Conditions: Teratoma
Keywords: Teratoma, Germ Cell tumor, incurable teratoma, CDK4/6, LEE011
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: no

Brief summary:
This was a multi-center, randomized, double blind (investigator and subject), placebo controlled Phase II study to determine the efficacy and safety of treatment with ribociclib versus placebo in subjects with progressive relapsed, refractory incurable teratoma. Eligible subjects were randomized in a 2:1 ratio to ribociclib or placebo.

After discontinuation of study treatment, patients were followed up for safety, disease progression and overall survival.

Detailed description:
Safety follow-up: After discontinuation of study treatment, all subjects were followed for safety for 30 days except in the case of death, loss to follow up, withdrawal of consent, or discontinuation of study treatment to enroll in the ribociclib rollover clinical trial (CLEE011X2X01B).

Disease progression follow-up: Subjects who discontinued study drug for any reasons other than disease progression were followed for efficacy every 8 weeks during the first 12 months. After 12 months, they were followed for every 12 weeks until disease progression, death, discontinuation from the study for any other reason (i.e. loss to follow-up or withdrawal of consent), the initiation of a new antineoplastic treatment, or until all subjects had been followed for at least 18 months after their first dose of study drug, or early study termination, whichever occurred first.

Survival follow-up: All subjects were followed for survival via a phone call (or during a clinic visit) every 12 weeks and up to one additional time per quarter if a survival update was required to meet safety or regulatory needs. The safety follow-up was carried out until any of the following occurred (whichever occurred first): death, withdrawal of consent, loss to follow-up, at least 18 months had elapsed from when the last subject had started treatment, or when 80% of subjects had died or were lost to follow-up, or early study termination.

Arms:
arm 1: 600 mg daily dosing days 1-21 of a 28 day cycle arm 2: 600 mg daily dosing days 1-21 of a 28 day cycle

Interventions: intervention 1: LEE011 intervention 2: LEE011 Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Clinical Development
LEE011
Protocol CLEE011X2201 / NCT02300987
A randomized, blinded, placebo-controlled, phase II trial of 
LEE011 in patients with relapsed, refractory, incurable 
teratoma with recent progression
Authors
Document type
Amended Protocol Version 03 (Clean)
EUDRACT number
2014-000428-12
Version number
03
Development phase
II
Document status
Final
Release date
18-Aug-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
 


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Table of contents
Table of contents..................................................................................................................................... 2
List of figures.......................................................................................................................................... 6
List of tables............................................................................................................................................ 6
List of abbreviations ............................................................................................................................... 8
Glossary of terms.................................................................................................................................. 11
Amendment 3 (18-Aug-2017)............................................................................................................... 12
Amendment 2........................................................................................................................................ 13
Amendment 1........................................................................................................................................ 15
Protocol summary:................................................................................................................................ 18
1
Background........................................................................................................................................... 21
1.1
Overview of disease pathogenesis, epidemiology and current treatment................................ 21
1.1.1
Disease pathogenesis............................................................................................ 21
1.1.2
Epidemiology........................................................................................................ 21
1.1.3
Current treatment.................................................................................................. 21
22
22
23
24
2
Rationale............................................................................................................................................... 25
2.1
Study rationale and purpose .................................................................................................... 25
2.2
Rationale for the study design ................................................................................................. 25
2.3
Rationale for dose and regimen selection................................................................................ 26
2.4
Rationale for choice of combination drugs.............................................................................. 26
2.5
Rationale for choice of comparators drugs.............................................................................. 26
3
Objectives and endpoints...................................................................................................................... 27
4
Study design.......................................................................................................................................... 28
28
29
29
30
30
30
30
4.2
Timing of interim analyses and design adaptations................................................................. 31
4.3
Definition of end of the study.................................................................................................. 31
4.4
Early study termination ........................................................................................................... 31
5
Population............................................................................................................................................. 31
5.1
Patient population.................................................................................................................... 31
5.2
Inclusion criteria...................................................................................................................... 32
 


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5.3
Exclusion criteria..................................................................................................................... 32
6
Treatment.............................................................................................................................................. 35
6.1
Study treatment........................................................................................................................ 35
6.1.1
Dosing regimen..................................................................................................... 35
6.1.2
Study drug administration..................................................................................... 35
6.1.3
Guidelines for continuation of treatment.............................................................. 36
6.1.4
Treatment duration ............................................................................................... 36
6.2
Dose modifications.................................................................................................................. 36
6.2.1
Dose modification and dose delay........................................................................ 36
6.2.2
Follow-up for toxicities ........................................................................................ 41
6.2.3
Anticipated risks and safety concerns of the study drug....................................... 41
6.3
Concomitant medications ........................................................................................................ 41
6.3.1
Permitted concomitant therapy............................................................................. 41
6.3.2
Permitted concomitant therapy requiring caution................................................. 41
6.3.3
Prohibited concomitant therapy............................................................................ 41
6.4
Patient numbering, treatment assignment or randomization ................................................... 42
6.4.1
Patient numbering................................................................................................. 42
6.4.2
Treatment assignment or randomization............................................................... 42
6.4.3
Drug supply and storage....................................................................................... 43
6.4.4
Study drug compliance and accountability........................................................... 43
6.4.5
Disposal and destruction....................................................................................... 44
7
Visit schedule and assessments............................................................................................................. 44
7.1
Study flow and visit schedule.................................................................................................. 44
7.1.1
Screening.............................................................................................................. 48
7.1.2
Treatment period................................................................................................... 48
7.1.3
Discontinuation of Study Treatment..................................................................... 49
7.1.4
Withdrawal of Consent......................................................................................... 50
7.1.5
Follow-up Period.................................................................................................. 50
7.2
Assessment types..................................................................................................................... 51
7.2.1
Efficacy assessments ............................................................................................ 51
7.2.2
Safety and tolerability assessments....................................................................... 53
57
57
59
7.2.6
Other assessments................................................................................................. 60
8
Safety monitoring and reporting ........................................................................................................... 60
8.1
Adverse events ........................................................................................................................ 60
8.1.1
Definitions and reporting...................................................................................... 60
8.1.2
Laboratory test abnormalities ............................................................................... 62
8.2
Serious adverse events............................................................................................................. 62
 


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8.2.1
Definitions ............................................................................................................ 62
8.2.2
Reporting.............................................................................................................. 63
8.3
Emergency unblinding of treatment assignment ..................................................................... 64
8.4
Pregnancies.............................................................................................................................. 64
8.5
Warnings and precautions ....................................................................................................... 64
8.6
Data Monitoring Committee.................................................................................................... 65
8.7
Steering Committee................................................................................................................. 65
9
Data collection and management.......................................................................................................... 65
9.1
Data confidentiality ................................................................................................................. 65
9.2
Site monitoring........................................................................................................................ 66
9.3
Data collection......................................................................................................................... 66
9.4
Database management and quality control.............................................................................. 67
10
Statistical methods and data analysis.................................................................................................... 67
10.1
Analysis sets............................................................................................................................ 68
10.1.1
Full Analysis Set................................................................................................... 68
10.1.2
Safety Set.............................................................................................................. 69
10.1.3
Per-Protocol Set.................................................................................................... 69
69
10.2
Patient demographics/other baseline characteristics ............................................................... 69
10.3
Treatments (study treatment, concomitant therapies, compliance) ......................................... 69
10.3.1
Study Treatment ................................................................................................... 69
10.3.2
Concomitant therapies .......................................................................................... 70
10.3.3
Compliance........................................................................................................... 70
10.4
Primary objective .................................................................................................................... 70
10.4.1
Variable ................................................................................................................ 70
10.4.2
Statistical hypothesis, model, and method of analysis.......................................... 70
10.4.3
Handling of missing values/censoring/ discontinuations...................................... 71
10.4.4
Supportive analyses .............................................................................................. 71
10.5
Secondary objectives............................................................................................................... 71
10.5.1
Key secondary objective(s)................................................................................... 71
10.5.2
Other secondary efficacy objectives..................................................................... 71
10.5.3
Safety objectives................................................................................................... 72
74
74
75
75
10.7
Interim analysis ....................................................................................................................... 76
10.8
Sample size calculation ........................................................................................................... 76
11
Ethical considerations and administrative procedures.......................................................................... 76
11.1
Regulatory and ethical compliance.......................................................................................... 76
 


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11.2
Responsibilities of the investigator and IRB/IEC/REB........................................................... 77
11.3
Informed consent procedures .................................................................................................. 77
11.4
Discontinuation of the study.................................................................................................... 77
11.5
Publication of study protocol and results ................................................................................ 78
11.6
Study documentation, record keeping and retention of documents......................................... 78
11.7
Confidentiality of study documents and patient records ......................................................... 79
11.8
Audits and inspections............................................................................................................. 79
11.9
Financial disclosures ............................................................................................................... 79
12
Protocol adherence................................................................................................................................ 79
12.1
Amendments to the protocol ................................................................................................... 79
13
References (available upon request) ..................................................................................................... 80
14
Appendices............................................................................................................................................ 82
14.1
Appendix 1 – Guidelines for response duration of overall response, TTF, TTP, 
progression free survival and overall survival (based on RECIST v1.1) harmonization of 
efficacy analysis of solid tumor studies................................................................................... 82
14.1.1
Introduction .......................................................................................................... 83
14.1.2
Efficacy assessments ............................................................................................ 83
14.1.3
Definitions ............................................................................................................ 83
14.1.4
Disease measurability........................................................................................... 83
14.1.5
Eligibility based on measurable disease ............................................................... 84
14.1.6
Methods of tumor measurement – general guidelines.......................................... 84
14.1.7
Baseline documentation of target and non-target lesions ..................................... 86
14.1.8
Follow-up evaluation of target and non-target lesions ......................................... 86
14.1.9
Follow-up and recording of lesions ...................................................................... 87
14.1.10
Non-nodal lesions................................................................................................. 87
14.1.11
Nodal lesions ........................................................................................................ 87
14.1.12
Determination of target lesion response ............................................................... 88
14.1.13
Determination of non-target lesion response........................................................ 90
14.1.14
New lesions........................................................................................................... 90
14.1.15
Evaluation of overall lesion response................................................................... 91
14.1.16
Efficacy definitions............................................................................................... 91
14.1.17
Best overall response............................................................................................ 92
14.1.18
Time to event variables......................................................................................... 94
14.1.19
Progression free survival ...................................................................................... 94
14.1.20
Overall survival .................................................................................................... 94
14.1.21
Time to progression.............................................................................................. 94
14.1.22
Time to treatment failure ...................................................................................... 95
14.1.23
Duration of response............................................................................................. 95
14.1.24
Time to response................................................................................................... 96
14.1.25
Definition of start and end dates for time to event variables................................ 96
14.1.26
Handling of patients with non-measurable disease only at baseline..................... 97
 


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14.1.27
Sensitivity analyses............................................................................................... 98
14.1.28
Data handling and programming rules................................................................ 100
14.1.29
Study/project specific decisions ......................................................................... 100
14.1.30
End of treatment phase completion .................................................................... 100
14.1.31
End of post-treatment follow-up (study phase completion)................................ 101
14.1.32
Medical validation of programmed overall lesion response............................... 101
14.1.33
Programming rules ............................................................................................. 102
14.1.34
Calculation of ‘time to event’ variables.............................................................. 102
14.1.35
Incomplete assessment dates .............................................................................. 102
14.1.36
Incomplete dates for last known date patient alive or death............................... 102
14.1.37
Non-target lesion response ................................................................................. 103
14.1.38
Study/project specific programming................................................................... 103
14.1.39
Censoring reason ................................................................................................ 103
14.1.40
References (available upon request)................................................................... 104
14.2
Appendix 2 - ECOG/WHO performance status scale ........................................................... 105
106
14.4
Appendix - 4 Prohibited concomitant medications ............................................................... 110
14.4.1
Prohibited medications ....................................................................................... 110
List of figures
Figure 4-1
Study design..........................................................................................29
106
108
List of tables
Table 3-1
Objectives and related endpoints ..........................................................27
Table 6-1
Dose and treatment schedule.................................................................35
Table 6-2
Dose adjustments ..................................................................................36
Table 6-3
Study drug dose adjustment and management recommendation for 
hematological adverse reactions ...........................................................37
Table 6-4
Study drug dose adjustment and management recommendation for 
hepatic toxicities....................................................................................38
Table 6-5
Study drug dose adjustment and management recommendation..........39
Table 6-6
Study drug dose adjustment and management recommendation for 
all other adverse reactions.....................................................................40
Table 7-1
Visit evaluation schedule ......................................................................45
Table 7-2
Disease assessment collection plan.......................................................52
Table 7-3
Local clinical laboratory parameters collection plan ............................54
 


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Table 7-4
ECG collection plan..............................................................................56
57
59
59
Table 14-1
Response criteria for target lesions .......................................................88
Table 14-2
Response criteria for non-target lesions................................................90
Table 14-3
Overall lesion response at each assessment ..........................................91
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only.................................................................................98
Table 14-5
Options for event dates used in PFS, TTP, duration of response..........99
Table 14-6
ECOG performance status...................................................................105
Table 14-7
List of prohibited medications during LEE011 treatment...................110
Table 14-8
List of medications to be used with caution1 during LEE011 
treatment..............................................................................................111
 


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List of abbreviations
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical Classification System
AUCinf
Area Under the Curve from Time Zero to Infinity
AUClast
Area Under the Curve from Time Zero to the Last Measureable Concentration Time
BOR
Best Overall Response
BSEP
Bile Salt Export Pump
BUN
Blood Urea Nitrogen
CDK
Cyclin-Dependent Kinase
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax
Maximum Plasma Concentration after a Single Dose
CNS
Central Nervous System
CPL
Clinical Program Lead
CR
Complete Response
CRF
Case Report/Record Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CYP
Cytochrome 
DCR
Disease Control Rate 
DDI
Drug-Drug Interaction
DLT
Dose-Limiting Toxicity
DMC
Data Monitoring Committee
DOR
Duration of Response
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
 
 
EOT 
End of Treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FMO3
Flavin-Containing Monooxygenase 3
GCP
Good Clinical Practice
GCT
Germ Cell Tumor
 


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GI
Gastrointestinal
GLP
Good Laboratory Practice
GTS
Growing Teratoma Syndrome
HA
Health Authority
HIV
Human Immunodeficiency Virus
HPF
High Powered Field
HR
Heart Rate or Hazard Ratio
IB
Investigator’s Brochure
IC50
Concentration resulting in 50% Inhibition
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
LPLV
Last Patient First Visit  
LVEF
Left Ventricular Ejection Fraction
MI
Myocardial Infarction
MRI
Magnetic Resonance Imaging
MT
Malignant Transformation
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition Scan
NSGCT
Non-Seminomatous Germ Cell Tumor
NYH
New York Heart
ORR
Overall Response Rate
OS
Overall Survival
PD
Pharmacodynamic or Progressive Disease
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per Protocol Set
PRBC
Packed Red Blood Cells
pRB
Retinoblastoma Protein 
PR
Partial Response or Interval between P Wave and QRS Complex
PT
Prothrombin Time
PVC
Premature Ventricular Contraction
QD
Daily
QRS
Part of ECG Wave representing Ventricular Depolarization
QT 
Measure of time between the Q Wave and the T Wave in Cardiology
QTcB
QT corrected with Bazett’s formula
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
RAP
Report and Analysis Plan
RB
Retinoblastoma gene
RBC
Red Blood Cell
 


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RECIST v1.1
Response Evaluation Criteria for Solid Tumors Version 1.1
RR
Interval between R waves
SAE
Serious Adverse Event
SEER
Surveillance, Epidemiology and End-Result
SD
Stable Disease
SEC
Study Evaluation Completion
T1/2
Half Life
Tmax
Time to Reach Maximum (peak) Plasma Concentration
TSH
Thyroid-Stimulating Hormone
TTP
Time to Progression
ULN
Upper Limit of Normal
US
United States
VES
Visit Evaluation Schedule
WBC
White Blood Cell
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: q28 days)
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 21 CFR Part 312.3 and is synonymous with “investigational 
new drug.”
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment arms of a study
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Placebo
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
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 drug
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 drug 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
Treatment arm
A treatment arm 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 
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Amendment 3 (18-Aug-2017)
Amendment rationale
The purpose of this amendment is:

To add language to facilitate unblinding of patient treatment status. 

To add language to allow patients receiving LEE011 to discontinue treatment in 
CLEE011X2201 and transfer to a Novartis rollover clinical trial (CLEE011X2X01B)
which will continue to provide treatment with LEE011.

To add language to allow placebo patients to crossover to LEE011 treatment if the 
investigator believes it is in the best clinical interest of the patient. 
Enrollment to this study was halted on 20-Nov-2015. Based on the small number of patients 
enrolled prior to the enrollment halt, the primary endpoint will not be obtained and therefore it 
is no longer necessary for patients to continue to receive placebo. With this in mind, ongoing 
patients will be unblinded in order to permit crossover to LEE011 for those patients receiving 
placebo.
Other changes implemented in this amendment:

To update the preclinical safety pharmacology and toxicology sections to include recent 
data on teratogenicity of LEE011.

