Conditions: Malignant Rhabdoid Tumors (MRT) Neuroblastoma
Keywords: LEE011 Phase 1 pediatric CDK4/6 inhibitor dose escalation malignant rhabdoid tumors MRT neuroblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
LEE011 is a small molecule inhibitor of CDK4/6. LEE011 has demonstrated in vitro and in vivo activity in both tumor models. The primary purpose of this study was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in pediatric patients and to delineate a clinical dose to be used in future studies. This study was also to have assessed the safety, tolerability, PK and preliminary evidence of antitumor activity of LEE011 in patients with MRT or neuroblastoma.

Detailed description:
Due to lack of efficacy, enrollment in the study was stopped at the end of dose escalation (sites were notified of the early enrollment halt on 7-Aug-2014) and the dose-expansion part was not conducted. Due to halted enrollment and/or lack of complete responses (CR) and partial responses (PR), efficacy analysis was only performed in terms of TTP for the patients treated during the dose-escalation part at the maximum tolerated dose (MTD) and recommended dose expansion (RDE).

Arms:
arm 1: None

Interventions: intervention 1: LEE011
Intervention descriptions: intervention 1: LEE011 is a small molecule inhibitor of CDK4/6.

Protocol document:
Prot_000.pdf: 
Clinical Development
LEE011
Clinical Trial Protocol CLEE011X2102 / NCT01747876
A phase I, multi-center, open-label study of LEE011 in 
patients with malignant rhabdoid tumors and 
neuroblastoma
Authors
Document type
Amended Protocol Version (Clean)
EUDRACT number
2012-004228-40
Version number
2.0
Development phase
I
Document status
Final
Release date
23-Feb-2016
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 ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 2 ....................................................................................................................11
Summary of previous amendment(s).................................................................................12
Amendment 1 ....................................................................................................................12
Protocol summary..............................................................................................................15
1
Background........................................................................................................................17
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............17
1.2
Introduction to investigational treatment...............................................................18
1.2.1
Overview of LEE011 ............................................................................18
2
Rationale............................................................................................................................21
2.1
Study rationale and purpose...................................................................................21
2.2
Rationale for the study design ...............................................................................21
2.3
Rationale for dose and regimen selection..............................................................22
3
Objectives and endpoints...................................................................................................22
4
Study design ......................................................................................................................24
4.1
Description of study design ...................................................................................24
4.2
Timing of interim analyses and design adaptations...............................................25
4.3
Definition of end of the study................................................................................25
4.4
Early study termination..........................................................................................26
5
Population..........................................................................................................................26
5.1
Patient population..................................................................................................26
5.2
Inclusion criteria ....................................................................................................26
5.3
Exclusion criteria...................................................................................................27
6
Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................29
6.1.1
Dosing regimen.....................................................................................29
6.1.2
LEE011 administration .........................................................................30
6.1.3
Treatment duration................................................................................31
6.2
Dose escalation guidelines.....................................................................................31
6.2.1
Starting dose for the dose escalation part..............................................31
6.2.2
Guidelines for dose escalation and determination of (MTD/ RDE) .....32
 


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6.2.3
Definitions of DLTs..............................................................................33
6.3
Dose modifications................................................................................................34
6.3.1
Dose modification and dose delay ........................................................34
6.4
Concomitant medications ......................................................................................35
6.4.1
Permitted concomitant therapy .............................................................35
6.4.2
Concomitant therapy requiring caution.................................................35
6.4.3
Prohibited concomitant therapy ............................................................36
6.5
Patient numbering, treatment assignment or randomization .................................36
6.5.1
Patient numbering .................................................................................36
6.5.2
Treatment assignment or randomization...............................................36
6.5.3
Treatment blinding................................................................................36
6.6
Study drug dispensation.........................................................................................36
6.6.1
Study drug packaging and labeling.......................................................37
6.6.2
Study drug compliance and accountability ...........................................37
6.6.3
Disposal and destruction .......................................................................37
7
Visit schedule and assessments .........................................................................................38
7.1
Study flow and visit schedule................................................................................38
7.1.1
Screening...............................................................................................42
7.1.2
Treatment period...................................................................................42
7.1.3
End of treatment (EOT) visit.................................................................43
7.1.4
Follow-up period...................................................................................44
7.2
Assessment types...................................................................................................44
7.2.1
Efficacy assessments.............................................................................44
7.2.2
Safety and tolerability ...........................................................................45
7.2.3
Pharmacokinetics ..................................................................................49
7.2.4
Biomarker assessments .........................................................................51
7.2.5
Total blood volume ...............................................................................52
8
Safety monitoring and reporting........................................................................................52
8.1
Adverse events.......................................................................................................52
8.1.1
Definitions and reporting ......................................................................52
8.1.2
Laboratory test abnormalities................................................................53
8.2
Serious adverse events...........................................................................................54
8.2.1
Definitions.............................................................................................54
8.2.2
Reporting...............................................................................................54
8.3
Pregnancies............................................................................................................55
8.4
Warnings and precautions......................................................................................55
9
Data collection and management.......................................................................................56
 


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9.1
Data confidentiality ...............................................................................................56
9.2
Site monitoring ......................................................................................................56
9.3
Data collection.......................................................................................................57
9.4
Database management and quality control............................................................57
10 Statistical methods and data analysis ................................................................................57
10.1
Analysis sets ..........................................................................................................58
10.1.1
Full analysis set.....................................................................................58
10.1.2
Safety set ...............................................................................................58
10.1.3
Dose-determining analysis set...............................................................58
10.1.4
Pharmacokinetic analysis set.................................................................58
10.2
Patient demographics/other baseline characteristics .............................................59
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................59
10.3.1
Study treatment .....................................................................................59
10.3.2
Concomitant therapies...........................................................................59
10.3.3
Compliance ...........................................................................................59
10.4
Primary objective...................................................................................................59
10.4.1
Variable.................................................................................................59
10.4.2
Statistical hypothesis, model, and method of analysis..........................59
10.4.3
Handling of missing values/censoring/discontinuations.......................61
10.4.4
Supportive analyses...............................................................................61
10.5
Secondary objectives .............................................................................................61
10.5.1
Population and grouping for the analyses .............................................61
10.5.2
Safety evaluation...................................................................................62
10.5.3
Tolerability............................................................................................63
10.5.4
Efficacy evaluation................................................................................64
10.5.5
Pharmacokinetics ..................................................................................64
10.6
Exploratory objectives...........................................................................................65
10.6.1
Biomarkers............................................................................................65
10.6.2
PK-QTc relationship .............................................................................66
10.7
Interim analysis......................................................................................................67
10.8
Sample size calculation..........................................................................................68
10.9
Power for analysis of key secondary variables......................................................68
11 Ethical considerations and administrative procedures ......................................................68
11.1
Regulatory and ethical compliance........................................................................68
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................68
11.3
Informed consent procedures.................................................................................69
11.4
Discontinuation of the study..................................................................................69
 


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11.5
Publication of study protocol and results...............................................................70
11.6
Study documentation, record keeping and retention of documents.......................70
11.7
Confidentiality of study documents and patient records .......................................71
11.8
Audits and inspections...........................................................................................71
11.9
Financial disclosures..............................................................................................71
12 Protocol adherence ............................................................................................................71
12.1
Amendments to the protocol..................................................................................71
13 References (available upon request)..................................................................................72
14 Appendices ........................................................................................................................74
14.1
Appendix 1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).........74
14.2
Appendix 2: International Neuroblastoma Response Criteria (INRC)..................98
14.3
Appendix 3: Revised Assessment in Neuro-Oncology (RANO) Criteria .............99
14.4
Appendix 4: Karnofsky Performance Status Scale (for patients greater than 
16 years old) ........................................................................................................100
14.5
Appendix 5: Lansky Score (for patients less than or equal to 16 years old) .......101
14.6
Appendix 6: Medication and herbals to be excluded or to be used with 
caution..................................................................................................................101
14.7
Appendix 7: Prior calibration and operating characteristics of the Bayesian 
logistic regression model (BLRM) ......................................................................104
List of figures
Figure 4-1
Overview of study design......................................................................25
List of tables
Table 3-1
Objectives and related endpoints ..........................................................23
Table 6-1
Provisional dose levels..........................................................................31
Table 6-2
Criteria for defining dose-limiting toxicities.........................................34
Table 7-1
Visit evaluation schedule ......................................................................39
Table 7-2
Local clinical laboratory parameters collection plan ............................47
Table 7-3
Central ECG collection plan .................................................................48
Table 7-4
Pharmacokinetic blood collection log – dose escalation part ...............49
Table 7-5
Pharmacokinetic blood collection log – dose expansion part ...............50
Table 7-6
Biomarker sample collection plan.........................................................51
Table 7-7
Maximum total blood volume (pediatric patients)................................52
Table 10-1
ECG parameters and abnormal values ..................................................63
Table 10-2
Non-compartmental pharmacokinetic parameters ................................64
 


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Table 10-3
PK-QTc mixed effect models................................................................67
Table 14-1
INRC definition.....................................................................................98
Table 14-2
RANO definition...................................................................................99
Table 14-3
Summary of RANO response criteria .................................................100
Table 14-4
Karnofsy Performance Status Scale....................................................100
Table 14-5
Lansky score........................................................................................101
Table 14-6
List of contraindicated CYP3A substrates, inducers or inhibitors......102
Table 14-7
List1 of medications which are CYP3A substrates, inducers or 
inhibitors to be used with caution .......................................................102
Table 14-8
List1 of medications which are CYP1A2 substrates with narrow 
therapeutic index (NTI) or strong inhibitors of CYP1A2...................103
Table 14-9
BSEP transporter: List of medications causing inhibition to be used 
with caution.........................................................................................103
Table 14-10
QT prolongation: List of excluded medications..................................104
Table 14-11
QT prolongation: List of medications to be used with caution...........104
Table 14-12
Data from CLEE011X2101 study.......................................................106
Table 14-13
Prior parameters for bivariate normal distribution of model 
parameters log(alpha) and log(beta)....................................................107
Table 14-14
Prior probabilities of under, targeted and over dosing for LEE011 
doses (derived from the prior in Table 14-12) ....................................107
Table 14-15
Scenarios .............................................................................................109
 


