
continue to have a pre-dose ECG on day 1 of cycle 7 and all subsequent cycles. Additional ECGs at 2 hours post-dose, will be performed for these patients on day 1 
of cycle 9 and every 3rd cycle. 
2. 
Cardiac imaging will be performed at screening, C2D1, C3D1 and then every other cycle (e.g., Cycle 5, 7, 9 etc.) up to end of treatment or as clinically indicated. 
3. 
Thyroid function test is required at screening, Day 1 of cycles 2, 4, 6 and every four cycles after cycle 6. 
4. 
Blood PK will be collected at cycle 1 up to cycle 6. Additional samples may be collected if clinically indicated. 
5. 
The screening window for the pre dose tumor biopsy 28 days. 
6. 
Phase Ib only: optional on-treatment tumor biopsy to be submitted on C1D15 (± 7 days) only when a newly obtained tumor sample is submitted at screening. 
 
7. 
Screening tumor assessments must be performed within 28 days of the start of treatment. 
8. 
Subsequent tumor assessments will be performed on day 22 (± 7 days) of cycles 2 and 4 and 6 and then every four cycles. 
9. 
For phase II only: disease progression and survival follow up will be performed every three months. 
10. Pregnancy test will be performed at screening, C1D1, on Day 1 of every other cycle (3, 5, 7 and etc.) and at end of treatment. Serum beta-hCG test at 
screening/C1D1, serum or urine at subsequent cycles 
11. Post dose tumor biopsy should be performed on C1D15 (±4 days). 
12. Collection of PT, aPTT, and international normalized ratio (INR) will be performed at screening and C1D1. 


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Table 7-2 
Visit evaluation schedule (21-day cycle) 
Day of cycle 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 day 
f/u 
Disease 
Progression and 
Survival f/u 
-14 to -1 
1 
2 
8 
14 
15 
1 
14 
1 
1 
14 
Within 14 
days of last 
dose 
 
Phase II only 
Demography/Informed 
Consent 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 
5.2 / 5.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Antineoplastic Therapy 
7.1.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
7.2.2.1. 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
Weight 
7.2.2.3. 
X 
X 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
Height 
7.2.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
7.2.2.2. 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Ophthalmic Examination 
7.2.2.5.6. 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
ECOG Performance Status 
7.2.2.4. 
X 
X 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
ECGs 
7.2.2.5.7. 
X 
X 
 
X 
X 
 
X 
X 
X 
X1 
 
X 
 
 
Cardiac MUGA/ECHO 
7.2.2.5.8. 
X 
 
 
 
 
 
X 
 
X 
X2 
 
X 
 
 
Hematology 
7.2.2.5.1. 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Biochemistry including BNP, 
Troponin I and/or Troponin T 
7.2.2.5.9. 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
Coagulation12 
7.2.2.5.3. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Total CPK/CK (If CK ≥3x 
ULN, follow isoenzymes and 
myoglobin in blood or urine 
weekly) 
7.2.2.5.2. 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 


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Day of cycle 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 day 
f/u 
Disease 
Progression and 
Survival f/u 
-14 to -1 
1 
2 
8 
14 
15 
1 
14 
1 
1 
14 
Within 14 
days of last 
dose 
 
Phase II only 
Thyroid Function Tests 
(TSH only. If TSH abnormal, 
total T3 and free T4 should 
be performed) 
7.2.2.5.4. 
X 
 
 
 
 
 
X 
 
 
X3 
 
X 
 
 
Pregnancy Test 
7.2.2.5.5. 
X 
X 
 
 
 
 
 
 
X10 
X10 
 
X 
 
 
PK Sampling (phase Ib) 
7.2.3. 
 
X 
X 
X 
X 
X 
X 
 
X 
X4 
 
 
 
 
PK Sampling (phase II) 
7.2.3. 
 
X 
 
X 
X 
 
X 
 
X 
X4 
 
 
 
 
Archival or Newly Obtained 
Tumor Biopsy (Phase Ib) 
7.2.4. 
X5 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 
(Phase II) 
7.2.4. 
X5 
 
 
 
X11 
 
 
 
 
 
 
 
 
 
7.2.4. 
 
 
 
 
 
 
 
 
 
 
 
 
Standard MRI / CT Tumor 
Assessment 
7.2.1. 
X7 
 
 
 
 
 
 
X8 
X8 
X 
 
X9 
Brain MRI/CT 
7.2.1. 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEK162 Dosing 
 
 
Days 1-14 in a 21-day cycle 
 
 
 
LEE011 Dosing 
 
 
Days 1-14 in a 21-day cycle 
 
 
 
Antineoplastic therapies 
since discontinuation of 
study medication 
 
X 
X 
X 
Phone calls for survival and 
CT/MRI scans for disease 
progression f/u (every 3 
months if applicable) 
 
 
 
 
 
X 


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Day of cycle 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
End of 
Treatment 
(EOT) 
30 day 
f/u 
Disease 
Progression and 
Survival f/u 
-14 to -1 
1 
2 
8 
14 
15 
1 
14 
1 
1 
14 
Within 14 
days of last 
dose 
 
Phase II only 
Prior/concomitant 
medications 
 
X 
Continuous 
X 
 
Adverse Events 
 
X 
Continuous 
X 
X 
 
1. 
ECGs will be performed at screening and up to cycle 6 or as clinically indicated. If a QTcF value of ≥ 481 ms is observed at any time prior to cycle 7, the patient will 
continue to have a pre-dose ECG on day 1 of cycle 7 and all subsequent cycles. Additional ECGs at 2 hours post-dose, will be performed for these patients on day 1 
of cycle 9 and every 3rd cycle. 
2. 
Cardiac imaging will be performed at screening, C2D1, C3D1 and then every other cycle (e.g., Cycle 5, 7, 9 etc.) up to end of treatment or as clinically indicated. 
3. 
Thyroid function test is required at screening, Day 1 of cycles 2, 4, 6 and at every four cycles after cycle 6. 
4. 
Blood PK will be collected at cycle 1 up to cycle 6. Additional samples may be collected if clinically indicated. 
5. 
The screening window for the pre dose optional tumor biopsy 28 days. 
6. 
Phase Ib only: optional on-treatment tumor biopsy to be submitted on C1D14 (±1 day) only when a newly obtained tumor sample is submitted at screening. 
 
7. 
Screening tumor assessments must be performed within 28 days of the start of treatment. 
8. 
Subsequent tumor assessments will be performed every 6-8 weeks per standard of care. 
9. 
For phase II only: disease progression and survival follow up will be performed every three months. 
10. Pregnancy test will be performed at screening, C1D1, on Day 1 of every other cycle (3, 5, 7 and etc.) and at end of treatment. Serum beta-hCG test at 
screening/C1D1, serum or urine at subsequent cycles 
11. Post dose tumor biopsy should be performed on C1D14 (±1 day). 
12. Collection of PT, aPTT, and international normalized ratio (INR) will be performed at screening and C1D1. 


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7.1.1 
Pre-screening assessments 
Not applicable. 
7.1.2 
Screening 
The informed consent form (ICF) must be dated and signed prior to any per protocol 
screening procedures. Once the ICF is signed, all AEs per the descriptions below will be 
captured in the Adverse Event CRF. 
The screening period starts once a patient has provided written informed consent to participate 
in the study and ends on the day of first dose of LEE011 and MEK162. Screening assessments 
must be performed within 14 days prior to the first dose of LEE011 and MEK162 with the 
exception of the efficacy assessments and pre-treatment tumor biopsy which must be 
performed within 28 days. 
7.1.2.1 
Eligibility screening 
The procedures for eligibility check, patient identification number assignments, and 
coordination among the sites involved will be provided in a separate document prior to study 
start. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Disposition page eCRF. The only information on eCRFs which will be entered 
for screen failures will be: 
• Demography 
• Informed Consent 
• Inclusion/Exclusion Criteria 
• Screening Disposition page 
No other data will be entered into the clinical database for screen failure patients, unless the 
patient experiences a SAE. SAE information will be entered onto the AE page for the purpose 
of reconciliation. 
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. 


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7.1.3 
Treatment period 
The treatment period commences on the first day of the first cycle (C1D1) of LEE011 and 
MEK162 and ends after the last dose of LEE011 and MEK162. 
During the study treatment period, patients will be regularly monitored to assess the safety 
and early anti-tumor activity of the treatment. For the purpose of scheduling and evaluations, 
a treatment cycle will consist of 21/28 days. 
For details of assessments during the treatment period, refer to Table 7-1 or Table 7-2. 
7.1.4 
End of treatment visit 
At the time the patients discontinues study treatment; a visit should be scheduled as soon as 
possible and within 14 days after the decision to discontinue has been made, at which time all 
of the assessments listed for the End of Treatment (EOT) visit will be performed. An End of 
Treatment Phase Disposition CRF page should be completed, giving the date and reason for 
stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
Patients who discontinue study treatment also should return for 30-day safety follow up (see 
Section 7.1.5), disease progression follow up (if applicable, see Section 7.1.5.2) and survival 
follow up (only for Phase II patients, see Section 7.1.5.3) assessments at visits according to 
Table 7-1 or Table 7-2 and should not be considered withdrawn from the study. If patients 
refuse to return for these visits or are unable to do so, every effort should be made to contact 
them or a knowledgeable informant by telephone to obtain the follow-up information. 
If a patient discontinues study treatment, but continues study assessments, the patient remains 
on study until such time as he/she completes protocol criteria for ending study assessments. 
At that time, the reason for study completion should be recorded on the Study Phase 
Completion Disposition CRF page. 
If using IRT, the Investigator must contact the IRT to register the patient’s discontinuation. 
End of treatment/Premature withdrawal visit is not considered as the end of the study. 
7.1.4.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• Unacceptable AE (s) or failure to tolerate study treatment 
• Delay in dosing > 21 consecutive days 
• Pregnancy of the patient 
• Patient withdrew consent 
• Lost to follow-up 


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• Disease progression 
• Initiation of new cancer therapy 
7.1.4.2 
Replacement policy 
Escalation phase Ib: 
Patients will not be replaced on study. However, if a patient is considered as non-evaluable 
for the DDS, enrollment of a new patient to the current cohort will be considered if there is 
less than the required number of evaluable patients. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.3.2. 
Phase II: 
Patients will not be replaced. 
7.1.5 
Follow-up period 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
7.1.5.1 
30-day safety follow-up period 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Information related to AE (including concomitant medication taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected for 30 days after the last dose of study 
treatment. All AEs suspected to be related to study treatment should be followed up weekly, 
or as clinically indicated, until resolution or stabilization. 
7.1.5.2 
Disease progression follow-up assessments (Phase II only) 
Patients enrolled in the Phase II part of the study who discontinue study treatment for any 
reason other than disease progression will be followed up with CT/MRI scans every three 
months as detailed in Table 7-1 or Table 7-2 and Section 7.2.1, until disease progression, the 
initiation of subsequent anticancer therapies, death, or until patients have been followed for at 
least 12 months after their first dose of study treatment, have been lost to follow-up or 
withdrew consent, whichever occurs first. Newly started antineoplastic therapies during this 
follow up period must be recorded on the Antineoplastic therapy since discontinuation eCRF. 
7.1.5.3 
Survival follow-up period (Phase II only) 
All patients enrolled in the Phase II part of the study will be followed for survival 
approximately every three months per phone call until death, or until all patients have been 
followed for at least 12 months after their first dose of study treatment, or have been lost to 
follow-up or withdrew consent, whichever occurs first. One additional phone call per quarter 
may be allowed. Possible newly started antineoplastic therapies during this follow up period 
must be recorded on the Antineoplastic therapy since discontinuation eCRF. 


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7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be evaluated locally by the investigator according to the guideline 
(Version 3.0) based on RECIST version 1.1 (see Appendix 2). The following assessments are 
required at screening/baseline (within 28 days of the start of treatment): 
• Chest, abdomen and pelvis CT or MRI. The preferred radiologic technique is CT with 
intravenous (i.v.) contrast. If a patient is known to have a contraindication to CT contrast 
media or develops a contraindication during the trial, a non-contrast CT of the chest (MRI 
is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of the abdomen and pelvis should be performed. 
• Brain MRI or CT with intravenous (i.v.) contrast scan to assess CNS disease. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then brain 
MRI without contrast or brain CT with/without contrast is acceptable. 
• Color photography of any skin lesions present. Color photography should include a metric 
ruler. Palpable subcutaneous tumors may be measured by physical examination using a 
ruler or calipers. Ultrasound should not be used to measure sites of disease. 
• If bone metastases are suspected, a whole body bone scan per institutional standard of care 
(e.g. Tc-99 bone scan, whole body bone MRI, FDG-PET or sodium fluoride positron 
emission tomography (NaF PET). Localized CT, MRI or X-rays should be acquired for all 
skeletal lesions identified on the screening bone scan, which are not visible on the chest, 
abdomen and pelvis CT/MRI. 
• If clinically indicated, CT or MRI of other areas of disease (e.g., neck) as appropriate. 
Subsequent tumor evaluations will be performed on Day 22 (±7 days) of cycles 2, 4 and 6. 
After cycle 6 tumor evaluations will be performed on Day 22 (±7 days) of every 4th cycle 
(e.g., C10, C14, C18), or sooner if there is clinical evidence of disease progression. 
For the 21-day dosing schedule, subsequent tumor evaluations will be performed every 6 to 8 
weeks (Day 14 ±7 days) per standard of care, or sooner if there is clinical evidence of disease 
progression. After cycle 6 tumor evaluations will be performed on Day 14 (±7 days) of every 
4th cycle or sooner if there is clinical evidence of disease progression. 
Tumor evaluations will also be performed at EOT. If the last prior tumor evaluation was 
within 28 days of EOT or objective evidence of progressive disease has already been 
documented, then tumor evaluations do not need to be repeated at EOT. 
Tumor evaluations after the screening assessment will include evaluation of all sites of 
disease identified at baseline, using the same technique that was used at screening. Chest, 
abdomen, pelvis scans need to be repeated at each tumor assessment visit (including if 
negative at baseline). 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. 


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All radiological and photographic assessments obtained for patients enrolled during phases Ib 
and II part of the study will be centrally collected and subjected to quality checks by an 
imaging CRO selected by the Sponsor. The site manual provided by the designated imaging 
CRO will provide further details regarding image collection. 
7.2.2 
Safety and tolerability assessments 
Safety and tolerability assessments will include adverse event reporting and changes from 
baseline in laboratory measures and vital signs. Tolerability will be assessed by the incidence 
of AEs leading to study drug delay or discontinuation. For details on AE collection and 
reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A full physical examination (PE) that evaluates all major organ systems will be performed at 
baseline. This should include a complete ophthalmologic and dermatologic exam. Subsequent 
PEs should be focused on sites of disease, clinical signs and symptoms, and include eye and 
skin exams. 
Significant findings that were present prior to the signing of 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. 
PEs to be performed for each schedule are outlined in Table 7-1 or Table 7-2. 
7.2.2.2 
Vital signs 
Vital signs (heart rate, blood pressure and temperature) will be obtained in the same position, 
either sitting or supine, as appropriate prior to any blood collection. 
Vital signs to be obtained for each schedule are outlined in Table 7-1 or Table 7-2. 
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 at screening. Subsequently, only weight 
measurements will be required. Assessments to be obtained for each schedule are outlined in 
Table 7-1 or Table 7-2. 
7.2.2.4 
Performance status 
Performance status will be scored using the ECOG performance scale (see Appendix 1). 
Performance status to be obtained for each dosing schedule as outlined in Table 7-1 or 
Table 7-2. 


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7.2.2.5 
Laboratory evaluations 
Laboratory tests will be collected and analyzed by the study site’s local laboratory. More 
frequent examinations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded on the Unscheduled Lab eCRFs. 
At any time during the study, abnormal laboratory parameters which are clinically relevant 
(e.g., require dose modification and/or interruption of study drug, lead to clinical symptoms or 
signs, or require therapeutic intervention), whether specifically requested in the protocol or 
not, must be recorded in the AE eCRF. 
The Sponsor will be provided with a copy of the laboratory certification and tabulation of the 
normal ranges for each parameter required. 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. 
For all visits, there is a ± 3 days window on assessments to take into account scheduling over 
public or religious holidays except for assessments that are dose administration dependent 
such as ECG’s and PK. Laboratory assessments that were completed within 72 hours before 
Cycle 1, Day 1 (C1D1) do not need to be repeated. 
7.2.2.5.1 Hematology 
Please refer to Table 7-3 for a list of tests to be performed. 
For timing of assessments for each schedule, refer to Table 7-1 or Table 7-2. 
7.2.2.5.2 Clinical chemistry 
Please refer to Table 7-3 for a list of tests to be performed. 
For timing of assessments for each schedule, refer to Table 7-1 or Table 7-2. 
7.2.2.5.3 Coagulation 
Please refer to Table 7-3 for a list of tests to be performed. 
For timing of assessments for each schedule, refer to Table 7-1 or Table 7-2. 
7.2.2.5.4 Thyroid 
Please refer to Table 7-3 for a list of tests to be performed. Only TSH is required at screening 
and subsequent visits. Only when TSH is abnormal, total T3 and free T4 should be performed. 
For timing of assessments for each schedule, refer to Table 7-1 or Table 7-2. 


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Table 7-3 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Complete blood count (CBC) with differential - white blood count (WBC), absolute neutrophil 
count (including bands), lymphocyte, monocyte, eosinophil, and basophil counts, hemoglobin, 
hematocrit, and platelet count. 
Chemistry 
Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, AST (SGOT), 
ALT (SGPT), total bilirubin (if a total bilirubin elevation ≥ Grade 2 occurs then direct and 
indirect bilirubin should be measured), LDH, albumin, calcium, magnesium, phosphate, 
alkaline phosphatase 
Coagulation 
PT, aPTT and International normalized ratio (INR) will be collected at Screening and C1D1 
Cardiac/Muscle 
Enzymes 
Brain natriuretic peptide (BNP), troponin I and/or troponin T. 
Total creatine phosphokinase (CK/CPK). If total CK ≥3 X ULN, then measure isoenzymes 
and myoglobin in blood or urine weekly 
Thyroid 
TSH only. If TSH abnormal, total T3 and free T4 should be performed 
Pregnancy 
Serum beta-hCG test at screening/baseline, serum or urine at subsequent cycles 
7.2.2.5.5 Pregnancy assessments 
Serum beta-hCG pregnancy test will be performed at screening and C1D1. If screening 
assessments are performed within 72 hours of initial study treatment then C1D1 is not 
required. For follow up assessments, serum beta-hCG or urine tests will be performed on Day 
1 of every other cycle (e.g. C3D1, C5D1, C7D1 and etc.) and at end of treatment. 
For females to be considered “of non-childbearing potential”, patient should meet one of the 
following: 
• Surgically sterile for at least 6 weeks (hysterectomy with bilateral oophorectomy or tubal 
ligation). Documentation of sterilization method must be provided. The date of 
sterilization will be recorded. 
• 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 have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to study entry. 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. 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to the 
Sponsor 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; follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the Sponsor study drug of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 


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7.2.2.5.6 Ophthalmic examination 
Full ophthalmological examination performed by trained ophthalmologist including slit lamp 
examination, color vision test, visual acuity testing, visual field testing, tonometry (intraocular 
pressure [IOP]), optical coherence tomography (OCT), dilated indirect fundoscopy and color 
fundus photography with attention to retinal abnormalities, especially retinal pigmented 
epithelial detachment (RPED) and retinal vein occlusion (RVO) is required. Each time point 
is indicated in Table 7-1 or Table 7-2. If screening ophthalmic examination is collected within 
72 hours of C1D1, it does not have to be repeated. 
7.2.2.5.7 Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed after the patient has been resting for 5-10 min 
prior to each time point indicated in Table 7-4 or Table 7-5. 
On cycle 1 day 1 (pre-dose), 3 ECG recordings must be taken at a minimum of 2-minute 
intervals. The combined QTcF values from these 3 ECGs will be averaged to provide a single 
baseline value for each patient. 
If an abnormal ECG is obtained at any time, patient’s electrolytes must be reviewed and 
repeat ECG measurements must be done after correction of electrolyte abnormalities. 
All ECGs will be transmitted to a central laboratory and will be centrally reviewed by an 
independent reviewer. 
In the event that a QTcF value of  481 ms is observed at any time prior to cycle 7, the patient 
will continue to have a pre-dose ECG on day 1 of cycle 7 and all subsequent cycles. 
Additional ECGs at 2 hours post-dose, will be performed for these patients on day 1 of cycle 9 
and every 3rd cycle. 
 