To correct minor typographical and grammatical errors throughout the document.
Study status:
The CLEE011X2201 study started enrollment on 26-February-2015. Enrollment to this study 
was halted on 20-Nov-2015. Prior to recruitment halt, a total of 10 patients were enrolled. As 
of 18-Aug-2017, there are 4 patients on treatment, 3 of which are blinded and 1 has crossed 
over to LEE011 treatment.
Changes to the protocol

Section 1.2.1.3 – updated preclinical safety pharmacology and toxicology

Section 4.1 – revised treatment procedures after early study termination

Section 4.1.2 – added language to facilitate unblinding of ongoing patients and allow 
placebo patients to crossover to LEE011 treatment if the investigator believes it is in the 
best clinical interest of the patient

Section 4.1.3, 4.1.4 and 4.1.5 – revised follow-up procedures after early study termination

Section 4.1.6 – revised crossover treatment procedures after study termination and
following patient enrollment to a LEE011 rollover clinical trial (CLEE011X2X01B)

Section 4.3 – added language to permit patient rollover to CLEE011X2X01B

Section 4.3 – revised to align with Section 10.4 regarding when a primary CSR will be 
produced

Section 7.1.3 – added transfer to a LEE011 rollover clinical trial (CLEE011X2X01B) as a 
reason for end of  treatment 

Section 7.1.3 – changed parent/guardian decision to patient/parent/guardian decision
 


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
Section 7.1.5.1 – revised follow-up procedures following patient enrollment to a LEE011 
rollover clinical trial (CLEE011X2X01B)

Section 7.1.5.2 and 7.1.5.3 – revised follow-up procedures after early study termination

Section 10 – revised to clarify CSR reporting after early study termination or patient 
enrollment to a LEE011 rollover clinical trial (CLEE011X2X01B)

Section 14.1.30 and 14.1.31 – added transfer to a LEE011 rollover clinical trial
(CLEE011X2X01B) as a reason for end of  treatment and study phase completion

Section 14.1.30 and 14.1.31 – changed parent/guardian decision to patient/parent/guardian 
decision
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Boards
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities (HAs). 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.
Amendment 2
Amendment rationale
The main purpose of this amendment is to address recently observed safety findings. These
safety findings and the resulting changes follow:
1. 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. As a result, new guidelines for management of QTcF prolongation were 
instituted throughout the LEE011 program in order to improve safety. These changes 
include:
a. additional ECG assessments
b. the addition of continued ECG monitoring for all cycles in the event of a patient 
QTcF ≥ 481 ms at any time before Cycle 9 Day 1
c. in the event of QTcF prolongation:
i. follow-up of electrolyte abnormalities until normalization 
ii. mandated site review of concomitant medications 
iii. mandated site review of dosing regimen 
2. 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. 
3. Further clarification to withdrawal of consent and lost to follow-up process
 


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4. DNA sequencing of cancer related genes has been removed because similar data in 
patients receiving single agent LEE011 has already been generated, thus this analysis 
would have been of limited utility. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

All inclusion and exclusion criteria contained in section 5.2 and section 5.3 were added to 
the protocol summary for consistency

Section 1.2.3 - Clinical pharmacokinetics of LEE011 updated with the most recent 
available data 

 

Inclusion criteria #4 – clarification of inclusion criterion

Exclusion criteria #2 – clarification of exclusion criterion

Exclusion criteria #15 – added phosphorus and sodium as electrolytes correctable by oral 
supplementation to be consistent with LEE011 protocol guidelines

Table 6-3 – table revised to detail study drug adjustments and management 
recommendation for hematological adverse reactions

Table 6-4 – table added to detail study drug dose adjustment and management 
recommendations for hepatic toxicities

Section 6.2.1.1 – added to include additional follow-up guidance for hepatic toxicities

Section 6.2.1.2 – added to include additional follow-up guidance for QTc prolongation

Section 6.2.1.3 – added to include additional guidance for all other adverse reactions  

Table 6-6 – added to clarify dose adjustment and management recommendations by 
CTCAE grade

Section 7.1 - study flow and visit schedules have been updated to include additional 
ECGs

Section 7.1.3 Discontinuation of study treatment – renamed section and clarified section

Section 7.1.4 – Withdrawal of Consent – section added for clarification

Section 7.1.5 – Follow-up Period – added clarification  

Section 7.2.2.5.2 – added sodium and phosphorus to the list of labs included in “clinical 
chemistries”

Section 7.2.2.6.1. – added ECGs to be completed in triplicate at screening 

Section 7.2.4 – deleted next generation sequencing

Table 7-4 – added additional ECG collection plan per recommended guidance for LEE011 
program 

Table 7-6 – deleted DNA sequence of cancer related genes (by next generation sequencing)
and reduced number of slides needed 
 


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
Section 10.1.1 – The Full Analysis Set definition was updated to include the clarification 
of the grouping of patients undergoing crossover from placebo to LEE011 after RECIST 
progression. 

Sections 10.2, 10.3.2 and 10.6.1.3.2.- updated to include the addition of FAS2 analysis, 
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.
Amendment 1
Amendment rationale
In order to investigate a more homogeneous patient population, patients with pathologic 
evidence of malignant transformation will no longer be included in this study.
The median progression-free survival (PFS) expectation for patients receiving placebo has
been adjusted from 3 months to 2 months, in response to feedback from investigators. The 
median PFS expectation for the LEE011 treatment arm remains 6 months. The trial was 
modified from 90 patients to 42 patients. It remains adequately powered (alpha = 0.05, power 
= 80%).
The interim analysis for efficacy will no longer be performed due to the changes in the 
baseline assumption of median PFS leading to a smaller study sample size. Based on the small 
sample size, it is not considered beneficial to perform are in interim analysis of the PFS data. 
Note, safety data will continue to be reviewed during the course of the study.
In order to maintain consistency throughout the LEE011 program cardiac imaging 
(MUGA/ECHO) will be required at screening and end of treatment (EOT) visits for all 
patients to more completely evaluate underlying cardiac disease.
The following additional changes have been made:

New safety and efficacy data from the newest edition of the IB for LEE011 were included 
as necessary. Obsolete data was excluded from the protocol.

Typographical and grammatical errors were corrected throughout the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. All
inclusion and exclusion criteria contained in section 5.2 and section 5.3 were added to the 
protocol summary for consistency.
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Section 1.1.3 – Current treatment – deleted information regarding malignant transformation
Section 1.2.1.3 – Safety pharmacology and toxicology – changes reflect clarity and 
consistency between other LEE011 protocols 
Section 1.2.2 – Clinical experience – updated information about AEs from [LEE011 
Investigator Brochure] 
Section 1.2.2.1 Safety and efficacy of LEE011 – updated information from [LEE011 
Investigator Brochure]
Section 1.2.3 – Clinical pharmacokinetics of LEE011 – updated information from [LEE011 
investigator brochure] 
Section 2.2 – Rationale for Study Design – deleted stratification for malignant transformation 
patients 
Section 3 – Objective and endpoint – added duration of response (DOR) for consistency to 
statistical section 10  
Section 4.1 – Study Design – removed malignant transformation and reduced the number of 
patients to be enrolled in the trial from 90 to 42 
Figure 4-1 Study design – revised to remove malignant transformation stratification and 
provide clarity to overall study design
Section 4.2 – Timing of interim analyses and design adaptations – the interim analysis was 
removed   
Section 5.2 Inclusion criteria – Inclusion criterion #5 – malignant transformation patients 
excluded from protocol 
Section 5.3 Exclusion Criteria – Exclusion criterion #3 –Pathologic evidence of malignant 
transformation patients added as exclusion criteria
Section 5.3 Exclusion Criteria – Exclusion criterion #14 – removed as this is a drug in capsule 
packaging and there are no excipients 
Section 6.3.3 Prohibited concomitant therapy – revised for clarity and consistency with other 
LEE011 protocols
Table 7-1 – Visit Evaluation Schedule – removed urinalysis and added cardiac imaging
Table 7-3 – Local clinical laboratory – deleted urinalysis as other LEE011 studies have 
collected data with no safety signal concern.  
Section 7.2.2.6.2 – Cardiac Imaging – ECHO or MUGA scans added at screening and EOT 
visits.
Table 7-4 – ECG collection plan – removed C2D21 pre dose and 4 hr post dose time points as 
other LEE011 studies have collected data with no safety signal concern
 
 
 


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Section 8.6 – Data Monitoring Committee – revised to delete interim analysis
Section 10 – Statistical methods and data analysis – various modifications to remove 
malignant transformation stratification, remove the interim analysis and to change the number 
of PFS event for the primary efficacy analysis
Section 14 – Table 14-8 – List of medications to be used with caution during treatment with 
LEE011 – medications removed and added based on new information.
IRB
A copy of this amended protocol will be sent to the Institutional Review Boards
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities (HAs).
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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Protocol summary: 
Protocol number
CLEE011X2201
Title
A randomized, blinded, placebo-controlled, phase II trial of LEE011 in patients with 
relapsed, refractory, incurable teratoma with recent progression
Brief title
Study of the efficacy and safety of LEE011 in patients with relapsed, refractory, 
incurable teratoma with recent progression
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The primary purpose of this study is to determine the anti-tumor activity of LEE011 
for relapsed/refractory, progressive teratoma for which there is no curative therapy. 
Targeting the D-Cyclin-CDK axis to inhibit teratoma growth is driven by biological 
rationale, supporting clinical evidence, and the need for effective targeted therapy in 
this indication. Evidence of anti-tumor activity in this study will be used to inform 
future development of LEE011 in other tumors where this pathway may be critical 
for tumorigenesis.
Primary Objective(s) and 
Key Secondary Objective
To assess the efficacy of LEE011 compared to placebo in patients with 
relapsed/refractory teratoma with recent progression
Secondary Objectives
To assess other measures of efficacy of LEE011 compared with placebo
To assess safety and tolerability of LEE011 compared with placebo
Study design
This is a multi-center, randomized, double blind (investigator and patient), placebo 
controlled phase II study to determine the efficacy and safety of treatment with 
LEE011 versus placebo in patients with progressive relapsed, refractory incurable 
teratoma. Eligible patients will be randomized at a 2:1 ratio to LEE011 or placebo. 
Study drug (LEE011 or placebo) will be administered orally once daily for 21 days 
followed by one week break (28-day cycle). The dose of LEE011 will be 600 mg.
Population
The study will be conducted in approximately 42 patients with 
relapsed/refractory/incurable teratoma with recent progression.
Inclusion criteria
1. Age ≥15 years old at time of informed consent.
2. Diagnosis of teratoma for which no additional standard surgical or medical 
therapy exists
3. Availability of an archival or newly obtained tumor sample (collected at diagnosis 
or progression) with accompanying pathology report
● Patients without an archival tumor sample may be permitted to participate after 
discussion between Novartis and the investigator
4. Patients must have completed at least 1 prior line of chemotherapy for germ cell 
tumor (except patients who present with primary, pure teratoma who need not have 
received any previous chemotherapy)
5. Radiographic progression, defined by RECIST v.1.1, after the last cancer 
treatment and within 12 weeks prior to enrollment, compared with scans within 1 
year of enrollment.
6. Measurable or evaluable extra-cranial disease as defined by RECIST v.1.1
7. Patients must have ECOG performance status of 0-1
Exclusion criteria
1. CNS disease unless radiation therapy and/or surgery has been completed and 
serial evaluation by CT (with contrast enhancement) or MRI over a minimum of 2 
months demonstrates stable disease. Patient must be asymptomatic and without 
need for treatment with systemic corticosteroids or anti-epileptic medications
2. Malignant germ cell tumors other than that being treated in this study, including 
tumors with elements of mixed histology such as embryonal carcinoma, 
choriocarcinoma, yolk sac tumor or seminoma. Note – this refers to the histology at 
the time of enrollment, not the histology at the time of initial presentation
3. Pathologic evidence of malignant transformation
4. Concurrent malignancy other than teratoma within 3 years of randomization, with 
the additional exceptions of treated NSGCT from which teratoma has emerged, 
 


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adequately treated basal or squamous cell carcinoma of the skin, curatively 
resected cervical cancer or curatively resected carcinoma in situ of any type
5. Prior treatment with any CDK4/6 inhibitor therapy
6. Any concurrent severe and/or uncontrolled medical condition that, in the 
investigator’s judgment serves as a contraindication to patient participation (e.g., 
chronic pancreatitis, active hepatitis, viral hepatitis or known HIV positivity). 
Baseline HIV screening is not required
7. Patients who have not recovered to ≤ CTCAE grade 1 from the acute toxic effects 
(except for alopecia) of all prior chemotherapy, immunotherapy, or radiotherapy
6. Impaired gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
9. Impaired cardiac function or any clinically significant cardiac disease, including 
any of the following
● Left ventricular ejection fraction (LVEF) < 45% or less than the institution’s 
lower limit of normal as determined by multiple gated acquisition scan (MUGA) or 
echocardiogram (ECHO)
● Congenital long QT syndrome or family history of unexpected sudden cardiac 
death
● QT corrected with Fridericia’s (QTcF) QTcF >450 msec for males and >470 
msec for females on screening ECG
● Clinically significant heart disease such as CHF requiring treatment (NYH 
grade ≥ 2), unstable angina pectoris or myocardial infarction within the past 3 
months. Any other clinically significant heart disease such as unstable arrhythmia, 
resting bradycardia, right bundle branch block, bifascicular block, or any heart 
disease that requires the use of a cardiac pacemaker ≤ 3 months prior to starting 
study drug
● Patients who are currently receiving medications with known risk of prolonging 
the QT interval or inducing Torsades de Pointes and are unable to discontinue or 
switch to an alternate medication
10. Concomitant therapy that precludes enrollment
● Systemic antineoplastic therapy or any experimental therapy within 3 weeks 
before the first dose of study drug (6 weeks for prior nitrosoureas, bevacizumab, or 
mitomycin C)
● Systemic corticosteroids within 2 weeks prior to starting study drug. Note: 
Corticosteroids are permitted for use as single doses, topical applications (e.g., for 
rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular)
11. Major surgery within 2 weeks of the first dose of study drug (mediastinoscopy, 
insertion of a central venous access device, or insertion of a feeding tube is not 
considered major surgery)
12. Received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 
weeks prior to randomization, or patient has not recovered to ≤ CTCAE grade 1 
related toxicity
13. Requirement for treatment with any of the prohibited medications including 
strong CYP3A inhibitors, strong CYP3A inducers, CYP3A substrates with a narrow 
therapeutic index, and medications with strong risk of QT prolongation
14. Have any of the following out-of-range laboratory values
● Absolute neutrophil count < 1.5× 109/L
● Platelet count < 100 × 109/L
● Hemoglobin <9.0 g/dL
● Potassium unless correctable by oral supplementation
● Calcium (corrected for serum albumin) unless correctable by oral 
supplementation  
● Magnesium unless correctable by oral supplementation  
● Serum creatinine ≥1.5 × ULN
● Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) > 3 × 
ULN for age; for patients with liver metastases ≥ 5 × ULN for age. 
● Total serum bilirubin >1.5 x ULN; or total bilirubin ≥3.0 × ULN with direct 
bilirubin within normal range in patients with well documented Gilbert’s Syndrome
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Investigational and 
reference therapy
LEE011
Efficacy assessments
Progression Free Survival (PFS) as per RECIST v1.1 (by local investigator 
assessment). Best Overall Response (BOR), Overall response rate (ORR), Duration 
of response (DOR), Disease Control Rate (DCR) at 4 months as per RECIST v1.1 
and Overall Survival (OS) and OS rate at 12 months.
Safety assessments
Safety will be assessed using the following criteria:
● Adverse events (AEs)
● Serious Adverse Events (SAEs)
● Physical Exams
● Vital signs
● Laboratory assessments
● Performance Status
● Cardiac assessments
Other assessments
 
 
Data analysis
The primary endpoint of the study is PFS, defined as the time from the date of 
randomization to the date of the first documented progression or death due to any 
cause. PFS will be assessed via the local investigator assessment according to 
RECIST v1.1. If a patient has not had an event, PFS will be censored at the date of 
the last adequate tumor evaluation. The primary efficacy analysis will be performed 
when there are approximately 23 PFS events and all patients have been followed 
for PFS for at least 6 months or have discontinued prior to this time for disease 
progression or death, or have withdrawn consent to follow-up or have been lost to 
follow-up or if the study is terminated early. 
A secondary objective is to further assess the efficacy of LEE011 compared with 
placebo. The evaluations of tumor responses will be based on local investigator 
assessment according to RECIST v1.1.
The following endpoints and analyses will be used to further assess the efficacy: 
● OS, defined as the time from date of randomization 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.
● BOR, defined as the best response recorded from the start of the treatment until 
disease progression/recurrence. Confirmation of complete and partial responses 
must be made at least 4 weeks apart.
● ORR, defined as the proportion of patients with a best overall response of CR or 
PR.
● DOR, defined for responder as the time between the date of first documented 
response (CR or PR) and the date of first documented progression or death due to 
underlying cancer. If progression or death due to underlying cancer has not 
occurred, then the patient is censored at the date of last adequate tumor 
assessment.
● DCR, defined as the proportion of patients with a best overall response of CR or 
PR or SD
Key words
Double blind randomized, Phase II, CDK 4/6 inhibitor, relapsed/refractory/incurable 
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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Disease pathogenesis
Teratomas consist of cell types derived from one or more of the germ layers (mesoderm,
endoderm and ectoderm) and arise most commonly in the gonads or midline structures 
including the anterior mediastinum, retroperitoneum, sacrococcygeal region, and the pineal 
gland. Teratoma classification is dichotomized into benign and malignant. Benign teratomas 
are distinguished as mature or immature based on the proportion of differentiated tissue 
observed. Malignant teratomas include mature/immature teratomas that have metastasized or 
contain non-germinal malignant patterns (malignant transformation) such as carcinoma or 
sarcoma (Gatcombe et al 2004). Teratomas may also arise within other germ cell tumor (GCT) 
types, most commonly non-seminomatous germ cell tumors (NSGCT). Metastatic sites of 
NSGCT often contain teratomatous elements at diagnosis (Sheinfeld et al 2003).  
Deregulation of the retinoblastoma tumor suppressor pathway in GCT has been well 
documented (Bartkova et al 2003). In the non-diseased state, cell cycle progression from 
G1→S is initiated by sequential phosphorylation at different sites of retinoblastoma protein 
(pRB) by both cyclin D-CDK4/6 complex and cyclin E-CDK2 complex and the subsequent 
release of bound E2F. The phosphorylation events mediated by CDK4/6 are prerequisites for 
those catalyzed by CDK2 (Bartek et al 1997). Upregulation of CDK4 and cyclin D2 is 
believed to be a central event in GCT tumorigenesis (Houldsworth et al 1997, Schmidt et al 
2001). Although pRB expression is absent or grossly reduced in undifferentiated GCT, more 
differentiated NSGCT such as teratocarcinomas and teratomas demonstrate strong expression 
of pRB (Strohmeyer et al 1991, Bartkova et al 2003).
1.1.2
Epidemiology
Malignant teratoma is rare in both pediatric and adult populations. Review of the Surveillance, 
Epidemiology, and End-Result (SEER) data revealed an incidence of 0.14/100,000 women-
years with 531 cases identified over the 30 year period reviewed from 1973-2002 (Smith et al 
2006). The frequency is higher in males. Growing Teratoma Syndrome (GTS), develops 
during or after treatment in about 2-7% of male patients with NSGCTs (Andre et al 2000). 
The US incidence of testicular GCT is 5.7/100,000 males (7,920 cases in 2013, SEER), this 
translates to about 355 cases of GTS annually. The incidence of testicular cancer is similar in 
Western Europe and Australia, but comparatively low in Asia and Africa at 1/100,000 males.
1.1.3
Current treatment
Unlike NSGCTs which are sensitive to cytotoxic chemotherapy, teratomas are highly chemo-
resistant and optimally treated by complete surgical resection (Speiss et al 2007). More than 
80% of cases of GTS are successfully managed by surgical resection. However, no standard 
therapy exists for progressive, unresectable teratoma in adult or pediatric patients (Andre et al 
2000). Case reports of efficacy with various agents including interferon (van der Gaast et al 
 


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1991, Ornadel et al 1995, Rustin et al 1984) and bevacizumab (Mego et al 2007) have been 
published. Given the known deregulation of the RB tumor suppressor pathway in GCTs and 
that nearly all malignant teratomas stain positively for nuclear pRB (Strohmeyer et al 1991, 
Bartkova et al 2003), treatment of  non-resectable malignant teratoma with a CDK 4/6 
inhibitor such as LEE011 is a rational approach.
 