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List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AR
Accumulation ratio
AST
Aspartate aminotransferase
AT
Atypical teratoid
BBB
Blood brain barrier
BLRM
Bayesian Logistic Regression Model
BMA
Bone marrow aspirate
BSA
Body surface area
BSEP
Bile Salt Export Pump
C1D1
Cycle 1, Day 1
CBC
Complete blood count
CCND1
Cyclin D1
CM
Centimeter
Cmax
Maximum concentration
CNS
Central nervous system
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CSF
Cerebrospinal fluid
CRO
Contract Research Organization
CSR
Clinical study report
CV
Coefficient of Variation
DDS
Dose determining set
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology
DOR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EIAED
Enzyme-inducing antiepileptic drug
EOT
End of Treatment
EWOC
Escalation with overdose control
FAS
Full analysis set
FMO3
Flavin-containing monooxygenase 3
FDA
Food and Drug administration
Gd
Gadolinium
Gd-MRI
gadolinium chelate-enhanced brain tumor magnetic resonance imaging
GI
Gastrointestinal
h
Hours
HR
Heart rate
IC50
50% inhibition
ICF
Informed consent form
 


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IEC
Independent ethics committee
IB
Investigator’s Brochure
IN
Investigator notification
INRC
International neuroblastoma response criteria
INRG
International neuroblastoma risk group
IRB
Institutional review board
KG
Kilogram
LC/MS/MS
Liquid chromatography-tandem mass spectrometry assay
LLOQ
Lower limit of quantification
LVEF
Left ventricular ejection fraction
MedDRA
Medical dictionary for regulatory activities
mIBG
Metaiodobenzylguanidine
MRT
Malignant rhabdoid tumor
MTD
Maximum Tolerated Dose
MXR
Mitoxantrone-resistant protein
NCI CTCAE
National cancer institute common terminology criteria for adverse events
ORR
Overall response rate
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PE
Physical examination
Pgp
P-glycoprotein
PHI
Protected health Information
PK
Pharmacokinetic
PIB
Powder in Bottle
QTc 
QTc Corrected Q-T interval
QTcB 
QTcF Corrected Q-T interval (Bazett)
QTcF 
QTcF Corrected Q-T interval (Fredericia)
Rb
Retinoblastoma protein
PRBC
Packed red blood cell
PVC
Premature ventricular contractions
RANO
Revised Assessment in Neuro-Oncology
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RDE
Recommended dose for expansion
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RT
Rhabdoid Tumor
RTK
Rhabdoid Tumor of the Kidney
SAE
Serious Adverse Event
SD
Standard deviation
SEC
Study Evaluation Completion
SGOT
Serum glutamic oxaloacetic aminotransferase
SGPT
Serum glutamic pyruvic aminotransferase
SUSAR
Suspected unexpected serious adverse event
T1/2
Terminal half-life
TDI
Time-dependent inhibition
 


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TTP
Time to progression
ULN
Upper limit of normal
WBC
White blood cell
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Patient Number
A unique identifier number (consisting of the center number and a patient-
specific number) assigned to each patient who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study drug
Any drug administered to the patient as part of the required study procedures; 
includes investigational drug
Study drug discontinuation
Point/time when patient permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature patient withdrawal
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
 


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Protocol No. CLEE011X2102
Amendment 2
Amendment rationale
The primary purpose of this amendment is to add language that describes the option for 
patients to discontinue treatment in CLEE011X2102 and transfer to a Novartis LEE011 
rollover protocol which will continue to provide LEE011.
In addition, for consistency across clinical trials within the LEE011 programs, language has 
also been updated within the following sections:

Definition of highly effective contraception method

Permitted concomitant therapy

Dosing administration 
Changes to Protocol
Sections 4.3, 6.1.3, and 7.1.3 have been updated to include language regarding transfer to the 
LEE011 rollover protocol.
Section 5.3 Exclusion criterion bullet 16 definition of highly effective contraception method 
has been updated to align with new internal guidelines.
Section 6.1.2 LEE011 administration was updated to allow administration with food and to 
include additional citrus fruit to avoid to align with new internal program language.
Section 6.4.1.1 Corticosteroid section was added to include restrictions for corticosteroid use 
to align with new internal program language.Tables 7-4 and 7-5 sample numbers and PK 
collection numbers were removed to align with internal guidelines.
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, the changes herein affect the Informed Consent and sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amended Protocol Version 02 (Clean)
Protocol No. CLEE011X2102
Summary of previous amendment(s)
Amendment 1
18 July 2013
The primary purpose of this amendment was to add additional timepoints to the ECG 
monitoring to better evaluate and characterize the cardiac repolarization effects of LEE011. In 
addition, the eligibility criterion was modified to allow the enrollment of patients with tumors 
other than malignant rhabdoid tumor (MRT) and neuroblastoma who have documented 
aberrations in the D-cyclin-CDK4/6-INK4a-Rb pathway to the dose escalation part of the 
study. Information on alternate formulations was added and language around continuous 
dosing regimen was removed. In addition, updates to some sections, and minor revisions and 
corrections were made to improve the consistency and clarity of the protocol.
Amendment 1
Amendment rationale 
The primary purpose of this amendment is to add additional timepoints to the ECG 
monitoring to better evaluate and characterize the cardiac repolarization effects of LEE011. In 
addition, the eligibility criterion is modified to allow the enrollment of patients with tumors 
other than malignant rhabdoid tumor (MRT) and neuroblastoma who have documented 
aberrations in the D-cyclin-CDK4/6-INK4a-Rb pathway to the dose escalation part of the 
study. Information on alternate formulations has been added and language around continuous 
dosing regimen has been removed. In addition, updates to some sections, and minor revisions 
and corrections have been made to improve the consistency and clarity of the protocol.
Emerging safety data from the adult phase 1 study (CLEE011X2101) suggests LEE011 has an 
effect on the cardiac repolarization. Asymptomatic grade 1 or 2 QTcF prolongation has been 
observed with increasing frequency starting at 600 mg up to 1200 mg. One patient had an 
asymptomatic grade 3 QTcF prolongation as a dose limiting toxicity at 900 mg, the declared 
maximum tolerated dose (MTD) in adults. The CLEE011X2101 study is currently exploring 
intermediate doses to determine the appropriate recommended dose for expansion (RDE) 
based on safety, PK, and PD data. The RDE in adults will most likely be 600 mg with the 3 
week on 1 week off regimen. The starting dose in this study, CLEE011X2102, assumed an 
adult MTD of 600 mg and remains appropriate. Due to the QTcF changes observed in the 
adult study, additional time points are being added with triplicate measurements to obtain a 
more robust evaluation of the ECG changes in pediatric patients. 
Besides MRT and neuroblastoma, the D-cyclin-CDK4/6-INK4a-Rb pathway is disrupted in 
many pediatric tumors including osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, 
medulloblastoma, and high grade gliomas. Gene profiling technologies are increasingly 
identifying pediatric patients with tumors that have these pathway abnormalities and are hence 
likely to derive benefit from therapy with LEE011. Therefore, patients who have documented 
evidence of D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities (e.g. cyclin D amplification, 
CDK4 amplification, p16 loss etc.) will be allowed to enroll in the dose escalation part of the 
study.
 


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Amended Protocol Version 02 (Clean)
Protocol No. CLEE011X2102
LEE011 will soon be available in a Powder in Bottle (PIB) form for dissolution in water or 
Ora-Sweet (or equivalent) and a liquid formulation is also under development. This 
amendment adds language for the use of these alternate dosing formulations when available. 
Evaluation of the continuous dosing regimen was performed in the adult phase 1 study 
(CLEE011X2101). This regimen was not well tolerated and will not be pursued any longer. 
Therefore all references to this alternate dosing regimen will be removed from this protocol. 
Changes to Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions

Section 1.2.1.2 Clinical experience has been updated with CLEE011X2101 clinical 
experience.

Table 3-1 Objectives and endpoints has been updated to include PK parameters as a 
secondary endpoint

Section 5.2 Inclusion Criterion #2 revised to include “in dose escalation part, other tumors 
with documented evidence of D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities”

Sections 6.1 Study Treatment and 6.6 Study drug dispensation revised to include Powder 
in Bottle and liquid formulations.

Section 6.1.1 Alternate dosing regimen of LEE011 revised to remove daily continuous 
dosing regimen (28 day cycle).

Section 6.1.2 LEE011 administration text has been revised to standardize with other 
LEE011 protocols and now reads “Any doses that are missed (not taken within 6 hours of 
the intended time) should be skipped and should not be replaced or made up on a 
subsequent day.”

Sections 6.1.2 LEE011 administration and 7.2.3.1 PK blood sample collection and 
handling has been revised to include additional PK timepoints due to administration or 
formulation switch.

Section 6.2.2 Guidelines for dose escalation and determination of (MTD/ RDE) has been 
revised to standardize with Novartis standard language.

Section 7.2.1 Efficacy assessments has been revised to include “All radiological 
assessments obtained for all patients enrolled during the study 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.”

Section 7.2.2.5.5 Electrocardiogram has been revised to include additional ECG 
timepoints (C1D8 and C1D15) and for all timepoints to be performed in triplicate.

Section 10.5.2.4 Electrocardiogram has been added to describe ECG analyses.  

Section 10.6.2 PK-QTc relationship has been added to describe PK-QTc relationship 
analyses.
 


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


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Protocol summary
Protocol number
LEE011X2102
Title
A phase I, multi-center, open-label study of LEE011 in patients with malignant rhabdoid 
tumors and neuroblastoma
Brief title
Study of safety and efficacy in patients with malignant rhabdoid tumors (MRT) and 
neuroblastoma
Sponsor and 
Clinical Phase
Novartis; Phase I
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
LEE011 is a small molecule inhibitor of CDK4/6. In the Novartis Cell Line Encyclopedia 
screen, malignant rhabdoid tumor (MRT) and neuroblastoma cell lines were among the
most sensitive to LEE011. LEE011 has demonstrated in vitro and in vivo activity in both 
tumor models.
The primary purpose of this study is to determine the maximum tolerated dose (MTD) 
and/or recommended dose for expansion (RDE) in pediatric patients and to delineate a 
clinical dose to be used in future studies. This study will also assess the safety, tolerability, 
PK and preliminary evidence of antitumor activity of LEE011 in patients with MRT, 
neuroblastoma or other tumors with D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities.
Primary Objective
Estimate the MTD and/or RDE of LEE011 as a single agent when administered orally to 
patients 
Secondary 
Objectives
Objective 1: Characterize the safety and tolerability of LEE011
Objective 2: Characterize pharmacokinetics of LEE011 and any clinically significant 
metabolites that may be identified
Objective 3: Assess the anti-tumor activity of LEE011
Study design
This is a two-part, phase 1 study, with a dose escalation part followed by an expansion 
part. The expansion part will start after the MTD/RDE has been determined. The expansion 
part will include 2 groups of patients, one restricted to MRT patients with either CNS or 
extra-CNS primary and the second including neuroblastoma patients. LEE011 will be 
administered orally, once daily for 21 days followed by a 1 week break (28-day cycle).
Population
Patients, aged 12 months to 21 years, with MRT or neuroblastoma
Inclusion criteria
●
Confirmed diagnosis of MRT, neuroblastoma, or in the dose escalation part, other 
tumors with D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities, that has progressed 
despite standard therapy or for which no effective standard therapy exists.
●
Age ≥ 12 months and ≤ 21 years
●
Patients with CNS disease should be on stable doses of steroids for at least 7 days 
prior to first dose of LEE011 with no plans for escalation.
●
In expansion part, patients must have at least one measurable disease as defined by 
RECIST v1.1.
●
Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of at least 
50.
●
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to enrollment.
 