Each ECG tracing should be labeled with the study number, patient initials, subject number, 
date, and kept in the source documents at the study site. Clinically significant abnormalities at 
screening should be recorded on the relevant medical history/current medical conditions 
eCRF page. 
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7.2.2.5.8 Cardiac imaging - MUGA (multiple gated acquisition) scan or bilateral 
echocardiogram 
Cardiac imaging by MUGA/bilateral ECHO to be performed as outlined in Table 7-1 or Table 
7-2 at screening, C2D1, C3D1, every other cycle, at end of treatment or as clinically indicated 
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7.2.3 
Pharmacokinetics 
7.2.3.1 
PK blood sample collection and handling 
All blood samples will be taken either by direct venipuncture or through an indwelling 
cannula (e.g., inserted in a forearm vein, or central venous line) according to the Phase 1b 
schedule described in Table 7-6 and Table 7-7, and for the Phase II schedule described in 
Table 7-8 and Table 7-9. Residual plasma samples after the PK concentration analysis may be 
used for drug metabolism investigations or other bio-analytical purposes (e.g. cross check 
between different sites, stability assessment). Given the exploratory nature of the work, the 
analytical method used for those assessments will not be validated. 
Refer to the [CMEK162X2114 Laboratory Manual] for detailed instructions for the collection, 
handling and shipping of samples. 
Table 7-6 
Pharmacokinetic blood collection log (Phase Ib) 28-day cycle 
Cycle 
Day 
Scheduled time points* 
(hours) 
Dose 
reference 
identifier for 
LEE011 
Sample 
number 
for 
LEE011 
Dose 
reference 
identifier for 
MEK162 
Sample 
number for 
MEK162 
1 
1 
pre-dose 
1 
101 
1 
201 
1 
1 
0.5h post-dose (± 15 min) 
1 
102 
1 
202 
1 
1 
1h post-dose (± 15 min) 
1 
103 
1 
203 
1 
1 
2h post-dose (± 15 min) 
1 
104 
1 
204 
1 
1 
4h post-dose (± 30 min) 
1 
105 
1 
205 
1 
1 
8h post-dose (± 30 min) 
1 
106 
1 
206 
1 
2 
24h post dose (± 1 h, pre-dose 
for the next dose) 
1 
107 
2 
207 
1 
8 
pre-dose 
2 
108 
3 
208 
1 
15 
pre-dose 
3 
109 
4 
209 
1 
21 
pre-dose 
4 
110 
5 
210 
1 
21 
0.5h post-dose (± 15 min) 
4 
111 
5 
211 
1 
21 
1h post-dose (± 15 min) 
4 
112 
5 
212 
1 
21 
2h post-dose (± 15 min) 
4 
113 
5 
213 
1 
21 
4h post-dose (± 30 min) 
4 
114 
5 
214 
1 
21 
8h post-dose (± 30 min) 
4 
115 
5 
215 
1 
22 
24h post dose (± 1 h, pre-dose 
for the next dose) 
4 
116 
6 
216 
2 
1 
pre-dose 
5 
117 
7 
217 
3 
1 
pre-dose 
6 
118 
8 
218 
4 
1 
pre-dose 
7 
119 
9 
219 
5 
1 
pre-dose 
8 
120 
10 
220 
6 
1 
pre-dose 
9 
121 
11 
221 
Unscheduled 
Anytime 
2001+ 
3001+ 
*All measurement times are relative to dose of LEE011+MEK162 unless otherwise specified. 
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Table 7-7 
Pharmacokinetic blood collection log (Phase Ib) 21-day cycle 
Cycle 
Day 
Scheduled time points* 
(hours) 
Dose 
reference 
identifier for 
LEE011 
Sample 
number 
for 
LEE011 
Dose 
reference 
identifier for 
MEK162 
Sample 
number for 
MEK162 
1 
1 
pre-dose 
1 
1501 
1 
1601 
1 
1 
0.5h post-dose (± 15 min) 
1 
1502 
1 
1602 
1 
1 
1h post-dose (± 15 min) 
1 
1503 
1 
1603 
1 
1 
2h post-dose (± 15 min) 
1 
1504 
1 
1604 
1 
1 
4h post-dose (± 30 min) 
1 
1505 
1 
1605 
1 
1 
8h post-dose (± 30 min) 
1 
1506 
1 
1606 
1 
2 
24h post dose (± 1 h, pre-dose 
for the next dose) 
1 
1507 
2 
1607 
1 
8 
pre-dose 
2 
1508 
3 
1608 
1 
14 
pre-dose 
3 
1509 
4 
1609 
1 
14 
0.5h post-dose (± 15 min) 
3 
1510 
4 
1610 
1 
14 
1h post-dose (± 15 min) 
3 
1511 
4 
1611 
1 
14 
2h post-dose (± 15 min) 
3 
1512 
4 
1612 
1 
14 
4h post-dose (± 30 min) 
3 
1513 
4 
1613 
1 
14 
8h post-dose (± 30 min) 
3 
1514 
4 
1614 
1 
15 
24h post dose (± 1 h, pre-dose 
for the next dose) 
3 
1515 
5 
1615 
2 
1 
pre-dose 
4 
1516 
6 
1616 
3 
1 
pre-dose 
5 
1517 
7 
1617 
4 
1 
pre-dose 
6 
1518 
8 
1618 
5 
1 
pre-dose 
7 
1519 
9 
1619 
6 
1 
pre-dose 
8 
1520 
10 
1620 
Unscheduled 
Anytime 
8001+ 
9001+ 
*All measurement times are relative to dose of LEE011+MEK162 unless otherwise specified. 
Table 7-8 
Pharmacokinetic blood collection log (Phase II) 28-day cycle 
Cycle 
Day 
Scheduled time points* 
(hours) 
Dose 
reference 
identifier of 
LEE011 
Sample 
number 
of 
LEE011 
Dose 
reference 
identifier of 
MEK162 
Sample 
number of 
MEK162 
1 
1 
Pre-dose 
1 
301 
1 
401 
1 
1 
0.5h post-dose (± 15 min) 
1 
302 
1 
402 
1 
1 
2h post-dose (± 15 min) 
1 
303 
1 
403 
1 
1 
4h post-dose (± 30 min) 
1 
304 
1 
404 
1 
8 
Pre-dose 
2 
305 
2 
405 
1 
15 
Pre-dose 
3 
306 
3 
406 
1 
21 
Pre-dose 
4 
307 
4 
407 
1 
21 
0.5h post-dose (± 15 min) 
4 
308 
4 
408 
1 
21 
2h post-dose (± 15 min) 
4 
309 
4 
409 
1 
21 
4h post-dose (± 30 min) 
4 
310 
4 
410 
2 
1 
Pre-dose 
5 
311 
5 
411 
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Cycle 
Day 
Scheduled time points* 
(hours) 
Dose 
reference 
identifier of 
LEE011 
Sample 
number 
of 
LEE011 
Dose 
reference 
identifier of 
MEK162 
Sample 
number of 
MEK162 
3 
1 
Pre-dose 
6 
312 
6 
412 
4 
1 
Pre-dose 
7 
313 
7 
413 
5 
1 
Pre-dose 
8 
314 
8 
414 
6 
1 
Pre-dose 
9 
315 
9 
415 
Unscheduled 
Anytime 
4001+ 
5001+ 
*All measurement times are relative to dose of LEE011+MEK162 unless otherwise specified. 
Table 7-9 
Pharmacokinetic blood collection log (Phase II) 21-day cycle 
Cycle 
Day 
Scheduled time points* 
(hours) 
Dose 
reference 
identifier of 
LEE011 
Sample 
number 
of 
LEE011 
Dose 
reference 
identifier of 
MEK162 
Sample 
number of 
MEK162 
1 
1 
Pre-dose 
1 
1701 
1 
1801 
1 
1 
0.5h post-dose (± 15 min) 
1 
1702 
1 
1802 
1 
1 
2h post-dose (± 15 min) 
1 
1703 
1 
1803 
1 
1 
4h post-dose (± 30 min) 
1 
1704 
1 
1804 
1 
8 
Pre-dose 
2 
1705 
2 
1805 
1 
14 
Pre-dose 
3 
1706 
3 
1806 
1 
14 
0.5h post-dose (± 15 min) 
3 
1707 
3 
1807 
1 
14 
2h post-dose (± 15 min) 
3 
1708 
3 
1808 
1 
14 
4h post-dose (± 30 min) 
3 
1709 
3 
1809 
2 
1 
Pre-dose 
4 
1710 
4 
1810 
3 
1 
Pre-dose 
5 
1711 
5 
1811 
4 
1 
Pre-dose 
6 
1712 
6 
1812 
5 
1 
Pre-dose 
7 
1713 
7 
1813 
6 
1 
Pre-dose 
8 
1714 
8 
1814 
Unscheduled 
Anytime 
1301+ 
1401+ 
*All measurement times are relative to dose of LEE011+MEK162 unless otherwise specified. 
Analytical method 
7.2.3.1.1 LEE011 
The plasma samples from all patients will be assayed for concentrations of LEE011 and 
LEQ803 at a designated CRO using a validated liquid chromatography-tandem mass 
spectrometry assay (LC/MS/MS). Values below the lower limit of quantification (LLOQ) of 
1.00 ng/mL will be reported as 0 ng/mL. Missing values will be labeled accordingly. 
7.2.3.1.2 MEK162 
Plasma concentrations of MEK162 and its metabolite, AR00426032, will be measured at a 
designated CRO using a validated LC/MS/MS assay with an LLOQ of 1.00 ng/mL. Values 
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below the lower limit of quantification (LLOQ) of 1.00 ng/mL will be reported as 0 ng/mL. 
Missing values will be labeled accordingly. 
Refer to the [CMEK162X2114 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipping of samples. 
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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s) or medical condition(s). 
AEs occurring after the signing of the informed consent should be recorded in the Adverse 
Events eCRF under the signs, symptoms or diagnosis associated with them. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 If CTCAE grading does not exist for an adverse event, the severity of 
mild, moderate, severe, and life-threatening, or grades 1 - 4, will be used. CTCAE grade 5 
(death) will not be used in this study; rather, this information will be collected in the End of 
Treatment eCRF page. AE monitoring should be continued for at least 30 days following the 
last dose of study treatment. 
Abnormal laboratory values or test results occurring after signing the informed consent form 
constitute AEs only if they induce clinical signs or symptoms, or require therapy, (e.g., any 
hematologic abnormality that requires transfusion or hematological stem cell support) or 
changes in study medication(s), or are of CTCAE Grade 3 Such abnormal laboratory values 
or test results should be recorded on the AE eCRF under the signs, symptoms or diagnosis 
associated with them. In addition, isolated abnormal laboratory values that are considered 
clinically significant (e.g., cause study discontinuation or constitutes in and of itself a SAE) 
should be recorded on the AE eCRF. The occurrence of AEs should be sought by non-
directive questioning of the patient during the screening process after signing informed 
consent and at each visit during the study. AEs also may be detected when they are 
volunteered by the patient during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. As far as possible, each AE should be 
evaluated to determine: 
1. The CTCAE grade 1-4. 
2. Causality (reasonable possibility that AE is related to the study treatment; no, or yes). 
3. Its duration (start and end dates or if continuing at final exam). 
4. Action taken with respect to study treatment (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable). 
5. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown). 
6. Whether it is serious, where a SAE is defined as in Section 8.2. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements (Section 8.2). 
CCI


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All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e., further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this AE; concomitant medication 
given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The 
action taken to treat the adverse event should be recorded on the AE eCRF. 
Once an AE 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 drug, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (i.e., RECIST 1.1 criteria) 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. 
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Abnormal laboratory values or test results that constitute adverse events or underlying 
conditions should not be reported separately in addition to the respective adverse events or 
underlying diagnosis. 
Additionally, laboratory abnormalities that are considered clinically significant due to 
induction of clinical signs or symptoms, or requiring concomitant therapy (e.g. any 
hematologic abnormality that requires transfusion or cytokine treatment) or changes in study 
medication(s), should be recorded on the Adverse Events eCRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for adverse events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. 
Laboratory abnormalities, that do not meet the criteria of clinical significance, as judged by 
the investigator, should not be reported as adverse events except CTCAE grade ≥ 3. 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 and should not contribute 
to designation of a lab parameter abnormality as a SAE. 
8.1.3 
Adverse events of special interest 
Not Applicable. 


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8.1.3.1 
Definitions and reporting 
Not Applicable. 
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, unless 
hospitalization is for: 
a. Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes). 
b. 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. 
c. Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
d. 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. 
• Any SAEs that are expected due to the condition being treated, including if the SAE is a 
primary outcome measure, and whether there has been a clear agreement with regulators 
not to consider these as SAEs, provided the information is collected elsewhere. 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring; 
• after the patient has provided informed consent and until at least 30 days after the patient 
has stopped study treatment/participation. 
• after the patient is enrolled and until at least 30 days after the patient has stopped study 
treatment. 
• after the patient begins taking study drug and until at least 30 days after the patient has 
stopped study treatment. 
• after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-
blind treatment, etc.) and until at least 30 days after the patient has stopped study 
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• after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication) and until at least 30 days 
after the patient has stopped study treatment. 
They must be reported to the Sponsor within 24 hours of learning of its occurrence. (Any 
SAEs experienced after this 30 days period should only be reported to the Sponsor if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form within the OCRDC system (where available) or on 
the paper SAE Form. The Investigator must assess the relationship to each specific study drug 
(if there is more than one study drug) and complete the electronic or paper SAE Report Form 
in English. 
When SAEs are recorded electronically in the OCRDC system, these should be entered, saved 
and e-signed within 24 hours of awareness of the SAE. These data will automatically be 
submitted to the Sponsor immediately after investigator signature or 24 hours after entry, 
whichever occurs first. 
When SAEs are recorded on the paper SAE form, these should be faxed within 24 hours of 
awareness of the SAE to the Sponsor. The telephone and fax number of the contact persons in 
the local department of Drug Safety and Epidemiology, 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. 
Note that any follow up information provided 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. 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. 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 drug, the 
Sponsor may urgently require further information from the investigator for Health Authority 
reporting. The Sponsor 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 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to the 
Sponsor within 24 hours of learning of its occurrence. The pregnancy should be followed up 
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and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the Sponsor. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the Sponsor study drug of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between [Investigators Brochure] updates 
will be communicated in the form of Investigator Notifications. This information will be 
included in the patient informed consent and should be discussed with the patient during the 
study as needed. 
8.5 
Data Safety Monitoring Board 
A Drug Safety Monitoring Board (DSMB) will not be in place for this trial. Instead, the 
Sponsor and the investigators of the dose-escalation part will meet at the end of each 
treatment cohort to discuss and evaluate all of the gathered safety data. At the dose escalation 
teleconference the clinical course (safety information including both DLTs and all = CTCAE 
Grade 2 toxicity data during the first cycle of treatment, and PK data) for each patient in the 
current dose cohort will be described in detail. Updated safety data on other ongoing patients, 
including data in later cycles, will be discussed as well. 
Dose escalation decisions will be based on a clinical synthesis of all relevant available data 
and not solely on DLT information. Selection of the actual dose for the next cohort of patients 
will be guided by the Bayesian logistic regression model’s (with EWOC) recommendation, 
and a medical review of relevant clinical, PK and laboratory data. The parties must reach a 
consensus on whether to declare MTD, escalate the dose any further, or whether to de-escalate 
and/or expand recruitment into particular cohorts. 
At these meetings, the Sponsor and the investigators must reach a consensus on whether to 
escalate the dose any further, or whether to de-escalate and/or expand recruitment into 
particular cohorts. The Sponsor or designee will prepare minutes from these meetings and 
circulate them to the investigators. 
8.6 
Steering Committee 
Not applicable. 