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2
Rationale
2.1
Study rationale and purpose
Deregulation of the retinoblastoma tumor suppressor pathway in GCT has been well 
documented (Bartkova et al 2003). Upregulation of CDK4 and cyclin D2 is believed to be a 
central event in GCT tumorigenesis (Houldsworth et al 1997, Schmidt et al 2001). Inhibition 
of CDK4/cyclinD1 and CDK6/cyclinD3 complexes prevents the phosphorylation of pRB and
renders a cell unable to proceed through cell division. Differentiated NSGCT such as 
teratocarcinomas and teratomas demonstrate strong expression of pRB (Strohmeyer et al 1991, 
Bartkova et al 2003). 
Treatment for relapsed/refractory/unresectable teratoma remains a high unmet medical need 
and use of a CDK 4/6 inhibitor such as LEE011 is a rational approach. A phase I study with 
palbociclib; another selective CDK 4/6 inhibitor, (PD-0332991) included 3 patients with 
progressive Growing Teratoma Syndrome (GTS) despite maximal surgical excision. Two 
patients maintained stable disease for 18 and 24 months at the time of the report, and the third 
had partial response and remained progression free on therapy at 22 months (Vaughn et al 
2009).
The primary purpose of this study is to determine the anti-tumor activity of LEE011 for 
relapsed, refractory, progressive, incurable teratoma. Targeting the D-Cyclin-CDK axis to 
inhibit teratoma growth is driven by biological rationale, supporting clinical evidence, and the 
need for effective targeted therapy in this indication. Evidence of anti-tumor activity in this 
study will be used to inform future development of LEE011 in other tumors where this 
pathway may be critical for tumorigenesis.
2.2
Rationale for the study design
This is a randomized double blind (investigator and patient), placebo-controlled, phase II 
study of LEE011 in patients with progressive relapsed/refractory teratoma for whom standard
therapeutic options are not available. The two-arm randomized design minimizes allocation 
bias, balancing both known and unknown prognostic factors in the assignment of treatment. 
Blinding will minimize the risk of overstating LEE011 effect. Given the variable growth rate 
of teratomas, documentation of radiologic progression within 12 weeks prior to enrollment 
(compared to a prior scan within 1 year) will be required.
A placebo-controlled design with crossover, at time of documented disease progression per 
RECIST v1.1, permits a more objective assessment of clinical improvement and radiologic 
response, while at the same time permitting all enrolled patients access to LEE011. There is
no accepted standard therapy for patients eligible for enrollment in this study and case reports 
of individualized regimens are discouraging (van der Gaast et al 1991, Ornadel et al 1995, 
Rustin et al 1984). Patients will be randomized 2:1 to the experimental arm in order to 
 


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increase the probability of patients receiving active drug upfront and maximize collection of 
safety data. The presence of a placebo arm will also help to facilitate the evaluation of
whether adverse events are related to LEE011. The use of a cross-over design will impact the 
ability to provide a robust estimate of overall survival, which is acceptable given the 
exploratory nature of this phase II study. 
Preclinical and clinical studies suggest that the vast majority of teratoma have pRB (Bartkova 
et al 2003); therefore, pre-screening for pRB status will not be required but will be assessed 
retrospectively. 
2.3
Rationale for dose and regimen selection
The LEE011 dose will be 600 mg QD for 21 days followed by a one week break as 
established in the [CLEE011X2101] study (28 day cycle). The MTD of LEE011 administered 
as single agent is 900 mg QD for 21 days followed by a one week break; however, the 
recommended dose for future development is 600 mg QD (3 weeks on/1 week off schedule) 
due to lower risk for QTcF prolongation, acceptable safety profile, adequate exposures, and 
preliminary evidence of clinical activity. 
2.4
Rationale for choice of combination drugs
Not applicable
2.5
Rationale for choice of comparators drugs 
Not applicable
 


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To assess the efficacy of LEE011 compared to placebo in patients 
with relapsed/refractory teratoma with recent progression
PFS as per RECIST v1.1 (by local investigator assessment).
Secondary
Refer to Section 10.5.2
and Section 10.5.3
To assess other measures of efficacy of LEE011 compared with 
placebo 
To assess safety and tolerability of LEE011 compared with placebo 
BOR, ORR, DOR, DCR at 4 months as per RECIST v1.1 and OS, 
OS Rate at 12 months. 
Incidence and severity of adverse events and serious adverse 
events, changes in laboratory values, electrocardiograms, and vital 
signs will be used to assess the safety as per CTCAE v.4.03. Dose 
interruptions and changes will be used to assess the tolerability.
 


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Study design
 


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4.2
Timing of interim analyses and design adaptations 
No formal interim analysis will be conducted for this study.
4.3
Definition of end of the study
The study data will be analyzed and a primary clinical study report (CSR) will be written 
based on all patients’ data at the time when there are approximately 23 PFS events for the 
primary efficacy analysis and all patients have been followed for PFS for at least 6 months or 
have discontinued prior to this time for disease progression or death, or have withdrawn 
consent  to follow-up, or have been lost to follow-up (see Section 10.4.2), or enrollment in the 
LEE011 rollover clinical trial (CLEE011X2X01B), or early study termination, whichever
occurs first. Additional data for patients continuing on study or in any survival follow-up
period past the data cutoff date for the primary CSR will be reported in a final CSR once the 
treatment period, safety follow-up, disease progression follow-up and survival follow-up
periods have ended for all patients as described in Section 7.1.4. In the case when the study is 
terminated early (Section 4.4) and no CSR has been already reported, all data prior to the 
study termination will be reported in a final CSR (see Section 4.4).
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
patients should be seen as soon as possible and the same assessments should be performed as 
described in Section 7.1.3 for an EOT/premature withdrawal 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 study.
5
Population
5.1
Patient population
The study will be conducted in patients, 15 years old or older, with a diagnosis of teratoma 
that have radiographic progression within 12 weeks of enrollment. 
Patients who do not meet all the inclusion or exclusion criteria can be re-screened once for 
consideration in the trial. If a patient is re-screened, the same patient ID number should be 
used. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.  
 


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5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Age ≥15 years old at time of informed consent.
2. Diagnosis of teratoma for which no additional standard surgical or medical therapy exists. 
3. Availability of an archival or newly obtained tumor sample (collected at diagnosis or 
progression) with accompanying pathology report.

Patients without a tumor sample may be permitted to participate after discussion 
between Novartis and the investigator.
4. Patients must have completed at least 1 prior line of chemotherapy for germ cell tumor
(except patients who present with primary, pure teratoma who need not have received any 
previous chemotherapy)
5. Radiographic progression, defined by RECIST v.1.1, after the last cancer treatment and 
within 12 weeks prior to enrollment, compared with scans within 1 year of enrollment.
6. Measurable or evaluable extra-cranial disease as defined by RECIST v.1.1.
7. Patients must have ECOG performance status of 0-1.
8. Written informed consent/assent before any study-specific screening procedures. For 
pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the 
signature of at least 1 parent or guardian will be required. Investigators will also obtain 
assent of patients according to local, regional or national guidelines.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. CNS disease unless radiation therapy and/or surgery has been completed and serial 
evaluation by CT (with contrast enhancement) or MRI over a minimum of 2 months 
demonstrates stable disease. Patient must be asymptomatic and without need for treatment 
with systemic corticosteroids or anti-epileptic medications.
2. Malignant germ cell tumors other than that being treated in this study, including tumors 
with elements of mixed histology such as embryonal carcinoma, choriocarcinoma, yolk 
sac tumor or seminoma. Note – this refers to the histology at the time of enrollment, not 
the histology at the time of initial presentation.
3. Pathologic evidence of malignant transformation.
4. Concurrent malignancy other than teratoma within 3 years of randomization, with the 
additional exceptions treated NSGCT from which teratoma has emerged, of adequately 
treated basal or squamous cell carcinoma of the skin, curatively resected cervical cancer or 
curatively resected carcinoma in situ of any type.
5. Prior treatment with any CDK4/6 inhibitor therapy
6. Any concurrent severe and/or uncontrolled medical condition that, in the investigator’s 
judgment serves as a contraindication to patient participation (e.g., chronic pancreatitis, 
active hepatitis, viral hepatitis or known HIV positivity). Baseline HIV screening is not 
required.
7. Patients who have not recovered to ≤ CTCAE grade 1 from the acute toxic effects (except 
for alopecia) of all prior chemotherapy, immunotherapy, or radiotherapy.
 


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8. Impaired gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection).
9. Impaired cardiac function or any clinically significant cardiac disease, including any of the 
following: 

Left ventricular ejection fraction (LVEF) < 45% or less than the institution’s lower 
limit of normal as determined by multiple gated acquisition scan (MUGA) or 
echocardiogram (ECHO)

Congenital long QT syndrome or family history of unexpected sudden cardiac death

QT corrected with Fridericia’s (QTcF) QTcF >450 msec for males and >470 msec for 
females on screening ECG

Clinically significant heart disease such as CHF requiring treatment (NYH grade ≥ 2), 
unstable angina pectoris or myocardial infarction within the past 3 months. Any other 
clinically significant heart disease such as unstable arrhythmia, resting bradycardia, 
right bundle branch block, bifascicular block, or any heart disease that requires the 
use of a cardiac pacemaker ≤ 3 months prior to starting study drug.

Patients who are currently receiving medications with known risk of prolonging the 
QT interval or inducing Torsades de Pointes and are unable to discontinue or switch 
to an alternate medication.
10. Concomitant therapy that precludes enrollment: 

Systemic antineoplastic therapy or any experimental therapy within 3 weeks before 
the first dose of study drug (6 weeks for prior nitrosoureas, bevacizumab, or 
mitomycin C). 

Systemic corticosteroids within 2 weeks prior to starting study drug. Note: 
Corticosteroids are permitted for use as single doses, topical applications (e.g., for 
rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular).
11. Major surgery within 2 weeks of the first dose of study drug (mediastinoscopy, insertion 
of a central venous access device, or insertion of a feeding tube is not considered major 
surgery)
12. Received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to 
randomization, or patient has not recovered to ≤ CTCAE grade 1 related toxicity. 
13. Requirement for treatment with any of the prohibited medications including strong 
CYP3A4/5 inhibitors, strong CYP3A4/5 inducers, CYP3A4/5 substrates with a narrow 
therapeutic index, and medications with strong risk of QT prolongation (Appendix 4).
14. Participation in a prior investigational study within 30 days prior to enrollment or within 
5-half-lives of the investigational product, whichever is longer.
15. Have any of the following out-of-range laboratory values:

Absolute neutrophil count ≤1.5× 109/L

Platelet count ≤100 × 109/L

Hemoglobin ≤9.0 g/dL

Potassium unless correctable by oral supplementation  
 


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
Calcium (corrected for serum albumin) unless correctable by oral supplementation

Magnesium unless correctable by oral supplementation  

Serum creatinine ≥1.5 × ULN

Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) > 2.5 × ULN 
for age; for patients with liver metastases ≥ 5 × ULN for age. 

Total serum bilirubin > ULN except for patients with Gilbert’s syndrome who may 
only be included if the total bilirubin is ≥1.5 × ULNINR ≥1.5
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 hCG 
laboratory test.
17. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 weeks after stopping dosing. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient), 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 starting study drug. In case of 
oophorectomy alone, only when the reproductive status of the female has been 
confirmed by follow-up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

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.
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 females should have been stable on the same oral 
contraceptive for a minimum of 3 months before starting study drug. 
18. 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.
19. Sexually active males, unless they use a condom during intercourse, while taking study 
drug and for 3 weeks after stopping study drug and should not father a child during this 
 


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period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. 
6
Treatment
6.1
Study treatment
All dosages of study drug prescribed and dispensed to the patient and all dose changes during 
the study must be recorded on the Dosage Administration Record eCRF.
The investigator or responsible site personnel should instruct the patient to take the study drug 
as per protocol (promote compliance). Study drug accountability must be performed on a 
regular basis. Patients will be instructed to return unused study drug 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 drug for 
subsequent dosing.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Strength
Dose
Frequency and/or 
Regimen
LEE011
Capsule for oral use
200 mg/capsule
600 mg
Daily (21 days followed by 
one week break)
LEE011 matching 
Placebo
Capsule for oral use
N/A
N/A
Daily (21 days followed by 
one week break)
LEE011 and placebo will be supplied to investigational sites by Novartis or its designee as 
200 mg hard gelatin capsules as individual patient supply packaged in bottles as double blind 
supply. Storage conditions are described on the medication label. Study drug will be taken 
orally, once a day for 21 consecutive days followed by a one week break as part of each 28-
day cycle of treatment. The study drug will be administered as a flat-fixed dose, not by body 
weight or body surface area. 
6.1.2
Study drug administration 
Study drug should be taken as follows:

Patients should be instructed to take his/her daily dose with a glass of water (~250 ml/8
oz.) in the morning at approximately the same time (+/- 1 hour). Patients may take study 
drug with or without food. Patients should be instructed to swallow capsules whole and 
not chew, crush or open, unless otherwise instructed.  If patients cannot tolerate his/her 
daily dose in the morning, due to GI related side effects, then after cycle 1 it can be taken 
in the evening for the remainder of the study.

 

If vomiting occurs no re-dosing of the patient is allowed before the next scheduled dose.
 


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
 

Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped until the next day. 
6.1.3
Guidelines for continuation of treatment
Not applicable
6.1.4
Treatment duration
Efficacy, safety and survival data will continue to be collected as per visit schedule (Table 7-
1). Patients may continue treatment with study drug until disease progression as assessed by 
RECIST v1.1 (Appendix 1), 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. Patients who progress on placebo may crossover to LEE011 and 
receive treatment until subsequent tumor progression, discontinuation at the discretion of the 
investigator or patient’s withdrawal of consent (see Section 4.1.6). Patients receiving LEE011 
may be allowed to continue treatment following progression if in the opinion of the 
investigator they are receiving clinical benefit. Details supporting continuation must be sent to 
Novartis for approval within 7 days of documented progression. For patients continuing on 
LEE011 after unblinding due to clinical benefit (not crossover patients), subsequent tumor 
assessments should be conducted according to local practice.
6.2
Dose modifications
6.2.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study drug. These changes must be 
recorded on the Dosage Administration Record eCRF. For patients undergoing a dose delay or 
reduction mid-cycle, upon restarting LEE011 during that cycle the, dosing should resume per 
the original cycle schedule. The planned 7-day break should begin on the originally planned 
date regardless of mid-cycle interruptions. Day 1 of subsequent cycles may be delayed if 
necessary to allow for toxicity resolution. If the study drug is delayed for more than 21 days 
due to drug toxicity, then study drug should be discontinued.
Severe or intolerable AEs may require dose reduction and/or interruption of study drug. Refer 
to Table 6-2 for guidance.
Table 6-2
Dose adjustments
Dose level
Daily dose
Frequency 
*-2
200 mg
Daily (21 days), followed by one week break
*-1
400 mg
Daily (21 days), followed by one week break
1 (starting dose)
600 mg
Daily (21 days), followed by one week break
*Dose level-1 and -2 represent treatment doses for patients requiring a dose reduction from the starting dose 
level. No dose reduction below dose level -2 is permitted for this study.   
 