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Exclusion criteria
●
Prior history of QTc prolongation or QTcF > 450 ms on screening ECG.
●
Patients with the following laboratory values during screening:
●
Serum creatinine > 1.5 x upper limit of normal (ULN) for age
●
Total bilirubin >1.5 x ULN for age
●
Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) > 3 
x ULN for age; aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase/SGOT > 3 x ULN for age except in patients with tumor involvement of the 
liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN for age. For the purpose of this 
study, the ULN for SGPT/ALT is 45 U/L.
●
Patients who are currently receiving treatment with agents that are metabolized 
predominantly through CYP3A4/5 and have a narrow therapeutic window and/or agents 
that are known strong inducers or inhibitors CYP3A4/5 are prohibited. In particular, 
enzyme-inducing antiepileptic drugs (EIAEDs).
●
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may interfere with the interpretation of study results, and in the judgment of the 
investigator would make the patient inappropriate for the study.
Investigational 
and reference 
therapy
LEE011
Efficacy 
assessments
●
Overall response rate (ORR), duration of response (DOR) and time to progression 
(TTP) as per RECIST 1.1 in patients. In addition, response by INRC for neuroblastoma 
patients and response by RANO Criteria for primary CNS tumors patients.
Safety 
assessments
●
Incidence rate of Dose Limiting Toxicities (DLT) during the first cycle of LEE011 
treatment
●
Adverse events and serious adverse events, changes in laboratory values, 
assessments of physical examinations, vital signs and electrocardiograms
Other 
assessments
●
Plasma concentration time profiles, PK parameters, including but not limited to AUCtau, 
Cmax, Tmax, CL/F, accumulation ratio (Racc), and T1/2,acc
●
Data analysis
The primary purpose of the study is to estimate the MTD and/or the RDE of LEE011 when 
administered as a single agent orally in patients The corresponding primary endpoint is the 
incidence of DLTs in cycle 1.
Estimation of the MTD of the treatment will be based upon the estimation of the probability 
of DLT in Cycle 1 for patients in the DDS (see definition below), using an adaptive BLRM 
guided by the EWOC principle. Unless otherwise specified, the Full Analysis Set (FAS) will 
be the default analysis set used for all analyses. It includes all patients who received at 
least one dose of LEE011.
For all safety analyses, the safety set will be used. It includes all patients who received at 
least one dose of LEE011, and have at least one valid post-baseline safety assessment.
The dose-determining set (DDS) will be used for the estimation of MTD. It consists of all 
patients from the safety set who meet a minimum exposure criterion as outlined in Section 
10 and have sufficient safety evaluations, or discontinue earlier due to DLT.
Anti-tumor activity will be summarized in terms of overall response rate (ORR), duration of 
response (DOR), and time to progression (TTP)
All biomarker data will be listed and summarized using frequency tables. In particular,
 
The study data will be analyzed and reported based on all patients’ data of the dose 
escalation and expansion parts. Details of the statistical analysis and data reporting will be 
provided in the Novartis Report and Analysis Plan (RAP) document finalized prior to 
database lock.
Key words
Phase I, pediatric, open-label, dose escalation, malignant rhabdoid tumors, MRT, 
neuroblastoma
 


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Malignant Rhabdoid Tumors
Malignant Rhabdoid Tumors are extremely aggressive malignancies that generally occur in 
infants and young children. The most common locations are in the kidney and central nervous 
system (CNS), although they can arise in most soft-tissue sites. Rhabdoid tumors in all 
anatomical locations have a similar molecular origin (Biegel 2006). The incidence rate of 
MRT is about 1 per million children per year (Woehrer et al 2010). These tumors have no 
standard or effective therapeutic regimens. Most patients receive intensive multimodality 
treatment including surgery, radiotherapy, chemotherapy, and sometimes high-dose 
chemotherapy with stem-cell rescue. Despite this aggressive approach, prognosis for children 
with MRT is poor. Mean survival with surgical intervention alone is 3 months and with 
adjuvant chemotherapy and radiotherapy is 8 months (Tekautz et al 2005). Therefore, the 
development of new strategies with less toxicity burden and with more targeted drugs is 
warranted.
Near-uniform biallelic inactivating mutations in 
 
 a gene that encodes a core subunit of the SWI/SNF chromatin remodeling complex, 
are seen in more than 95% of MRTs (Versteege et al 1998). Studies have revealed that MRTs 
are exquisitely dependent on cyclin D1 (CCND1) for genesis and survival, and loss of 
INI1leads to de-repression of cyclin D1 in primary mouse and human MRTs (Tsikitis 2005, 
Fujisawa 2005, McKenna 2008). Genetic abrogation of CCND1 eliminates MRT formation in 
Ini1+/−mice, and siRNA-mediated knockdown of CCND1 is sufficient to induce G0/G1 
arrest and apoptosis in MRT cells (Tsikitis et al 2005). These studies, suggest that targeting 
Cyclin D1 or the Cyclin/CDK axis could be an effective means of inhibiting MRT growth.
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most 
common cancer in infancy, with an annual incidence of about 650 cases per year in the US. 
The median age at diagnosis is 17 months (London et al 2005). The tumors arise in tissues of 
the sympathetic nervous system, typically in the adrenal medulla or paraspinal ganglia. These 
tumors are biologically heterogeneous with a broad spectrum of clinical behavior. 
Approximately 50% of patients present with metastatic disease. Genetic alterations in ALK 
have been reported in approximately 15% (Mosse et al 2008) and MYCN amplifications in 
about 25% of tumors (Brodeur et al 1984). Patients with segmental chromosomal aberrations 
display wide phenotypic variability and have poor prognosis. Outcomes in patients with 
standard risk neuroblastoma have improved over the past decades (Cohn et al 2009). However, 
despite intensive therapy, the survival rates among children with high-risk neuroblastoma 
have shown only modest improvement; 50 to 60% of the patients relapse and no salvage 
treatment regimens are known to be curative (Maris 2010). Novel approaches to treating these 
patients are required to improve their outcome.
 


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The Rb signaling pathway is important for neuronal differentiation and migration (McClellan 
and Slack 2006). High incidence of Cyclin D1 and CDK4 over-expression has been observed 
in neuroblastoma cell lines (Molenaar et al 2008). Copy number defects of G1-cell cycle 
genes (CCND1, CDK4 and CDK6) occur in 30% of patients and correlate with high 
expression of E2F target genes and a poor prognosis (Molenaar et al 2012). Therefore, 
targeting the CCND1/CDK4 axis may provide therapeutic benefit to high-risk neuroblastoma 
patients.
1.2
Introduction to investigational treatment
1.2.1
Overview of LEE011
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits 
highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cyclinD3 complexes, 
with concentration resulting in 50% inhibition (IC50) values of 10 nM and 39 nM, respectively, 
in isolated enzyme assays. It is inactive against the majority of other kinases. It is currently 
being tested in a clinical trial in adult cancer patients [CLEE011X2101].
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacology
LEE011 inhibits the growth of many tumor cell types in vitro and in vivo, including mantle 
cell lymphoma, liposarcoma, melanoma, and carcinomas of the esophagus, breast, lung and 
pancreas. Regardless of the various genetic aberrations that may be present in the cancer cells, 
the anti-tumor activity of LEE011 requires the presence of functional retinoblastoma protein 
(Rb).
In the Novartis Cell Line Encyclopedia screen, MRT and neuroblastoma cell lines were 
among the most sensitive to LEE011. In in vitro pharmacology studies, LEE011 induces anti-
proliferative effects in MRT (A204, G401) and neuroblastoma cell lines (SK-N-DZ, CHP212, 
IMR-32, KP-N-YN, KELLY, SK-N-BE(2)).
In in vivo pharmacology studies, LEE011 demonstrated tumor growth suppression in MRT 
and neuroblastoma xenograft models. ALK mutation & MYCN status in neuroblastoma cells 
do not appear to be associated with LEE011 sensitivity. The majority (90-100%) of MRT and 
neuroblastoma tumors have functional Rb.
1.2.1.1.2 Nonclinical PKs and metabolism
The PK of LEE011 was investigated in four different species: mouse, rat, dog and monkey.
After oral administration to rats, LEE011 was moderately absorbed (48 to 84%) with 
bioavailability ranging from 10% and 65% across animal species. Maximum serum drug 
concentration (Cmax) was between 2 and 4 hours (h). The terminal half-life (T1/2) of LEE011 
was moderate in rodents and monkeys (2 to 7 h), and was comparatively longer (18 h) in dogs. 
The predicted human PK parameters based on allometric scaling were 1259 mL.min-1 (75.5 
L.h-1) for CL/F, 2334 L for Vss/F, with a T1/2 of around 21 hours.
 