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study. 
• Who will have access to that information and why. 
• Who will use or disclose that information. 
• The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
patient 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 (Patient 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 Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient 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 
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The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Sponsor 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, allows modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
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 OCRDC 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. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
the Sponsor (or a designated CRO). 
Data about all study treatments dispensed to patients and all IRT assigned dosage changes will 
be tracked using an Interactive Response Technology. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Sponsor 
personnel (or 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 
Data will be analyzed by the Sponsor and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to the Sponsor before publication or 
presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 


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respect to demographic and baseline characteristics, efficacy and safety observations and 
measurements and all relevant PK and PD measurements. 
The following rules will be followed for reporting results unless stated otherwise: 
• Phase Ib dose escalation data: Cohorts of patients treated with the same dose 
combination and regimen during the dose escalation part will be pooled into a common 
treatment group. All summaries, listings, figures and analyses will be displayed / 
performed by treatment group unless otherwise specified. 
• Phase II data: All summaries, listings, figures and analyses will be performed by study 
arm. 
The analysis of study data will be based on all patients’ data of the dose escalation and phase 
II parts up to the time when all patients have potentially completed at least six cycles of 
treatment or discontinued the study. Any additional data for patients continuing to receive 
study treatment past the cut-off date for the primary CSR, as allowed by the protocol, will be 
reported once all patients have discontinued the study. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected, will not be included in 
any analysis, but will be reported in the CSR as separate listings. 
10.1 
Analysis sets 
10.1.1 
Full analysis set 
The FAS includes all patients who received at least one dose of LEE011 or MEK162. Patients 
will be classified according to the planned treatment combination. The FAS will be used for 
all listings of raw data. Unless otherwise specified the FAS will be the default analysis set 
used for all analyses. 
10.1.2 
Safety set 
The safety set includes all patients who received at least one dose of LEE011 or MEK162, 
and have at least one valid post-baseline safety assessment. The statement that a patient had 
no AEs (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received is defined 
as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
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10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with the following requirements of the CSP. 
• Diagnosis corresponds to that defined in inclusion criteria (Section 5.2) prior treatment 
corresponds to that defined in inclusion criteria (Section 5.2). 
• The patient received at least 50% of the planned dose of each compound within the first 8 
weeks of study. 
• Treatment the patient was evaluated for primary efficacy variable at or beyond week 10, 
or discontinued due to adverse event, disease progression, or died prior to the first 
evaluation of the primary efficacy variable. 
Patients will be evaluable for efficacy under the PPS if they have at least one tumor evaluation 
with an overall lesion response assessed differently from ‘unknown’ or ‘not assessed’ under 
the RECIST 1.1 at or beyond week 10. 
A patient who discontinued the study prior to being evaluated for the primary efficacy 
variable at the week 10 evaluation for a reason(s) other than adverse event, PD or death, or for 
whom the evaluation(s) at week 10 and beyond were all of ‘unknown’ or ‘not assessed’ status 
per RECIST 1.1 will not be included in the per-protocol set. 
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint (Section 10.4). 
10.1.4 
Dose-determining analysis set 
The dose-determining set (DDS) includes all patients from the safety set who either 
completed a minimum exposure requirement and have sufficient safety evaluations or 
discontinued prematurely due to a dose limiting toxicity (DLT). 
A patient is considered to have met the minimum exposure criterion if having received at least 
75% of the planned daily combination doses of MEK162 (BID), 75% of the planned daily 
combination doses of LEE011 and at least 50% of the planned combination doses of the two 
compounds administered together (in the same day) within the first 21/28 days of treatment. 
The length of the DLT evaluation period is cycle 1. 
Patients who do not experience DLT during the first cycle will be considered to have 
sufficient safety evaluations if they have been observed for at least 1 cycle (21 or 28 days) 
following the first dose and are considered by both the Sponsor and Investigators to have 
enough safety data to conclude that a DLT did not occur. 
10.1.5 
Pharmacokinetic analysis set 
The PK analysis set (PAS) consists of all patients who have at least one blood sample 
providing evaluable PK data. The PAS will be used for summaries (tables and figures) and 
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Note: patients will be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of the analyses. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients in the FAS. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
The actual dose and duration in days of LEE011 and MEK162 treatment as well as the dose 
intensity (computed as the ratio of actual dose received and actual duration) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose received/planned 
duration), will be listed and summarized by means of descriptive statistics. The summary data 
will be presented for each treatment cycle individually, as well as for all study days as a single 
category. The total daily doses of LEE011 and MEK162 for each patient will be summarized 
using descriptive statistics (e.g. mean, median, and modal doses). The FAS will be used. 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (Anatomical 
therapeutic chemical classification system) term and dose group 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 by treatment group. Compliance to the study drug will be assessed by the number 
of dose reductions and dose interruptions, see Section 10.5. 
10.4 
Primary objective 
Phase Ib 
The primary purpose of the Phase Ib part of the study is to estimate the MTD(s) and/or RP2D 
of the LEE011 and MEK162 combination in patients with locally advanced or metastatic 
NRAS mutant melanoma. 
The corresponding method of analysis is an adaptive Bayesian logistic regression model 
(BLRM) guided by the escalation with overdose control (EWOC) principle (Babb 1998). 


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Phase II 
The primary purpose of the Phase II part of the study is to assess the anti-tumor activity of the 
RP2D of the LEE011 and MEK162 combination in patients with locally advanced or 
metastatic NRAS mutant melanoma. 
10.4.1 
Variable 
Phase Ib 
The primary variable is the incidence of dose limiting toxicities (DLTs) in Cycle 1. 
Estimation of the MTD(s) of the combination treatment will be based upon the estimation of 
the probability of DLT in Cycle 1 for patients in the dose-determining set. 
Phase II 
The primary variable is the Overall Response Rate (ORR), defined as the proportion of 
patients with a best overall response (BOR) of complete response (CR) or partial response 
(PR) as assessed per RECIST 1.1. 
Estimation of the true ORR in this part of the study will be based upon observed ORR for 
patients in the FAS. The true ORR is estimated using a Bayesian design. The Primary analysis 
of the ORR will be based on the investigator’s assessment of overall lesion responses. 
10.4.2 
Statistical hypothesis, model and method of analysis 
Phase Ib 
An adaptive BLRM guided by the EWOC principle will guide the dose escalation of the 
combination treatment to its MTD(s)/RP2D. A 5-parameter BLRM for combination treatment 
will be fitted on the Cycle 1 dose-limiting toxicity data (i.e. absence or presence of DLT) 
accumulated throughout the dose escalation to model the dose-toxicity relationship of 
MEK162 and LEE011 when given in combination. All information currently available about 
the dose-DLT relationships of single agents MEK162 and LEE011 will be summarized in 
prior distributions. For this study, available clinical data from studies [ARRAY-162-111] 
(first-in-human MEK162 oncology study) and [LEE011X2101] will be used to derive 
informative priors for the BLRM parameters describing the dose-DLT relationships of the 2 
agents when given as monotherapy. 
Any additional information on the dose-DLT relationship generated by these studies will be 
incorporated into the prior distribution before the first dose escalation decision is made within 
this study in order to reflect all relevant information at that time. No pre-clinical data 
informing on the toxicity of the combination treatment is available. Therefore, a weakly 
informative prior will be used for the interaction parameter. This prior allows for the cases of 
synergistic or antagonistic safety profiles, i.e. increases or decreases in the odds of DLT over 
independence. 
The 5-parameter BLRM is formulated in the following way: Let π1(d1)be the probability of a 
DLT if LEE011 is given as a single agent at dose d1, and π2(d2)the probability of a DLT if 
MEK162 is given as a single agent at dose d2. 


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The dose-response relationship is then modeled as: 
logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
logit(π2(d2)) = log(α2) + β2log(d2/d2*) 
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2)) 
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))), 
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1 *= 350 mg and d 2*= 30 mg (BID) are the 
reference doses of LEE011 and MEK162 respectively, α1, α2, β1, β1 > 0 and -∞ < η < ∞ is a 
scalar. 
Details for prior specification of the model parameters and performance of the BLRM under 
different hypothetical data scenarios are presented in Appendix 5. 
If a different dosing schedule will be considered, historical data collected for the initially 
planned regimen will be taken into account in order to derive an informative prior estimation 
of the dose-DLT relationship for the new dosing schedule. This informative prior will be 
combined with DLT data for the new dosing schedule using a 2-parameter BLRM (full details 
in Appendix 5). 
Dose recommendation 
Dose recommendations will be based on summaries of the posterior distribution of model 
parameters and the posterior distribution of DLT rates, including the mean, median, standard 
deviation, 95%-credibility 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. 
Decisions on dose escalation will follow the procedure as outlined in Section 6.2.3. 
Listings of DLTs 
DLTs will be listed and their incidence summarized by primary system organ class, worst 
Grade based on the CTCAE version 4.03 and type of AE. 
Phase II 
A Bayesian design will be used in order to estimate the distribution of the ORR  
(see Section 10.4.1) and to provide inferential summaries (e.g., mean, median, interval 
probabilities) in relation to the Phase II population (NRAS mutant melanoma). 
The primary analysis will be performed when all patients have completed at least 6 cycles of 
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Patients who discontinue early due to progressive disease (PD), who are of Unknown (UNK) 
response, were not assessed (NA) at or beyond week 10 or who are lost to follow up prior to 
week 10 will be considered as failures in the analyses of ORR. Definitions of CR, PR, SD, 
PD, UNK and NA are per RECIST v1.1 (See Appendix 2). 
For a Bayesian design we are required to specify a prior distribution for the parameter of 
interest ORR. For the current study, the prior clinical assumption for the combination of 
MEK162 and LEE011 in the selected patient populations is used in order to derive a 
minimally informative unimodal Beta prior distribution that reflects the level of uncertainty 
around ORR before starting the current trial (See Appendix 5). 
At completion of the study, this prior distribution will be updated with all the data available 
from the patients in the FAS by arm. All responses and progressions will be determined as per 
RECIST 1.1. 
Once updated, the distribution summarizes the probability that the true ORR at the RP2D used 
in the study arm lies in the following categories: 
• [0, 25%) unacceptable efficacy. 
• [25%, 35%) moderate efficacy. 
• [35%, 100%] substantial efficacy. 
If the observed ORR is equal or greater than or equal to 35%, then this will be considered as 
preliminary evidence of clinically relevant activity of the combination in NRAS-mutant 
population. Note that for a sample size of n = 40 (See Section 10.8), if the observed ORR is 
greater than or equal to 35% (i.e. ≥ 14 CR or PR), then the true ORR has posterior risk of 
being in the unacceptable efficacy category of less than 10%. If the observed ORR is between 
25% and 35% then this will be considered as evidence of moderate activity and the inferential 
summaries for the 3 categories above will be assessed. If the observed ORR is less than 25% 
(i.e. ≤ 9 CR or PR) then inactivity will be declared. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Phase Ib: Patients who are ineligible for the DDS will be removed from the primary analysis 
and additional patients may be recruited. Their data will be used for all remaining analyses. 
Phase II: Patients with BOR categorized as unknown (UNK) response or not assessed (NA) 
will be considered as failures in the primary analyses of ORR using the FAS. 
Events (e.g. AEs, concomitant medication, etc.) will be summarized using the data cut-off 
date as the date of completion, with an indication within listings that the event is continuing. 
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event with the appropriate censoring as described in the 
above paragraph. 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. 
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10.4.4 
Supportive analyses 
If deemed necessary, a sensitivity analysis to the investigators assessment CT/MRI scans 
readings will be performed using the central CT/MRI assessments (RECIST v1.1) mentioned 
in Section 7.2.1. The same method of analysis as for the primary analysis will be applied, 
using the FAS. 
Moreover, the primary analysis of the phase II will be repeated using the PPS. 
 
 
10.5 
Secondary objectives 
10.5.1 
Key secondary objectives 
Not applicable. 
10.5.2 
Other secondary efficacy objectives 
Phase Ib 
Individual lesion measurements will be listed along with the overall lesion response. Best 
overall response (BOR), duration of response (DOR) for patients who experience a CR or PR 
at any time on study, PFS and TTP will be listed by patient and treatment group. Kaplan-
Meier analyses of PFS will be provided only if there are at least 10 patients within the same 
treatment group. 
Phase II 
Individual lesion measurements BOR, PFS, DOR, TTP and OS data will be listed by patient. 
PFS and TTP will be presented graphically using Kaplan Meier plots. In addition, the 
PFS/TTP distributions will be summarized by presenting the median time with accompanying 
95% confidence interval along with the Kaplan-Meier estimates for PFS and TTP at 10 weeks 
and 4, 8 and 12 months. DOR will be presented graphically using Kaplan Meier plots for all 
patients who achieved a CR or PR on study. Similarly, the median DOR and corresponding 
95% confidence interval will be presented. Moreover, Kaplan Meier plots will also be shown 
for OS, along with the median time accompanying 95% confidence interval and estimates for 
OS at 4 and 12 months. 
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10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for analyses 
For all safety analyses, the safety set will be used. 
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. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group. 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by CTCAE version 4.03, the study’s biostatistical and reporting 
team will grade laboratory data accordingly. For laboratory tests covered by CTCAE, a Grade 
0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be 
used. For laboratory tests where Grades are not defined by CTCAE, results will be graded by 
the low/normal/high classifications based on laboratory normal ranges. 
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by a clinical meaningful limit. 
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
• Frequency table for newly occurring on-treatment Grades 3 or 4. 
• Shift tables using CTCAE Grades to compare baseline to the worst on-treatment value. 
• For laboratory tests where CTCAE Grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
Grades and the classifications relative to the laboratory normal ranges. 


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10.5.3.4 Other safety data 
Any other safety information collected will be listed and notable values will be flagged. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. Additionally, the following outputs will 
be produced: 
ECG 
• shift table baseline to worst on-treatment result for overall assessments. 
• listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
• shift table baseline to worst on-treatment result. 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
Ocular 
• Listing of ocular assessments for all patients with at least one abnormality. 
• Table with frequency of ocular events by cycle will be produced by treatment group. 
10.5.3.5 Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized. Cumulative dose, dose intensity and relative dose 
intensity of MEK162 and LEE011 will be listed by patient and summarized. Categories for 
relative dose intensity for MEK162 and LEE011 will be specified as < 0.5,  0.5 - < 0.75,  
0.75 - < 0.9,  0.9 - < 1.1 and  1.1. The number and proportion of patients within each 
category will be presented. 
10.5.4 
Pharmacokinetics 
PK parameters will be determined for all PK-evaluable patients using non-compartmental 
method(s) using Phoenix (Pharsight, Mountain View, CA). PK parameters listed in 
Table 10-1 will be estimated and reported, when feasible. The parameters that require terminal 
phase determination may not be adequately calculated by non-compartmental methods. 
 
For plasma LEE011, LEQ803, and MEK162, the LLOQ is 1.0ng/mL. All concentrations 
below the LLOQ or missing data will be labeled as such in the concentration data listings. 
Concentrations below the LLOQ will be treated as zero in summary statistics. The PK 
parameters displayed on Table 10-1 will be estimated and reported. 
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Table 10-1 
Non-compartmental pharmacokinetic parameters 
Variable 
Definition 
Cmax 
Maximum observed plasma concentration after drug administration (mass x volume-1) 
Cmax,ss 
Maximum observed plasma concentration during a dosing interval at steady state (mass x 
volume-1) 
Cmin,ss 
Measured concentration at the end of a dosing interval at steady state (taken directly before 
next administration) (mass x volume-1) 
Tmax 
Time to reach Cmax (time) 
Tmax,ss 
Time to reach Cmax at steady state (time) 
AUCtau 
Area under the concentration-time curve during a dosing interval (mass x time x volume-1) 
AUCtau,ss 
Area under the concentration-time curve during a dosing interval at steady state (mass x time x 
volume-1) 
CL/F 
Apparent total plasma clearance of drug after oral administration (volume x time-1) 
Racc 
Accumulation ratio calculated as AUCtau,ss/AUCtau,dose1 
t1/2, acc 
Effective elimination half-life 
In addition, in case drug accumulation is observed upon multiple dosing, additional PK 
parameters describing drug accumulation will be added to the analysis (i.e. effective half-life) 
and specified in the RAP. 
10.5.4.1 Data handling principles 
10.5.4.1.1 
Analysis sets 
Only PK blood samples with the 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 analyses. The PAS 
will be used. 
10.5.4.1.2 
Basic tables, figures and listings 
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented 
for all parameters by treatment group and study day. When a geometric mean is presented, it 
will be stated as such. CL/F will be assessed for MEK162, LEE011 and LEQ803, and only 
median values and ranges will be given for Tmax. 
Descriptive graphical plots of individual plasma concentration by time will be generated, as 
will mean concentration time profiles for MEK162, LEE011 and LEQ803. 
 
 
 
10.5.4.1.3 
Advanced data analysis methods 
 
 
Also, PK/PD analyses may be explored to identify possible PK/PD relationships with relevant 
clinical markers and/or safety parameters (e.g. retinal events). 
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PK of MEK162, LEE011 and LEQ803 in this combination trial may be compared to historical 
data from the respective monotherapy studies, if feasible, to assess drug-drug interaction 
potential. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.7 
Interim analysis 
Phase Ib 
No formal interim analyses are planned. However, the dose escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose escalation phase, the next dose combination MEK162 and LEE011 
has to be chosen depending on the observed data. 
Phase II 
No interim analysis will be performed for the phase II due to the expectation that all patients 
will be recruited prior to any analysis timepoint. 
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10.8 
Sample size calculation 
Phase Ib 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including 
approximately 15 patients in total and at least six patients at the MTD(s)/RP2D level per 
dosing schedule, as described in Section 6.2.3. Multiple cohorts may be sequentially or 
alternatively enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD/RP2D for further elaboration of safety 
and pharmacokinetic parameters as required. Approximately 15 patients are expected to be 
treated per each dosing schedule in the dose escalation part for the model to have reasonable 
operating characteristics relating to its MTD(s) recommendation. 
Phase II 
Based on the prior distribution for the ORR specified in Appendix 5 and efficacy intervals 
described in Section 10.4.2, it is estimated that, given an observed ORR equal to 35%, 
approximately 40 patients should be enrolled for the model to have less than 10% posterior 
risk of the true ORR being less than 25% (i.e. unacceptable efficacy). 
10.9 
Power for analysis of key secondary variables 
Not Applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to the 
Sponsor before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to the Sponsor or designee’s monitors, auditors, 
Clinical 
Quality 
Assurance 
representatives, 
designated 
agents 
of 
the 
Sponsor, 
IRBs/IECs/REBs and regulatory authorities as required. 


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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 patient’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 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 4.4. 
11.5 
Publication of study protocol and results 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
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 patients. As part of participating in an 
Array BioPharma-sponsored study, each site will permit authorized representatives of the 
sponsor(s) and regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits and evaluation of the 
study safety and progress. Source data are all information, original records of clinical 


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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, 
patients’ 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 
patient 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 CRF is 
the primary data collection instrument for the study. The investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported in the CRFs and all 
other required reports. Data reported on the CRF, that are derived from source documents, 
should be consistent with the source documents or the discrepancies should be explained. All 
data requested on the CRF must be recorded. Any missing data must be explained. Any 
change or correction to a paper CRF should be dated, initialed, and explained (if necessary) 
and should not obscure the original entry. For electronic CRFs an audit trail will be 
maintained by the system. The investigator should retain records of the changes and 
corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to 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 and upon changes to site 
staff as applicable. 


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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 
References (available upon request) 
Ascierto PA (2012) Efficacy and safety of oral MEK162 in patients with locally advanced and 
unresectable metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutation. J 
Clin Oncol 30, (suppl; abstr 8511) 2012 ASCO meeting. 
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stats in Med; 17(10): 1103-1120. 
Curtin JA, Fridlyand J, Kageshita T, et al (2005) Distinct sets of genetic alterations in 
melanoma. N Engl J Med; 353: 2135-2147. 
Davies MA, Stemke-Hale K, Lin E, et al (2009) Integrated molecular and clinical analysis of 
AKT activation in metastatic melanoma. Clin Cancer Res; 15(24): 7538-46. 
Devitt B, Liu W, Salemi R, et al (2011) Clinical outcome and pathological features associated 
with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res; 24(4): 666-72. 
Dumaz N, Hayward R, Martin J, et al (2006) In melanoma, RAS mutations are accompanied 
by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer 
Res; 66(19): 9483-91. 
Eskandarpour M, Huang F, Reeves KA, et al (2009) Oncogenic NRAS has multiple effects on 
the malignant phenotype of human melanoma cells cultured in vitro. Int J Cancer; 124(1): 16-
26. 
FDA Guidelines (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
Goel VK, Lazar AJF, Warneke CL, et al (2006) Examination of mutations in BRAF, NRAS, 
and PTEN in primary cutaneous melanoma. J Invest Dermatol; 126: 154-160. 
Guideline on Clinical Trials in Small Populations (CHMP/ EWP/83561/05). Available at 
http://.emea.europa.eu/pdfs/human/ewp/8356105en.pdf (February 1, 2007). 
Hodis E, Watson IR, Kryukov GV, et al (2012) A landscape of driver mutations in melanoma. 
Cell; 150(2): 251-63. 
Jemal A, Siegel R, Jiaquan X, et al (2010) Cancer statistics. CA: Cancer J Clin. 2010 Sept-
Oct; 60(5): 277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7. 
Kelleher FC, McArthur G (2012) Targeting NRAS in melanoma. Cancer J; 18(2): 132-6. 
Kwong LN, Costello JC, Liu H, et al (2012) Oncogenic NRAS signaling differentially 
regulates survival and proliferation in melanoma. Nature Medicine; 18: 1503-1510. 
National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03. 
Available at: NCI CTCAE site (http:/evs.nci.nih.gov/ftp1/CTCAE/About.html). 
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stats in Med; 27(13): 2420-2439. 
Neuenschwander B, Capkum-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials; 7(1): 5-18. 
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J of Clin Oncol; 25(31): 4982-4986. 