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Recommendations for dose reduction, interruption or discontinuation of study drug in the 
management of AEs are summarized in Table 6-3. Clinical judgment of the treating physician 
and an individualized risk/benefit assessment should guide the management plan for each 
patient. A maximum of two study drug dose reductions (minimum dose is 200 mg) is allowed 
before study drug must be discontinued. Once a dose reduction has occurred, the dose level 
may not be re-escalated until the adverse event resolves to grade 1 and dose change has been 
authorized by the Novartis team.
Table 6-3
Study drug dose adjustment and management recommendation for 
hematological adverse reactions
Toxicity/Grade
Dose Adjustment and Management Recommendations
Thrombocytopenia
Grade 1(≥75 x 109/L)
No dose adjustment required.
Grade 2 (≥50 x 109/L – < 75 x 109/L)
Dose interruption until recovery to grade ≤ 1. 
Re-initiate study drug at the same dose.
Grade 3 (≥25 x 109/L - < 50 x 109/L)
Dose interruption until recovery to grade ≤ 1. 
Re-initiate study drug at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to grade ≤ 1 and reduce study drug to the next
lower dose level.
Grade 4(< 25 x 109/L)
Dose interruption until recovery to grade ≤ 1.
Re-initiate study drug at the next lower dose level. 
If toxicity recurs at grade 4: discontinue study drug.
Absolute neutrophil count (ANC)
Grade 1 (≥1.5 x 109/L)
No dose adjustment required.
Grade 2 (≥1.0 - < 1.5 x 109/L)
No dose adjustment required.
Grade 3 (≥0.5 - < 1.0 x 109/L)
Dose interruption until recovery to ≥1.0 x 109/L. 
Re-initiate study drug at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption
until recovery to ≥ 1.0 x 109/L.
If resolved in ≤7 days, then maintain dose level.
If resolved in > 7 days, then reduce study drug dose to the 
next lower dose level.
Grade 4 (< 0.5 x 109/L)
Dose interruption until recovery to ≥ 1.0 x 109/L. 
Re-initiate study drug at the next lower dose level.
If toxicity recurs at grade 4: temporary dose interruption until 
recovery to ≥1.0 x 109/L and reduce study drug at the next 
lower dose level.
Febrile neutropenia
Grade 3
ANC < 1.0 x 109/L with a single temperature of
> 38.3 ºC (101 ºF) or a sustained temperature of
≥38 ºC (100.4 ºF) for more than one hour
Dose interruption until improvement of ANC ≥ 1.0 x 109/L
and no fever. 
Restart at the next lower dose level. If febrile neutropenia 
recurs, discontinue study drug.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue study drug
Anemia
(Hemoglobin)
Grade 1 (≥10.0 – LLN g/dL)
No dose adjustment required.
Grade 2 (≥8.0 – <10.0 g/dL)
No dose adjustment required.
Grade 3 (< 8.0 g/dL)
Dose interruption until recovery to grade ≤2. 
 


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Toxicity/Grade
Dose Adjustment and Management Recommendations
Re-initiate study drug at the same dose.
Grade 4
Life-threatening consequences;
urgent intervention indicated
Discontinue study drug.
Table 6-4
Study drug dose adjustment and management recommendation for 
hepatic toxicities
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48-72h later)
Maintain dose level with LFTs monitored bi-weekly
Grade 2 (> 1.5 – 3.0 x ULN)
Dose interruption of study drug 
If resolved to ≤ grade 1 in ≤21 days, then maintain dose
level
If resolved to ≤ grade 1 in > 21 days or toxicity recurs,
then reduce 1 dose level
If toxicity recurs after two dose reductions, discontinue 
study drug
Grade 3 (> 3.0 – 10.0 x ULN)
Dose interruption of study drug 
If resolved to ≤ grade 1 in ≤ 21 days, lower 1 dose level of 
study drug
If resolved to ≤ grade 1 in > 21 days or toxicity recurs,
discontinue study drug
Grade 4 (> 10.0 x ULN)
Discontinue study drug
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’s Syndrome, pharmacologic treatment, viral hepatitis, 
alcoholic or autoimmune hepatitis, other hepatotoxic drugs.
For patients with Gilbert’s Syndrome, these dose modifications apply to changes in direct bilirubin only. Bilirubin 
will be fractionated if elevated.
AST or ALT
AST or ALT without bilirubin elevation > 2 x ULN
Same grade as baseline or increase from baseline 
grade 0 to grade 1
(confirmed 48 – 72 h 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
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 study drug 
If resolved to ≤ baseline value in ≤ 21 days, then
maintain dose level
If resolved to ≤ baseline value in > 21 days or toxicity
recurs, then reduce 1 dose level
If toxicity recurs after two dose reductions or recovery to
≤ baseline value is > 28 days, discontinue study drug
Increase from baseline grade 0 or 1 to grade 3 (> 5.0
– 20.0 x ULN)
Dose interruption of study drug until resolved to ≤ baseline
value, then lower 1 dose level of study drug 
If recovery to ≤ baseline value is > 28 days, discontinue
study drug
If toxicity recurs, discontinue study drug
Grade 4 (> 20.0 x ULN)
Discontinue study drug
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
Discontinue study drug
 


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HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
AST or ALT ≥ grade 3 (> 5 x ULN) in patients with 
grade 1 or 2 at baseline, and total bilirubin  > 2 x ULN
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.
6.2.1.1
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’s 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 
(Cytomegalovirus (CMV), Epstein Barr Virus (EBV) or Herpes Simplex Virus (HSV); 
autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis (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.
6.2.1.2
Additional follow-up for QTc prolongation
Table 6-5
Study drug dose adjustment and management recommendation 
Grade
Dose Modification
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 study drug 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.
 


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Grade
Dose Modification
● Check compliance with correct dose and administration of study drug 
1
QTc 450-480 ms
No dose adjustment required.
2
QTc 481-500 ms
Interrupt study drug 
Perform a repeat ECG one hour after the first QTcF of ≥ 481 ms.
If QTcF ≤ 481 ms, restart study drug 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 study drug at the same dose. No dose adjustment 
required for first occurrence.
If QTcF ≥ 481 ms recurs, study drug should be reduced by 1 dose level. Refer 
to Table 6-2 for dosing schedule.
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
3
QTc ≥ 501 ms on at least two
separate ECGs
Interrupt study drug. Transmit ECG immediately and confirm 
prolongation/abnormalities with central assessment.
Perform a repeat ECG one hour after the first QTcF of > 501 ms.
If QTcF remains ≥501 ms, consult with a cardiologist (or qualified specialist) 
and repeat cardiac monitoring as indicated, until the QTcF returns to < 481 ms.
If QTcF returns to < 481 ms, study drug will be reduced by 1 dose level. Refer 
to Table 6-2 for dosing schedule.
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 study drug
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 study drug.
● Obtain local cardiologist consultation.
● Perform a repeat ECG one hour after 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.
6.2.1.3
Guidance for all other adverse reactions
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium 
for all adverse reactions, if indicated. If electrolyte values are below the lower limit of normal, 
interrupt study drug administration, correct electrolytes with supplements as soon as possible, 
and repeat electrolyte testing until documented normalization of the electrolytes.
Table 6-6
Study drug dose adjustment and management recommendation for all 
other adverse reactions
Grade
Dose Adjustment and Management Recommendations
1
No dose adjustment recommended. Initiate appropriate medical therapy and monitor.
2
Dose interruption until recovery to grade ≤ 1. Initiate appropriate medical therapy and monitor. Re-initiate 
study drug at the same dose.
If the same toxicity recurs at grade 2, interrupt study drug until recovery to grade ≤1. Re-initiate study 
drug at the next lower dose level.
3
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor. Re-initiate 
study drug at the next lower dose level.
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade ≤1 and reduce study drug 
dose the next lower dose level.
If toxicity recurs at grade 3, discontinue study drug
 


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Grade
Dose Adjustment and Management Recommendations
4
Discontinue study drug and treat with appropriate medical therapy.
6.2.2
Follow-up for toxicities
Patients who complete study drug or whose study drug is interrupted or permanently 
discontinued due to an AE must be followed at least once a week for 4 weeks, and then at 4-
week intervals until resolution or stabilization of the event. All patients will be followed for 
onset of any new serious adverse events for 30 days following the last dose of study treatment.
6.2.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. 
6.3
Concomitant medications 
6.3.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as packed red blood cells (PRBC), pain medications, anti-emetics 
and anti-diarrheals are allowed. Hematopoietic growth colony stimulating factors may be used 
therapeutically or as secondary prophylaxis, see Appendix 4. 
The patient (patient’s guardian if appropriate) must be instructed to notify the treating 
physician of new medications after the start of the study drug. All medications (other than 
study drug) and significant non-drug therapies (including blood transfusions and physical 
therapy) administered within 30 days of first dose of study drug and during  the study  must be 
listed on the Concomitant Medications/Significant Non-Drug therapies eCRF as appropriate. 
Patients taking concomitant medications chronically should be maintained on the same dose 
and dosing schedule throughout the study, as medically feasible.  
6.3.2
Permitted concomitant therapy requiring caution 
The following therapies are permitted in this study; however, they should be used with 
caution: 

Moderate inhibitors or inducers of CYP3A4/5

Sensitive substrates of CYP3A4/5 with wide therapeutic index

Known inhibitors of BSEP

Sensitive substrates of the renal transporters, MATE1 and OCT2, and sensitive substrates 
of BCRP

Medications that carry a possible risk for QT prolongation
6.3.3
Prohibited concomitant therapy
The following medications are prohibited during treatment in this study (Appendix 4):

Strong inhibitors or inducers of CYP3A4/5

Substrates of CYP3A4/5 with narrow therapeutic index
 


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
Medications with a known risk for QT prolongation

Other investigational and antineoplastic therapies

Herbal medications

Primary prophylactic hematopoietic growth factors

Palliative radiotherapy

Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, 
Seville oranges or products containing the juice of each during the entire study and 
preferably for an additional 7 days before the first dose of study medications, due to 
potential CYP3A interaction with the study medications. Orange juice is allowed.
Refer to the LEE011 Investigator’s Brochure and Appendix 4 for information on possible 
interactions with other drugs.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each patient is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed
even if the patient is re-screened. If the patient fails to be randomized or start treatment for 
any reason, the reason will be entered into the Screening Disposition eCRF.
IRT must be notified within 2 days of a patient screen failure.
6.4.2
Treatment assignment or randomization
Patients will be randomized to 1 of the 2 treatment arms in a 2:1 ratio. LEE011 and placebo 
will be supplied to investigational sites by Novartis or its designee as hard gelatin capsules
(200 mg) as individual patient supply packaged in bottles. Storage conditions are described on 
the medication label. 
Block randomization will be used to allocate patients between treatment arms. The 
randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization 
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using a validated system that automates the random assignment of medication numbers to 
medication packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. 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 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller.
For patient’s crossing over to LEE011, the investigator or his/her designee will call or log on 
to the IRT and confirm that the patient fulfills the criteria to crossover. The IRT will assign a 
unique medication number for the study drug to be dispensed to the patient.
The medication label will be in the local language and comply with the legal requirements of 
each country. The study drug packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to one of the treatment arms and a dose 
level. Responsible site personnel will identify the study drug package(s) to dispense to the 
patient by using the IRT and obtaining the medication number(s). Site personnel will add the 
patient number on the label. Immediately before dispensing the package to the patient, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document (Drug Label Form) for that patient’s unique patient number.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
6.4.3
Drug supply and storage
Study drug will be centrally supplied by Novartis DSM or a Novartis 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.
6.4.4
Study drug compliance and accountability
6.4.4.1
Study drug compliance
Compliance will be assessed by the investigator or study personnel at each patient visit and 
information provided by the patient or caregiver will be captured in the Drug Accountability 
eCRF. This information must be captured in the source document at each patient visit.
6.4.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drug 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 
 


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all unused study drug and packaging on a regular basis, at the end of the study and at the time 
of study drug discontinuation.
At study close-out and as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.4.4.3
Handling of other study treatment
Not applicable.
6.4.5
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility by the, 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 Novartis.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 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. 
No eCRF will be used as a source document. 
After the screening period, all assessments have a ±3 day window unless otherwise indicated 
 
If study drug is being held due to toxicity, then the scheduled visits and assessments 
 
 should still be performed per protocol, unless otherwise specified. Additional 
assessments may be performed as clinically indicated.
 


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Table 7-1
Visit evaluation schedule
Category
Protocol Section
Screening
Treatment Cycles
EOT 
Crossover cycles
Crossover EOT
Follow-Ups
Cycle 1
Cycle 
2 
Subsequent 
Cycles
Cycle 1
Cycle 
2
Subsequent 
Cycles
30-Day
Progression
Survival
Day of cycle 
-14 to-1
1
8
15
21
1
21
1
1
8
15
21
1
21
1
Obtain informed 
consent
D
7.1.1
X
IVRS/IRT 
registration
D
4.1
X
Demography
D
7.1.1.3
X
Inclusion/exclusion 
criteria
D
5.2 / 5.3
X
X
Medical history 
D
7.1.1.3
X
Diagnosis and 
extent of cancer
D
7.1.1.3
X
Prior antineoplastic 
therapy
D
7.1.1.3
X
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
D
7.2.2.4
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Category
Protocol Section
Screening
Treatment Cycles
EOT 
Crossover cycles
Crossover EOT
Follow-Ups
Cycle 1
Cycle 
2 
Subsequent 
Cycles
Cycle 1
Cycle 
2
Subsequent 
Cycles
30-Day
Progression
Survival
Day of cycle 
-14 to-1
1
8
15
21
1
21
1
1
8
15
21
1
21
1
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid panel
D
7.2.2.5.3
X
X
X
Coagulation
D
7.2.2.5.4
X
X
X
Pregnancy test 
D
7.2.2.5.5
X
X
X
X
X
X
X
X
X
ECG
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac imaging 
(MUGA/ECHO)
D
7.2.2.6.2
X
X
X
Collection of 
archival paraffin 
blocks/slides 
or newly obtained 
tumor sample 
D
7.2.4.1
X
Tumor assessments
D
7.2.1
X
Every 8 weeks for first 12 months 
from C1D1, then every 12 weeks
X
Every 8 weeks for the first 12 
months from C1D1, then every 12 
X
X
 


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Category
Protocol Section
Screening
Treatment Cycles
EOT 
Crossover cycles
Crossover EOT
Follow-Ups
Cycle 1
Cycle 
2 
Subsequent 
Cycles
Cycle 1
Cycle 
2
Subsequent 
Cycles
30-Day
Progression
Survival
Day of cycle 
-14 to-1
1
8
15
21
1
21
1
1
8
15
21
1
21
1
weeks
Study Drug 
administration 
D
6.1.2
Continuous daily dosing days 1-21 of each cycle then one week break 
Adverse Events
D
8.1
Continuous from signed ICF up to 30 days after last dose of study treatment.
Prior/concomitant 
medications
D
6.3
Continuous from consent to 30-Day follow-up
Assessment of 
Patient Disposition
D
7.1.3
X
X
X
Antineoplastic 
therapy since 
discontinuation 
D
7.1.5.2
X
X
X
Survival Follow-up 
(telephone call/clinic 
visit every 12 
weeks)
D
7.1.5.3
X
 


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7.1.1
Screening
The Study IRB/IEC approved Informed Consent Form (ICF) must be signed and dated before 
any screening procedures are performed; however, procedures that are part of the clinical 
routine during the initial diagnostic work-up of the patient may be performed before signing 
the ICF. A copy of the ICF must be given to the patient (or patient’s guardian as appropriate). 
The Investigator or designee must record the date when the study informed consent was 
signed in the medical records of the patient. 
For patients under 18 years of age, consent will be obtained from parent(s) or legal guardian(s) 
and the signature of at least 1 parent or guardian will be required. Investigators will also 
obtain assent of minor patients according to local, regional or national guidelines. 
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 study drug. Screening assessments have to be 
completed within 14 days prior to the first dose of study drug except for imaging and
hematologic laboratories. Baseline tumor imaging may be done up to 28 days prior and 
hematologic laboratories (ANC, platelet count, and hematocrit) up to 72 hours prior to first 
dose of study drug. 
Abnormal laboratory values of potassium, magnesium or calcium correctable by oral 
supplementation must document a normalized laboratory value prior to randomization. 
7.1.1.1
Eligibility screening
When the patient is considered eligible for study treatment, the study site should enter the 
information into the IRT/IVRS system to register and randomize the patient.  
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to start on study drug for any reason will be 
considered a screen failure. The reason for not starting study drug will be entered on the 
Screening Phase Disposition eCRF. The demographic information, informed consent, and 
Inclusion/Exclusion eCRF must also be completed for screen failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experiences a Serious Adverse Event during the Screening Phase (See Section 8 for SAE 
reporting details). The IRT must be notified within 2 days of the screen failure.
7.1.1.3
Patient demographics and other baseline characteristics
Baseline data on patient characteristics to be collected includes: general demographics, 
relevant medical history, cancer diagnosis, tumor burden, and prior medications and 
antineoplastic therapies.
7.1.2
Treatment period
During the treatment period, the patient must follow the Investigator’s instructions with 
regards to contraception, concomitant medications, and dosing regimen (see Section 6.1.1). 
There is no fixed treatment duration. Patients may continue study drug until disease 
progression, unacceptable toxicity, discretion of the investigator or patient withdrawal of 
 