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The binding of LEE011 to plasma proteins was moderate (unbound fraction in plasma for 
humans is 30 ± 2%). 3H-LEE011 and its metabolites are extensively distributed into the 
organs and tissues of rats including choroid, ciliary body and meninges with the exception of 
the brain. The highest radioactivity concentrations were found in tissues such as pituitary 
gland, pineal gland, spleen, kidney and adrenal medulla with remarkably high exposure in the 
thyroid gland. Distribution of LEE011 and/or its metabolites into melanin-containing 
structures was seen in pigmented rats.
Oxidative metabolism of LEE011 is dominated by CYP3A4 with a minor contribution of 
about 20% by flavin-containing monooxygenase 3 (FMO3). LEE011 is a moderate substrate 
of P-glycoprotein (Pgp). LEE011 is a time-dependent CYP3A4 inhibitor and a reversible 
inhibitor of CYP1A2. LEE011 was found to inhibit the mitoxantrone-resistant protein (MXR), 
and human bile salt export pump (BSEP) but not rat or dog BSEP. LEQ803 (N-
demethylation) is a major metabolite in the rat and monkey, the main metabolite in humans 
and the only metabolite in dogs. This metabolite was found to interact with hERG channels in 
vitro.
In rat ADME studies, LEE011 was predominantly excreted with bile. The elimination of 
unchanged drug was limited. A minor proportion of the administered dose is excreted in urine. 
The bulk of the administered dose (87.3%) was excreted within 24 hours.
Overall, the elimination of LEE011 may potentially be affected by co-administered drugs that 
inhibit or induce CYP3A4. LEE011 may inhibit CYP3A4, CYP1A2 and BSEP depending on 
the dose administered.
Please refer to LEE011 Investigator Brochure (IB) for additional details.
1.2.1.1.3 Safety pharmacology and toxicology
In vitro, LEE011 did not show mutagenic or phototoxic potential.
Safety pharmacology studies did not reveal any effects on CNS or respiratory functions. In the 
dog telemetry study, prolongation of the average QT and QTc was observed with the potential 
to induce premature ventricular contractions (PVCs) at higher exposure levels. LEE011 and 
LEQ803 likely contributed to the QT prolonging effects seen in vivo.
In rats and dogs, LEE011 induced bone marrow hypocellularity, lymphoid depletion, atrophy 
of the skin and intestinal mucosa, decreased bone formation and testicular atrophy. These are 
consistent with the mechanism of action of LEE011. In addition, an increased number of 
ovarian corpora lutea was observed in a single female dog at the highest dose tested. The liver, 
bile system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder calculi, 
and inspissated bile) were identified as additional target organs of toxicity which are not likely 
related to the primary pharmacology of LEE011. Correlating hematological and/or 
biochemistry changes were seen for the effects described in the bone marrow, lymphoid 
system and liver. All the described changes were fully reversible in rats and dogs.
Based on its mechanism of action and preclinical toxicology studies, the major potential 
toxicities for LEE011 include myelosuppression, hepatic toxicity, and prolongation of the QT 
interval. The risk of these toxicities may be amplified by concomitant administration of strong 
inhibitors of CYP3A4.
 


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Please refer to LEE011 Investigator Brochure (IB) for additional details.
1.2.1.2
Clinical experience
As of 4 February 2013, 56 patients have been treated with single agent LEE011 in the first-in-
human phase I study [CLEE011X2101] in which LEE011 is administered orally, once daily 
for 21 days followed by a 1 week rest (28-day cycle). Doses tested include 50 mg (n=4), 70 
mg (n=2), 140 mg (n=4), 260 mg (n=4), 280 mg (n=4), 350 mg (n=5), 400 mg (n=5), 600 mg 
(n=4), 900 mg (n=13), 750 mg (n=8), and 1200 mg (n=3). In all, 8 DLTs have been observed. 
DLTs include grade 3 mucositis (n=1) in the 50 mg cohort, grade 3 pulmonary embolism 
(n=1) in the 280 mg cohort, grade 3 hyponatremia (n=1) and prolonged grade 3/4 neutropenia 
(n=1) in the 400 mg cohort, grade 4 thrombocytopenia (n=1) in the 750 mg cohort, grade 3 
asymptomatic QTc prolongation with grade 3 neutropenia (n=1) in the 900 mg cohort and 
grade 4 febrile neutropenia (n=1) and grade 4 thrombocytopenia (n=1) in the 1200 mg 
cohort. The grade 3 mucositis observed in the 50 mg cohort was later determined to be due to 
herpes simplex virus (HSV) infection. A DLT related to mucositis has not been observed 
since.  Four cases of Grade 1 or 2 mucositis have been observed in doses up to 350 mg; 
mucositis has not been observed at higher doses. The grade 3 pulmonary embolism was 
observed in a patient with NSCLC who had diffuse bilateral lung disease and a central venous 
catheter. The grade 3 hyponatremia was asymptomatic and readily corrected with saline 
infusion. 
Grade 3 or 4 neutropenia and/or thrombocytopenia not meeting DLT criteria were seen in 
increasing frequency starting from 600 mg up to 1200 mg. Asymptomatic grade 1 or 2 QTc 
prolongation were observed in increasing frequency starting at 600 mg up to 1200 mg; 1 
patient (25%) in the 600 mg cohort, 2 patients (25%) in the 750 mg cohort, 4 patients (31%) 
in the 900 mg cohort, and 3 patients (100%) in the 1200 mg cohort. The most frequently 
reported treatment-related AEs include fatigue, nausea, anemia, asthenia, neutropenia, 
vomiting, 
leukopenia, 
increased 
blood 
creatinine, 
decreased 
appetite, 
diarrhea, 
hypoalbuminemia, lymphocytopenia, myalgia, thrombocytopenia, dizziness, erythema, 
hyperglycemia, mucosal inflammation and stomatitis. The majority have been grades 1 or 2 
and reversible. 
The MTD of LEE011 for the 3 weeks on/1 week off schedule was determined to be 900 mg. 
Continuous dosing with LEE011 at 600 mg was also evaluated. This dosing regimen was not 
well tolerated and will therefore not be pursued further. The study continues to explore 
intermediate doses to establish the RDE and further assess the safety, tolerability, and 
preliminary anti-tumor activity of LEE011.
1.2.1.3
Clinical pharmacokinetics 
Preliminary PK data up to the 1200 mg dose cohort in phase I study [CLEE011X2101] 
haveshown slightly over-proportional increases in exposure across the dose range tested.
Steady-state is reached by day 8. Accumulation ratio (Racc) calculated from AUCtau on day 
21 and AUCtau after a single dose on day 1 across the studied doses of 50 to 600 mg ranged 
from 1.55- to 2.94-fold. Effective T1/2 (T1/2,eff) based on drug accumulation ranges from 24 
hours (50 mg QD dose) to 40 hours (600 mg QD dose).
 


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2
Rationale
2.1
Study rationale and purpose
As described in Section 1, targeting the D-Cyclin/CDK axis may be an effective means of 
inhibiting growth of MRT and neuroblastoma. Evaluation of LEE011 in pediatric patients at 
this early stage in development is driven by the strong biological rationale, supporting 
preclinical data, and the urgent need for effective targeted therapies in these 2 indications. It 
has been well established that children have similar or higher threshold for toxicity when 
compared to adults despite multiple intensive prior therapies (Lee 2005; Kim 2008; EMA 
2003). Safety and PK data from pediatric patients will be used to guide dose-escalation and 
refine dosing in this study. 
Enrollment includes patients with neuroblastoma or MRT because LEE011 has shown most 
in vitro and in vivo activity in these 2 indications. Evidence of anti-tumor activity in these 2 
indications will be used to inform future development of LEE011 in these and other pediatric 
tumors where this pathway may be critical for tumorigenesis. Preclinical studies showed more 
than 95% of MRT and neuroblastoma have an intact pRb. Therefore, pre-screening for pRb 
status will not be required.
The D-cyclin-CDK4/6-INK4a-Rb pathway is also disrupted in many other pediatric tumors 
including osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, medulloblastoma, and high 
grade gliomas. Gene profiling technologies are increasingly identifying pediatric patients with 
tumors that have these pathway abnormalities and have the potential to derive benefit from 
therapy with LEE011. Therefore, patients who have documented evidence of D-cyclin-
CDK4/6-INK4a-Rb pathway abnormalities (e.g. cyclin D amplification, CDK4 amplification, 
p16 loss etc.) will be allowed to enroll in the dose escalation part of the study. 
Although in preclinical studies, LEE011 does not cross the blood brain barrier (BBB), 
exploration of its activity in MRT and other brain tumors is considered worthwhile due to the 
tumors’ dependency on the cyclinD/CDK pathway and the potential for LEE011 to benefit 
these patients who have no effective therapy. Evaluation of LEE011 in patients with primary 
CNS MRT is supported by evidence that the BBB in most CNS tumors is disrupted. Systemic 
chemotherapy has been effective in many cases (Deeken and Loscher 2007). Moreover, 
surgery and radiation therapy performed as initial treatment in these patients increase the 
likelihood that this barrier will be disrupted. The superior outcomes of doxorubicin-based 
regimens in MRT, a drug that does not cross the BBB, attest to this fact (Chi et al 2009).
The primary purpose of this study is to determine the MTD and/or RDE in pediatric patients, 
and to delineate a clinical dose to be used in future studies. This study will also assess the 
safety, tolerability, PK and preliminary evidence of antitumor activity of LEE011 in patients 
with MRT, neuroblastoma or other tumors with D-cyclin-CDK4/6-INK4a-Rb pathway 
abnormalities.
2.2
Rationale for the study design
This is a multi-center, open-label phase 1 study limited to patients aged 12 months to 21 years 
old who have MRT or neuroblastoma. Patients with both primary CNS and extra-CNS MRT 
will be eligible. In addition, patients who have documented evidence of D-cyclin-CDK4/6-
 