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Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin. 2012 Jan-
Feb;62(1):10-29. doi: 10.3322/caac.20138. Epub 2012 Jan 4. 
Smalley KS, Contractor R, Nguyen T, et al (2008) Identification of a novel subgroup of 
melanomas with KIT/Cyclin-dependant kinase-4 overexpression. Cancer Res; 68(14): 5743-
52. 
Smalley KS, Lioni M, Dalla Palma M, et al (2008) Increased cyclin D1 expression can 
mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther; 
7(9): 2876-83. 
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. 
van Elsas A, Zerp S, van der Flier S, et al (1995) Analysis of N-ras mutations in human 
cutaneous melanoma: tumor heterogenicity detected by polymerase chain reaction/single-
stranded conformation polymorphism analysis. Cancer Res; 139: 57-67. 
Walker GJ, Flores JF, Glendening JM, et al (1998) Virtually 100% of melanoma cells lines 
harbor alterations at the DNA level within CDKN2A, CDKN2B, or one of their downstream 
targets. Genes Chromosomes Cancer; 22(2): 157-63. 
Wang Y, Becker D (1996) Differential expression of the cyclin-dependent kinase inhibitors 
p16 and p21 in human melanocytic system. Oncogene Mar 7;12(5):1069-75. 
World cancer report (2008) Lyon, France: International Agency for Research on Cancer, 
2008. 
Yang G, Rajadurai A, Tsao H (2005) Recurrent patterns of dual RB and p53 pathway 
inactivation in melanoma. J Invest Dermatol; 125: 1242-1251. 


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14 
Appendices 
14.1 
Appendix 1: ECOG Performance Status 
Table 14-1 
ECOG performance scale 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 


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14.2 
Appendix 2: Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) 
14.2.1 
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). 
The efficacy assessments described in Section 14.2.2 and the definition of best response 
(Section 14.2.9) are based on the RECIST criteria but also give more detailed instructions and 
rules for determination of best response. Section 14.2.10 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions, as the RECIST criteria 
do not define these variables in detail. Section 14.2.18 of this guideline describes data 
handling and programming rules. This section may be used in the analysis plan(s) to provide 
further details needed for programming. 
14.2.2 
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. 
14.2.3 
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 14.2.21. 
• Measurable lesions (both nodal and non-nodal). 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
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• 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. 
14.2.4 
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 14.2.21. 
14.2.5 
Methods of tumor measurement-general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 


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• 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. 
• 
 
 
 
 
CCI


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• 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. 
14.2.6 
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 14.2.3. 
• Nodal target: See Section 14.2.3. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
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14.2.7 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of the longest diameter for all target lesions will be 
calculated (at baseline and throughout the study). At each assessment response is evaluated 
first separately for the target (Table 14-2) and nontarget lesions (Table 14-3) identified at 
baseline. These evaluations are then used to calculate the overall lesion response considering 
both the target and nontarget lesions together (Table 14-4) as well as the presence or absence 
of new lesions. 
The response for nontarget lesions is CR only if all nontarget lesions which were evaluated at 
baseline are now all absent. If any of the nontarget lesions is still present, the response can 
only be ‘Incomplete response/Stable disease’ unless any of the lesions was not assessed (in 
which case response is UNK) or there is unequivocal progression of the nontarget lesions (in 
which case response is PD). 
If tumor markers are used as nontarget lesions to evaluate response, please specify criteria for 
CR, SD and PD in the protocol, e.g. CR=’Normalization of tumor marker level’, 
PD=’Elevation of tumor markers to certain level’, SD=’Not qualifying for CR or PD’. These 
criteria are indication and study specific. In that case, the protocol should clearly specify that 
additional criteria are used to complement RECIST criteria. 
14.2.8 
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. 
14.2.8.1 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. 


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14.2.8.2 Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
14.2.9 
Determination of target lesion response 
Table 14-2 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter of all target lesions, 
taking as reference the baseline sum of the longest diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the longest diameter of all measured target 
lesions, taking as reference the smallest sum of longest diameter of all target 
lesions recorded at or after baseline. 
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. 
SOD for CR may not be zero when nodal lesions are part of target lesions 
 
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 
 
Methodology change See Section 14.2.5. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
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• 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 14-2 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 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. 


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• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
Table 14-3 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Incomplete Response/ Stable 
Disease (SD): 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more nontarget 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 14.2.9 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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14.2.10 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 14.2.11). 
• 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 14.2.5. 
14.2.11 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 14-4. 
Table 14-4 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Incomplete response/SD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
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 14.2.6. 
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. 
14.2.12 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at 
baseline. Section 14.2.21 outlines the special considerations that need to be given to patients 
with no measurable disease at baseline in order to apply the same concepts. 
14.2.13 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed. 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
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• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• 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. 
• Calculated overall lesion response (based on measurements from either Investigator or 
Central Review). 


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The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
• Overall response rate (ORR) is the proportion of patients with a best overall response of 
CR or PR. This is also referred to as ‘Objective response rate’ in some protocols or 
publications. 
• Disease control rate (DCR) is the proportion of patients with a best overall response of 
CR or PR or SD. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
• Early progression rate (EPR) is the proportion of patients with progressive disease 
within 8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach). 
14.2.14 Time to event variables 
The protocol should state which of the following variables is used in that study. 
14.2.15 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. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
14.2.16 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”). 


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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. 
14.2.17 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. 
14.2.18 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. 
14.2.19 Duration of response 
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates. 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 


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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. 
14.2.20 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 14.2.18. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 


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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. 
14.2.21 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 the duration of responses, the randomization/date 
of treatment start will be used as the start date. 
For the calculation of duration of responses the following start date should be used: 
• 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. 
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, 
the date of discontinuation is used as date of progression. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.2.17). 
Example: (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline – 3 months – 6 months – missing – missing – PD. Date of next scheduled 
assessment would then corresponds to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 


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• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last contact date from that survival follow-up page is used. If no 
survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.2.22 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 14-5. 
Table 14-5 
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 14.2.7. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 


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determination and/or timing of progression can incorporate data from patients with only non-
measurable disease. 
14.2.23 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 14.2.20, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered: 
Table 14-6 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression)1 
(1) = default unless specified differently in 
the protocol or analysis plan 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment 
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 
Censored 
Censored 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP) 
1 =Definitions can be found in Section 14.2.20. 
2 =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.2.16. 
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. 


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• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-6 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. 
14.2.24 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). 
14.2.25 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. 


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
14.2.26 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 14 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) 
14.2.27 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 


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• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
14.2.28 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’ 
opinion does not match the programmed calculated response based on RECIST criteria. This 
may be queried for clarification. However, the investigator response assessment will never be 
overruled. 
If the Sponsor elects to invalidate an evaluation of overall lesion response upon internal or 
external review of the data, the calculated overall lesion response at that specific assessment is 
to be kept in a dataset. This must be clearly documented in the RAP documentation and 
agreed before database lock. This dataset should be created and stored as part of the ‘raw’ 
data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
14.2.29 Programming rules 
The following should be used for programming of efficacy results: 
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. 
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 14.2.16. If all measurement dates have no 
day recorded, the 1st of the month is used. 


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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. 
Incomplete dates for last contact or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
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)’. 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
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 (treatment / study evaluation / survival) 
• Lost to follow-up (during treatment* / study evaluation* / survival) 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event (treatment / study evaluation) 
• Lost to follow-up (during treatment / study evaluation) 
• Withdrew consent (during treatment* / study evaluation) 
• Study evaluation stopped (when follow-up for progression is stopped after certain number 
of events or at certain time, i.e. reason=’Administrative problems’ on study evaluation 
completion page, or when patients are not followed for progression after treatment 
completion) 
• Death due to reason other than underlying cancer (only used for TTP) 
• New cancer therapy added 
*Note = this category is to be used if no further information is available (as information on 
death may be available in patients who were originally lost to follow-up, and information on 
progression may be received in patients who withdrew consent to continue study drug). 


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Medication and herbals to be excluded or to be used with caution 
Any patient who requires a prohibited medication should not be enrolled on a trial for 
LEE011 and MEK162 until further information becomes available. 
Note: This is not a comprehensive list of cytochrome P450 isoenzymes and transporter 
substrates or their inducers or inhibitors, and QT prolongation medications. This is only meant 
to be used as a guide. Please contact the medical monitor with any questions. 
14.2.30 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; 45: 228-247. 
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; 92: 205-216. 


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14.3 
Appendix 3: List of prohibited concomitant therapies and 
therapies to be used with caution 
Table 14-7 
List of prohibited medications during LEE011 and MEK162 treatment 
Category 
Drug Name 
Strong CYP3A Inhibitors – AUC substrate 
increased by ≥ 5 fold 
clarithromycin, conivaptan, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
sequinavir/ritonavir, telaprevir, telithromycin, voriconazole, 
indinavir/ritonavir, tipranoavir/ritonavir, cobicistat, 
troleandomycin, danoprevir/ritonavir, eltegravir/ritonavir 
grapefruit juice 
 
Strong CYP3A Inducers – AUC decreased by ≥ 
80% 
mitotane, enzalutamide ,carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin2, Avasimibe, St. John's wort1,2 
CYP3A substrates with narrow therapeutic index 
(NTI) 
Quinidine, astemizole, terfanadine, cyclosporine, sirolimus, 
tacrolimus, diergotamine, cisapride, ergotamine, pimozide, 
alfentanil, fentanyl, thioridazine, diergotamine, 
dihydroergotamine, ergotamine 
Medications with knows risk of QT prolongation
Amiodarone, anagrelide, arsenic trioxide, astemizole (Off US 
mkt), azithromycin, bepridil (Off US mkt), chloroquine, 
chlorpromazine, cisapride (Off US mkt), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone 
(Not on US mkt), dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, grepafloxacin (Off market worldwide), 
halofantrine, haloperidol, ibutilide, levofloxacin, levomethadyl (Off 
US mkt), mesoridazine (Off US mkt), methadone, moxifloxacin, 
ondansetron, pentamidine, pimozide, probucol (Off US mkt), 
procainamide (Oral off US mkt), quinidine, sevoflurane, sotalol, 
sparfloxacin (Off US mkt), sulpiride (Not on US Mkt), terfenadine 
(Off US mkt), thioridazine, vandetanib 
1 
Herbal product 
2 
PgP Inducer 
 
This list of CYP substrates was compiled from Clinical Pharmacology internal memo: drug-drug Interactions (DDI) 
database, 2015, which is compiled primarily from the FDA’s “Guidance for Industry, Drug Interaction Studies”, the 
Indiana University School of Medicine’s Drug Interactions Database, the University of Washington’s Drug 
Interaction Database, and crediblemeds.org 
 
Table 14-8 
List 1 of medications to be used with caution during LEE011 and 
MEK162 treatment 
Category 
Drug Name 


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Category 
Drug Name 
Sensitive CYP3A substrates2 
Alpha-dihydroergocryptine, alfentanil, almorexant, 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, neratinib, nisoldipine, perospirone, quetiapine, 
ridaforolimus, saquinavir, sildenafil, simeprevir, simvastatin, 
ticagrelor, terfenadine, ticagrelor, tilidine,tipranavir, 
tolvaptan, triazolam, vardenafil, vicriviroc, voclosporin. 
 
 
Moderate CYP3A inhibitors  
amprenavir, aprepitant, atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, nilotinib imatinib, tofisopam, 
cyclosporin, ciprofloxacin, verapamil, dronedarone, 
crizotinib, casopitant, amprenavir, atazanavir/ritonavir, 
duranavir, netupitant, schisandra sphenanthera3, cimetidine, 
lomitapide 
 
 
Moderate CYP3A Inducers  
bosentan, efavirenz, etravirine, modafinil, nafcillin, genistein, 
ritonavir, thioridazine, tipranavir, semagacestat, talviraline, 
lopinavir, lersivirine 
 
Known inhibitors of BSEP 
Atorvastatin, cerivastatin, cyclosporine, glyburide, reserpine, 
rifampicin, troglitazone, valinomycin, 
BCRP 
Substrates 
Atorvastatin daunorubicin, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, pitavastatin, 
rosuvastatin, SN-38 (irinotecan), ethinyl estradiol, 
simvastatin, sulfasalazine, sofosbuvir, topotecan, 
sulfasalazine 
MATE 1/2 substrates 
Acyclovir, cimetidine, ganciclovir, fexofenadine4, metformin4, 
procainamide, topotecan, glycopyrronium4, topotecan 
Substrates of CYP2B6 
Bupropion, efavirenz, methadone, nevirapine, sibutramine, 
BCRP 
Inhibitors 
abacavir, amprenavir, atazanavir4, atorvastatin, cerivastatin, 
cyclosporine4, daunomycin, delavirdine, efavirenz, elacridar, 
eltrombopag4 erlotinib, fluvastatin, fumitremorgin, gefitinib, 
lopinavir, nelfinavir, nilotinib, pitavastatin, rosuvastatin, 
saquinavir, simvastatin, sulfasalazine, SN-38 (irinotecan), 
pantoprazole 
P-gp inhibitors 
alogliptin, amiodarone5, azithromycin5, canaglifozin, 
captopril5, carvedilol5, clarithromycin5, conivaptan5, 
cremophor RH40, curcumin, diltiazem5, dronedarone5, 
elacridar5, erythromycin5, felodipine5, fluvoxamine5, ginko3,5, 
indinavir5, indinavir/ritonavir5, itraconazole5, ketoconazole, 
lapatinib, lopinavir/ritonavir, mibefradil5, milk thisle3,5, 
mirabegron, nelfinavir5, nifedipine5, nitredipine5, paroxetine5, 
propafenone, quercetin5 , quinidine5, ranolazine5, rifampin5, 
ritonavir5, sequinavir/ritonavir5, schisandra chinesis 
extract3,5, simepravir, St. John’s wort extract3,5, talinolol5, 
telaprevir5, telmisartan5, ticagrelor5, tipranavir/ritonavir5, 
tolvaptan5, valspodar, vandetanib, verapamil5, voclosporin. 
 


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Category 
Drug Name 
UGT1A1 inhibitors 
atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, 
ketoconazole, nilotinib, pazopanib, propofol, regorafenib, 
sorafenib, silybum marianum3 (also known as milk thistle), 
valeriana officinalis3, 
 


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Category 
Drug Name 
UGT1A1 inducers 
carbamazepine, rifampicin, testosterone propiate, cigarette 
smoke 
1 
Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria as specified in Section 5.3 of the Study Protocol or listed in Table 14-7. 
2 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
co-administered with a potent inhibitor. 
3 
Herbal product 
4 
Have been shown to have DDI in vivo. Others reports as substrates in vitro 
5 
Dual P-gp and CYP3A4 inhibitor 
 
This list of CYP substrates was compiled from Clinical Pharmacology internal memo: drug-drug Interactions (DDI) 
database, 2015, which is compiled primarily from the FDA’s “Guidance for Industry, Drug Interaction Studies”, the 
Indiana University School of Medicine’s Drug Interactions Database, the University of Washington’s Drug 
Interaction Database, and crediblemeds.org 
 
 


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14.4 
Appendix 4: Guidance on medications with a risk of Torsades de 
Pointes 
Table 14-9 
Drugs with a conditional risk of Torsades de Pointes 
Generic Name 
Brand Name 
Class/Clinical Use 
Amisulpride 
Solian® and others 
Antipsychotic, atypical / 
Amitriptyline 
Elavil® 
Tricyclic Antidepressant / depression 
Ciprofloxacin 
Cipro® 
Antibiotic / bacterial infection 
Clomipramine 
Anafranil® 
Tricyclic Antidepressant / depression 
Desipramine 
Pertofrane® 
Tricyclic Antidepressant / depression 
Diphenhydramine 
Benadryl®, Nytol® 
Antihistamine / Allergic rhinitis, insomnia 
Doxepin 
Sinequan® 
Tricyclic Antidepressant / depression 
Fluconazole 
Diflucan® 
Anti-fungal / fungal infection 
Fluoxetine 
Sarafem®, Prozac® 
Anti-depressant / depression 
Galantamine 
Reminyl® 
Cholinesterase inhibitor / Dementia, 
Alzheimer's 
Imipramine 
Norfranil® 
Tricyclic Antidepressant / depression 
Itraconazole 
Sporanox® 
Anti-fungal / fungal infection 
Ketoconazole 
Nizoral® 
Anti-fungal / fungal infection 
Nortriptyline 
Pamelor® 
Tricyclic Antidepressant / depression 
Paroxetine 
Paxil® 
Anti-depressant / depression 
Protriptyline 
Vivactil® 
Tricyclic Antidepressant / depression 
Ritonavir 
Norvir® 
Protease inhibitor / HIV 
Sertraline 
Zoloft® 
Anti-depressant / depression 
Solifenacin 
VESIcare® 
muscarinic receptor anatagonist / treatment 
of overactive bladder 
Trazodone 
Desyrel® 
Anti-depressant / Depression, insomnia 
Trimethoprim-Sulfa 
Septra® or Bactrim® 
Antibiotic / bacterial infection 
Trimipramine 
Surmontil® 
Tricyclic Antidepressant / depression 
Substantial evidence supports the conclusion that these drugs prolong the QT interval and have a risk of TdP but 
only under certain known conditions (e.g. excessive dose, drug interaction, etc.). 
Table 14-10 
Drugs with a possible risk of Torsades de Pointes 
Generic Name 
Brand Name 
Class/Clinical Use 
Alfuzosin 
Uroxatral® 
Alpha1-blocker / Benign prostatic 
hyperplasia 
Amantadine 
Symmetrel® 
Dopaminergic/Anti-viral / Anti-infective/ 
Parkinson's Disease 
Artenimol+piperaquine 
Eurartesim® 
Anti-malarial / 
Atazanavir 
Reyataz® 
Protease inhibitor / HIV 
Chloral hydrate 
Noctec® 
Sedative / sedation/ insomnia 
Clozapine 
Clozaril® 
Anti-psychotic / schizophrenia 
Dolasetron 
Anzemet® 
Anti-nausea / nausea, vomiting 
Dronedarone 
Multaq® 
Anti-arrhythmic / Atrial Fibrillation 
Eribulin 
Halaven® 
Anti-cancer / metastatic breast neoplasias 
Escitalopram 
Cipralex®, Lexapro® 
Anti-depressant / Major depression/ 
Anxiety disorders 