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consent. At time of documented progression per RECIST v1.1, patients may be unblinded and 
those randomized to placebo will be evaluated for crossover to LEE011. Patients should 
receive LEE011 within 28 days of the last radiological assessment. Safety labs and assessment 
are not required to be repeated for patients who start crossover C1D1 within 14 days of 
completing treatment. Patients initially randomized to the LEE011 arm may be permitted to 
continue on LEE011, despite progression, if the investigator documents ongoing clinical 
benefit for the patient in the source documentation, in a comment in the eCRF, and discussed 
decision with CPL. Please refer to Section 4.1.6.
7.1.3
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the study or be discontinued from the study at the 
discretion of the investigator at any time. If a patient decides to discontinue from the study 
treatment, the investigator must make every effort (e.g. telephone, e-mail, letter) to determine 
the primary reason for this decision and record this information in the patient’s chart and on 
the appropriate CRF pages.  They may be considered withdrawn if they state an intention to 
withdraw, fail to return for visits, or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being
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 assessment. At 
that time, the reason for study completion should be recorded on the Study Phase Completion 
Disposition CRF page.
End of treatment/premature withdrawal visit is not considered as the end of the study.
Patients who prematurely discontinue study drug should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the EOT visit will be performed 
(Table 7-1). This visit should take place no more than 14 days after the last dose of study drug. 
An EOT eCRF should be completed, giving the date and reason for stopping the study 
treatment. End of treatment/premature withdrawal visit is not considered as the end of study. 
The investigator must contact the IRT to register the patient’s discontinuation.
All patients who discontinue study drug should return for assessments according to Table 7-1
including: safety follow-up (Section 7.1.5.1), disease progression follow-up (if applicable, 
Section 7.1.5.2) and survival follow-up (Section 7.1.5.3).
An End of Phase Disposition eCRF should be completed upon completion of the Disease 
Progression Follow-Up Period.
Patients may be discontinued from the study drug if any of the following occur:

Patient withdrew consent

Adverse event

Lost to follow-up

Death

Non-compliance with study drug
 


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
Physician decision

Progressive disease

Protocol deviation

Study terminated by sponsor

Technical problems

Patient/parent/guardian decision

Transfer to another Novartis clinical study that continues to provide LEE011 (e.g. 
CLEE011X2X01B)
Patients must be withdrawn from the study drug if any of the following occur:

Pregnancy

Death
7.1.4
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visit or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation.  All biological samples that have already been collected may be 
retained and analyzed at a later date (or a required by local regulations).
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information.
LEE011 must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow-up.  
7.1.5
Follow-up Period
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show “due diligence” by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient; e.g. dates of telephone calls, 
registered letters, etc.  A patient should not be considered lost to follow-up until due diligence 
has been completed.  Patients lost to follow-up should be recorded as such on the appropriate 
Disposition CRF
7.1.5.1
Safety follow-up
All patients must have safety evaluations 30 days after the last dose of study drug, except, in 
the case of death, loss to follow-up, withdrawal consent, or discontinuation of study treatment 
to enroll in the LEE011 rollover clinical trial (CLEE011X2X01B). Information related to 
AEs (including concomitant medication taken for ongoing AEs) and initiation of anti-
neoplastic treatments will be collected. All AEs suspected to be related to study drug should 
 


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be followed weekly, or as clinically indicated, until resolution or stabilization. Antineoplastic 
therapies and/or tumor directed surgical procedures initiated during the safety follow-up 
period must be recorded on the Antineoplastic Therapy since Discontinuation of Study Drug 
eCRF.
7.1.5.2
Disease progression follow-up
Patients who discontinue study drug for any reason other than disease progression will be 
followed for efficacy (i.e., tumor assessments) every 8 weeks during the first 12 months and 
every 12 weeks thereafter until disease progression, death, discontinuation from the study for 
any other reason (i.e., loss to follow-up or withdrawal of consent), the initiation of a new 
antineoplastic treatment, or until all patients have been followed for at least 18 months after 
their first dose of study drug, or early study termination, whichever occurs first. 
Antineoplastic therapies and/or surgical procedures initiated during the disease progression 
follow-up period must be recorded on the Antineoplastic Therapy since Discontinuation of 
Study Drug eCRF.
7.1.5.3
Survival follow-up phase
All patients will be followed for survival via a phone call (or during a clinic visit) every 12 
weeks and up to one additional time per quarter if a survival update is required to meet safety 
or regulatory needs, until any of the following (whichever occurs first): death, withdrawal of 
consent, loss to follow-up, at least 18 months from when the last patient started treatment, or 
when 80% of patients have died or been lost to follow-up, or early study termination. 
Antineoplastic therapies or tumor directed surgical procedures initiated during the survival 
follow-up period must be recorded on the Antineoplastic Therapy since Discontinuation of
Study Drug eCRF.
7.1.5.4
Replacement policy
Not applicable.
7.2
Assessment types
7.2.1
Efficacy assessments
All patients will have disease response assessments per the RECIST v 1.1 (Appendix 1). Each 
lesion that is measured at baseline (screening), must be measured by the same method 
throughout the study so that the comparison is consistent. Tumor response will be evaluated 
locally by the investigator according to the Novartis guideline (Version 3.0) based on RECIST 
v 1.1 (See Appendix 1). 
The following assessments in Table 7-2 are required at screening/baseline (within 28 days of 
the start of treatment). FDG-PET scans are not required for this study. Sites may perform 
combined PET/CT scans per their local standard of care, provided the CT is of similar 
diagnostic quality as a CT performed without PET, including the utilization of oral and 
intravenous contrast media. If acquired according to local standard of care, FDG-PET may be 
relied upon to document progressive disease in accordance with RECIST v1.1.
 


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Tumor assessments during the Blinded Treatment Period will be performed locally every 8 
weeks (+/-3 days) for the first year following C1D1 and every 12 weeks thereafter until 
disease progression, death, discontinuation from the study for any other reason (i.e., loss to 
follow-up or withdrawal of consent) or initiation of a new antineoplastic treatment, whichever 
occurs first. Tumor evaluations may be performed sooner if there is clinical concern for 
disease progression. Tumor evaluation is required at EOT for patients who discontinue study 
drug before the first scheduled post-baseline tumor assessment and for patients whose 
previous tumor assessment did not demonstrate PD; however, if the last prior tumor 
evaluation was within 28 days of EOT, then tumor evaluations do not need to be repeated at 
EOT.
The primary investigator’s or designee’s assessment will be used for the primary endpoint 
analysis and for treatment decision making. 
All radiological assessments obtained for all patients will be centrally collected and subjected 
to quality checks by an imaging CRO selected by Novartis. The site manual provided by the 
designated imaging CRO will provide further details regarding image collection. Additionally 
a central review of tumor assessments may be performed as supportive analysis if indicated.
Table 7-2
Disease assessment collection plan
Procedure
Screening: day−28 
to day -1
Blinded Treatment 
phase
End of treatment*
CT or MRI (Chest, 
Abdomen, Pelvis)
Mandated
Every 8 weeks during the 
first 12 months then every 
12 weeks thereafter 
Mandated
Brain CT or MRI
Only if existing or 
suspected brain 
metastases 
As clinically indicated 
As clinically indicated
Whole body bone scan **
As clinically 
indicated 
As clinically indicated
As clinically indicated
Bone X-ray, CT or MRI
Only if skeletal 
abnormalities 
identified by whole 
body bone scan at 
screening, which are 
not visible in the 
chest, abdomen, 
pelvis CT/MRI.
If bone lesion at 
screening, every 8 weeks 
during the first 12 months 
then every 12 weeks 
thereafter 
Mandated only if bone lesion at 
screening
Skin color Photography
Only if skin lesions 
at screening
If skin lesions at 
screening, every 8 weeks 
during the first 12 months 
then every 12 weeks 
thereafter 
Mandated if skin lesions at 
screening
CT or MRI of any disease 
outside of chest, abdomen 
and pelvis (e.g., neck)
Only if suspected 
lesion at screening
If lesion identified at 
baseline, every 8 weeks 
during the first 12 months 
then every 12 weeks 
thereafter 
Mandated if lesion at screening
*Tumor evaluation at EOT is required for patients who discontinue study drug before the first scheduled post-
baseline tumor assessment and for patients whose previous tumor assessment did not demonstrate PD and was 
done at least 8 weeks prior to EOT visit. 
** Whole body bone scan according to institutional guidelines (e.g., Tc-99 bone scan, whole body bone MRI, 
sodium fluoride positron emission tomography (NaF PET) or fluorodeoxyglucose (FDG) PET). 
 


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7.2.2
Safety and tolerability assessments
Safety and tolerability will be monitored by assessing the changes from baseline in physical 
exam, vital signs and laboratory measures and by collecting the AEs at every visit. All safety 
assessments should be performed pre-dose unless otherwise specified. For details on AE 
collection and reporting, see Section 8.2.
7.2.2.1
Physical examination
A complete physical examination that evaluates all major organ systems will be performed 
during the screening period. Subsequent physical examinations should be focused on sites of 
disease to explore clinical signs and symptoms. Significant findings that were present prior to 
the signing of informed consent must be included in the Medical History eCRF. Significant 
new findings that begin or worsen after informed consent must be recorded on the Adverse 
Event eCRF.
Physical exams to be performed are outlined in Table 7-1. 
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 performed as per Table 7-1. 
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. Assessments to be performed are outlined in 
Table 7-1.
7.2.2.4
Performance status
Assessment of ECOG performance status will be performed at screening and regularly 
throughout the study irrespective of the time of dosing (Appendix 2).
Performance status to be performed as per Table 7-1.
7.2.2.5
Laboratory evaluations
The clinical laboratory analyses described below are to be performed by the sites local 
laboratory according to the time points indicated in Table 7-1. More frequent assessments
may be performed at the investigator’s discretion if medically indicated and should be 
recorded on the Unscheduled Visit eCRF.
Abnormal laboratory values that are clinically relevant (e.g., require a dose modification 
and/or interruption of study drug, lead to clinical symptoms or signs, or require therapeutic 
intervention) must be documented in the Adverse Event eCRF. 
Novartis must be provided with a copy of the site’s local laboratory certification and 
tabulation of the normal ranges for each parameter required at study start and should be kept 
up to date on an ongoing basis if there are any changes. In addition, if at any time a patient has 
 


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laboratory parameters obtained from a different outside laboratory, Novartis 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 if not explicitly specified otherwise. Laboratory assessments that 
were completed within 72 hours before Cycle 1, Day 1 (C1D1) do not need to be repeated.
Table 7-3
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Red blood cells, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils), 
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, 
Chloride, Creatinine, Direct Bilirubin, Glucose, Indirect Bilirubin, Magnesium, Phosphate, 
Potassium, Sodium, Total Bilirubin, Total Protein, Blood Urea Nitrogen (BUN) or Urea 
Coagulation
aPTT, Fibrinogen, INR ,PT
Thyroid
TSH; if indicated T3, T4 [free]
Pregnancy
Serum beta-HCG required at screening (only for women of child-bearing potential); 
subsequent testing may be serum or urine.
7.2.2.5.1 Hematology
Please refer to Table 7-3 for a list of tests to be performed. For timing of assessments, refer to 
Table 7-1.
7.2.2.5.2 Clinical chemistry
Please refer to Table 7-3 for a list of tests to be performed. 
If during screening, an abnormal laboratory value of potassium, magnesium and/or calcium 
can be corrected by oral supplementation than a repeat blood test must be completed to 
confirm the abnormal laboratory value is within normal limits before the patient is allowed to 
randomize.
If total bilirubin elevation ≥grade 2 then direct and indirect bilirubin should also be measured.
For timing of assessments, refer to Table 7-1.
7.2.2.5.3 Thyroid
Please refer to Table 7-3 for a list of tests to be performed. If TSH is elevated then T3 and T4 
will be measured. 
For timing of assessments, refer to Table 7-1.
7.2.2.5.4 Coagulation
Please refer to Table 7-3 for a list of tests to be performed. 
For timing of assessments, refer to Table 7-1.
 


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7.2.2.5.5 Pregnancy and assessments of fertility
When highly effective contraception is required, pregnancy testing is required at screening 
and as indicated in Table 7-1. At screening a serum pregnancy test must be performed. Urine 
or serum pregnancy tests are sufficient for all visits after screening.  
Pregnancy tests are required at the following visits: 

Screening

Day 1 of all cycles

EOT Visit
If a patient becomes pregnant, the study drug must be stopped immediately. If a pregnancy 
test (urine or serum) is positive, but the patient is not thought to be pregnant the study drug 
should be held until it is determined that the test was false positive, and pregnancy is excluded. 
For females to be considered “of non-childbearing potential”, the patient must meet one of the 
following:

Prior to onset of menarche (pre-menarche)

Surgically sterile (have had surgical bilateral oophorectomy with or without hysterectomy) 
or tubal ligation at least six weeks before starting study drug. In case of oophorectomy 
alone, only when the reproductive status of the female has been confirmed by follow-up 
hormone level assessment.

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). 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of discovery. Pregnancy should be recorded on a Clinical Trial 
Pregnancy Form and reported by the investigator to the local Novartis Drug Safety and 
Epidemiology (DS&E). The pregnancy should be followed 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. Follow-up
data should be recorded on the initial Clinical Trial Pregnancy Form and include an 
assessment of the possible relationship between any pregnancy outcome and the Novartis 
study drug. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form.
7.2.2.6
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12-lead ECG will be performed after the patient has been resting for 5-10 minutes 
prior to each time point indicated in Table 7-4. At screening between Day -14 and Day -1, 
triplicate ECGs should be taken approximately 2 minutes apart. The combined QTcF values 
from these triplicate ECGs will be averaged to provide a single baseline value for each patient. 
 
 
 


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Each ECG tracing should be labeled with the study number, patient initials (where regulations 
permit), patient number, date, and kept in the source documents at the study site. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF. Each ECG tracing should be transmitted to a central laboratory and will be 
centrally reviewed by an independent reviewer. Clinically significant abnormalities at 
screening should be recorded on the relevant medical history/current medical conditions 
eCRF. Clinically significant findings must be discussed with Novartis prior to enrolling the 
patient in the study. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF.
Table 7-4
ECG collection plan
Scheduled time points (hours)
Screening
Anytime during the screening period
Cycle
Day
Sampling Time
1
1
Pre-dose
1
8
Pre-dose
1
8
2h post-dose (±30 min)
1
8
4h post-dose (±30 min)
1
15
Pre-dose
1
15
2h post-dose (±30 min)
1
15
4h post-dose (±30 min)
2
1
Pre-dose
2
21
Pre-dose
2
21
2h post-dose (±30 min)
3
1
Pre-dose
3
1
2h post-dose (±30 min)
4-5
1
Pre-dose
6
1
Pre-dose
6
1
2h post-dose (±30 min)
All other cyclesa
1
Pre-dose
9 and every 3rd cycleb
1
Pre-dose
9 and every 3rd cycleb
1
2h post-dose (+/- 30 min) 
Unscheduled
As clinically indicated
EOT
Within 14 days of last dose
 
a Patients with QTcF ≥481 ms at any time prior to cycle 7; 
bPerform pre-dose ECG on the first day of every cycle.  Additionally, 2 h post-dose in every 3rd cycle (Cycle 9, 12,
15, 18 etc)
7.2.2.6.2 Cardiac imaging – ECHO (echocardiogram) or MUGA (multiple gated 
acquisition) scan
Ventricular heart function will be evaluated by ECHO or MUGA at Screening and at the EOT
visits. The same imaging modality should be used throughout the study.
 


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7.2.6
Other assessments 
No additional tests will be performed on patients entered into this study.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event (AE) is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after a patient’s signed 
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Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History eCRF. Adverse event monitoring should be continued for at 
least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (CTCAE grade 1-4)
2. Its duration start and end dates or Ongoing at End of Study
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a SAE is defined as in Section 8.2.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF
Once an 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 treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria), should not be reported as a serious adverse 
event. Adverse events separate from the progression of malignancy (example, deep vein 
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progression) will be reported as per usual guidelines used for such events with proper 
attribution regarding relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes 
in study treatment), should be recorded on the Adverse Events CRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until 
they have returned to normal or an adequate explanation of the abnormality is found. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an AE, should not be reported as 
such. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE 
unless it meets the definition of serious as defined below and/or as per investigator’s 
discretion. A dose hold or medication for the lab abnormality may be required by the protocol 
in which case the lab abnormality would still, by definition, be an adverse event and must be 
reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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8.2.2
Reporting
For patients who sign the ICF, SAE collection starts at time of study informed consent 
whether the patient is a screen failure or not. To ensure patient safety, every SAE, regardless 
of suspected causality, occurring after the patient has provided informed consent and until at 
least 30 days after the patient has stopped study treatment must be reported to Novartis within 
24 hours of learning of its occurrence.
SAEs considered by the investigator to be possibly related to a biopsy procedure will be 
indicated as such in the AE eCRF. This information will be followed up for 30 days after the 
biopsy procedure
Any SAEs experienced after this 30 day period (should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
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8.3
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
treatment name if available, patient number and instructions for contacting the local Novartis 
CPO (or any entity to which it has delegated responsibility for emergency code breaks) will 
be provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to 
ensure that the investigator and/or back-up can always be reached in case of emergency then 
the procedure above is not required.
Study drug must be held if emergency unblinding is required.
An assessment will be completed by the appropriate site personnel and the CPL after an 
emergency unblinding to assess whether or not study drug must be discontinued and whether 
the patient will be eligible for crossover from placebo to LEE011, if applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
 


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Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
An independent data monitoring committee will not be formed for this phase II study. Patients 
will be closely monitored for safety by participating study sites and Novartis clinical study 
team. Teleconferences with investigators will be held for reviewing reported safety data on 
individual patients as necessary. The Novartis clinical study team will distribute minutes of 
these meetings, including a description of any potential safety signals, to all participating 
investigators. 
8.7
Steering Committee
A Steering Committee consisting of members of the Oncology Translational Medicine 
Leadership Team will be formed for this study. If at any time the monitoring of the study data 
requires a decision to be taken on the continuation of the study, the relevant data (e.g., safety 
data or primary analysis and predictive probability of success (PPOS)) will be communicated 
to the Steering Committee for decision making purposes.
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 and 
sponsor, 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 
 


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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, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's medical record. The investigator must also keep the original signed informed consent 
form (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements. Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and allow modification or verification of the entered data by the investigator staff.
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.
 