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INK4a-Rb pathway abnormalities will be allowed to enroll in the dose escalation part of the 
study. Patients must have disease that has progressed following standard therapy or for which 
no standard treatment option exists. The study includes an expansion at the MTD and/or RDE 
in order to better evaluate safety, tolerability, and preliminary evidence of antitumor activity 
in MRT and neuroblastoma.
There will be no pre-screening for Rb in the study due to the high frequency of intact Rb in 
these tumor types. Rb gene status and presence of Rb protein in tumors will be determined 
retrospectively in those patients who enroll in the study.
This study will utilize a BLRM which is a well-established method to estimate the MTD 
and/or RDE in cancer patients. The adaptive BLRM will be guided by the EWOC principle to 
control the risk of DLT in future patients on study. This method is more likely to assign fewer
patients to either sub-therapeutic or severely toxic dose levels and estimate the MTD with 
smaller average bias and error than the up-and-down methods such as 3+3. The use of 
Bayesian response adaptive models for small datasets has been accepted by EMA (“Guideline 
on clinical trials in small populations” February 1, 2007) and endorsed by numerous 
publications (Babb 1998; Neuenschwander 2008; Neuenschwander 2010), and its 
development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
2.3
Rationale for dose and regimen selection
The MTD of LEE011 for the 3 weeks on/1 week off schedule is 900 mg.  The RDE in adults 
will most likely be 600 mg on the same regimen.  The dose from the adult Phase 1 study that 
will be used to calculate the starting dose in children is 600 mg/d. This is based upon review 
of the safety, tolerability, and PK observed at this dose level and higher. At the 600 mg/d dose 
in adults, LEE011 was well tolerated with an acceptable safety profile. At this dose, systemic 
exposures corresponding to efficacy in preclinical models was observed. On target toxicity, 
neutropenia, was seen but not dose-limiting. Therefore, using the 600 mg/d dose from the 
adult study for calculating the starting dose in children offers a high probability of beginning 
at an active dose and a low probability of excessive toxicity.
The first cohort of children in this trial will be treated with a dose of 280 mg/m2/d, which is 
80% of the current well tolerated dose (600 mg/d) in the ongoing adult study 
[CLEE011X2101] divided by the average adult body surface area (BSA) of 1.72 m2. Refer to 
Section 6.2.1 for details.
In adults, LEE011 is dosed once daily orally, and the T1/2, acc ranges from 24.2 to 40 hours. 
This supports once daily dosing in children. LEE011 will be dosed once a day for 21 
consecutive days followed by a 7-day planned break as part of each 28-day cycle of treatment 
consistent with the regimen used in [CLEE011X2101]. 
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
 


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
Determine the MTD and/or RDE of LEE011
Incidence rate of DLTs in Cycle 1
Secondary
Refer to Section 10.5.
(1) Characterize the safety and tolerability of LEE011
(2) Characterize the PK of LEE011 and any clinically 
significant metabolites that may be identified
(3) Assess the anti-tumor activity of LEE011
(1) AEs and serious adverse events (SAEs), changes in laboratory values and 
electrocardiograms (ECGs).
(2) Plasma concentration time profiles of LEE011, PK parameters, including but 
not limited to AUCtau, Cmax, Tmax, CL/F, accumulation ratio (Racc), and 
T1/2,acc
(3) Overall response rate (ORR), duration of response (DOR), and time to 
progression (TTP) per RECIST 1.1. In addition, for neuroblastoma, response by 
INRC. In addition, for primary CNS tumors, response by RANO Criteria.
Exploratory
Refer to Section 10.6.
(1)
 
(2) Evaluate PD effects in patients with neuroblastoma
(3) To characterize the relationship between QTc 
prolongation and exposure to LEE011 and/or any of its 
relevant metabolites.
(1)
 
(2) Changes in biomarkers associated with the pharmacologic activity of LEE011 
(
 by comparing pre-
treatment and post-treatment samples when available.
(3) ECG interval parameters (e.g. QTcF, QTcB, QT, QRS, RR, PR, HR), plasma 
concentration time profiles of LEE011and PK parameters such as Cmin, Cmax, 
AUCtau
 


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4
Study design
4.1
Description of study design
This is a phase 1, multi-center, open-label study, with a dose escalation part followed by an 
expansion part. Eligible patients aged 12 months to 21 years old whose tumor has progressed 
following standard therapy, or for which no standard, effective therapy exists will be enrolled 
in the study. LEE011 will be administered orally, once daily for 21 days followed by a 1 week 
break (28-day cycle) at the starting dose of 280 mg/m2/d.. For the purpose of scheduling 
assessments and establishing the MTD/RDE, a cycle is defined as 28 days in length.
During the dose escalation part, 3-6 newly enrolled patients in successive cohorts will receive 
increasing doses of LEE011 with the dosing schedule specified above. A BLRM using the 
EWOC principle will be used to guide dose escalation. During the course of dose escalation, 
additional patients  may be enrolled to previously tested lower dose levels that have been 
assessed as safe and well-tolerated if there is no slot available in the current cohort under 
testing. It is expected that approximately 10 patients may be enrolled and treated within this 
context. In all, it is anticipated that approximately 28 patients will be treated during the 
escalation part.
Once the MTD/RDE has been determined, the expansion part will begin to better characterize 
the safety, tolerability and PK profile of LEE011, as well as assess preliminary antitumor 
activity of LEE011. During the expansion part of the study LEE011 will be dosed at the MTD, 
or at a lower RDE, if the available data suggest that the MTD is not appropriate for multiple 
cycles of therapy. This part will include 2 arms, one restricted to neuroblastoma patients and 
the second to MRT patients with either CNS or extra-CNS primary. A minimum of 8 patients 
each will be required for CNS and extra-CNS primary MRT. Enrollment will proceed in 
parallel. Patients enrolled during the expansion part of the study are required to have 
measurable disease. Approximately 18 patients will be treated in each arm, for a total of 
approximately 36 patients in the expansion part.
All patients will be required to provide archival tumor biopsies (at diagnosis or relapse) unless 
otherwise agreed upon by Novartis and the investigator. At screening, all patients with 
neuroblastoma will undergo bilateral bone marrow aspirates (BMA) and/or biopsy and will be 
examined for presence of disease per standard institutional practice. Patients with bone 
marrow involvement at study entry will have repeat bone marrow evaluations for disease 
response at periodic intervals during the study. If feasible, pre- and post-treatment bone 
marrow samples (BMA and/or biopsy) will be collected from these patients. All patients with 
primary CNS tumors (including MRT) will be required to have a cerebrospinal fluid (CSF) 
sample drawn at screening and examined for presence of tumor cells unless otherwise agreed 
upon by Novartis and the investigator. Patients with CSF positive for disease at screening will 
require a repeat CSF examination for confirmation of Complete Response (CR). If CSF is 
collected as part of efficacy assessment or if CSF is collected as part of routine/standard care 
at any time after patient has received first dose of LEE011, a sample will be requested for 
testing LEE011 levels in the CSF. If feasible, a PK blood sample corresponding to the timing 
of CSF collection will also be requested.
 


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Patients will continue to receive treatment with LEE011 until disease progression, occurrence 
of unacceptable toxicity that precludes any further treatment, or if treatment is discontinued at 
the discretion of the investigator or by patient’s withdrawal of consent. All patients will have 
an EOT visit within 14 days of permanently discontinuing LEE011 and will be followed for 
30 days after last dose of study treatment. Analysis of the study data may occur after all 
patients have had the opportunity to complete at least 6 cycles of treatment.
Approximately 64 patients will be treated in the entire study.
Figure 4-1
Overview of study design
4.2
Timing of interim analyses and design adaptations
No formal interim analyses are planned.
4.3
Definition of end of the study
The study data will be analyzed and reported in the primary Clinical Study Report (CSR) 
taking into account all patients’ data of the dose escalation and expansion parts up to the time 
when all patients continuing to receive treatment have completed at least six cycles of 
treatment with LEE011, all patients have discontinued from the study, the study is terminated 
early, or another clinical study that can continue to provide drug becomes available and all 
 


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patients ongoing are transferred to that clinical study, whichever comes first. After the 
primary CSR analysis, any additional data collected will be included in a supplementary 
analysis once all patients have discontinued the study. It will be reported in an addendum to 
the CSR, as appropriate.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be contacted within 24 hours, informed to stop taking the study drug and be 
seen as soon as possible.  The same assessments should be performed as described in Section 
7.1.3 and Section 7.1.4 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
No pre-screening for Rb will be required. Testing for Rb will be done retrospectively.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria in order to be offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Age ≥ 12 months and ≤ 21 years at time of signing consent form
2. Confirmed diagnosis of MRT, neuroblastoma or in dose escalation part, other tumors with 
documented evidence of D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities, that has 
progressed despite standard therapy or for which no effective standard therapy exists.
a. MRT includes diagnoses of Atypical Teratoid/Rhabdoid Tumor (AT/RT), and 
Rhabdoid Tumor of the Kidney (RTK) and other soft tissues as defined by 2 of the 3 
following criteria: a) Morphology and immunophenotypic panel consistent with 
rhabdoid tumor b) Loss of 
confirmed by immunohistochemistry c) 
Molecular confirmation of tumor-specific bi-allelic 
loss/mutation is 
encouraged in cases where 
immunohistochemistry is equivocal, and 
required if 
 immunohistochemistry is not available. Patients should have 
either a+b or a+c.
b. Diagnoses of neuroblastoma must be either by histologic verification of 
neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased 
urinary catecholamines.
c. Patients with other tumor types who have documented evidence of D-cyclin-CDK4/6-
INK4a-Rb pathway abnormalities (e.g. cyclin D amplification, CDK4 amplification, 
p16 loss, etc.) will be allowed to enroll in the dose escalation part of the study.
3. Patients with CNS disease should be on stable doses of steroids for at least 7 days prior to 
first dose of LEE011 with no plans for escalation.
 


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4. Patients must meet the following hematologic criteria:
a. Peripheral absolute neutrophil count (ANC) ≥ 1000/μL without growth factor support 
within 7 days prior to first dose of LEE011
b. Platelet count ≥ 75,000/μL without platelet transfusions within 7 days prior to first 
dose of LEE011
c. Hemoglobin ≥ 8.0 g/dL without blood transfusions within 7 days prior to first dose of 
LEE011
5. Patients with bone marrow metastatic disease who do not meet the above criteria will be 
eligible to enroll in the expansion part of the study with the following count criteria. 
These patients will not be evaluable for hematologic toxicity or hematologic DLT.
a. ANC > 750/μL within 7 days prior to first dose of LEE011
b. Platelet count > 50,000/μL (may receive platelet transfusions) within 7 days prior to 
first dose of LEE011
c. Hemoglobin ≥ 7.5 g/dL (may receive RBC transfusions) within 7 days prior to first 
dose of LEE011
6. Extent of disease (Refer to Appendix 1, Appendix 2 and Appendix 3).

For the dose escalation part of the study patients must have evaluable and/or 
measurable disease.