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Generic Name 
Brand Name 
Class/Clinical Use 
Famotidine 
Pepcid® 
H2-receptor antagonist / Peptic ulcer/ 
GERD 
Felbamate 
Felbatrol® 
Anti-convulsant / seizure 
Fingolimod 
Gilenya® 
Immunosuppressant / Multiple Sclerosis 
Foscarnet 
Foscavir® 
Anti-viral / HIV infection 
Fosphenytoin 
Cerebyx® 
Anti-convulsant / seizure 
Gatifloxacin 
Tequin® 
Antibiotic / bacterial infection 
Gemifloxacin 
Factive® 
Antibiotic / bacterial infection 
Granisetron 
Kytril® 
Anti-nausea / nausea and vomiting 
Iloperidone 
Fanapt® 
Antipsychotic, atypical / Schizophrenia 
Indapamide 
Lozol® 
Diuretic / stimulate urine & salt loss 
Isradipine 
Dynacirc® 
Anti-hypertensive / high blood pressure 
Lapatinib 
Tykerb®, Tyverb® 
Anti-cancer / breast cancer, metastatic 
Levofloxacin 
Levaquin® 
Antibiotic / bacterial infection 
Lithium 
Lithobid®, Eskalith® 
Anti-mania / bipolar disorder 
Moexipril/HCTZ 
Uniretic® 
Anti-hypertensive / high blood pressure 
Nicardipine 
Cardene® 
Anti-hypertensive / high blood pressure 
Nilotinib 
Tasigna® 
Anti-cancer / Leukemia 
Octreotide 
Sandostatin® 
Endocrine / acromegaly, carcinoid 
diarrhea 
Ofloxacin 
Floxin® 
Antibiotic / bacterial infection 
Ondansetron 
Zofran® 
Anti-emetic / nausea and vomiting 
Oxytocin 
Pitocin® 
Oxytocic / Labor stimulation 
Paliperidone 
Invega® 
Antipsychotic, atypical / Schizophrenia 
Perflutren lipid microspheres 
Definity® 
Imaging contrast agent / 
Echocardiography 
Quetiapine 
Seroquel® 
Anti-psychotic / schizophrenia 
Ranolazine 
Ranexa® 
Anti-anginal / chronic angina 
Risperidone 
Risperdal® 
Anti-psychotic / schizophrenia 
Roxithromycin* 
Rulide® 
Antibiotic / bacterial infection 
Sertindole 
Serdolect®, Serlect® 
Antipsychotic, atypical / Anxiety, 
Schizophrenia 
Sunitinib 
Sutent® 
Anti-cancer / RCC, GIST 
Tacrolimus 
Prograf® 
Immunosuppressant / Immune 
suppression 
Tamoxifen 
Nolvadex® 
Anti-cancer / breast cancer 
Telithromycin 
Ketek® 
Antibiotic / bacterial infection 
Tizanidine 
Zanaflex® 
Muscle relaxant / 
Vardenafil 
Levitra® 
phosphodiesterase inhibitor / vasodilator 
Venlafaxine 
Effexor® 
Anti-depressant / depression 
Voriconazole 
VFend® 
Anti-fungal / anti-fungal 
Ziprasidone 
Geodon® 
Anti-psychotic / schizophrenia 
Substantial evidence supports the conclusion that these drugs cause QT prolongation but there is insufficient 
evidence that they, when used as directed in labeling, have a risk of causing TdP. 


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14.5 
Appendix 5: Statistical details for the Phase Ib part: Bayesian 
logistic regression model (BLRM), priors, design properties for 
hypothetical data scenarios and design operating characteristics 
An adaptive Bayesian design using escalations with overdose control EWOC will guide the 
dose-escalation of the combination treatment to its MTD(s)/RP2D. The use of Bayesian 
response adaptive designs 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 and frequentist operating characteristics). 
14.5.1 
Statistical model and prior distributions 
This section is organized in the following way: 
• A short motivation is provided. 
• The single-agent prior distribution for LEE011 is derived. 
• The single-agent prior distribution for MEK162 is derived. 
• The prior distribution for the interaction parameter (eta) is derived. 
• Numerical values and summary statistics at different dose levels are shown. 
Motivation 
A 5-parameter BLRM (refer to the protocol Section 10.4.2 for detail) will be used to model 
the dose limiting toxicity rate of the first cycle to assess the dose-toxicity relationship of 
LEE011 in combination with MEK162. 
Details regarding dose recommendation are described in Section 10.4.2 of the protocol. 
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which comprise the single-agent parameters for LEE011 and MEK162, and for 
the interaction parameter (see model definition in Section 10.4.2). Derivation of these is 
provided in the following subsections. 
LEE011 
Currently available historical data of LEE011 administered on 3 weeks on/1 week off 
schedule from study [CLEE011X2101] up to October 31st 2012 have been used in order to 
derive the prior for the BLRM parameters (log(α1),log(β1)).The bivariate normal prior for the 
model parameters (log(α1),log(β1)) is obtained as follows: 
1. The following non-informative prior for (log(α1),log(β1)) was used: 
• The median DLT rate at the LEE011 combination reference dose (350 mg QD) was 
assumed 1/10, i.e. mean (log(α1)) = log(1/9). 
• A doubling in dose was assumed to double odds of DLT, i.e. mean(log(β1)) = 0. 


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• The standard deviation of log(α1) was set to 2, and the standard deviation of log(β1) to 
1, which allows for considerably prior uncertainty for the dose-toxicity profile. 
• The correlation between log(α1) and log(β1) was set to 0. 
2. Data from 37 patients eligible for the dose-determining set of the on-going study 
[CLEE011X2101] were used to update the dose-toxicity profile (see Table 14-11). 
3. Heterogeneity between the historical and current study was incorporated by between-trial 
standard deviations τ1 and τ2 for log(α1) and log(β1). Both τ1 and τ2 were set to follow a 
log-normal distribution. Mean log(0.5) and standard deviation 0.01 was chosen for τ1, and 
mean log(0.25) and standard deviation 0.01 for τ2, which correspond to substantial 
between-trial variability. 
Table 14-11 
Data from study [LEE011X2101] 
Dose of LEE011 (QD - 3 weeks on/1 week off) 
No of DLTs/No of evaluable patients 
50 mg 
1/4 
70 mg 
0/2 
140 mg 
0/3 
280 mg 
1/4 
400 mg 
2/4 
260 mg 
0/4 
350 mg 
0/5 
600 mg 
0/4 
900 mg 
1/7 
MEK162 
Currently available historical data of MEK162 administered on BID continuous over 28 days 
schedule from study [ARRAY-162-111] has been used in order to derive the prior for the 
BLRM parameters (log(α2),log(β2)).The bivariate normal prior for the model parameters 
(log(α2),log(β2)) is obtained as follows: 
1. The following non-informative prior for (log(α2),log(β2)) was used: 
• The median DLT rate at the MEK162 combination reference dose (30 mg BID) was 
assumed 1/5, i.e. mean (log(α2)) = log(1/4). 
• A doubling in dose was assumed to double odds of DLT, i.e. mean(log(β2)) = 0. 
• The standard deviation of log(α2) was set to 2, and the standard deviation of log(β2) to 
1, which allows for considerably prior uncertainty for the dose-toxicity profile. 
• The correlation between log(α2) and log(β2) was set to 0. 
2. Data from 15 patients eligible for the dose-determining set of the on-going study 
[ARRAY-162-111] were used to update the dose-toxicity profile (see Table 14-12). 
3. Heterogeneity between the historical and current study was incorporated by between-trial 
standard deviations τ3 and τ4 for log(α2) and log(β2). Both τ3 and τ4 were set to follow a 
log-normal distribution. Mean log(0.25) and standard deviation 0.01 was chosen for τ3, 
and mean log(0.125) and standard deviation 0.01 for τ4, which correspond to moderate 
between-trial variability. 


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Table 14-12 
Data from study [ARRAY-162-111] 
Dose of MEK162 (BID continuous 28 days) 
No of DLTs/No of evaluable patients 
30 mg 
0/3 
45 mg 
0/3 
60 mg 
0/6 
80 mg 
2/3 
Interaction parameter 
The prior reflecting the current uncertainty about the toxicity of the combination treatment is 
used for the parameter modeling the interaction (η). Because a potential interaction between 
the small molecules MEK162 and LEE011 cannot be excluded a priori, the parameter η is 
given a prior normal distribution with median = 0.095 (~1.1 fold increase in odds of DLT 
compared to independence at the combination reference dose) and 97.5th percentile = 0.698 
(~2 fold increase on odds of DLT at the combination reference dose). This assumes, a priori, 
that there will be a small interaction, but also allows for the potential of both synergism and 
antagonism between the safety profiles of the 2 drugs. 
Since the interaction is dose-dependent (see model definition in Section 10.4.2), the prior for 
the interaction parameter has a simple interpretation only at the combination reference dose of 
MEK162 = 30mg and LEE011 = 350mg. Table 14-13 shows the prior median and 95% 
interval for the interaction at all provisional dose levels and the combination reference dose. 
Table 14-13 
A priori interaction at provisional dose levels 
LEE011 mg (QD - 3 weeks 
on/1 week off) 
MEK162 mg (BID continuous 28 days) 
30 
45 
100 
1.03 (0.87, 1.22) 
1.04 (0.81, 1.35) 
200 
1.06 (0.75, 1.49) 
1.09 (0.65, 1.81) 
350 
1.10 (0.61, 2.00) 
1.15 (0.47, 2.83) 
400 
1.12 (0.56, 2.21) 
1.18 (0.42, 3.28) 
600 
1.18 (0.42, 3.28) 
1.28 (0.28, 5.94) 
Presented are median (95% probability interval). The a priori interaction at the combination reference dose is 
highlighted in bold. 
Numerical values and summary statistics 
Table 14-14 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-
15 summarizes the prior distribution of DLT rates corresponding to the prior. 


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Table 14-14 
Prior, posterior and predictive distribution of model parameters 
Parameters 
Means 
Standard deviations 
Correlation 
1. Weakly-informative priors for LEE011 and MEK162 
log(α1),log(β1) 
-2.197, 0.000 
2.000, 1.000 
0.000 
log(α2),log(β2) 
-1.386, -0.000 
2.000, 1.000 
0.000 
2. Posterior from available data 
log(α1),log(β1) 
-1.956, -0.929 
0.493, 0.673 
-0.050 
log(α2),log(β2) 
-2.887, 0.195 
1.056, 0.859 
-0.629 
3. Prior used for CMEK162X2114 (incorporates between-trial heterogeneity) 
log(α1),log(β1) 
-1.958, -0.939 
0.862, 0.751 
-0.034 
log(α2),log(β2) 
-2.930, 0.207 
1.117, 0.882 
-0.586 
eta 
0.095 
0.305 
N/A 
Table 14-15 
Prior summaries (derived from priors in Table 14-14) 
LEE011 doses 
(mg, QD - 3 
weeks on/1 
week off) 
Prior probabilities that Pr(DLT) is in 
interval: 
Mean 
SD 
Quantiles 
 
(0, 0.16) 
(0.16, 0.35) 
(0.35, 1) 
 
 
2.5% 
50% 
97.5% 
 
MEK162 = 30mg (BID) 
100 
0.556 
0.362 
0.081 
0.173 
0.113 
0.034 
0.145 
0.460 
200 
0.449 
0.429 
0.122 
0.202 
0.122 
0.046 
0.174 
0.511 
400 
0.319 
0.461 
0.220 
0.249 
0.144 
0.055 
0.219 
0.602 
600 
0.261 
0.421 
0.318 
0.290 
0.172 
0.055 
0.255 
0.695 
 
MEK162 = 45mg (BID) 
100 
0.374 
0.469 
0.157 
0.225 
0.134 
0.053 
0.195 
0.556 
200 
0.289 
0.486 
0.225 
0.256 
0.144 
0.063 
0.226 
0.608 
400 
0.211 
0.432 
0.357 
0.310 
0.174 
0.067 
0.278 
0.714 
600 
0.193 
0.353 
0.454 
0.358 
0.209 
0.058 
0.322 
0.817 
Note: bold values indicate dose combinations not meeting the overdose criterion. 
In any case, the prior parameters (log(α1),log(β1)) will be updated at the time of the first 
DETC in order to include all the historical DLT rate data collected from [CLEE011X2101] 
after October 31st 2012 and before the first dose escalation meeting. 
Note that if a different dosing schedule will be considered for LEE011 in combination with 
MEK162 BID, a Bayesian Meta-analytic approach will be used to take into account historical 
data collected for the LEE011 initially planned schedule in combination with MEK162 in the 
actual study, in order to derive an informative prior estimation of the dose-toxicity 
relationship for the new LEE011 dosing regimen administered with MEK162 BID. This 
informative prior will be updated with DLT data for combination administered with the new 
LEE011 dosing schedule using a 5-parameter BLRM. 


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Alternative regimen: LEE011 QD and MEK162 BID, both “3 weeks on and 1 
week off” 
Due to expected differences in levels of exposure between the MEK162 continuous and 
intermittent dosing schedules, the contribution of the data from the combination of LEE011 
QD “3 weeks on 1/week off” and MEK BID continuous dosing regimen will be applied 
appropriately, as follows: 
• Patients treated at the initial regimen, having the minimum treatment exposure as defined 
in DDS for the new schedule (Section 10.1) or DLT in the first 21 days of treatment and 
not experiencing DLT within the last 7 days of cycle 1 will be included in the historical 
dose determining set. 
• Only patients with DLT occurred within the first 21 days of treatment will be incorporated 
as historical DLT data. 
Table 14-16 shows the actual DLT data from initial combination dosing regimen, calculated 
according to the two criteria mentioned above. 
Table 14-16 
Current data from initial combination dosing regimen included as 
historical data for the new regimen 
LEE011 QD “3 week on/ 
1 week off” 
MEK162 dose (BID continuously) 
No. of DLTs/No. of evaluable patients 
200 mg 
45 mg 
1/6 
300 mg 
45 mg 
0/3 
Selection of the starting dose level is according to the EWOC principle, which recommends 
doses only for which the risk of excessive toxicity (true DLT rate exceeding 0.35) is less than 
25%. In addition, it must not exceed the combination of doses which is found to be safe in the 
previously tested schedule. 
Alternative regimen: LEE011 QD and MEK162 BID, both “2 weeks on and 1 
week off” 
Due to expected differences in levels of exposure between the MEK162 continuous and 
intermittent dosing schedules, as well as between LEE011 QD given with initial regimen (3 
weeks on/1 week off) and alternative regimen (2 weeks on/1 week off), the contribution of the 
data from the combination at the initial dosing regimen will be appropriately applied, 
according to the approach presented in the previous section. In particular: 
• Patients treated at the initial regimen, having the minimum treatment exposure as defined 
in DDS for the new schedule (Section 10.1) or DLT in the first 14 days of treatment, and 
not experiencing DLT within the third week of cycle 1 will be included in the historical 
dose determining set. 
• Only patients with DLT occurred within the first 14 days of treatment will be incorporated 
as historical DLT data. 
In the case that also data from 3 weeks on/1 week off combination schedule (see section 
above) will be available at the time of the decision to explore this new regimen, then same 
logic will be adopted for inclusion of this set of data. 


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Selection of the starting dose level is according to the EWOC principle, which recommends 
doses only for which the risk of excessive toxicity (true DLT rate exceeding 0.35) is less than 
25%. In addition, it must not exceed the combination of doses which is found to be safe in the 
previously tested schedule. 
14.5.2 
Hypothetical dose escalation scenarios 
Table 14-17 shows on-study dosing recommendations for some hypothetical data scenarios, 
considering the initial dosing regimen. 
Note that the next dose combination is selected in concordance with the provisional dose 
levels specified in Section 6.2.3 of the protocol, to mimic possible on-study escalation steps. 
For example, in scenario 5, the next dose combination (600/45) is below the maximal increase 
allowed by the model and below the 100% increase limit. However, since this is one of the 
provisional dose levels suggested for the next cohort, it has been selected accordingly. 
In addition, if in one of the next dose combinations recommended by the model the suggested 
dose of MEK162 is below 45 mg, these combinations are not presented. The only exception is 
when there is no combination with a dose of MEK162 of at least 45 mg which satisfies the 
overdose criterion. Similarly, if in one of the next dose combinations recommended, at least 
one of the doses is above 600 mg for LEE011 with fixed MEK162 at 45 mg, these scenarios 
are not presented. 
Table 14-17 
On-study decisions for dosing 
Scenario 
Dose combination 
LEE011 /MEK162 
Npat 
Ntox 
Next dose 
combination 
(NDC) 
P(target) 
NDC 
P(over) 
NDC 
Median 
DLT rate 
1 
200/45 
3 
0 
400/45 
0.48 
0.18 
0.207 
2 
200/45 
3 
1 
200/45 
0.56 
0.23 
0.247 
3 
200/45 
3 
2 
100/30 
0.51 
0.20 
0.226 
4 
 
3 
3 
STOP 
 
 
 
5 
200/45 
400/45 
3 
3 
0 
0 
600/45 
0.41 
0.15 
0.177 
6 
200/45 
400/45 
3 
3 
0 
1 
400/45 
0.55 
0.21 
0.236 
7 
200/45 
400/45 
3 
3 
0 
2 
200/45 
0.62 
0.20 
0.245 
8 
200/45 
200/45 
3 
3 
1 
0 
400/45 
0.53 
0.22 
0.237 
9 
200/45 
200/45 
3 
3 
1 
1 
200/45 
0.60 
0.24 
0.264 
10 
200/45 
200/45 
3 
3 
1 
2 
100/30 
0.56 
0.16 
0.221 
11 
200/45 
400/45 
600/45 
3 
3 
3 
0 
0 
0 
1200*/45 
0.24 
0.17 
0.126 


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Scenario 
Dose combination 
LEE011 /MEK162 
Npat 
Ntox 
Next dose 
combination 
(NDC) 
P(target) 
NDC 
P(over) 
NDC 
Median 
DLT rate 
12 
200/45 
400/45 
600/45 
3 
3 
3 
0 
0 
1 
600/45 
0.50 
0.17 
0.215 
13 
200/45 
400/45 
600/45 
3 
3 
3 
0 
0 
2 
400/45 
0.63 
0.22 
0.260 
Note that the overdose criterion is defined as P(over) < 0.25. 
*Additional dose levels may be added if allowed by the BLRM. 
Within Table 14-17, it can be seen that the model leads to decisions that are in agreement with 
clinical sense: progressive increase of the combination doses if no DLT is observed, enrolling 
of a new cohort at the same dose combination when 1 DLT is reported, and decrease when 
more than 1 DLT is reported in a cohort. 
14.5.3 
Operating characteristics for Phase Ib 
14.5.3.1 Scenarios 
In order to show how the design performs, 5 hypothetical scenarios were investigated 
considering the initial dosing regimen and using the following scenarios: 
1. For scenario 1, the odds of DLT in are in line with the prior information, i.e. the 
simulation parameter values for the BLRM are set similar to the median values of the 
prior. 
2. For scenario 2 it was assumed that MEK162 would be the primary driver of toxicity. 
3. For scenario 3 it was assumed that LEE011 would be the primary driver of toxicity. 
4. Scenario 4 represents a scenario assuming low toxicity, i.e. the true underlying toxicity is 
lower than what would be predicted from the prior. 
5. Finally, Scenario 5 represents a scenario assuming high toxicity, i.e. the true underlying 
toxicity is higher than what would be predicted from the prior. 
Table 14-18 
True underlying probabilities of DLT for Scenario 1 
LEE011 doses (mg, QD - 3 weeks on/1 week off) 
MEK162 (mg, BID continuous over 28 days) 
 
30 
45 
200 
0.16 
0.19 
400 
0.21 
0.25 
600 
0.25 
0.30 
Bold values indicate dose combinations in the targeted toxicity interval (16%, 35%). 
Table 14-19 
True underlying probabilities of DLT for Scenario 2 
LEE011 doses (mg, QD - 3 weeks on/1 week off) 
MEK162 (mg, BID continuous over 28 days) 
 
30 
45 
200 
0.16 
0.32 
400 
0.21 
0.42 
600 
0.25 
0.50 
Bold values indicate dose combinations in the targeted toxicity interval (16%, 35%). 