 
ECG data collected during the study will be reviewed and processed centrally by 
a specialist CRO. Tumor histology samples collected during the study will be retrospectively 
reviewed by a central pathologist.
Designated investigational site staff will enter the information required by the protocol into 
the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
 


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review the eCRFs and laboratory paper requisition forms for accuracy and completeness and 
will instruct site personnel to make any required corrections or additions. One copy of the 
requisition form will be forwarded to each analytical laboratory with the respective sample(s) 
by the field monitor or by the designated investigational site staff, and one copy will be 
retained at the investigational site.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Oncology Translational Medicine.
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
This is a multi-center, randomized, double blind (investigator and patient), placebo controlled 
phase II study to determine the efficacy and safety of treatment with LEE011 versus placebo 
in patients with progressive relapsed, refractory incurable teratoma. Patients will be 
randomized at a 2:1 ratio to LEE011 or placebo.
 


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Data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation.
It is planned that the data from participating centers in this protocol will be combined, in the 
final safety and efficacy analysis. Data will be summarized with respect to demographic and 
baseline characteristics, efficacy and safety observations and measurements and all relevant 
 measurements using descriptive statistics (quantitative data) and contingency 
tables (qualitative data). 
The primary clinical study report (CSR) will be written based on all patients’ data at the time 
when there are approximately 23 PFS events for the primary efficacy analysis and all patients 
have been followed for PFS for at least 6 months or have discontinued prior to this time for 
disease progression or death, or have withdrawn consent to follow-up or have been lost to 
follow-up. Additional data for patients continuing on study or in any follow-up period past the 
data cutoff date for the primary CSR will be reported in a final CSR once the treatment period, 
safety follow-up, disease progression follow-up and survival follow-up periods have ended for 
all patients as described in Section 7.1.4. In the case when all patients are discontinued from 
study treatment to be enrolled in the LEE011 rollover clinical trial (CLEE011X2X01B), or 
when the study is terminated early (Section 4.4) and no CSR has already been reported, all 
data prior to study termination will be reported in a final CSR. 
Data will be analyzed by the two treatment arms unless stated otherwise. 
All data collected during the optional crossover to LEE011 from placebo will be listed 
separately. This data will be summarized within the planned analyses. The data will not be 
pooled with the data from patients receiving LEE011 from the outset of the study unless 
otherwise specified below. Data collected after progression on LEE011 (in the situation which 
a patient continues to receive the study drug due to clinical benefit) will be listed but will not 
be pooled in analyses with data collected prior to disease progression.
Further details of statistical analysis and reporting will be described in the RAP.
For screen failure patients the eCRF data collected (Section 7.1.1.2) will not be included in 
any analysis but will be reported in the CSR as separate listings.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study drug were assigned by 
randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment arm assigned at randomization. 
The FAS2 will consist of all patients from the placebo arm who had progression per RECIST
and crossed over to the LEE011 arm and received at least one dose of LEE011.
FAS will be the primary population for the analysis of efficacy endpoints.
 


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10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study drug.
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 study drug received when starting therapy with study treatment if the assigned 
treatment was never received.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) will consist of a subset of patients from the safety set who have an 
adequate tumor assessment at baseline, a follow-up tumor assessment ≥8 weeks after starting 
treatment (unless disease progression is observed before that time), and no major protocol 
deviations.
All major protocol deviations leading to exclusion from the PPS will be detailed in the RAP.
Patients will be classified according to treatment received.
The PPS will define the patients used in the sensitivity analysis of the primary endpoint 
(Section 10.4). If the PPS and the FAS are identical, then analyses described by the PPS 
below will not be performed.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively by treatment arm for 
the FAS and FAS2 Categorical data will be presented as frequencies and percentages. For 
continuous data, mean, standard deviation, median, 25th and 75th percentiles (if appropriate), 
minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
10.3.1
Study Treatment 
The actual dose and duration in days of the study drug 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 in the clinical study report. The 
summary data will be presented for all study days as a single category. The FAS and FAS2 
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10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by summarized by ATC term and treatment arm by 
means of contingency tables. The FAS and FAS2 will be used.
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 arm.
10.4
Primary objective
The primary objective of the study is to assess the efficacy of LEE011 compared to placebo in 
patients with relapsed/refractory teratoma with recent progression
10.4.1
Variable
The primary endpoint of the study is PFS, defined as the time from the date of randomization 
to the date of the first documented progression or death due to any cause. PFS will be assessed 
via the local radiology assessment according to RECIST v1.1. If a patient has not had an event, 
PFS will be censored at the date of the last adequate tumor evaluation (Appendix 1).
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy endpoint, PFS will be formally analyzed at the final analysis time point 
(Section 10.8). 
If the estimated hazard ratio at the final analysis is 0.48 or below, it will be considered as 
evidence of clinically relevant efficacy of LEE011 over placebo.
To claim the superiority of LEE011 to placebo, both criteria below need to be satisfied:

The log-rank test p-value (one-sided) is below 0.05

The estimated HR is 0.48 or smaller
The distribution of PFS between the two treatment arms will be compared using the log-rank 
test. The HR will be estimated using the Cox proportional hazard regression model. The 
estimated HR and related two-sided 90% confidence interval (CI) will be provided. 
In addition, PFS will be analyzed using Kaplan-Meier estimates (Kaplan and Meier 1958) 
(including graphical representation) with two-sided 90% confidence interval for median 
survival and survival probabilities for specific time-points (3, 6, 9, 12, 15, 18, 21 and 24 
months) will be presented for each treatment arm.
The final primary analysis of PFS will be conducted when a total of 23 PFS events are 
observed (See Section 10.8 for sample size calculation) and patients have been followed for 
PFS for at least 6 months or have discontinued prior to this time for disease progression or 
death, or have withdrawn consent to follow-up or have been lost to follow-up. This event 
number is associated with 80% power when the underlying hazard ratio is 0.33
 


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(corresponding to 2 months median PFS for placebo versus 6 months median PFS for 
LEE011). 
10.4.3
Handling of missing values/censoring/ discontinuations
For the analysis of PFS, patients without documented disease progression or death are 
censored at the time of last valid tumor assessment documenting non-progression (one of 
complete response, partial response, or stable disease). Patients without any valid post-
baseline tumor assessment response (one of CR, PR, SD, or PD) will be censored on the 
randomization date. Patients who have a PFS event (progression or death) after two or more 
consecutive missing assessments from the last valid tumor assessment will be censored on the 
last valid tumor assessment (or on the date of randomization among those without a post-
baseline tumor assessment).
For patients who have a PFS event (progression or death) after a single missing or non-
adequate tumor assessment, actual date of event will be used.
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 treatment will be summarized 
and listed. 
Other missing data will simply be noted as missing on appropriate tables/listing.
10.4.4
Supportive analyses
The primary analyses described above will also be repeated using the PPS if it differs from the 
FAS.
10.5
Secondary objectives
Please refer to Table 3-1 for the secondary objectives. The following subsections describe the 
analyses of related secondary objectives.
10.5.1
Key secondary objective(s)
None
10.5.2
Other secondary efficacy objectives
A secondary objective is to further assess the efficacy of LEE011 compared with placebo. The 
evaluations of tumor responses will be based on local investigator assessment according to 
RECIST v1.1.
The following endpoints and analyses will be used to further assess the efficacy: 

Overall Survival (OS), defined as the time from date of randomization 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.

Best Overall Response (BOR), defined as the best response recorded from the start of the 
treatment until disease progression/recurrence. Confirmation of complete and partial 
responses must be made at least 4 weeks apart.
 


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
Overall Response Rate (ORR), defined as the proportion of patients with a best overall 
response of CR or PR.

Duration of Response (DOR), defined for responder as the time between the date of first 
documented response (CR or PR) and the date of first documented progression or death 
due to underlying cancer. If progression or death due to underlying cancer has not 
occurred, then the patient is censored at the date of last adequate tumor assessment.

Disease Control Rate (DCR), defined as the proportion of patients with a best overall 
response of CR or PR or SD. 
CT/MRI assessments will be used for all efficacy assessments of anti-tumor activity on study.
BOR, ORR, and DCR at 4 months will be summarized as point estimate and corresponding 
95% exact confidence interval according to Clopper-Pearson method (Clopper and Pearson 
1934). The Kaplan-Meier plots for DOR will also be produced and the median DOR will be 
estimated for all patients who achieve a response of CR or PR.
OS will be analyzed using Kaplan-Meier estimates (including graphical representation) with 
confidence intervals of median survival for each treatment arm. The OS rate at 12 months and 
related 95% CI will be presented for each treatment arm. In addition, median OS and related 
95% CI will be presented for each treatment arm. 
10.5.3
Safety objectives
Another secondary objective is to characterize the safety and tolerability of LEE011 compared 
to placebo. Incidence and severity of AEs and SAEs, changes in laboratory values, 
electrocardiograms and vital signs will be used to assess the safety of LEE011 compared to 
placebo. Dose interruptions and changes will be used to assess the tolerability of LEE011 
compared to placebo.
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment arm with patients classified according to treatment received.
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 drug
2. on-treatment period: from day of first dose of study drug to 30 days after last dose of study 
drug
3. post-treatment period: starting at day 31 after last dose of study drug.
10.5.3.2 Adverse events (AEs)
All AEs recorded during the study will be summarized. The incidence of treatment-emergent 
AEs (new or worsening from baseline) will be summarized by primary system organ class, 
severity based on CTCAE version 4.03, type of adverse event, and relationship to treatment 
arm. Any other information collected (e.g., start/end dates and duration of adverse event, 
severity or relatedness to study medication) will be listed as appropriate. If applicable, these 
will be specified in the RAP.
 


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10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(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.
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by clinical meaningful limit. For laboratory tests where grades are not defined by 
CTCAE, results will be graded by the low/normal/high classifications based on laboratory 
normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment CTCAE Grade 3 or 4 toxicities

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
In addition to the above mentioned tables and listings,
 
 
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 detailed in the RAP modules. 
Additionally, the following outputs will be produced:
ECG
Definitions of notably abnormal resulted detailed in the RAP. 

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality
Cardiac Imaging

Left ventricular heart function evaluations will be summarized and listed. 
Vital signs
Definitions of notably abnormal results detailed in the RAP.

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
 


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10.5.3.5 Tolerability
The tolerability of the study drug will be assessed by summarizing the number of dose 
interruptions or changes. The reason for dose interruption and dose reduction and dose change 
will be listed by patient and summarized by arm.
Cumulative dose, dose intensity and relative dose intensity of LEE011 and placebo will be 
listed by patient and summarized. Categories for relative dose intensity of LEE011 and 
placebo 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.
 


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10.7
Interim analysis
No formal interim analyses are planned.
10.8
Sample size calculation
The sample size is determined based on the primary efficacy endpoint PFS.
Under the hypothesis in Section 10.4.2, 23 PFS events are required for a one-sided type I error 
of α = 0.05 and 80% power to reject H0 when the true log hazard ratio is HR = 0.33 using a 
log-rank test. It is assumed the median PFS for placebo is 2 months and median PFS for 
LEE011 is 6 months. Under an exponential survival model, a 3-fold increase of PFS (or a 
66.7% reduction in the hazard rate) is expected on treatment of LEE011 against placebo.
Patients will be randomized in a 2:1 ratio of LEE011 to placebo. It is assumed that the 
anticipated patient accrual rate will remain constant at 1.5 patients per month for the entire 
study. To observe 23 PFS events by the end of study, 36 patients are required. Assuming a 
15% drop-out rate, a total of approximately 42 patients will be randomized. 
The expected study duration is approximately 24 months (completed study) (inflated by 3 
months in order to take into account for a 15% drop-out rate). 
The sample size calculation was performed using software package EAST 5.4
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
 


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11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
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.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of 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
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
 


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11.5
Publication of study protocol and results
Novartis 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 a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, 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 case report form (CRF) is the primary data collection
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
 


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.
 


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References (available upon request)
Aaronson N, Ahmedzai S, Bergman B et al (1993). The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology- Journal of the National Cancer Institute. Journal of the National 
Cancer Institute 85: 365-376.
Andre F, Fizazi K, Culine, S et al (2000). The growing teratoma syndrome: results of therapy 
and long-term follow-up of 33 patients. European journal of cancer 36: 1389-1394.
Bartek J, Bartkova J, Lukas J. (1997). The retinoblastoma protein pathway in cell cycle 
control and cancer. Experimental cell research 237: 1-6.
Bartkova J, Rajpert-De Meyts E, Skakkebaek, N et al (2003). Deregulation of the G1/S-phase 
control in human testicular germ cell tumours. APMIS : acta pathologica, microbiologica, et 
immunologica Scandinavica 111: 252-265; discussion 265-256.
Clopper C, Pearson E (1934). The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 26: 404-413.
Comiter C, Kibel A, Richie J, et al (1998). Prognostic features of teratomas with malignant 
transformation: a clinicopathological study of 21 cases. The Journal of urology 159: 859-863.
Donadio A, Motzer R, Bajorin D, Kantoff, et al (2003). Chemotherapy for teratoma with 
malignant transformation. Journal of clinical oncology: official journal of the American
Society of Clinical Oncology 21: 4285-4291.
Fayers P, Aaronson N, Bjordal K, et al (2001). The EORTC QLQ-C30 Scoring Manual, 3rd 
edn (Brussels: European Organization for Research and Treatment of Cancer).
Gatcombe H, Assikis V, Kooby D, et al (2004). Primary retroperitoneal teratomas: a review of 
the literature. Journal of surgical oncology 86: 107-113.
Houldsworth J, Reuter V, Bosl G, et al (1997). Aberrant expression of cyclin D2 is an early 
event in human male germ cell tumorigenesis. Cell growth & differentiation: the molecular 
biology journal of the American Association for Cancer Research 8: 293-299.
Hwang I, Shih W, DeCani J (1990). Group sequential designs using a family of type I error 
probability spending functions. Statistics in Medicine 9: 1439-1445.
Kaplan E, Meier P (1958). Nonparametric Estimation from Incomplete Observations, Journal 
of the American Statistical Association. Journal of the American Statistical Association 53: 
457-481.
Mego M, Reckova M, Sycova-Mila Z, et al (2007). Bevacizumab in a growing teratoma 
syndrome. Case report. Annals of oncology: official journal of the European Society for 
Medical Oncology 18: 962-963.
Necchi A, Colecchia M, Nicolai, N, et al (2011). Towards the definition of the best 
management and prognostic factors of teratoma with malignant transformation: a single-
institution case series and new proposal. BJU international 107: 1088-1094.
Ornadel, D., Wilson, A., Trask, C.et al (1995). Remission of recurrent mature teratoma with 
interferon therapy. Journal of the Royal Society of Medicine 88, 533P-534P.
 


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Reilly, M.C., Zbrozek, A.S., and Dukes, E.M. (1993). The validity and reproducibility of a 
work productivity and activity impairment instrument. PharmacoEconomics 4, 353-365.
Rustin, G.J., Kaye, S.B., Williams, C.J. et al (1984). Response of differentiated but not 
anaplastic teratoma to interferon. British journal of cancer 50, 611-616.
Schmidt, B.A., Rose, A., Steinhoff, C et al. (2001). Up-regulation of cyclin-dependent kinase 
4/cyclin D2 expression but down-regulation of cyclin-dependent kinase 2/cyclin E in 
testicular germ cell tumors. Cancer research 61, 4214-4221.
Sheinfeld, J., Motzer, R.J., Rabbani, F.et al (2003). Incidence and clinical outcome of patients 
with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection 
for clinical stages I and IIA nonseminomatous germ cell tumors. The Journal of urology 170, 
1159-1162.
Smith, H.O., Berwick, M., Verschraegen, C.F. et al (2006). Incidence and survival rates for 
female malignant germ cell tumors. Obstetrics and gynecology 107, 1075-1085.
Spiess, P.E., Kassouf, W., Brown, G.A.et al (2007). Surgical management of growing 
teratoma syndrome: the M. D. Anderson cancer center experience. The Journal of urology 177, 
1330-1334; discussion 1334.
Strohmeyer, T., Reissmann, P., Cordon-Cardo, C. et al (1991). Correlation between 
retinoblastoma gene expression and differentiation in human testicular tumors. Proceedings of 
the National Academy of Sciences of the United States of America 88, 6662-6666.
van der Gaast, A., Kok, T.C., and Splinter, T.A. (1991). Growing teratoma syndrome 
successfully treated with lymphoblastoid interferon. European urology 19, 257-258.
Vaughn, D.J., Flaherty, K., Lal, P.et al (2009). Treatment of growing teratoma syndrome. The 
New England journal of medicine 360, 423-424.
 


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14
Appendices
14.1
Appendix 1 – Guidelines for response duration of overall 
response, TTF, TTP, progression free survival and overall 
survival (based on RECIST v1.1) harmonization of efficacy 
analysis of solid tumor studies
Document type:
TA Specific Guideline
Document status:
Version 3.1:
29-Nov-2011
Version 3:0:
19-Oct-2009
Version 2:0:
18-Jan-2007
Version 1:0:
13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):
Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
LPLV
Last patient last visit
MRI
Magnetic resonance imaging
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
 


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.28
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.4
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.26.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.
 


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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.
14.1.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.1.26.
14.1.6
Methods of tumor measurement – general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
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 Novartis calculated UNK response may be accepted from 
the investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
 


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


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


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14.1.12
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking 
as reference the smallest sum of diameter of all target lesions recorded at or after 
baseline. In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3. Methodology change (see Section 14.1.6).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline 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, 
 


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in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0” mm 
should be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.
 


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14.1.13
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-
target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have not 
been assessed or have been assessed using a different method than baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase. FDG-PET: can complement CT scans in assessing progression 
(particularly possible for ‘new’ disease). See Section 14.1.6.
14.1.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when no non-target lesions are identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.1.8
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
 


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14.1.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

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 
 


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other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
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.
 