For the dose expansion part of the study patients must have at least one measurable 
disease as defined by RECIST v1.1. Neuroblastoma patients with positive MIBG 
(metaiodobenzylguanidine) scan will be eligible and considered evaluable and 
measurable. Neuroblastoma patients with bone marrow-only disease will NOT be 
eligible. If palliative XRT has been administered, at least one measurable lesion must 
not have been irradiated. Previously irradiated lesions must demonstrate clear 
evidence of progression to be considered measurable.
7. All patients should submit an archival tumor biopsy specimen (collected at diagnosis or 
relapse). Patients who have no tumor tissue available may be permitted to participate after 
discussion with Novartis and the investigator.
8. Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of at least 50. 
Patients who are unable to walk because of paralysis, but who are sitting up in a 
wheelchair, will be considered ambulatory for the purpose of assessing the performance 
score. (Refer to Appendix 4, Appendix 5).
9. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to enrollment.
10. 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. Malignant disease, other than that being treated in this study.
2. Patients with the following laboratory values during screening:
 


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a. Serum creatinine > 1.5 x upper limit of normal (ULN) for age
b. Total bilirubin >1.5 x ULN for age
c. Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) > 3 x 
ULN for age; aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase/SGOT > 3 x ULN for age except in patients with tumor involvement of 
the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN for age. For the 
purpose of this study, the ULN for SGPT/ALT is 45 U/L.
3. Systemic antineoplastic therapy or any experimental therapy within 3 weeks before the 
first dose of LEE011 (6 weeks if prior nitrosourea or bevacizumab).
4. Radiotherapy within 2 weeks before the first dose of LEE011 (< 6 wks for therapeutic 
doses of MIBG)
5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of LEE011 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection)
6. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may interfere with the interpretation of study results, and in the judgment of the 
investigator would make the patient inappropriate for the study.
7. Major surgery within 2 weeks of the first dose of LEE011. Gastrostomy, insertion of a 
gastric feeding tube (G-tube), ventriculo-peritoneal shunt, endoscopic ventriculostomy and 
central venous access are not considered major surgery.
8. Autologous stem cell transplant following myeloablative therapy within 3 months prior to 
the first dose of LEE011 or prior allogeneic stem cell transplant at any time. Patients who 
received stem cell reinfusion following non-myeloablative therapy are eligible once they 
meet peripheral blood count criteria in Inclusion Criterion #4
9. Uncontrolled cardiovascular condition, including ongoing cardiac arrhythmias, congestive 
heart failure, angina, or myocardial infarction within 6 months prior to the first dose of 
LEE011.
10. Prior history of QTc prolongation or QTcF > 450 ms on screening ECG.
11. Left ventricular ejection fraction (LVEF) < 45%
12. Prior exposure to CDK4/6 inhibitor.
13. Patients who are currently receiving treatment with agents that are known to cause QTc 
prolongation in humans. (Refer to Appendix 6).
14. Patients who are currently receiving treatment with agents that are metabolized 
predominantly through CYP3A4/5 and have a narrow therapeutic window and/or agents 
that are known strong inducers or inhibitors CYP3A4/5 are prohibited. In particular, 
enzyme-inducing antiepileptic drugs (EIAEDs). (Refer to Appendix 6).
15. 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
16. Women of child-bearing potential (Refer to Section 7.2.2.5.4), defined as all women 
physiologically capable of becoming pregnant (who have attained menarche), unless they 
are using highly effective methods of contraception during dosing of study treatment and 
for 21 days after stopping study treatment. Highly effective contraception methods 
include:
 


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
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 taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
6
Treatment
6.1
Study treatment
For this study, the term “investigational or study drug” refers to LEE011. All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
6.1.1
Dosing regimen
LEE011 is provided to investigational sites in capsule, powder in bottle (PIB) or liquid forms 
for oral use. LEE011 will be taken orally, once a day for 21 consecutive days followed by a 7-
day planned break.
LEE011 dose will be scaled by Body Surface Area (BSA). The dose will be adjusted to the 
nearest 10 or 50 mg (higher or lower) as appropriate. The investigational site staff will inform 
each patient of their actual daily dose, and this will be recorded on the appropriate eCRF. The 
actual dose for each patient will be calculated using a BSA conversion as follows:
Actual dose = planned dose level (mg/m2) x individual patient (to nearest 10 or 50 mg, BSA
higher or lower as appropriate).
Individual patient BSA will be calculated using their height and weight as per standard site 
procedure. For the purpose of BSA calculations and potential dose readjustment at subsequent 
cycles, it is acceptable for the BSA to be calculated up to 7 days in advance of Day 1. Dosage 
adjustments for changes in BSA in subsequent cycles will be made as per standard site 
practice (e.g., if the BSA changes by ± 10% from the previous dose calculation).
For capsules, individual doses will consist of the minimum number of capsules possible given 
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The investigator should instruct the patient to take the study drug exactly as prescribed below. 
All dosages prescribed and dispensed to the patient, and all dose changes during the study 
must be recorded on the appropriate eCRF.
6.1.1.1
Alternate dosing regimen of LEE011
No alternate dosing regimen of LEE011 is planned.  
6.1.2
LEE011 administration
LEE011 may be administered orally in different ways:
1. Capsule: swallow whole or open capsule and pour contents onto semi-solid food or 
dissolve 
contents of opened capsule in water or Ora-Sweet (or equivalent) and 
administer orally or via feeding tube (e.g. nasogastric or gastric)
2. Powder in Bottle (PIB): dissolve powder in water or Ora-Sweet (or equivalent) and 
administer via feeding tube (e.g. nasogastric or gastric)
3. Liquid formulation. 
Since LEE011 shows high solubility across the pH range (> 6 mg/ml at pH 7-9 and > 25 
mg/ml at pH 4 or below), the exposure/bioavailability should not be limited by its dissolution 
rate due to different dosage form of administration. Preliminary in vitro and stability testing 
support this strategy. 
Patients may switch between the different methods of drug administration/formulation
depending on clinical status and swallowing abilities.  If changes in methods of drug
administration/formulation are made during the course of the study and not previously 
provided to patient, additional PK is recommended as outlined in Tables 7-4 or 7-5.  PK and 
safety will be monitored to ensure that there are no major changes related to methods of 
LEE011 administration.  Detailed instructions regarding preparation and administration of 
LEE011 capsules, PIB and liquid will be supplied separately to patients/caregivers and 
investigational sites.  
LEE011 should be taken as follows:

Patients should be instructed to take their once-a-day dose at approximately the same time 
each day.

On days when blood for PK samples need to be collected prior to taking study drug, the 
patient should take the dose in the clinic.

Each daily dose of LEE011 should be taken with water (preferably one cup) and
consumed over as short a time as possible unless otherwise instructed.

Patients taking capsules should be instructed to swallow capsules whole and to not chew 
or open them unless otherwise instructed.

Patients should prepare the dose as described in the Instructions for Use (to be supplied to 
Investigator sites separate to this protocol).

Ribociclib can be administered with or without food; however dietary habits around the 
time of dosing should be as consistent as possible throughout the study.
 


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
On days of PK/PD sampling, every effort must be made to capture the time of any 
vomiting within 4 hours of drug administration.

If vomiting occurs during the course of the treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose.

Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day.

Patients should inform the investigational site staff of any missed or delayed doses

Patients must avoid consumption of grapefruit products, pummelos, star-fruit, Seville 
oranges or products containing the juice of each during the entire study and preferably 7 
days before the first dose of study medications, due to potential CYP3A4 interaction with 
the study medications. Orange juice is allowed.
6.1.3
Treatment duration
Patients may continue to receive treatment with LEE011 until disease progression, occurrence 
of unacceptable toxicity that precludes any further treatment, if treatment is discontinued at 
the discretion of the investigator, the patient withdraws consent or the patient is enrolled in 
another Novartis study that can continue to provide LEE011. Patients who have localized 
disease progression but have evidence of clinical benefit may continue treatment with 
LEE011 after discussion with Novartis and investigator. Patients who continue on treatment 
after localized disease progression must discontinue treatment if there is subsequent systemic 
disease progression.
6.2
Dose escalation guidelines
6.2.1
Starting dose for the dose escalation part
The first cohort of patients in this trial will be treated with a dose of 280 mg/m2/d, which is 
80% of the current well tolerated dose (600 mg/d) in the ongoing adult study 
[CLEE011X2101] divided by the average adult body surface area (BSA) of 1.72 m2. Table 6-
1 describes the starting dose and the dose levels that may be evaluated during this trial.
Table 6-1
Provisional dose levels
Dose level
Proposed daily dose*
Increment from previous 
dose
Corresponding adult dose 
level
-1c
210 mg/m2
-25%
360 mg/d
1 (starting dose)
280 mg/m2
(starting dose)
480 mg/d
2
420 mg/m2
50%
720 mg/d
3
630 mg/m2
50%
1080 mg/d
This table is intended only as a guide. Values in table are examples and actual doses may vary.
* Additional dose levels may be added during the course of the study. Cohorts may be expanded at any dose 
level below MTD in order to better understand safety, PK or PD.
c Dose level -1 is a dose level that may be evaluated if the starting dose level is not well tolerated
Since the adult MTD has not been established, LEE011 doses higher than 630 mg/m2 may be evaluated 
depending on the data from the adult Ph1 study and observed safety, PK and PD.
 