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Table 14-20 
True underlying probabilities of DLT for Scenario 3 
LEE011 doses (mg, QD - 3 weeks on/1 week off) 
MEK162 (mg, BID continuous over 28 days) 
 
30 
45 
200 
0.16 
0.19 
400 
0.32 
0.38 
600 
0.48 
0.47 
Bold values indicate dose combinations in the targeted toxicity interval (16%, 35%). 
Table 14-21 
True underlying probabilities of DLT for Scenario 4 
LEE011 doses (mg, QD - 3 weeks on/1 week off) 
MEK162 (mg, BID continuous over 28 days) 
 
30 
45 
200 
0.10 
0.13 
400 
0.16 
0.18 
600 
0.22 
0.23 
Bold values indicate dose combinations in the targeted toxicity interval (16%, 35%). 
Table 14-22 
True underlying probabilities of DLT for Scenario 5 
LEE011 doses (mg, QD - 3 weeks on/1 week off) 
MEK162 (mg, BID continuous over 28 days) 
 
30 
45 
200 
0.28 
0.32 
400 
0.40 
0.44 
600 
0.52 
0.56 
Bold values indicate dose combinations in the targeted toxicity interval (16%, 35%). 
14.5.3.1.1 
Simulation detalis 
Data for 1000 trials were simulated for each scenario and the total minimum number of DLT 
to control the declaration of MTD was fixed to one. The starting dose combination was 
chosen as 200 mg LEE011 45 mg MEK162, and the maximal dose to jump to was orthogonal, 
and follows the protocol specifications (Section 10.4.2 of the protocol). If there is no 
combination of LEE011 which satisfies EWOC with MEK162 at 45 mg, MEK162 can be de-
escalated to 30 mg. 
Among the different dose combinations considered, the one maximizing the probability of the 
true DLT rate being in the targeted toxicity interval (16%, 35%) is selected. 
The number of patients to enroll in each cohort and stopping rules used to declare MTD were 
defined as: 
• Minimum cohort size: 3. 
• Minimum number of patients enrolled: 15. 
• Maximum number of patients enrolled: 60. 
• Minimum number of patients enrolled at a given dose combination in order to declare 
MTD: 6. 


Array BioPharma 
 
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Amended Protocol Version 03 (Clean) 
 
Protocol No. CMEK162X2114 
 
 
14.5.3.1.2 
Metrics to assess operating characteristics 
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were: 
1. Average proportion of patients receiving a target dose combination on study (I). 
2. Average proportion of patients receiving a dose combination with true P(DLT) ≥ 35% on 
study (II). 
3. Average proportion of patients receiving a dose combination with true P(DLT) < 16% on 
study (III). 
4. Probability of recommending a target dose combination as the MTD (correct final 
decision) (IV). 
5. Probability of recommending a dose combinations with true P(DLT) ≥ 35% as the MTD 
(patient risk) (V). 
6. Probability of recommending dose combination with true P(DLT) < 16% as the MTD 
(VI). 
14.5.3.1.3 
Operating characteristics 
Table 14-23 below summarizes the operating characteristics of the design for the 5 different 
scenarios studied using the metrics shown above. Additionally, the percentage of trials 
stopped before declaring MTD when all dose combinations were considered too toxic are 
presented. 
Table 14-23 
Results 
Scenario 
Metrics 
 
I 
II 
III 
IV 
V 
VI 
Stopped 
1 
1 
0 
0 
0.921 
0 
0 
0.079 
2 
0.911 
0.089 
0 
0.644 
0.087 
0 
0.269 
3 
0.776 
0.224 
0 
0.676 
0.243 
0 
0.081 
4 
0.410 
0 
0.590 
0.601 
0 
0.373 
0.026 
5 
0.910 
0.090 
0 
0.576 
0.091 
0 
0.333 
The simulated operating characteristics presented show that the combination model performs 
reasonably well under the hypothetical scenarios investigated. 
The proportion of patients treated at overly toxic dose combinations (metric II) is below 10% 
for all scenarios, excepted scenario 3, in which the combinations have either a true probability 
of DLT lying in the overdosing interval or have a true risk DLT a bit higher than the upper 
bound of the under-dosing interval. Furthermore, the identified MTD falls within the targeted 
interval (metric IV) in more than 55% for all scenarios, showing a good targeting of the MTD 
(even higher than 90% in Scenario 1). 
Of note for scenario 4, as there were no combinations which had true P(DLT) > 0.35, this 
explains why any of the recommended combinations not falling in the target interval is a 
combination with true P(DLT) < 0.16 (exception for the 2% of stopped trial). Therefore, 37% 
of all simulated trials declared a combination with P(DLT) < 0.16 as MTD. 


Array BioPharma 
 
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Amended Protocol Version 03 (Clean) 
 
Protocol No. CMEK162X2114 
 
 
The relatively high number of trials (around 30%) that were stopped in Scenario 2 and 5 
because all combinations were considered too toxic reflects the fact that even the lowest dose 
combination of 200 mg LEE011 and 30mg MEK162 has a considerable chance of DLT (16% 
and 28% in Scenario 2 and Scenario 5, respectively). Please note that in this context also 
Scenario 1 and 3 have the lowest dose combination with a considerable chance of DLT (16%) 
but they behave differently from scenario 2 because of two different reasons. In scenario 1 a 
lot of combinations have true risk of DLT lying in the middle of the target interval, so that the 
identified MTD falls very often within it. In scenario 3 the combinations have either a true 
probability of DLT lying in the overdosing interval or have a true risk DLT a bit higher than 
the upper bound of the under-dosing interval. This facilitates the model to identify an MTD 
falling in the overdosing interval rather than stopping the trial. 
In conclusion, the simulations performed illustrate that the model good and reasonable 
operating characteristics. 
14.5.4 
Statistical details for the Phase II part 
A Bayesian approach will be used in the Phase II in order to estimate ORR for the NRAS 
mutant populations and to provide inferential statements based on the uncertainty of this 
quantity. 
A Beta prior distribution that reflects the amount of uncertainty around the ORR before 
starting the phase II has been selected for the population to be enrolled in the phase II part 
NRAS mutant melanoma). Given that the Response rates to single agent therapies in NRAS 
mutant patients range between 15-25% (see Section 2.1), the prior mean ORR is 
conservatively set to be equal to 0.20 and the unimodal Beta prior distribution is constrained 
to be minimally informative. This leads to the following parameters for the Beta prior 
distribution: 
• a = 0.25. 
• b = 1. 
At completion of the study the prior distribution will be updated taking into account all of the 
data available from the evaluable NRAS mutant patients at RP2D. Once updated, the posterior 
distribution summarizes the probability that the true ORR at the RP2D lies in the categories 
specified in Section 10.4.2. 
The criteria defined to declare efficacy are provided in Section 10.4.2 and sample size 
justification is provided in Section 10.8. 

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
Clinical Trial Protocol CMEK162X2114 
A phase Ib/II, multicenter, open-label, study of LEE011 in combination with 
MEK162 in adult patients with NRAS mutant melanoma 
 
STUDY DRUG: MEK162/LEE011 
PROTOCOL NUMBER: CMEK162X2114 v03 
VERSION: 1.0 
DATE: 16MAY2018 
 
 
 
 
 
 
 
Property of Array BioPharma 
 
 
 
 
 


PPD
PPD
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Array BioPharma 
 
Page 3 
SAP 
16MAY2018 
 
CMEK162X2114 
 
Table of contents 
Approval Signatures....................................................................................................................2 
Table of contents ..................................................................................................................3 
1 
Introduction ..........................................................................................................................7 
1.1 
Study design .............................................................................................................7 
1.1.1 
Description of study design .....................................................................7 
1.1.2 
Definition of end of the study ..................................................................8 
1.2 
Objectives and endpoints .........................................................................................8 
1.3 
Data Analysis ...........................................................................................................9 
1.3.1 
Data analysis environments and general methodologies .........................9 
1.3.2 
Data included in the analysis ...................................................................9 
1.3.3 
Data analyses ...........................................................................................9 
2 
Definitions and general methodology ................................................................................10 
2.1 
General definitions .................................................................................................10 
2.1.1 
Naming conventions and definitions .....................................................10 
2.1.2 
Assessment windows, baseline and post-baseline definitions, missing 
data handling .........................................................................................11 
2.2 
Analysis sets ...........................................................................................................15 
2.3 
Sample size and power considerations ...................................................................16 
3 
Statistical methods used in reporting .................................................................................17 
3.1 
Patient disposition, background and demographic characteristics.........................18 
3.1.1 
Patient disposition .................................................................................18 
3.1.2 
Protocol deviations ................................................................................18 
3.1.3 
Background and demographic characteristics .......................................18 
3.1.4 
Medical history ......................................................................................18 
3.1.5 
Prior antineoplastic therapy ...................................................................19 
3.1.6 
Diagnosis and extent of cancer ..............................................................19 
3.2 
Treatments ..............................................................................................................20 
3.2.1 
Study medication ...................................................................................20 
3.2.2 
Prior and concomitant therapy...............................................................22 
3.2.3 
Anti-neoplastic therapies after discontinuation of study treatment .......22 
3.3 
Analysis of the primary endpoints .........................................................................22 
3.3.1 
Phase Ib .................................................................................................22 
3.3.2 
Phase II ..................................................................................................22 
Reporting of ORR to describe the anti-tumor activity in Phase II .........................23 
Supportive analyses................................................................................................23 


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Array BioPharma 
 
Page 5 
SAP 
16MAY2018 
 
CMEK162X2114 
 
List of abbreviations 
ADI 
Actual dose intensity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic-Therapeutic-Chemical classification 
AUC0-24h 
Area under the curve from time zero to 24 hours 
AUCinf 
Area under the curve from time zero to infinity 
AUClast 
Area under the curve from time zero to the last measureable concentration time 
BID 
Twice daily (Bis in diem in Latin) 
BLRM 
Bayesian logistic regression model 
BMI 
Body Mass Index 
BOR 
Best overall response 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CDK 
Cyclin-Dependent Kinase 
CK 
Creatinine Kinase 
CL/F 
Total body clearance of drug from the plasma 
Cmax 
Maximum plasma concentration after a single dose 
CPK 
Creatinine phosphokinase 
CR 
Complete response 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
Css 
Plasma concentration during steady state 
CT 
Computed tomography 
CTCAE 
NCI common terminology criteria for adverse events (version 4.0) 
DAR 
Dose Administration Record 
DDS 
Dose-determining set 
DI 
Dose intensity 
DLT 
Dose-limiting toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
ETDRS 
Early treatment diabetic retinopathy study 
EWOC 
Escalation with overdose control 
FAS 
Full analysis set 
HR 
Heart rate 
IB 
Investigational Brochure 
INR 
International normalized ratio 
IOP 
Intraocular pressure 
IU 
International units 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 


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Array BioPharma 
 
Page 7 
SAP 
16MAY2018 
 
CMEK162X2114 
 
1 
Introduction 
This document provides the detailed statistical methodology for the analysis of data from study 
CMEK162X2114. The output shells corresponding to this document can be found in separate 
documents. 
All changes to the planned analysis 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 the shells documents 
without the need to amend these documents. 
This document and shells may also serve as a reference for the creation of any outputs required 
outside of the CSR, e.g., IB updates, abstracts, poster presentations, or management updates. 
This document and shells were created based on final protocol version released 26-AUG-2015. 
1.1 
Study design 
1.1.1 
Description of study design 
This is a multi-center, open-label Phase Ib/II study in patients with locally advanced or 
metastatic NRAS mutant melanoma. The study has 2 parts – phases Ib and II.  
MEK162 will be administered orally twice daily (BID) and LEE011 orally once daily (QD). The 
starting doses of MEK162 and LEE011 will be 45 mg BID and 200 mg QD respectively. 
LEE011 will be administered for 21 days followed by a 1 week break and MEK162 will be 
administered on a continuous dosing schedule (28-day cycle). 
Should safety and PK data from the dose escalation part of this study and/or other 
MEK162/LEE011 study(s) indicate that alternate dosing regimens of MEK162 and LEE011 may 
be more appropriate, the following schedules will be considered:  
• LEE011 QD and MEK162 BID, both administered for 3 weeks followed by a 1 week 
planned break (28-day cycle) 
• LEE011 QD and MEK162 BID, both administered for 2 weeks followed by a 1 week 
planned break (21-day cycle) 
Phase Ib is the dose escalation part where successive cohorts of 3-6 newly enrolled patients 
receiving various dose pairs considering the recommendation from an adaptive Bayesian logistic 
regression model (BLRM) incorporating the Escalation With Overdose Control (EWOC) 
principle until Maximum Tolerated Dose (MTD) / Recommended Phase II dose (RP2D) is 
defined. Once the MTD/RP2D have been determined for each tested schedule, the Phase II part 
will begin at the RP2D on the chosen schedule to assess antitumor activity of the LEE011 and 
MEK162 combination.  
Patients will continue to receive treatment until disease progression, occurrence of unacceptable 
toxicity that precludes any further treatment, or if treatment is discontinued at the discretion of 
the investigator or by patient’s withdrawal of consent. Analysis of the study data will occur after 
all patients have had the opportunity to complete at least six cycles of treatment. 


Array BioPharma 
 
Page 8 
SAP 
16MAY2018 
 
CMEK162X2114 
 
Figure 1-1 
Study design 
 
1.1.2 
Definition of end of the study 
Phases Ib and II of the study will end when the treatment period, safety follow-up, disease 
follow-up, and survival follow-up (only for Phase II) have ended for all patients as described in 
Protocol Section 7.1.5, or when the study is terminated early.    
1.2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-1 
Objectives and related endpoints 
 
Objective 
Endpoint 
Primary 
 
Phase Ib: To estimate the 
MTD(s)and/or to identify the RP2D 
and schedule of LEE011 and MEK162 
in combination 
Incidence of dose limiting toxicities  in cycle 1 
Phase II: To describe the anti-tumor 
activity of the LEE011 and MEK162 
in combination at the RP2D   
ORR (CR and PR) according to RECIST 1.1 
Secondary 
 
Phase Ib: To characterize the PK 
profiles of LEE011 and MEK162 as 
well as any other clinically significant 
metabolites that may be identified. 
Plasma concentration-time profiles of LEE011 and 
MEK162, PK parameters, including but not limited 
to AUCtau, AUCtau,ss, Cmin,ss, Cmax, Cmax,ss,Tmax, 
Tmax,ss, accumulation ratio (Racc), and T½,acc, CL/F 
Phases Ib and II: To characterize the 
safety and tolerability of LEE011 and 
MEK162 
Incidence and severity of adverse drug reactions and 
serious adverse drug reactions. Changes in 
hematology and chemistry values, vital signs, 
electrocardiograms (ECGs), and dose interruptions, 
dose reduction and dose intensity. 
Phases Ib and II: To assess clinical 
efficacy of the LEE011 and MEK162 
combination 
Duration of response (DOR), Time to progression 
(TTP), Progression Free Survival (PFS) and Overall 
Survival (OS) as per RECIST 1.1. Best Overall 


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CMEK162X2114 
 
In Phase Ib, cohorts of patients treated with the same dose combination and regimen during the 
dose escalation part will be pooled into a common treatment group. 
In Phase II, based on the safety, tolerability, and efficacy, a single treatment group with RP2D 
and regimen will be selected to assess antitumor activity of the LEE011 and MEK162 
combination.  
MTD(s)  
The MTD will be established for all tested dosing regimens in Phase Ib. It is defined as the 
highest combination drug dosage not causing medically unacceptable dose-limiting toxicity 
(DLT) in more than 35% of the treated patients in the first cycle of treatment. 
2.1.2 
Assessment windows, baseline and post-baseline definitions, missing data 
handling 
2.1.2.1 
Date of first and last administration of study drug 
The date of first administration of study drug (LEE011 or MEK162) is derived as the first date 
when a non-zero dose of study drug was administered and recorded on the DAR eCRF. For the 
sake of simplicity, the date of first administration of study drug will also be referred as start of 
study drug. 
The date of last administration of study drug is the last date when a non-zero dose of study drug 
is administered and recorded on DAR eCRF.  
Dosing is reported in a continuous fashion. Week off (i.e., for 3+1 and 2+1 regimens) are not 
reported in data (one does not enter a new ‘0 dose’ record and new start date to indicate patient 
is in ‘off week’). 
2.1.2.2 
Date of first and last administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of the study drug is administered and recorded on DAR eCRF. (i.e., earliest date between 
first LEE011 dose and first MEK162 dose). For the sake of simplicity, the date of first 
administration of study treatment will also be referred as start of study treatment. 
The date of last administration of study treatment is derived as the latest date of the last 
administration of non-zero dose of the study drug and recorded on DAR eCRF. (i.e., latest date 
between last LEE011 dose and last MEK162 dose). 
2.1.2.3 
Study day 
The study day for all assessments/events will be calculated using the start date of study treatment 
as reference. For assessments/events (both efficacy and safety) 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. 


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Array BioPharma 
 
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CMEK162X2114 
 
• Non-compliance with study treatment 
• Physician decision 
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Study terminated by sponsor 
• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
2.1.2.6 
On-treatment assessment/event 
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. 
2.1.2.7 
End of treatment (EOT) 
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. The end of treatment assessments 
should occur within 14 days of the last study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Non-compliance with study treatment 
• Physician decision 
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Study terminated by sponsor 
• Technical problems 
• Subject/guardian decision 
• Death 
2.1.2.8 
Imputation rule of partial or missing dates 
For computation of time intervals (e.g., elapsed time between date of first study treatment to 
progression), the time interval should be set to missing when the imputation rule leads to a 
negative value. 
For patients who discontinue the study with ongoing events, the discontinuation date will be used 
as the completion date of the event. 


Array BioPharma 
 
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For AEs, concomitant medications and antineoplastic therapies, imputation rules for partial or 
missing dates are described below: 
Adverse event date imputation 
Missing and partial start and end dates for AEs will be handled according to Section 3.5.1. 
Concomitant medication date imputation 
The imputation of the start date and end date of concomitant medication use will follow the same 
conventions as for AE start date and end dates.  
Antineoplastic therapies date imputation 
Prior therapies 
Start date:  
In general, follow the same rules that are applied to the imputation of an AE/concomitant 
medication start date, except: 
• Completely missing start dates are imputed as treatment start date - 1; 
• If only day is missing, and month and year match that of the treatment start date, 
impute as treatment start date -1; 
• If both day and month are missing, and the year matches that of the treatment start 
date, then impute as treatment start date - 1.  
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. 
Completely missing end dates will not be imputed. 
Post therapies 
Start date: 
 
Imputed date = max(last date of study drug + 1, first day of the month), if day is missing; 
Imputed date = max(last date of study drug + 1, 01JAN), if day and month are missing.  
Completely missing start dates will be imputed as last date of study drug + 1. 
End date: No imputation. 
Date of initial diagnosis of cancer and date of most recent recurrence 
For date of initial diagnosis of cancer, missing day is defaulted to 15 and missing month and day 
is defaulted to July 01 respectively.  For date of most recent recurrence, if only day is missing 
then day is set to 15.  If both month and day are missing, then month and day will be set to July 
01.   