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Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of (Dent and Zee 2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach).
14.1.18
Time to event variables
14.1.19
Progression free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.
14.1.21
Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.
 


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Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
14.1.22
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment.
14.1.23
Duration of response
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by (Morgan 1988)
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates.
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in (Ellis et al 2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
 


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The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression.
14.1.24
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 14.1.23. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.25
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
 


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assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.25).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.26
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
 


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special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease.
14.1.27
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.
 


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Based on definitions outlined in Section 14.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one 
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more 
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1. =Definitions can be found in Section 14.1.25.
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in
Section 14.1.25.
3. =The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.

In the case of two or missing assessments (situation C2), option (3) may be considered 
jointly with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity 
analysis 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 
 


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without documented PD should be followed for progression after discontinuation of 
treatment. However, option (2) may be used as sensitivity analysis. If progression is 
claimed based on clinical deterioration instead of tumor assessment by e.g. CT-scan, 
option (2) may be used for indications with high early progression rate or difficulties to 
assess the tumor due to clinical deterioration.

Situation F: New cancer therapy given: the handling of this situation must be specified 
in detail in the protocol. However, option (1), i.e. censoring at last adequate assessment 
may be used as a default in this case.

Additional suggestions for sensitivity analyses

Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by 
replacing in Table 14-5 the “Date of last adequate assessment” by the “Date of previous 
scheduled assessment (from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.

In addition, analyses could be repeated using the Investigators’ assessments of response 
rather than the calculated response. The need for these types of sensitivity analyses will 
depend on the individual requirements for the specific study and disease area and have to 
be specified in the protocol or RAP documentation.
14.1.28
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.1.29
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.30
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the 
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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

Patient/parent/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)

Transfer to another Novartis clinical study that continues to provide LEE011 (e.g. 
CLEE011X2X01B)
14.1.31
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Patient/parent/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor

Transfer to another Novartis clinical study that continues to provide LEE011 (e.g. 
CLEE011X2X01B)
14.1.32
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
 


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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 Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.35
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.36
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
 


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14.1.37
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.39
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. reason 
“Sponsor decision” on study evaluation completion page), when patients are not followed 
for progression after treatment completion or when only UNK assessments are available 
just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
 


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


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14.2
Appendix 2 - ECOG/WHO performance status scale
Table 14-6
ECOG performance status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
 


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14.4
Appendix - 4 Prohibited concomitant medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Administration of study 
drug could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or LEE011. 
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
Database (release date: 29 Oct 2012), which was compiled from the Indiana University 
School of Medicine’s “Clinically Relevant” Table and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications for Dosing and Labeling (February 2012), and the University of Washington’s 
Drug Interaction Database. These lists are not comprehensive and are only meant to be used 
as a guide. Please contact the medical monitor with any questions.
14.4.1
Prohibited medications
Table 14-7
List of prohibited medications during LEE011 treatment
Category
Drug Name
Strong CYP3A Inhibitors 
boceprevir, 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
Strong CYP3A Inducers 
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort2, rifabutin, 
phenobarbital, mitotane, enzalutamide
CYP3A substrates with NTI1
quinidine, astemizole, terfanadine, cyclosporine, sirolimus, tacrolimus, 
diergotamine, cisapride, ergotamine, pimozide, alfentanil, fentanyl, thioridazine, 
diergotamine, dihydroergotamine, ergotamine
Medications that carry a strong 
risk for QT prolongation/TdP
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cisapride, citalopram, clarithromycin, cocaine, 
disopyramide, dofetilide, domperidone, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, grepafloxacin, halofantrine, haloperidol, ibutilide, 
levofloxacin, levomethadyl, mesoridazinet), methadone, moxifloxacin, 
ondansetron, pentamidine, pimozide, probucol, procainamide, quinidine, 
sevoflurane, sotalol, sparfloxacin, sulpiride, terfenadine, thioridazine, 
vandetanib
Other investigational and 
antineoplastic therapies
Other investigational anticancer therapies including chemotherapy, biologic or 
radiation therapy, and surgery must not be used while the patient is on the 
study. If such agents are required for a patient then the patient must be 
discontinued from the study.
Herbal medications
Herbal preparations/medications are prohibited throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, and ginseng. Patients should stop using these herbal 
medications 7 days prior to first dose of study drug.
Hematopoietic growth factors
Hematopoietic growth factors (e.g. erythropoietins, G-colony stimulating factor 
(CSF) and GM-CSF) are not to be administered for primary prophylaxis. Use of 
these drugs should be reserved to patients with severe neutropenia and anemia 
as per the labeling of these agents or as dictated by local practice (see also the 
guidelines established by the American Society of Clinical Oncology (ASCO)).
Palliative radiotherapy
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Category
Drug Name
may be carried out if required. Whenever possible, these patients should have a 
tumor assessment of the lesion(s) before they actually receive the radiotherapy 
in order to rule out progression of disease. In case of PD, patients should 
discontinue treatment. No dose modification of study treatment is needed 
during radiotherapy.
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
2 Herbal product
P-gp inducer
Table 14-8
List of medications to be used with caution1 during LEE011 treatment
Category
Drug Name
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 sphenanthera4 , cimetidine, 
lomitapide
Moderate CYP3A 
Inducers
bosentan, efavirenz, etravirine, modafinil, nafcillin, genistein, ritonavir, thioridazine, 
tipranavir, semagacestat, talviraline, lopinavir, lersivirine
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
Known inhibitors of 
BSEP
atorvastatin, cerivastatin, cyclosporine, glyburide, reserpine, rifampicin, troglitazone, 
valinomycin,
Sensitive substrates of 
MATE1 and OCT2
acyclovir, cimetidine, ganciclovir, fexofenadine1, metformin1, procainamide, topotecan, 
glycopyrronium1, topotecan, 6-beta-hydroxycortisol, amantadine, carboplatin, cisplatin, 
histamine, lamivudine, linagliptin, metformin, oxyplatin, oxybutynin, phenformin, 
picoplatin, pramsorafenib, tropisetron, trospium, varenicline, umeclidinium
Sensitive substrates of 
BCRP
rosuvastatin and sulfasalazine
Medications that carry 
a possible risk for QT 
prolongation
alfuzosin, apomorphine, aripiprazole, atazanavir, bedaquiline, bortezomib, bosutinib, 
clozapine, crizotinib, dabrafenib, dasatinib, dexmedetomidine, 
dihydroartemisinin+piperaquine, dolasetron, eribulin, famotidine, felbamate, fingolimod, 
foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, iloperidone, isradipine, 
lapatinib, lithium, mifepristone, mirabegron, mirtazapine, moexipril/hctz, nicardipine, 
nilotinib, norfloxacin, ofloxacin, olanzapine, oxytocin, paliperidone, pasireotide, 
pazopanib, perflutren lipid microspheres, pipamperone, promethazine, quetiapine, 
ranolazine, rilpivirine, risperidone, roxithromycin, saquinavir, sertindole, sorafenib, 
sunitinib, tacrolimus, tamoxifen, telavancin, telithromycin, tetrabenazine, tizanidine, 
tolterodine, toremifene, vardenafil, vemurafenib, venlafaxine, vorinostat, ziprasidone
1Any drug mentioned in the above list should be contraindicated if they are excluded based on any other exclusion 
criteria as specified in  of the Study Protocol or listed in Table 14-1
2Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
coadministered with a potent inhibitor.
3NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
 

SAP_001.pdf: 
Oncology Early Clinical Development
LEE011
Clinical Trial Protocol CLEE011X2201 / NCT02300987
A randomized, blinded, placebo-controlled, phase II trial of 
LEE011 in patients with relapsed, refractory, incurable 
teratoma with recent progression
Statistical Analysis Plan - Amendment 1
Author:
 Trial Statistician
Document type:
RAP Documentation
Document status:
Final 
Release date:
07-Dec-2016
Number of pages:
22
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted (Current)
24-
Jun-
2015
Prior 
to 
DB 
lock
Creation 
of 
initial 
version
N/A - First version
NA
07-
Dec-
2016
Prior 
to 
DB 
lock
Since the 
enrollment 
in 
the 
study was 
halted 
after only 
a 
few 
patients 
treated, 
short 
close-out 
CSR to be 
produced.
Aligned 
to 
Short 
close-out 
CSR 
guideline

[Protocol Section 10.3.1 Study 
Treatment]: The actual dose, dose 
intensity, relative dose intensity 
and total daily doses of each agent 
will not be summarized or listed. 

[Protocol Section 10.3.2 
Concomitant therapies]: 
Concomitant medications and 
significant non-drug therapies 
prior to and after the start of the 
study drug treatment will not be 
summarized or listed.

[Protocol Section 10.3.3 
Compliance]: The listing of 
patients with protocol deviations 
will be provided; no summary 
tables will be produced. 

[Protocol Section 10.4.2] The 
primary efficacy endpoint, PFS 
will not be analyzed. Log-rank 
test, HR estimates and related 
confidence interval and Kaplan-
Meier estimates with confidence 
interval for median survival and 
survival probabilities will not be 
performed.

[Protocol Section 10.5.2 Other 
secondary efficacy objectives]: 
BOR, ORR and DCR will not be 
summarized and corresponding 
confidence interval will not be 
produced. Kaplan-Meier plots for 
DOR will not be produced and the 
median DOR will not be 
estimated. Kaplan-Meier estimates 
for OS with confidence intervals 
will not be produce and OS rate 


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted (Current)
and related confidence interval 
will not be performed. Listing of 
Overall response, time to 
progression time to onset and 
duration of overall response will 
not be provided. Waterfall plot 
will not be produced.

[Protocol Section 10.5.3 Safety 
objectives]: Laboratory 
abnormalities, ECG, Cardiac 
Imaging and vital signs summary 
tables and listings will not be 
provided. Tolerability of the study 
drug will not be summarized and 
reason for dose interruption, dose 
reduction and dose change will not 
be listed by patient or summarized. 


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Table of contents
Table of contents .................................................................................................................4
1
Introduction .........................................................................................................................6
6
1.2
Objectives and endpoints.........................................................................................7
1.3
Data Analysis...........................................................................................................8
1.4
CSR related reporting events...................................................................................8
2
Definitions and general methodology .................................................................................9
2.1
General definitions...................................................................................................9
2.1.1
Study drug...............................................................................................9
2.1.2
Assessment windows, baseline and post baseline definitions, 
missing data handling..............................................................................9
2.2
Analysis sets ..........................................................................................................14
2.3
Interim analysis......................................................................................................15
3
Statistical methods used in reporting.................................................................................15
3.1
Enrollment status ...................................................................................................16
3.2
Patient disposition, background and demographic characteristics ........................16
3.2.1
Patient disposition.................................................................................16
3.2.2
Protocol deviations................................................................................16
3.2.3
Background and demographic characteristics.......................................16
3.2.4
Medical History.....................................................................................16
3.2.5
Prior antineoplastic therapy...................................................................16
3.2.6
Diagnosis and extent of cancer .............................................................17
3.2.7
Other baseline characteristics................................................................17
3.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................17
3.3.1
Study medication...................................................................................17
3.3.2
Prior and concomitant medication ........................................................17
3.4
Analysis of the primary variable(s) .......................................................................17
3.4.1
Primary variable(s)................................................................................18
3.4.2
Statistical model....................................................................................18
3.4.3
Supportive analyses...............................................................................18
3.4.4
Sample size calculation.........................................................................18
3.5
Efficacy evaluation (Secondary 
 Objectives)...............................19
3.6
Safety evaluation ...................................................................................................19
3.6.1
Adverse event........................................................................................19


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3.6.2
Deaths....................................................................................................20
3.6.3
Laboratory data .....................................................................................20
3.6.4
Tolerability............................................................................................20
20
21
21
4
Change to protocol specified analyses ..............................................................................21
5
References .........................................................................................................................22


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1
Introduction
This document describes the detailed statistical methodology for the Report Analysis Plan 
(RAP) of study CLEE011X2201 Protocol Amendment 2. The data will be analyzed by 
Novartis and/or designated CRO. It is planned that the data from all centers that participate in 
this protocol will be used. 
The purpose of the CSR is to report the assessment of clinical efficacy and safety of the 
LEE011 in patients with relapsed, refractory, incurable teratoma with recent progression.
The list of tables to provide at each analysis will be detailed in Module 7.
All changes to the planned analysis described in Modules 3, 7 and 8 required before or after 
database lock will be made through an amendment or an addendum, respectively. Note that 
obvious corrections will be made at the time of analysis to address minor formatting or 
spelling mistakes present in RAP modules without the need to amend these modules.


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1.2
Objectives and endpoints
The study objectives and corresponding endpoints are shown in Table 1-1.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To assess the efficacy of LEE011 compared 
to placebo in patients with 
relapsed/refractory teratoma with recent 
progression
PFS as per RECIST v1.1 (by local 
investigator assessment).
Secondary
To assess other measures of efficacy of 
LEE011 compared with placebo
BOR, ORR, DOR, DCR at 4 months as 
per RECIST v1.1 and OS,
OS Rate at 12 months.
To assess safety and tolerability of LEE011 
Incidence and severity of adverse events 
and serious adverse events, changes in 


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compared with placebo
laboratory values, electrocardiograms, 
and vital signs will be used to assess the 
safety as per CTCAE v.4.03. Dose 
interruptions and changes will be used to 
assess the tolerability.
1.3
Data Analysis
Data will be analyzed by Novartis and/or designated CRO according to the data analysis 
section 10 of the clinical study protocol [CLEE011X2201] and will be available in CSR 
Appendix 16.1. Important information will be given in the following sections and details are 
provided as applicable in CSR Appendix 16.1.9.
All statistical analysis will be performed using SAS® version 9.3.
1.4
CSR related reporting events
The following points will guide the production of all or subset of the planned analyses:

The primary CSR includes all outputs described in Module 7 based on all patients’ data at 
the time when there are approximately 23 PFS events for the primary efficacy analysis and 
all patients have been followed for PFS for at least 6 months or have discontinued prior to 
this time for disease progression or death, or have withdrawn consent to follow up or have 
been lost to follow up or if the study is terminated early [Protocol CLEE011X2201 
Section 4.4].

If there will be additional data for patients continuing on study or in survival follow-up 
past the data cutoff date for the primary CSR, they will be reported in a final CSR once the 


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treatment period, safety follow-up, disease progression follow-up and survival follow-up 
periods have ended for all patients as described in [Protocol CLEE011X2201 Section 
7.1.4]. The content of the final CSR is determined based on instructions outlined in [OTM 
Guidelines for Patients that Continue Beyond Study Data Cutoff].
2
Definitions and general methodology
2.1
General definitions
2.1.1
Study drug
Study drug is defined as LEE011 or matching placebo.
Study treatment is defined as LEE011 or matching placebo.
2.1.2
Assessment windows, baseline and post baseline definitions, missing 
data handling
2.1.2.1
Date of first administration of study drug/ treatment
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug was administered and recorded on the dose administration DAR eCRF. The date 
of first administration of study drug will also be referred as start of study drug.
2.1.2.2
Date of last administration of study drug/ treatment
The date of last administration of study drug is defined as the last date when a nonzero dose 
was administered and recorded on DAR (e)CRF. 
2.1.2.3
Study drug exposure
The following algorithm will be used to calculate the duration of study drug exposure (in 
cycles and in days) for patients takes at least 1 dose of the study drug:
Duration of exposure (days) = last date of exposure to study drug – date of first administration 
of the study drug + 1
For patients who did not take any drug, the duration of exposure is defined as zero. 
2.1.2.4
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date (randomization date).
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the assessment and the start of study treatment plus 1. (Note: if an adverse 
event starts before the start of study treatment the study day displayed on the listing will be 
negative and will be calculated as the difference between the date of the assessment and the 
start of study treatment.).


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The study day for all other non-safety assessments (i.e., tumor assessment, death, disease 
progression, tumor response, ECOG performance status, 
 
) is defined as the difference between the date of the event and the randomization date 
plus 1. In other words, all efficacy time-to-event variables (e.g. progression-free survival, 
overall survival, time to response) will be calculated from date of randomization. (Example: if 
randomization date is 15DEC2013, start of study drug is on 18DEC2013, and the date of 
death is 28DEC2013 then the study day when the death occurred is 14).
The study day will be displayed in data listings.
Study day is not to be used in numerical computations, for example in calculating exposure.
Cycle definition
The study day for all assessments is calculated using the randomization date as Day 1. 
The cycle number and day within cycle attributed to a visits or assessment will be derived 
according to the following rules:

C1D1 (cycle 1 day 1) coincides with the start date of drug/treatment

All pre-treatment assessments are displayed as Cycle 0 with a negative day (e.g., Day -1
for the day before the patient started treatment) or with day 1. 

Day 1 of a cycle corresponds to the day reported by investigator on the start of cycle log 
form.

For all cycles but the last, the end date of a cycle is defined as the day before Day 1 of the 
following cycle as recorded on the cycle log form.

The end date of the last cycle is when treatment administration is permanently 
discontinued at the latest of the following days:

Date of last administration

28 days after the first day of the last cycle or day of patient’s death if earlier when 
date of last administration is not known

All post-cycles assessments are displayed as follow-up and with, by analogy, Day 1 
representing the first day after the end of the last cycle.
The duration (in days) of a cycle is defined as the cycle end date – cycle start date + 1.
Cycle number and day within cycle are computed to be displayed in listings only.
2.1.2.5
Baseline
Baseline is considered as the last available assessment performed or value measured within 28 
days before the first administration of study treatment, unless otherwise stated under the 
related assessment section. Baseline could be the day before first treatment administration or 
the same day as first treatment administration if a pre-dose assessment/value is available (e.g., 
ECG, 
).