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6.2.2
Guidelines for dose escalation and determination of (MTD/ RDE)
For the purposes of dose escalation decisions, 3 to 6 patients will be enrolled in successive 
cohorts. The first cohort will be treated with the starting dose of 280 mg/m2/d. Patients must 
complete a minimum of 1 cycle of treatment with the minimum safety evaluation and drug 
exposure or have had a DLT within the first cycle of treatment to be considered evaluable for 
dose escalation decisions. Dose escalation decisions will occur when the cohort of patients has 
met these criteria. Dose escalation decisions will be made by Investigators and Novartis study 
personnel. Decisions will be based on a synthesis of all relevant data available from all dose 
levels evaluated in the ongoing study including safety information, DLTs, all CTCAE grade ≥ 
2 toxicity data during Cycle 1, and PK, data from evaluable patients. PK data from patients 
will be made available on an on-going basis throughout the study and dosing will be adapted 
accordingly. The recommended dose for the next cohort of patients will be guided by the 
BLRM with EWOC principle.
The adaptive Bayesian methodology provides an estimate of all dose levels of LEE011 that do 
not exceed the MTD and incorporates all DLT information at all dose levels for this 
estimation. In general, the next dose will have the highest chance that the DLT rate will fall in 
the target interval (16-33%) and will always satisfy the EWOC principle. In all cases, the dose 
for the next cohort will not exceed a 100% increase from the previous dose. Smaller increases 
in dose may be recommended by the Investigators and Sponsor upon consideration of all of 
the available clinical data.
If the first 2 patients in a previously untested dose level experience a DLT, the next cohort 
will be opened at the next lower dose level or an intermediate dose level (see Table 6-1, 
Appendix 7).  However, if the first 2 patients in a new cohort at a previously tested dose level 
experience a DLT, further enrollment to that cohort will stop and the BLRM will be updated 
with this new information. Re-evaluation of the available safety, PK, and PD data will occur. 
By incorporating information gained at the preceding dose cohorts, additional patients may be 
enrolled into this dose cohort only if the dose level still meets the overdose criteria and as 
agreed by Investigators and Novartis personnel. Alternatively, if recruitment to the same 
cohort may not resume, a new cohort of patients may be recruited to a lower dose as agreed 
by Investigators and Novartis personnel and if the BLRM predicts that the risk for this lower 
dose to exceed the MTD remains below 25% (EWOC).
Dose escalation will continue until identification of the MTD or a suitable lower dose for 
expansion. This will occur when the following conditions are met:
1. at least 6 patients have been treated at this dose
2. this dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or
b. minimum of 12 patients have already been treated on the trial.
3. it is the dose recommended for patients, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, see Section 6.2.2.1.
To better understand the safety, tolerability and PK of LEE011 additional cohorts of patients 
may be enrolled at preceding dose levels, or to intermediate dose levels before or while 
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If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional patients are 
enrolled at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels.
6.2.2.1
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including AEs and 
laboratory abnormalities that are not DLTs), the recommendations from the BLRM, and the 
available PK and PD information will all be evaluated by the Investigators and Novartis study 
personnel (including the study physician and statistician) during a dose decision meeting by 
teleconference. Drug administration at the next higher dose level may not proceed until the 
investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level.
Dose escalation will continue until MTD and/or the RDE is reached. The dose for the 
expansion part will either be the MTD, or a lower dose that is determined to be the RDE.
6.2.2.2
Intra-Patient dose escalation
The starting dose on this study is close to the predicted MTD and therefore, intra-patient dose 
escalation is not permitted at any time during this study. 
6.2.3
Definitions of DLTs
A DLT is defined as an AE or clinically significant abnormal laboratory value assessed as 
unrelated to disease, disease progression, inter-current illness, or concomitant medications 
that occurs within the first 28 days of treatment with LEE011 and meets any of the criteria 
included in Table 6-2. NCI CTCAE version 4.03 will be used for all grading. For the purpose 
of dose-escalation decisions, DLTs will be considered and included in the BLRM.
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
AEs or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE 
grade ≥ 2 AEs will be reviewed for all patients at the current dose level.
 


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Table 6-2
Criteria for defining dose-limiting toxicities
TOXICITY
DLT CRITERIA
Hematology
CTCAE grade 4 neutropenia lasting more than 7 consecutive days
CTCAE grade 4 thrombocytopenia
CTCAE grade 3 or 4 neutropenia with fever (temperature ≥ 38.5°C)
ECG QT Interval
QTc interval ≥ 501 ms on at least two separate ECGs
Gastro-intestinal
≥ CTCAE grade 3 nausea or vomiting despite optimal anti-emetic therapy
≥ CTCAE grade 3 diarrhea despite optimal anti-diarrhea treatment
Hepato-biliary
≥ CTCAE grade 3 total bilirubin
≥ CTCAE grade 3 ALT (isolated increases in AST without concomitant increases in 
ALT will not be considered dose-limiting, because of the non-specific nature of AST)
Non-hematologic events
≥ CTCAE grade 3, except for the exclusions noted below
Exceptions to DLT criteria
Grade 3 alopecia
< 72 hours of CTCAE grade 3 fatigue
Grade 3 fever or infection without neutropenia < 5 days duration
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant
CTCAE version 4.03 will be used for all grading.
Optimal therapy for vomiting or diarrhea will be based in institutional guidelines, with consideration of the 
prohibited medications listed in this protocol.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
If a patient experiences a DLT, then treatment with LEE011 must be interrupted. For all 
toxicity grades, if the toxicity resolves to grade 1 or baseline within 1 week of onset, treatment 
may be resumed at the same or a lower dose level at the investigator’s discretion and 
following discussion with Novartis. For toxicities that result in treatment delays of more than 
7 but not more than 21 days, treatment may be resumed at a lower dose level. If a patient 
requires a dose interruption of > 21 days from the intended day of the next scheduled dose, 
then the patient must be discontinued from the study. In this event, more frequent follow up as 
outlined in cycle 1 to monitor this toxicity may be appropriate. Changes to the dose or 
schedule must be recorded on the Dosage Administration Record eCRF. All patients will be 
followed for AEs and for SAEs for 30 days following the last dose of LEE011.
Patients who have dose-limiting neutropenia with no other dose-limiting toxicity may receive 
the same dose in the next cycle with myeloid growth factor support or receive study drug at 
the next lower dose level. If dose-limiting neutropenia recurs after myeloid growth factor 
support is added, then the patient should be given the next lowest dose level for subsequent 
cycles and myeloid growth factor support should be administered.
Patients with extensive involvement of bone marrow who are not evaluable for hematologic 
toxicity but who have dose-limiting neutropenia should receive the same dose in the next 
cycle with myeloid growth factor support or receive study drug at the next lower dose level. 
Since these patients are permitted to have platelet transfusions to meet platelet criteria, no 
dose modifications will be made for dose-limiting thrombocytopenia.
 


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If a patient experiences an adverse event that is considered to be related to LEE011 that 
requires interruption of treatment with LEE011, the following must be met in order to resume 
treatment with LEE011 (except for patients with bone marrow disease):

ANC must be ≥ 1,000 /µl

Platelet count must be ≥ 75,000 /µl

All non-hematologic toxicities must be ≤ grade 1 or returned to baseline

Absence of any other DLTs, as described in Table 6-2.
6.4
Concomitant medications
Refer to preclinical toxicity and/or clinical data found in the Investigator’s Brochure.
6.4.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents, such as packed red blood cells (PRBC)s, pain medications, anti-
emetics and anti-diarrheals are allowed. Stable doses of steroids from study entry and oral 
contraceptive pills are permitted. The use of any other potential new concomitant medications 
may be discussed between the investigator and the sponsor on a case by case basis.
Transfusions or growth factor support for white cell counts, platelets or red blood cells are not 
permitted during Cycle 1, unless the patient has already experienced a DLT. Transfusions and 
growth factor support should not be used prophylactically during Cycle 1. Patients with bone 
marrow metastatic disease who are not evaluable for hematological toxicities are exempt.
The patient and/or patient’s parent or guardian must be told to notify the investigational site 
about any new medications he/she takes after the start of the study drug. All medications 
(other than study drug) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered during the study must be listed on the Concomitant 
Medications or Significant Non-Drug Therapies eCRF, respectively.
6.4.1.1
Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing ribociclib 
drug exposure to subtherapeutic levels. Systemic corticosteroid treatment should not be given 
during the study, except for:

Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular);

A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency 
of 4 mg dexamethasone (e.g. for chronic obstructive   pulmonary disease, or as an 
antiemetic)
6.4.2
Concomitant therapy requiring caution
The following therapies are permitted in this study, however they should be used with 
caution:

Medications that are moderate inhibitors or inducers of CYP3A4/5. (Refer to Appendix 6).
 


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
Sensitive substrates of CYP3A4/5 that do not have a narrow therapeutic index (Refer to 
Appendix 6).

Known BSEP inhibitors listed in Appendix 6.

Agents that are metabolized predominantly by CYP1A2 with a narrow therapeutic index 
and agents that are strong inhibitors of CYP1A2 listed in Appendix 6.

Medications that carry a moderate-low risk for QT prolongation listed in Appendix 6.
Patients receiving such medications must be carefully monitored for potentiation of toxicity 
due to any individual concomitant medication, and may require dose titration of the drug 
substance.
6.4.3
Prohibited concomitant therapy
The following therapies are prohibited:

Strong inducers or inhibitors of CYP3A4/5. In particular EIAEDs. (Refer to Appendix 6).

Substrates of CYP3A4/5 with narrow therapeutic windows (Refer to Appendix 6)

Medications that carry a strong risk for QT prolongation (Refer to Appendix 6)

Concurrent anti-neoplastic therapy, including radiotherapy

Patients should be instructed not to take grapefruit products/juice, or Seville (sour) 
oranges/juice while receiving LEE011 treatment throughout the study due to its potential 
for CYP3A4/5 interaction.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Patient Number, that is assigned when the patient is 
first enrolled for screening and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient Number 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 
Number available to the investigator through the interface.
6.5.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort will be coordinated by the sponsor. No 
randomization list will be required for this study.
6.5.3
Treatment blinding
Treatment is not blinded for this study.
6.6
Study drug dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
 


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personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
LEE011 will be supplied as capsules for oral use of 10, 50, and 200 mg dosage strength. The 
capsules will be packaged in bottles.  LEE011 will also be supplied in Powder in Bottle (PIB) 
(1200mg in 125mL amber bottle) or in liquid form and will be packaged in bottles.
6.6.1
Study drug packaging and labeling
LEE011 capsules, PIB and liquid form will be packaged in bottles. Medication labels will be 
in the local language and comply with the legal requirements of each country. They will 
include storage conditions for the drug but no information about the patient. The study drug 
will be labeled and packaged under the responsibility of the Novartis drug supply 
management department. The medication will be supplied as open label supply to the sites in 
a way which allows the patient to take medication at home.
6.6.2
Study drug compliance and accountability
6.6.2.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee, and will be verified by determinations of LEE011 in plasma.
6.6.2.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.6.3
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Drug supply is to be destroyed at the site only if permitted by local 
regulations and authorized by Novartis.
 


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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.
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. All data obtained from these 
assessments must be supported in the patient’s source documentation. Laboratory assessments 
that were completed within 72 hours prior to Cycle 1, Day 1 (C1D1) do not need to be 
repeated.
 