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2.2 
Analysis sets  
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Log eCRF, and each patient’s demographic information will be captured in the 
Demography eCRF. No other data will be entered into the clinical database for screen failure 
patients. 
A patient must have given informed consent to participate in the study before being included in 
any analysis set.  
The number of patients in each analysis set will be summarized by treatment group, as well as 
listed by patient.   
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose of LEE011 or 
MEK162. Patients will be analyzed according to the planned treatment combination. 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. 
Safety Set 
The safety set includes all patients who received at least one dose of LEE011 or MEK162, and 
have at least one valid post-baseline safety assessment.  
Patients will be analyzed according to treatment received, where treatment received is defined as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
Per-protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with the following requirements of the clinical study protocol: 
• Diagnosis corresponds to that defined in inclusion criteria (Protocol Section 5.2); prior 
treatment corresponds to that defined in inclusion criteria (Protocol Section 5.2). 
• The patient received at least 50% of the planned dose of each compound (taken together) 
within the first 8 weeks of study for the 28-day cycle regimen or the first 6 weeks of study 
for the 21-day cycle regimen. For example, a patient discontinuing after 2 weeks will be 
excluded from the PPS even if no combination doses were missed. 
• The patient was evaluated for primary efficacy variable at or beyond week 10, or 
discontinued due to an AE, disease progression, or died prior to the first evaluation of the 
primary efficacy variable. 
Patients will be evaluable for efficacy under the PPS if they have at least one tumor evaluation 
with an overall lesion response assessed differently from ‘unknown’ or ‘not assessed’ under the 
RECIST 1.1 at or beyond week 10. 


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Phase II 
Based on the prior distribution for the ORR specified in Protocol Appendix 5 and efficacy 
intervals described in Protocol Section 10.4.2, it is estimated that, given an observed ORR equal 
to 35%, approximately 40 patients should be enrolled for the model to have less than 10% 
posterior risk of the true ORR being less than 25% (i.e., unacceptable efficacy). 
3 
Statistical methods used in reporting 
Unless noted otherwise, summaries described in this section will be based on the FAS. 
Summaries will be produced by treatment group and overall. Data will be listed individually by 
patient based on the FAS, unless noted otherwise.  
Unless specified otherwise, tables and figures will be generated in pairs, one for Phase Ib by 
treatment group for different dosing regimens (see below) and the other one for Phase II. 
For Phase Ib, dosing regimens will be presented in the following order: 28-day-cycle schedule 
followed by 21-day-cycle schedule. Within each dosing regimen, treatment groups will be 
presented in ascending order of LEE011 dose levels first, then ascending order of MEK162 dose 
levels. The last three columns will be “All 28-day patients”, “All 21-day patients”, and “All 
patients” if appropriate. For efficacy, the outputs will be presented by regimen (28-day, 21-day, 
overall) and within each regimen, by treatment group. 
Qualitative data (e.g., gender, race, etc.) will be summarized by frequency count and 
percentages. Percentages will be calculated using the number of patients in the relevant 
population or subgroup as the denominator.   
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (e.g., mean, standard deviation (SD), median, minimum, and maximum). 
Table 3-1                    Treatments 
MEK162 
LEE011 
Dosing 
Regimen 
Dosing 
Regimen 
45 mg 
Continuous 
200 mg 
3 weeks on/1 week off 
45 mg 
Continuous 
250 mg 
3 weeks on/1 week off 
30 mg 
Continuous 
300 mg 
3 weeks on/1 week off 
45 mg 
Continuous 
300 mg 
3 weeks on/1 week off 
30 mg 
2 weeks on/1 week off 
100 mg 
2 weeks on/1 week off 
30 mg 
2 weeks on/1 week off 
200 mg 
2 weeks on/1 week off 
30 mg 
2 weeks on/1 week off 
300 mg 
2 weeks on/1 week off 
45 mg 
2 weeks on/1 week off 
200 mg 
2 weeks on/1 week off 
45 mg 
2 weeks on/1 week off 
300 mg 
2 weeks on/1 week off 
45 mg 
2 weeks on/1 week off 
400 mg 
2 weeks on/1 week off 
45 mg 
2 weeks on/1 week off 
450 mg 
2 weeks on/1 week off 
45 mg 
2 weeks on/1 week off 
600 mg 
2 weeks on/1 week off 
Note: the continuous regimen is considered as a 28-day regimen for the table presentation. 


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3.1 
Patient disposition, background and demographic characteristics 
3.1.1 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. The number of 
patients who enrolled, completed, or discontinued the study will be summarized by treatment 
group. Specifically, the following will be tabulated using FAS as the denominator: 
• Number (%) of patients who are still on-treatment (based on non-completion of the ‘End of 
Treatment’ page), 
• Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered), 
• Primary reasons for study treatment discontinuation (based on discontinuation reason entered 
in the ‘End of Treatment’ page), 
• Number (%) of patients who discontinued from study (based on completion of the ‘Study 
Phase Completion’ eCRF page with discontinuation date and reason entered), 
• Primary reasons for study evaluation completion (based on discontinuation reason entered in 
the ‘Study Phase Completion’ eCRF page). 
Patient disposition will also be listed. 
Screen failure patients are those who have been screened, but never started the study treatment 
for any reason. The data collected on these patients will not be included in any analyses. A 
listing of patients and the reasons for screen failure will be presented.  
3.1.2 
Protocol deviations 
Protocol deviations will be tabulated and listed by treatment group.  
3.1.3 
Background and demographic characteristics 
Background and demographic characteristics including age, sex, race, ethnicity, height, weight, 
body mass index (BMI), and Eastern Cooperative Oncology Group (ECOG) (Oken et al., 1982) 
performance status will be listed and summarized by treatment group. 
BMI is derived using the following formula: 
BMI [kg/m2] = weight[kg] / (height[m]**2) 
In addition, the following derived variables derived from the demographic eCRF will be 
described: 
• age groups summarized by group (<65, ≥65 years), 
• weight summarized by group (<55, 55-<75, ≥75 kg). 
3.1.4 
Medical history 
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be summarized and listed by treatment. Separate summaries will be presented 
for current and historical medical conditions by primary system organ class and preferred term. 


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Medical history and current medical conditions are coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  
3.1.5 
Prior antineoplastic therapy 
Prior antineoplastic therapy will be listed in three separate listings: (i) medications, (ii) 
radiotherapy, and (iii) surgery. 
Prior antineoplastic medications will be summarized by treatment. The summary will include the 
total number of regimens (note: there can be more than one medication per regimen), setting at 
last medication, best response at last medication, time (in days) between end of last medication 
to start of study treatment, reason for discontinuation at last medication, and time (in months) 
from start of last medication to disease progression. The last medication is defined based on the 
last end date of all prior regimen components. Prior antineoplastic medications will also be 
summarized by Anatomical Therapeutic Chemical (ATC) class and preferred term.  
The summary of prior antineoplastic radiotherapy will include information about the last 
radiotherapy: time (in months) between radiotherapy and start of study treatment, locations, 
(including all locations recorded for each patient), and setting. 
The summary of prior antineoplastic surgery will include information about the last surgery: the 
time (in months) between surgery (non-biopsy procedure) and start of study treatment and 
presence of residual disease.  
Last surgery is determined based on the date of surgery. Last radiotherapy is determined based 
on the radiotherapy end date.  
3.1.6 
Diagnosis and extent of cancer 
Number (%) of patients in each of the categories will be summarized for the following variables: 
• melanoma type [cutaneous melanoma, non-cutaneous melanoma] 
• predominant histology/cytology [desmoplastic, nodular, lentigo maligna, superficial 
spreading, unknown, other] 
• stage at initial diagnosis and at time of study entry [stage: 0, I, IA, IB, IC, II, IIA, IIB, IIC, 
III, IIIB, IIIC, IV, IVA, IVB, IVC] 
• types of lesions (target, non-target) 
• metastases status and sites 
• NRAS molecular status (if mutated, type of mutation) 
In addition, the following continuous time intervals in days will be computed and summarized:  
• time since initial diagnosis of primary site to first dose of study treatment, calculated as (date 
of study treatment start – date of initial diagnosis of primary site + 1) 
• time since initial diagnosis of primary site to most recent recurrence/relapse, calculated as 
(date of most recent recurrence/relapse – date of initial diagnosis of primary site + 1) 
• time since most recent recurrence/relapse to first dose of study treatment, calculated as (date 
of study treatment start - date of most recent recurrence/relapse + 1) 


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Disease history will also be listed for each patient. 
3.2 
Treatments   
3.2.1 
Study medication 
Exposure to study drugs or study treatment will be summarized on the Safety Set in terms of the 
following derivations: 
• duration of study drug exposure, 
• duration of study treatment exposure,  
• cumulative dose for each study drug, 
• dose intensity (DI) and/or relative dose intensity (RDI) for each study drug, 
• percentage of actual days dosed during the treatment period, 
• percentage of days received planned doses during the treatment period. 
All doses of each study drug along with reasons for dose change/dose interruption will be listed. 
3.2.1.1 
Duration of study drug exposure 
For patients who take at least 1 dose of the study drug: 
Duration of exposure (days) = last date of exposure to the study drug – date of first 
administration of the study drug + 1. 
3.2.1.2 
Duration of study treatment exposure 
For patients who take at least 1 dose of any of the components of the study treatment: 
Duration of exposure of study treatment (days) = max(last date of exposure to LEE011, last date 
of exposure to MEK162) – min(date of first administration of LEE011, date of first 
administration of MEK162) + 1. 
The exposure duration may include periods of temporary interruption.  
3.2.1.3 
Cumulative dose 
The following definitions will be used: 
• Actual cumulative dose (mg) = sum of all actual doses of study drug taken during the dosing 
period (i.e., from first date of treatment administration until last date of treatment 
administration, including planned interruptions) 
• Planned cumulative dose (mg) = sum of all doses of study drug that was intended to have 
been taken during the treated period (planned interruptions are taken into account) 
The planned cumulative dose is obtained by multiplication of the treatment exposure in days by 
the planned dose per day (e.g., if treatment duration = 10 days, then planned cumulative dose = 
10 × daily dosing). Any planned interruptions will not be excluded for the planned cumulative 
dose calculations. 


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3.2.1.4 
Dose intensity and relative dose intensity 
Actual dose intensity (ADI; mg/day), planned dose intensity (PDI; mg/day), and RDI (%) will be 
summarized by treatment group and overall (using exposure duration) for each study drug.   
DI for patients with non-zero duration of exposure is defined as follows: 
ADI (mg/day) = actual cumulative dose (mg) / duration of exposure (days) 
PDI (mg/day) = planned cumulative dose (mg) / duration of exposure (days) 
RDI = ADI [mg/day] / PDI [mg/day]  
The number and proportion of patients who fall in the following categories for RDI will also be 
presented: 
• <0.5 
• 0.5 - <0.75 
• 0.75 - <0.9 
• 0.9 - <1.1 
• ≥1.1 
The calculation of planned dose is based on the initial assigned dose regardless of dose 
interruption. For patients who did not take any drug, the DI is by definition equal to zero. 
Duration of exposure, cumulative dose, actual dose intensity, and relative dose intensity will also 
be listed for study drug by patient. 
3.2.1.5 
Dose interruption and dose reduction 
Dose interruption 
When the actual dose equals zero (where the planned dose is not zero), between the first and last 
non-zero doses it will be considered a dose interruption. Note that for LEE011/MEK162, the 7-
day rest period is not to be considered a dose interruption. 
Frequency counts and percentages of patients who have dose interruptions, and the 
corresponding reasons, will be provided. The number of dose interruptions per patient, and the 
duration of dose interruptions (days) will be summarized.   
Dose reductions 
For LEE011 and MEK162, the corresponding eCRF allows the recording of dose changes 
including dose reduction and dose interruption.  
For MEK162 dose records, a dose reduction is identified as a non-zero actual dose that is less 
than the last previous non-zero dose that is divisible by 30, and (for cases where both the current 
and previous non-zero records are both not divisible by 30) less than the immediate previous 
non-zero actual dose.  For LEE011 dose records, a dose reduction is identified as a non-zero 
actual dose that is less than the immediate previous non-zero actual dose.  For both MEK162 and 
LEE011 dose records, in cases where a patient’s first non-zero dose record is below the treatment 
planned dose, this dose will be counted a dose reduction as well. 


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Frequency counts and percentages of patients who have dose reductions, and the corresponding 
reasons, will be provided. 
3.2.2 
Prior and concomitant therapy 
Concomitant therapies are defined as any medications (excluding study treatment or prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered during 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. 
Prior and concomitant medications/significant non-drug therapies will be listed and summarized 
by treatment group in the safety set.  Separate tables and listings will be produced for medication 
that were stopped prior to start of study drug, medications that started prior to study drug and 
continued during study, and medication that were started after start of study drug.  
Antineoplastic therapies since discontinuation of study drug will be listed by ATC class and 
preferred term by means of frequency counts and percentages in separate summaries using the 
safety set. 
3.2.3 
Anti-neoplastic therapies after discontinuation of study treatment 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and tabulated by 
ATC class and preferred term. 
3.3 
Analysis of the primary endpoints 
3.3.1 
Phase Ib  
The primary variable is the incidence of dose limiting toxicities (DLTs) in Cycle 1. Patients who 
are ineligible for the DDS will be removed from the primary analysis and additional patients may 
be recruited. Their data will be used for all remaining analyses. 
The following outputs will be presented: 
• DLTs occurring during the first cycle will be listed and summarized by primary system organ 
class, preferred term, and treatment group.  
• A summary of the posterior distribution of DLT rates at the end of Phase Ib will be 
presented. 
• A summary of the prior and posterior parameter estimates for the BLRM will be produced. 
3.3.2 
Phase II 
The primary variable is the ORR, defined as the proportion of patients with a best overall 
response (BOR) of CR or PR as assessed per RECIST 1.1. 
The primary analysis of the ORR will be based on the investigator’s assessment of overall lesion 
responses per RECIST 1.1. 


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End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page, or during 
follow-up as recorded on the ‘Study Phase 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. 
Refer to Protocol Appendix 2 for cases when there is no documentation of radiologic 
evidence of progression and the patient discontinued for ‘Disease progression’ due to 
documented clinical deterioration of disease. The date of discontinuation is used as date of 
progression in this case. 
• 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), then the 
date of start of treatment is used. 
• 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 contact date from that survival follow-up page is used. If no 
survival follow-up is available, then the date of discontinuation is used as the last contact 
date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
The censoring and event date options to be considered for the PFS/DOR/TTP analysis are 
presented in Table 3-2. 
Table 3-2                    Options for event dates/censored dates used in PFS/DOR/TTP 
Situation 
 
Date 
Outcome 
A 
No baseline assessment 
Date of first 
administration of 
study treatment a 
Censored 
B 
Progression at or before next scheduled 
assessment 
Date of progression 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
Date of progression 
or death 
Progressed 
C2 
Progression or death after two or more 
missing assessments 
Date of last adequate 
assessment b 
Censored 
D 
No progression 
Date of last adequate 
assessment b 
Censored 


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E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim 
 
Information 
ignored. Outcome 
derived based on 
radiology data 
only. 
F 
New anticancer therapy given 
Date of last adequate 
assessment b 
Censored 
a 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. 
b Last adequate tumor assessment is defined in Protocol Section 7.2.1 
Kaplan-Meier plot and estimates 
An estimate of the survival function will be constructed using the Kaplan-Meier (product-limit) 
method (Kaplan & Meier, 1958) as implemented in PROC LIFETEST. 
The median survival is obtained along with 95% confidence intervals as calculated from the 
PROC LIFETEST output (using method of [Brookmeyer & Crowley, 1982]).  
Kaplan-Meier estimates with 95% confidence intervals at specific time points will be 
summarized. The confidence intervals are constructed using Greenwood’s formula for the 
standard error of the Kaplan-Meier estimate. When the estimated survival function is close to 
zero or unity, symmetric intervals are inappropriate since they can lead to confidence limits that 
lie outside the interval [0, 1]. Any limit that is greater than unity will be replaced by 1.0. Any 
limit that is less than zero will be replaced by 0.0. 
3.4.1.2 
Construction of waterfall graphs 
The waterfall graph is used to depict anti-tumor activity. This plot displays both BOR and the 
best percentage change from baseline in the sum of the longest diameter of all target lesions for 
each patient.  
The assessments with an unknown overall response will not be excluded as long as the sum of 
the longest diameter is correctly computed on the same lesions assessed at baseline. 
The best overall response will be shown above each of the displayed bars in the graph. 
Patient with missing/unknown best percentage change from baseline represented by a special 
symbol (e.g., *) in the waterfall graph. 
Patients will be ordered in the graph using the following display (from left to right): 
• Bars above the horizontal axis representing tumor growth 
• Bars under the horizontal axis representing tumor shrinkage 
•  “Zero” bars with the * symbol representing patients with missing best percentage change 
Waterfall plots will show the cut-off limits for target lesions for PR (-30%) as dotted lines. 


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3.4.1.3 
Confidence intervals for Overall Response Rate 
ORR is the proportion of patients with a best overall response of CR or PR. Patients will be 
summarized in terms of percentage rate with 95% confidence interval. An exact binomial 
confidence interval (implemented using the SAS procedure FREQ with the EXACT statement 
for one-way tables) will be calculated (Clopper & Pearson, 1934). 
3.4.2 
Handling of missing data and special cases 
No measurable lesion at baseline 
Evaluation using RECIST 1.1 criteria implies that patients have a measurable lesion at baseline. 
However, patient without a measurable lesion may be enrolled in the study. According to 
RECIST 1.1 guidelines, the overall response should be UNK or PD.  
In Phase I studies when the presence of target lesions is not mandatory for enrollment, to avoid 
the presence of too many “UNK”, the overall response will be derived based on non-target 
lesions only when no target lesion is available. For patients with only non-target lesions at 
baseline, the overall response will be determined based on post-baseline non-target lesions and 
new lesions as shown in Table 3-3 below. In general, the non-CR/non-PD response for these 
patients is considered equivalent to an SD response in endpoint determination. As a result, the 
overall lesion response can be CR, Non-CR/Non-PD, PD or UNK.  Hence, the BOR can be 
derived as CR, Non-CR/Non-PD, PD or UNK according to RECIST 1.1 guideline for these 
patients.     
Table 3-3 
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 Protocol Appendix 2. 
3.4.3 
Reporting of BOR, DOR, TTR, TTP, PFS and OS per RECIST as secondary 
endpoints 
Response and progression evaluation will be performed according to the RECIST version 1.1 (as 
described in detail in Protocol Appendix 2) whenever it applies. 
Best overall response (BOR) 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), death, or early study discontinuation. Only overall tumor 
assessments reported by investigator and performed before the start of any further anti-neoplastic 
therapies (i.e. any additional secondary anti-neoplastic therapy or surgery) will be considered in 
the assessment of best overall response.  