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If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times.
For those patients eligible to crossover to LEE011 treatment after initial progression, baseline 
will be adjusted to the last assessment prior to secondary treatment phase. Re-baseline could 
be the day before first treatment after crossover administration or the same day as first 
treatment administration after crossover if a pre-dose assessment/ value is available. 
If time is not recorded, a specific assessment performed the day of first dose administration 
will be considered as baseline if, according to protocol, it should be performed before the first 
dose.
If patients have no value as defined above, the baseline results will be set to missing.
2.1.2.6
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment
assessments/events. On-treatment assessment/event is defined as any assessment/event 
obtained in the time interval:
Date of first administration of study treatment through the date of last administration of study 
treatment + 30 days, i.e. including the lower and upper limits. (Note: However, the calculation 
of study treatment duration may use different rules as specified in Section 3.3.1.1.)
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF.
If the last date of study treatment is missing, on-treatment assessments/events include any 
assessment/event recorded in the database and which occur after the start date of study 
treatment.
Data listings will include all assessments/events, flagging those which are not on-treatment 
assessments/events.
Note: The date of first administration of study treatment in the randomized treatment phase 
and the date of last administration of study treatment in the randomized treatment phase are 
defined in sections 2.1.3.1 and 2.1.3.2, respectively.
For patients who crossed over to LEE011, the placebo group will include all events before the 
date of first administration of LEE011 and will not include the 30 days are described above. 
While the LEE011 crossed over group will include all events after the date of first 
administration of LEE011 and will include the 30 days.
2.1.2.7
Last contact date
The last contact date will be derived for patients not known to be dead at the analysis cut-off
using the last complete date among the following:

All assessment dates (e.g. vital signs assessment, performance status/
,). 
Note, only a true on study assessment date or patient contact date will be used. If there is a 


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visit date without evidence of any actual assessment performed that date will not be used. 
No dates post cut-off will be used.

Medication dates including study medications, concomitant medications, and 
antineoplastic therapies administered after study treatment discontinuation.

Adverse event dates.

Last contact date collected on the ‘Survival information’ eCRF (only if the patient status is 
not unknown).

Randomization date.

The cut-off date will not be used for last contact date, unless an actual assessment or 
patient contact was performed.
Important note: imputed dates (e.g. the analysis cut-off date programmatically imputed to 
replace the missing end date of a dose administration record) will not be used to derive the 
last contact date.
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.1.2.8
Scheduled study visit and window for the analysis
In order to summarize longitudinal data per time point, assessments will be allocated to visits 
using predefined time windows. Unless otherwise specified, when more than one assessment 
is available for a visit, all assessments will be listed under the visit while only the assessment 
closest to the planned day for the visit will be used for summaries and analyses.  
Time windows are provided in Table 2-1. Time windows for measurements to be described by 
visit.


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Table 2-1
Time windows
Assessment
Visit
Time Window
Efficacy Assessments
Tumor response for 
imaging assessments
Screening
Baseline
C3D1
Week 8 ± 3 days
every 8 weeks (2 cycles) during the first 12 month, 
i.e. C5D1 ± 3 days, C7D1 ± 3 days, C9D1 ± 3 days, C11D1 ± 3 days, 
C13D1 ± 3 days
C16D1
Week 60 ± 3 days
every 12 weeks (3 cycles) …
i.e. C19D1 ± 3 days, C22D1 ± 3 days, C25D1 ± 3 days …
EOT
EOT - 28 days
Notes:
C = cycle, D = Day
All other assessments (i.e. laboratory evaluations etc.) the reported visit will be used
2.1.2.9
Imputation rule of partial or missing dates/data
Imputation rule of partial or missing dates 
The following rule will be applied to handle partial dates. When the day is missing, it is 
imputed to the 15th of the month (e.g., DEC2007 imputed to 15DEC2007). When the day and 
month are both missing then the date is imputed to July 1st of that year (e.g., 2007 imputed to 
01JUL2007). All imputed data are flagged in the listings.
Standard imputation rules for adverse events (AEs) and concomitant medications partial or 
missing dates will be used. 
For computation of time intervals (e.g. elapse time between initial diagnosis to first 
recurrence/relapse), time interval should be set to missing when the imputation rule leads to a 
negative value.
As of the date of data cutoff for the purposes of reporting, continuing events (e.g. adverse 
events, concomitant medication, etc.) will be summarized using the cut-off date as the date of 
completion, with an indication within listings that the event is continuing.
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event with the appropriate censoring.
Handling of missing data
Unless otherwise specified missing data will not be imputed. Handling of missing data will 
depend on the nature of the data:

Baseline characteristics: number of patient with missing data will be reported and 
descriptive statistics will be computed on patients with non-missing data.

RECIST best overall response (BOR): patients with missing or unknown BOR will be 
considered as failure in the overall response rate computation (see Section 3.5.1.1)


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
Time-to-event endpoints: appropriate statistical methods will be used to account for 
censored patients (see Section 3.5.1.2) 

 laboratory data, ECG data, vital signs: number of patient with 
missing data will be reported and descriptive statistics will be computed on patients with 
non-missing data.
Missing data will simply be noted as missing on appropriate tables/listings.
2.2
Analysis sets 
For inclusion in any analysis set it is required that a patient has correctly consented and has 
received at least one dose of study treatment. For those incorrectly consented patients, they 
will be excluded from all analysis.
The following analysis sets which will be derived prior to database lock will be used.
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study drug were assigned by 
randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment arm assigned at randomization.
The FAS2 will consist of all patients from the placebo arm who had progression per RECIST
v1.1, crossed over to the LEE011 arm and received at least one dose of LEE011.
Note that patients who were screened and are eligible but never started treatment will not be 
included in the FAS and FAS2. 
The FAS and FAS2 will be used for all listings of raw data of placebo and LEE011 arm, and 
LEE011 crossover arm, respectively. Unless otherwise specified, FAS will be the default 
analysis set used for all summary tables and figures. 
Safety Set
The safety set includes all randomized patients who received at least one dose of study drug, 
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, which is defined as:

The treatment assigned if it was received at least once, or

The first study drug received when starting therapy with study treatment if the assigned 
treatment was never received.
Table 2-2 summarized protocol deviations leading to exclusion from analysis sets. Severity 
codes are defined in [Validation and Analysis Planning (VAP) Module 3]. Patients were 
excluded from the analysis sets defined above based on the protocol deviations entered in the 
database. 


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Table 2-2
Summary of protocol deviations leading to exclusion from analysis 
sets
Analysis set
Protocol deviations [severity codes leading to exclusion]
Full analysis set
Patient not correctly consented [8]
Patient who did not receive at least one dose of study drug [8]
Full analysis set 2
Patient who did not receive at least one dose of study drug [8]
Safety set
Patient not correctly consented [8]
Patient who did not receive at least one dose of study drug [8]
Patient has no safety assessments (including no record that
No adverse event occurred) [5]
[8] exclude from all analysis / [5] exclude from all safety analyses / [1] exclude from per protocol set / 
2.3
Interim analysis
Not applicable.
3
Statistical methods used in reporting
Data will be summarized with respect to demographic and baseline characteristics, and safety 
observations using descriptive statistics (quantitative data) and contingency tables (qualitative 
data). They will be reported using FAS.
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. 
Listing will be reported separately for:
(a) Patients randomized in placebo arm, until they stop to switch to LEE011 or 
discontinued the study, whichever occurs first
(b) Patients randomized in LEE011 arm
(c) Patients who crossover to LEE011 arm from the time of first LEE011 dose
Summary tables will be reported only for patients in (a) and (b) specified above.
Listings of all raw data will be produced and ordered by treatment arm, center, country and 
patient.  Unless otherwise specified, if multiple measurements are available for one time point 
(or period), an average will be provided to represent the time point (or time period). Unless 
specified otherwise, all percentage is with respect to big N.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the only information collected on the eCRF is the 
screening log and the demography pages.  These will not be included in any analysis, but will 
be reported in the CSR as separate listings.


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3.1
Enrollment status
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.2
Patient disposition, background and demographic 
characteristics
The FAS will be used for all baseline disease characteristics and demographic summaries and 
data listings.
Baseline demographic, reasons for screen failure and serious adverse events will be listed for 
screened failure patients. 
3.2.1
Patient disposition
The FAS will be used for the patient disposition summaries. Based on the four eCRF pages 
‘End of Treatment Phase Disposition’, ‘End of Post Treatment Phase Disposition’, ‘End of 
Crossover disposition’ and ‘End of Post Treatment Phase Disposition 2’ will be combined by 
treatment.  A listing of study completion by treatment will be produced. Patients are 
considered to be ongoing if they have not discontinued due to any reason (e.g., disease 
progression, AE, withdrawn consent).
3.2.2
Protocol deviations 
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.2.3
Background and demographic characteristics
Background and demographic characteristics including age, gender, race, ethnicity, height, 
weight, ECOG performance status, tumor type and medical conditions will be listed and 
summarized using descriptive statistics. The summaries will be based on the assessments from 
the screening visit (baseline). The FAS and FAS2 (for listing) will be used.
In addition, the following derived variables derived from the demographic eCRF will be 
described:

age groups summarized by class (<65, ≥65 years)

Body mass index (BMI) calculated as weight/(height**2) (kg/m2) where weight is 
measured in kg and height in m 
3.2.4
Medical History
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.2.5
Prior antineoplastic therapy
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.


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3.2.6
Diagnosis and extent of cancer
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.2.7
Other baseline characteristics
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
3.3.1
Study medication
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated.  See details in Section 4.
3.3.1.1
Duration of study treatment exposure
The following algorithm will be used to compute the duration of study treatment exposure for 
patients who took at least 1 dose of any of the components of the study treatment:
Duration of exposure (days) = (last date of exposure to any study treatment component) –
(date of first administration of any treatment component) + 1.
Both date of first administration of study treatment and last date of exposure to study 
treatment are defined in Section 2.1.3.3 and Section 2.1.3.5, respectively. 
For patients who did not take any drug the duration of drug exposure is by definition equal to 
zero. 
3.3.2
Prior and concomitant medication
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.4
Analysis of the primary variable(s)


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3.4.1
Primary variable(s)
The primary endpoint of the study is PFS, defined as the time from the date of randomization
to the date of the first documented progression or death due to any cause. PFS will be assessed
via the local radiology assessment according to RECIST v1.1. If a patient has not had an event, 
PFS will be censored at the date of the last adequate tumor evaluation [Protocol 
CLEE011X2201 Appendix 1].
3.4.2
Statistical model
The primary efficacy endpoint, PFS will be formally analyzed at the final analysis time point 
[Protocol CLEE011X2201 Section 10.8].
If the estimated hazard ratio at the final analysis is 0.48 or below, it will be considered as 
evidence of clinically relevant efficacy of LEE011 over placebo.
To claim the superiority of LEE011 to placebo, both criteria below need to be satisfied:

The log-rank test p-value (one-sided) is below 0.05

The estimated HR is 0.48 or smaller
The distribution of PFS between the two treatment arms will be compared using the log-
rank test. The HR will be estimated using the Cox proportional hazard regression model. The 
estimated HR and related two-sided 90% confidence interval (CI) will be provided.
In addition, PFS will be analyzed using Kaplan-Meier estimates [Kaplan and Meier 1958]
(including graphical representation) with two-sided 90% confidence interval for median 
survival and survival probabilities for specific time-points (3, 6, 9, 12, 15, 18, 21 and 24 
months) will be presented for each treatment arm.
The final primary analysis of PFS will be conducted when a total of 23 PFS events are 
observed (See [Protocol CLEE011X2201 Section 10.8] for sample size calculation) and 
patients have been followed for PFS for at least 6 months or have discontinued prior to this 
time for disease progression or death, or have withdrawn consent to follow up or have been 
lost to follow up. This event number is associated with 80% power when the underlying 
hazard ratio is 0.33 (corresponding to 2 months median PFS for placebo versus 6 months 
median PFS for LEE011).
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.4.3
Supportive analyses
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.4.4
Sample size calculation
The sample size is determined based on the primary efficacy endpoint PFS.
Under the hypothesis in Section 3.4.2, 23 PFS events are required for a one-sided type I error 
of α = 0.05 and 80% power to reject H0 when the true log hazard ratio is HR = 0.33 using a 


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log-rank test. It is assumed the median PFS for placebo is 2 months and median PFS for 
LEE011 is 6 months. Under an exponential survival model, a 3-fold increase of PFS (or a 
66.7% reduction in the hazard rate) is expected on treatment of LEE011 against placebo.
 
 
The expected study duration is approximately 24 months (completed study) (inflated by 3 
months in order to take into account for a 15% drop-out rate).
The sample size calculation was performed using software package EAST 5.4.
3.5
Efficacy evaluation (Secondary 
Objectives)
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.
3.6
Safety evaluation
The assessment of safety is based on the type of AEs and frequency of AEs as well as on the 
number of laboratory values that fall outside of pre-determined ranges (Common Toxicity 
Criteria [CTC] version 4.03 grading limits or normal ranges as appropriate). 
The Safety set will be used for summaries and listings of all safety data in Section 14 of the 
CSR. Safety analyses will be performed per treatment received (see Section 2.1.1.2). The FAS 
will be used for Section 16 of the CSR, including for safety listings. These listings will be 
displayed per intended treatment as per all analyses performed on the FAS (see Section 2.2). 
Differences between treatment received and intended treatment, if any, will be provided in a 
listing. 
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. All safety assessments will be listed, and those collected later 
than 30 days after study treatment discontinuation will be flagged.
For patients who crossed over to LEE011, the placebo group will include all events before the 
date of first administration of LEE011 and will not include the 30 days are described above. 
While the LEE011 crossed over group will include all events after the date of first 
administration of LEE011 and will include the 30 days.
3.6.1
Adverse event
Adverse events are 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) 
will not be used since this information will be collected on the “End of Treatment”,  “Study 
evaluation completion” or “Survival information” CRF pages. 


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Separate summaries and listing for adverse events (AEs) and serious AEs (SAEs) recorded 
during the study, and all death (on-treatment and post-treatment, with appropriate flag 
variable to identify on-treatment death) will be provided. Additional summaries and listing
based on the relationship to study drug by treatment, study drug discontinuation, requiring 
dose adjustment or delay will be produced.Listing and summaries will be produced according 
to the following rules: 

Patients reporting and experiencing multiple occurrences of a specific AE will have 
occurrences listed but will be counted only once in the appropriate event 
category/class and according to the worst observed grade within summary tables. 

AEs will be summarized by presenting the number and percentage of patients having 
at least one AE, and having at least one AE in each primary system organ class and for 
each preferred. AE will be sorted by descending frequency or alphabetically (system 
organ class [SOC] and preferred term [PT]).

An adverse event of special interest is a grouping of adverse events that are of 
scientific and medical concern specific to compound LEE011. These groupings are 
defined using MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high 
level group terms), HLT (high level terms) and PTs (preferred terms). Customized 
SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a customized 
group of search terms which defines a medical concept for which there is no official 
SMQ available or the available SMQ does not completely fit the need. It may include 
a combination of single terms and/or an existing SMQ, narrow or broad. For each 
specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on-treatment period will be summarized. Summaries of these AESIs 
will be provided by treatment, (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, fatal outcome, etc.).
A listing of all grouping levels down to the MedDRA preferred terms used to define 
each AESI will be generated.
3.6.2
Deaths
Summary of all deaths will be produced by treatment, system organ class and preferred term. 
All deaths will be listed for the FAS, on treatment deaths will be flagged. 
3.6.3
Laboratory data
Summary of notable hepatic laboratory values will be produced by treatment. Liver function 
test values will be listed. No other laboratory data will be analyzed.
3.6.4
Tolerability
These analyses will not be provided, since the enrollment in the study was halted after only a 
few patients treated. See details in Section 4.


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Change to protocol specified analyses
Since the enrollment in the study was halted after only a few patients treated (10 patients), 
only the outputs defined in the document “Guidelines for short, closeout CSRs” (released on 
the 17-Sept-2014) will be produced.
Therefore, the following analyses will not be performed:

[Protocol Section 10.3.1 Study Treatment]: The actual dose, dose intensity, relative dose 
intensity and total daily doses of each agent will not be summarized or listed. 

[Protocol Section 10.3.2 Concomitant therapies]: Concomitant medications and significant 
non-drug therapies prior to and after the start of the study drug treatment will not be 
summarized or listed.

[Protocol Section 10.3.3 Compliance]: The listing of patients with protocol deviations will 
be provided; no summary tables will be produced. 

[Protocol Section 10.4.2] The primary efficacy endpoint, PFS will not be analyzed. Log-
rank test, HR estimates and related confidence interval and Kaplan-Meier estimates with 
confidence interval for median survival and survival probabilities will not be performed.

[Protocol Section 10.5.2 Other secondary efficacy objectives]: BOR, ORR and DCR will 
not be summarized and corresponding confidence interval will not be produced. Kaplan-
Meier plots for DOR will not be produced and the median DOR will not be estimated. 
Kaplan-Meier estimates for OS with confidence intervals will not be produce and OS rate 
and related confidence interval will not be performed. Listing of Overall response, time to 
progression time to onset and duration of overall response will not be provided. Waterfall 
plot will not be produced.

[Protocol Section 10.5.3 Safety objectives]: Laboratory abnormalities, ECG, Cardiac 
Imaging and vital signs summary tables and listings will not be provided. Tolerability of 
the study drug will not be summarized and reason for dose interruption, dose reduction 
and dose change will not be listed by patient or summarized. 


 

 
 


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References
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41. 
Neuenschwander, Branson and Gsponer (2008). Critical aspects of the Bayesian approach to 
phase I cancer trials, Statistics in medicine 27, 2420-2439