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Confirmation of complete and partial responses (CR and PR, respectively) must be made at least 
4 weeks apart. Stable disease must occur >6 weeks after the start of treatment. Patients with an 
unknown clinical response will be treated as non-responders.  
As a default, any assessments taken more than 30 days after the last dose of study treatment will 
not be included in the BOR derivation. 
If any alternative cancer therapy is taken while on study any subsequent assessments will be 
excluded from the BOR determination. 
The BOR for each patient is determined from overall (lesion) responses.  
Duration of response (DOR) is defined as the time from the first day of overall response 
(CR/PR) to the first documented disease progression or date of death due to underlying cancer. 
Only patients with confirmed response (CR/PR) will be included in the analysis. If progression 
or death has not occurred, the patient is censored at the date of last adequate tumor assessment 
other than unknown. The censoring and event date options to be considered for the DOR analysis 
are presented in Table 3-2. 
Time to overall response (TTR) is the time between treatment start date until the first 
documented, confirmed response of CR or PR. Patients who do not achieve a confirmed PR or 
CR will be censored as follows: 
• at the last adequate tumor assessment date when they do not have a PFS event (i.e., did 
not progress or die due to any cause). In this case patients have not yet progressed so they 
theoretically still have a chance of responding; 
• at maximum follow-up (i.e., first patient first visit (FPFV) to last patient last visit (LPLV) 
used for the analysis) when they have 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 makes use of the ranking of 
times to response it is sufficient to assign the worst possible censoring time which could 
be observed in the study which is equal to the maximum follow-up time (i.e., time from 
FPFV to LPLV). 
Time to progression (TTP) is the time from date of start of treatment to the date of first 
documented progression or death due to melanoma. If a patient has not had an event, TTP is 
censored at the date of last adequate tumor assessment other than unknown. The censoring and 
event date options to be considered for the TTP analysis are presented in Table 3-2. 
Progression-free survival (PFS) is defined as the time from the date of first study treatment 
intake to the date of the first radiologically documented disease progression or death due to any 
cause. In the case where a patient does not have documented progression but has disease 
progression as the reason for end of treatment/study evaluation completion, i.e., clinical 
progression, it will not be considered as a PFS event. A patient who has not progressed or died at 
the last patient last visit (LPLV) date will be censored at the date of last adequate tumor 
assessment other than unknown.  
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 


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of these patients will be censored at the date of the last tumor evaluation with overall lesion 
response of CR, PR or SD. 
Overall survival (OS) is defined as the time from start date of treatment to date of death due to 
any cause.  
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”).  
If a patient is not known to have died, survival will be censored at the date of last known date 
patient alive. The follow-up data should contain the date the patient was last seen alive / last 
known date patient was alive, or the date of death and the reason of death 
3.4.4 
Phase Ib 
The following Phase Ib listings will be presented for all available dosing regimens. 
• individual lesion measurements (by RECIST 1.1 criteria) 
• overall and best lesion response 
• time to onset and DOR per RECIST v1.1 for patients who experience a CR or PR at any time 
on study 
• time to disease progression and death  
In addition, a summary table for BOR per RECIST 1.1 will be provided by treatment group in 
FAS.  A Kaplan-Meier analysis of PFS will be provided in table and figure form, where Phase Ib 
28-Day schedule patients are grouped together and 21-Day schedule patients are grouped 
together. 
Waterfall plots for best overall response and best percentage change from baseline for all target 
lesions for each patient will be produced by treatment group. 
3.4.5 
Phase II 
All of the tables, listings, and figures described above for Phase Ib will also be presented for 
Phase II, by patient at RP2D. 
PFS, TTP, DOR, TTR, and OS will be presented graphically using Kaplan-Meier plots at RP2D.  
Summary statistics from the Kaplan-Meier distribution will be presented at RP2D, including the 
median, 25th percentile, 75th percentile, and estimates at 2 months, 4, 8, and 12 months for PFS, 
TTP, DOR, TTR, and OS (OS only for 4 and 12 months, TTR confirmed responders subset only 
for 2, 3, and 4 months). These statistics will be provided as point estimates with 95% confidence 
intervals. The confidence intervals are constructed using Greenwood’s formula (Collett 1944, p. 
23) for the standard error of Kaplan-Meier estimate. Number of events and number of censored 
for PFS, TTP, TTR, DOR, and OS will be summarized as well. The same descriptive summary 
of TTR on confirmed responders (i.e., patients achieving at least one confirmed CR or PR) only 
will also be presented. 


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3.5 
Safety evaluation for secondary endpoints  
The assessment of safety will be based mainly on the type and frequency of AEs, and on the 
number of laboratory values that fall outside of pre-determined ranges (CTCAE version 4.03 
grading limits or normal ranges, as appropriate). Other safety data (e.g., ECG, vital signs) will be 
presented, as appropriate. All safety data will be listed.  
The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication. 
• On-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication. 
• Post-treatment period: starting at day 31 after last dose of study medication. 
The Safety Set will be used for summaries and listings of all safety data, with the exception of 
DLTs for which the DDS will be used and will be presented by treatment groups for Phase I.  
The safety summary tables will include assessments collected no later than 30 days after study 
treatment discontinuation.  
3.5.1 
Adverse event 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. Although CTCAE version 4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death, CTCAE grade 5 (death) was 
not used since this information was collected on the “End of Treatment” or “Study phase 
completion” pages.  
Separate listings for AEs, serious AEs (SAEs), AEs leading to study drug discontinuation, and 
death recorded during the study will be provided. Summary tables for AEs will include only AEs 
that started or worsened during the on-treatment period (treatment-emergent AEs [TEAEs]). 
However, all safety data (including those from the pre- and post-treatment periods) will be listed 
and safety data collected during the pre-treatment and post-treatment periods are to be flagged. 
All AE summaries will be summarized (frequency counts and percentages) by system organ 
class and/or preferred term, and maximum severity grades, except where otherwise noted. 
The following AE summaries will be produced: 
• AEs regardless of study drug relationship (including CTC grade 3/4) 
• AEs suspected to be study drug related (including CTC grade 3/4) 
• AEs leading to discontinuation of any study drug 
• AEs requiring dose adjustment or study drug interruption 
• AEs requiring dose adjustment, by outcome 
• AEs requiring study drug interruption, by outcome 
• AEs leading to discontinuation of any study drug, by outcome 
• SAEs regardless of study drug relationship 
• SAEs suspected to be study drug related 
• AEs that are not serious, regardless of study drug relationship 


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• Dose limiting toxicities 
• Deaths, with cause of death by primary system organ class and preferred term.  
Missing and partial dates for AEs will be handled according to rules specified below.  
There will be no attempt to impute the following: 
• Completely missing AE start dates;  
• AE start dates missing the year. 
For a partial AE start date, the date imputation will be based on the temporal relationship 
between the partial date and start of treatment date. 
For a partial AE end date or completely missing end date (AE is ongoing), the date imputation 
will be based on the temporal relationship 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 3-4.  
Table 3-4 
AE start date imputation example scenarios 
Partial 
AE start date 
Treatment 
start date 
Temporal 
relationship 
compared to 
treatment start 
Imputed Date 
12mmyyyy 
20OCT2001 
Uncertain 
<blank> 
ddmmm2000 
20OCT2001 
Before 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
01JAN2002 
ddmmm2001 
20OCT2001 
Uncertain 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
01NOV2001 
 
Table 3-5 provides examples of the different considered imputations for AE end date. 
Table 3-5 
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 


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Partial 
AE end date 
Minimum (Last 
contact date, 
30-day FU 
date) 
Ongoing 
Imputed Date 
ddmmm2001 
20OCT2001 
Yes 
      31DEC2001 
ddSEP2001 
20OCT2001 
No 
30SEP2001 
ddOCT2001 
20OCT2001 
No 
20OCT2001 
ddOCT2001 
20OCT2001 
Yes 
31OCT2001 
3.5.2 
Laboratory data 
Samples for laboratory tests will be collected and analyzed by the study site’s local laboratory. 
More frequent examinations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded on the Unscheduled Lab eCRFs. 
All laboratory values will be converted into SI units when applicable and the severity grade 
calculated using CTCAE, version 4.03, unless otherwise indicated. A severity grade of 0 will be 
assigned when the value is within normal limits. If a local laboratory normal range overlaps into 
the higher (i.e., non-zero) CTC grade, the laboratory value will still be considered within normal 
limits and will be assigned a CTC grade of zero. 
When not collected, Corrected Calcium will be derived from Calcium and Albumin results as per 
the following formula: 
Corrected Calcium (mmol/L) = [4*Calcium(mmol/L) –  0.8*(0.1*Albumin(g/L) – 4)]/4 
The following summaries will be produced for the laboratory data by laboratory parameter: 
• shift tables from baseline to the worst post-baseline value (expressed in CTC grades);  
• shift tables from baseline to the worst post-baseline value using the low/normal/high 
classifications based on laboratory reference ranges for laboratory parameters where CTC 
grades are not defined; 
• frequency table of laboratory abnormalities: number and percent of patients with newly 
occurring or worsening post-baseline CTC grade of 3 or 4. 
In addition, a summary of the number and percentage of patients with notable hepatic laboratory 
values will be produced.  
The following listings will be produced for the laboratory data: 
• laboratory abnormalities of CTC grade 3 and 4; 
• laboratory normal ranges by laboratory identification number and laboratory group; 
• all laboratory data with values flagged to show corresponding CTC grades and/or the 
classifications relative to the laboratory reference ranges (i.e., High [H] or Low [L]); 
• newly occurring notable hepatic laboratory values. 


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Table 3-6                   Clinical Laboratory Parameters Collection Plan 
Test Category 
Test Name 
Hematology 
Complete blood count (CBC) with differential - white blood count (WBC), absolute 
neutrophil count (including bands), lymphocyte, monocyte, eosinophil, and basophil 
counts, hemoglobin, hematocrit, and platelet count. 
Chemistry 
Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, 
aspartate aminotransferase (AST [SGOT]), alanine aminotransferase (ALT 
[SGPT]), total bilirubin (if a total bilirubin elevation ≥ Grade 2 occurs then direct 
and indirect bilirubin should be measured), lactate dehydrogenase (LDH), albumin, 
calcium, corrected calcium, magnesium, phosphate, alkaline phosphatase  
Coagulation 
Prothrombin time (PT), activated partial thromboplastin time (aPTT) and 
International normalized ratio (INR) will be collected at Screening and C1D1 
Cardiac/Muscle 
Enzymes 
Brain natriuretic peptide (BNP), troponin I and/or troponin T. 
Total creatine phosphokinase (CK). If total CK ≥3 X ULN, then measure 
isoenzymes and myoglobin in blood or urine weekly 
Thyroid 
Thyroid stimulating hormone (TSH) only. If TSH abnormal, T3 and free T4 to be 
performed. 
Pregnancy 
Serum beta-hCG test at screening/baseline, serum or urine every other cycle, and 
atEOT 
Table 3-7 
Laboratory parameters to be presented in grade shift tables based on CTC grade 
Hematology 
Chemistry 
Cardiac enzymes 
 
White Blood Cells (WBC) 
↑↓ 
AST (SGOT) 
↑ 
Creatine phosphokinase 
↑ 
Hemoglobin 
↑↓ 
ALT (SGPT) 
↑ 
 
 
Platelet count 
↓ 
Phosphate 
↓ 
 
 
Absolute Neutrophils 
↓ 
Total Bilirubin 
↑ 
 
 
Absolute Lymphocytes 
↑↓ 
Albumin 
↓ 
 
 
 
 
Creatinine 
↑ 
 
 
 
 
Alkaline Phosphatase 
↑ 
 
 
 
 
Glucose (hyper & hypo) 
↑↓ 
 
 
 
 
Corrected Calcium (hyper & 
hypo) 
↑↓ 
 
 
 
 
Sodium (hyper & hypo) 
↑↓ 
 
 
 
 
Magnesium (hyper & hypo) 
↑↓ 
 
 
 
 
Potassium (hyper & hypo) 
↑↓ 
 
 
↑ Indicates that CTC grade increases as the parameter increases, these parameters are to be included in the 
summary of maximum post-baseline lab parameters 
↓ Indicates that CTC grade increases as the parameter decreases, these parameters are to be included in 
the summary of minimum post-baseline lab parameters 


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Table 3-8 
Laboratory parameters to be presented in shift tables based on local laboratory 
normal ranges 
Hematology  
Chemistry 
Thyroid function test 
Cardiac enzymes 
Absolute eosinophils 
Urea 
TSH 
BNP 
Absolute basophils 
Blood urea nitrogen (BUN) Free T4  
Troponin I 
Absolute monocytes 
LDH 
Total T3 
Troponin T 
Hematocrit 
Indirect bilirubin 
 
 
RBC 
Direct bilirubin 
 
 
 
Bicarbonate 
 
 
 
Chloride 
 
 
Time to resolution of AST/ALT elevations is defined as the time from the first day of AST or 
ALT elevation (grade 3 or higher) to the day of first resolution (ALT grade 2 or less if the ALT 
was elevated or AST grade 2 or less if the AST was elevated). Only patients with elevated AST 
or ALT will be included in the analysis. If resolution has not occurred, the patient is censored at 
the date of last record available.  
Patients with elevated ALT only ==> Time to resolution of ALT 
Patients with elevated AST only ==> Time to resolution of AST 
Patients with elevated AST and ALT ==> Lowest {Time to resolution of ALT; Time to 
resolution of AST}. 
Time to resolution of AST/ALT elevations (grade 3 or higher) will be presented graphically.  
Three groups will be presented separately in a plot: 
o Phase I - 21-day schedule 
o Phase I – 28-day schedule 
o Phase II – 28-day schedule 
Plots will only be presented for each of the above groups if there are at least 10 patients in that 
group with elevated AST or ALT. 
Number and percentage of patients will be provided for predefined categories of notable hepatic 
lab values (Table 3-9) which includes ALT, AST, alkaline phosphatase (ALP), and total bilirubin 
(TBL) parameters.   
Table 3-9 
Laboratory parameters to be presented based on local laboratory normal ranges 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN;>20 ULN 
AST 
>3xULN; >5xULN; >8xULN >10xULN;>20 ULN 
AT (ALT or AST) 
>3xULN; >5xULN; >8xULN >10xULN;>20 ULN  
TBL 
>1.5xULN, >2xULN 
ALP 
>2xULN, >3xULN 
AT & TBL 
AT >3xULN & TBL >2xULN; 
AT >5xULN & TBL >2xULN; 


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Parameter 
Criterion 
AT >10xULN & TBL >2xULN 
ALP & TBL 
ALP >3xULN & TBL >2xULN 
AT & TBL & ALP 
AT >3xULN & TBL >2xULN & ALP <2xULN  
3.5.2.1 
Pregnancy test 
Pregnancy is defined as the state of a female after conception and until the termination of 
gestation, confirmed by a positive serum βHCG laboratory test (> 5 mIU/mL). 
The following pregnancy tests are to be performed for childbearing potential females (see details 
in Protocol Section 7.2.2.5.5): 
• Screening/baseline – within 72 hours of initial study treatment (serum) 
• Follow-up - every other cycle (serum or urine) [Cycle 3, 5, 7 and etc.] 
• End of treatment (serum or urine) 
Pregnancy test results by treatment will be listed. A positive pregnancy test is cause for 
immediate withdrawal from the study. 
3.5.3 
Vital signs, weight, and physical examinations  
All vital signs measures (oral temperature, sitting/supine blood pressure, and sitting/supine pulse, 
height, and weight) will be listed by parameter, treatment group, patient and time point (cycle), 
and the notable values will be flagged. 
The rate of newly occurring or worsening vital sign abnormalities as defined in the Table 3-10 
will be summarized and displayed in the listings. 
The number and percentage of patients with at least one post-baseline vital sign abnormality (in 
both directions, i.e., both clinically notable high and low values) will be displayed in summary 
tables. 
Summary statistics for baseline, last value, and change from baseline to last value, will be 
provided for each parameter. In addition, a shift table of baseline to worst post-baseline results 
will be presented. 
Table 3-10 
Notable vital signs ranges 
Vital sign 
Criteria for clinically notable ranges 
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 
Weight [kg] 
≥20% decrease from baseline or >=10% increase from 
baseline 
Oral body Temperature [°C] 
≥37.5 °C / ≤36 °C  


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Array BioPharma 
 
Page 40 
SAP 
16MAY2018 
 
CMEK162X2114 
 
• AUCinf, AUClast, AUClast,ss, AUCtau, AUCtau,ss, Cmax, Cmax,ss, T1/2, T1/2,ss,  
Racc (AUC and Cmax), T1/2,acc,  
Secondary 
• CL/F, CL/F,ss, Vz/F, Vz/F,ss, Tmax, Tmax,ss, Tlast, Tlast,ss, Ctrough,ss 
Table 3-15 
Non-compartmental pharmacokinetic parameters 
Variable 
Definition 
Cmax 
Maximum observed plasma concentration after drug administration (mass x volume-1) 
Cmax,ss 
Maximum observed plasma concentration during a dosing interval at steady state (mass x 
volume-1) 
Ctrough,ss 
Measured concentration at the end of a dosing interval at steady state (taken directly before 
next administration) (mass x volume-1) 
Tmax 
Time to reach Cmax (time) 
Tmax,ss 
Time to reach Cmax at steady state (time) 
Tlast 
Time at which the last measurable concentration was observed [time] 
Tlast,ss 
Time at which the last measurable concentration was observed at steady state [time] 
AUClast 
Area under the concentration-time curve from time zero to the last measurable concentration 
sampling time [mass x time x volume-1] 
AUClast,ss 
Area under the concentration-time curve from time zero to the last measurable concentration 
sampling time at steady state [mass x time x volume-1] 
AUCinf 
 
Area under the concentration-time curve from time zero to infinity with extrapolation of the 
terminal phase [mass x time x volume-1] 
AUCtau 
Area under the concentration-time curve during a dosing interval (mass x time x volume-1) 
AUCtau,ss 
Area under the concentration-time curve during a dosing interval at steady state (mass x time 
x volume-1) 
CL/F 
Apparent total plasma clearance of drug after oral administration (volume x time-1) 
CL/F,ss 
Apparent total plasma clearance of drug after oral administration at steady state (volume x 
time-1) 
Vz/F 
Apparent volume of distribution during terminal phase (associated with z) after oral 
administration (volume) 
Vz/F,ss 
Apparent volume of distribution during terminal phase (associated with z) after oral 
administration at steady state (volume) 
T1/2 
Elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve [time] 
T1/2, ss 
Elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve at steady state [time] 
Racc_AUC 
Accumulation ratio calculated as AUCtau,ss/AUCtau 
Racc_Cmax 
Accumulation ratio calculated as Cmax,ss/Cmax 
MR_AUC 
Metabolite ratio based on AUCtau on Day 1 and steady-state AUCtau for the metabolite 
compared to parent ratio, corrected for molecular weight, calculated for AR00426032 and 
LEQ803 
MR_Cmax 
Metabolite ratio based on Cmax on Day 1 and steady-state Cmax for the metabolite compared 
to parent ratio, corrected for molecular weight, calculated for AR00426032 and LEQ803 
T1/2,acc 
Effective elimination half-life (time) 


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Array BioPharma 
 
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