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Table 7-1
Visit evaluation schedule
Visit Name
Protocol 
Section
Screening
Treatment Period
EOT
SEC
Cycle 1
Cycle 2
Cycles 3-6
Subsequent cycles
1
2
3
4
5
6
7
8
9
10
11
12…
22
23…
777
778
Day of Cycle
-21
to
-1
1
2
8
15
22
1
15
22
1
15
22
1
22
Last
30 day
follow-
up
Obtain Main Informed 
Consent
7.1.1.
X
Patient History
Demography
7.1.1.3.
X
Inclusion/exclusion
criteria
5.2/5.3.
X
Medical History
7.1.1.3.
X
Prior Antineoplastic
therapies
7.1.1.3.
X
Diagnosis and extent
of cancer
7.1.1.3.
X
Prior/concomitant
medications
6.4.
Continuous
Physical examination
7.2.2.1.
X
X
X
X
X
X
X
X
X
X
X
Performance status
7.2.2.4.
X
X
X
X
X
X
Height, Weight, BSA
7.2.2.3.
X
X
X
X
X
X
Vital signs
7.2.2.2.
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
assessments
7.2.2.5.
Hematology
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
X
X
Chemistry
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
X
X
Thyroid
7.2.2.5.3.
X
X
C4, 
C8, 
X
 


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Visit Name
Protocol 
Section
Screening
Treatment Period
EOT
SEC
Cycle 1
Cycle 2
Cycles 3-6
Subsequent cycles
1
2
3
4
5
6
7
8
9
10
11
12…
22
23…
777
778
Day of Cycle
-21
to
-1
1
2
8
15
22
1
15
22
1
15
22
1
22
Last
30 day
follow-
up
C6
C10,C12, 
etc.
Pregnancy test
7.2.2.5.4.
X
X
Cardiac
ECHO
7.2.2.5.6.
X
X
ECG
7.2.2.5.5.
X
X
X
X
X
X
X
X
X
Efficacy assessments
7.2.1.
Tumor evaluation
7.2.1.
Xa
X
C4, C6
C10, C14, 
C18, etc.
X
MIBG imaging
(neuroblastoma only)
7.2.1.
Xa
If positive at 
Screening
If positive 
at 
Screening 
C4, C6
If positive at 
Screening 
C10, C14, 
C18, etc.
X
BMA and/or Biopsy
(neuroblastoma only)
7.2.1.
Xa
If positive at 
Screening
If positive 
at 
Screening 
C4, C6
If positive at 
Screening 
C10, C14, 
C18, etc.
X
CSF Cytologyb
7.2.1.
Xa
If positive at 
Screening 
only to 
confirm CR
If positive 
at 
Screening 
C4, C6 to 
confirm CR
If positive at 
Screening 
C10, C14, 
C18, etc.to 
confirm CR
Safety
Adverse events
8.1.
Continuous
Predictive and 
Pharmacodynamic 
7.2.4.
 


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Visit Name
Protocol 
Section
Screening
Treatment Period
EOT
SEC
Cycle 1
Cycle 2
Cycles 3-6
Subsequent cycles
1
2
3
4
5
6
7
8
9
10
11
12…
22
23…
777
778
Day of Cycle
-21
to
-1
1
2
8
15
22
1
15
22
1
15
22
1
22
Last
30 day
follow-
up
Biomarkers
Collection of archival
tumor blocks/slides
7.2.4.1.
X
BMA and/or Biopsy
(neuroblastoma 
only)a
7.2.4.2.
X
If positive at 
Screening
If positive 
at 
Screening 
C4, C6
If positive at 
Screening 
C10, C14, 
C18, etc.
LEE011 administration
6.1.2.
Days 1-21
Days 
1-21
Days 1-21
Days 1-
21
PK blood samplingc
7.2.3.
X
Xd
X
X
X
X
C3
CSF for PKb
7.2.3.2.
if available when collected for efficacy assessment or routine/ standard clinical purposes
Antineoplastic 
therapies since 
discontinuation of 
study treatment
7.1.4.
X
X
a Screening window = -28 to- 1 day(s) prior to first dose of LEE011
b only for primary CNS (including MRT)
c An additional PK blood sample will be required if a patient has CSF collected (see Section 7.2.3.2).
d escalation only, C1D2
 


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7.1.1
Screening
The informed consent form (ICF) must be dated and signed prior to any screening procedures 
not performed as part of the initial diagnostic work-up of the patient are conducted. Once the 
ICF is signed, all AEs per the descriptions below will be captured in the Adverse Event CRF.
The screening period starts once a patient has provided written informed consent to participate 
in the study and ends on the day of first dose of LEE011. Screening assessments have to be 
done within 21 days prior to the first dose of LEE011 except for baseline tumor imaging scans, 
CSF cytology, and bone marrow aspirates and/or biopsies which may be done within 28 days 
prior to the first dose of LEE011 and/or hematologic (ANC, platelet count, and hematocrit) 
inclusion criteria within 7 days prior to first dose of LEE011.
7.1.1.1
Eligibility screening
The procedures for eligibility check, patient identification number assignments, and 
coordination among the sites involved will be provided in a separate document prior to study 
start.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Log eCRF, and each patient’s demographic information will be added on the 
Demography eCRF. No other data will be entered into the clinical database for screen failure 
patients.
7.1.1.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at baseline include general 
demographics, relevant medical history, the diagnosis and extent of their tumor(s) and prior 
antineoplastic therapies.
7.1.2
Treatment period
The treatment period commences on the first day of the first cycle (C1D1) of LEE011 and 
ends after the last dose of LEE011.
Patients who enter the study will be treated with daily dosing of oral LEE011 for 21 
consecutive days followed by a 7 day planned break  until the patient experiences 
unacceptable toxicity that precludes any further treatment, disease progression, and/or 
treatment is discontinued at the discretion of the investigator or by patient’s premature 
withdrawal.
During the study treatment period, patients will be regularly monitored to assess the safety 
and early anti-tumor activity of the treatment. For the purpose of scheduling and evaluations, 
a treatment cycle will consist of 28 days.
For details of assessments during the treatment period, refer to Table 7-1.
 


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7.1.3
End of treatment (EOT) visit
At any time, patients may voluntarily withdraw from the study or be removed from it at the 
discretion of the investigator. If withdrawal occurs, or if the patient fails to return for visits, 
effectively withdrawing, the investigator must determine the primary reason for a patient’s 
premature withdrawal, record this information on the End of Treatment eCRF, and notify 
Novartis. Patients may be withdrawn from study treatment for one of the following reasons:
1. Adverse event(s)
2. Disease progression
3. Protocol violation/deviation
4. Patient withdrew consent
5. Lost to follow-up
6. Death
7. Transfer to another Novartis clinical study that continues to provide LEE011.
Patients who discontinue study treatment for any of the above reasons (except death) should 
be scheduled for an EOT visit within 14 days of permanently discontinuing LEE011 at which 
time all of the assessments listed for the EOT visit will be performed. An EOT eCRF will be 
completed, giving the date and reason for stopping the study treatment.
The EOT completion evaluations are outlined in Table 7-1.
All patients who discontinue study treatment, including those who refuse to return for a final 
visit, should be contacted 30 days after discontinuing study drug for safety evaluations and a 
list of antineoplastic therapies received since discontinuation. See Section 7.1.4. A Study 
Evaluation Completion (SEC) eCRF will then be completed, giving the date and reason for 
study discontinuation.
For patients who refuse to return for visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone. Patients lost to follow up should 
be recorded as such on the SEC eCRF. A patient is considered “lost-to-follow up” if the 
patient fails to show up for a scheduled follow-up visit and no response despite at least 3 
documented failed attempts to contact the patient, such as via phone calls and/or registered 
letters. The investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc.
Patients that transition into the rollover clinical trial will perform end of treatment procedures.
However, follow-up for safety, survival and disease progression will not be performed.
7.1.3.1
Patient replacement
Escalation part:
Patients will not be replaced on study. However, if a patient is considered as non-evaluable 
for the DDS, enrollment of a new patient to the current cohort will be considered if there is 
less than the required number of evaluable patients. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.2.
 


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Expansion part:
Patients will not be replaced.
7.1.4
Follow-up period
All patients will have safety evaluations completed 30 days after the last dose of LEE011. At 
this time AE, SAE and concomitant medications (including subsequent antineoplastic 
therapy) information during the follow-up period will be recorded on the AE eCRF and 
Novartis will be informed as necessary.  For eCRF purposes, this will be referred to a Study 
Evaluation Completion (SEC).
Patients lost to follow-up should have this documented on the appropriate eCRF and attempts 
made to contact the patient to ascertain the reason and required study information, as 
described in Section 7.1.3.
7.2
Assessment types
7.2.1
Efficacy assessments
All patients will have disease response assessment per RECIST v1.1 (Appendix 1). Patients 
with primary CNS tumors (including MRT) will have response assessment per RANO criteria 
(Appendix 3) whenever possible, in addition to RECIST. Disease response in neuroblastoma 
patients will be assessed per INRC (Appendix 2) whenever possible in addition to RECIST. 
Response assessments for patients with MIBG-positive disease and bone marrow-positive 
disease will also be done when applicable, per standard institutional practice. Disease 
response and progression will be determined locally by the investigator. All imaging 
procedures at screening must be completed within 28 days of the first dose of LEE011.
For patients with primary CNS (including MRT), the method of measurement should follow 
the neuro-oncology criteria of tumor response using 2-dimensional and volumetric 
measurements (if available) on gadolinium chelate-enhanced brain tumor magnetic resonance 
imaging (Gd-MRI) (Appendix 3). All Gd-MRIs (standard brain tumor magnetic resonance 
imaging [MRI] including both pre-contrast and post-contrast images using a Gadolinium (Gd) 
chelate as the contrast agent) should be performed when the patient is on a non-increasing 
dose of corticosteroids for at least 7 days.
For patients with non-CNS tumors, the method of measurement should follow standard 
practice (ie, computed tomography [CT] or MRI scans) and response will be assessed using 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Appendix 1). Patients 
with neuroblastoma will undergo MIBG scanning, and bone marrow aspirate and/or biopsy 
for presence of disease per standard institutional practice at screening. The use of 123I for 
MIBG imaging is recommended for all scans. MIBG scans and bone marrow aspirates and/or 
biopsies should be performed within 28 days of the first dose of LEE011. Visible skin lesions 
and easily palpable subcutaneous tumors may be measured by physical examination using a 
ruler or calipers. Ultrasound should not be used to measure tumor lesions.
Each lesion that is measured at baseline (screening), must be measured by the same method 
throughout the study so that the comparison is consistent.
Antitumor activity in patients with non-measurable disease will only be noted.
 


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Subsequent tumor evaluations will be performed on Day 22 (±7 days) of cycles 2, 4 and 6. 
After cycle 6 tumor evaluations will be performed on Day 22 (±7 days) of every 4th cycle (e.g., 
C10, C14, C18), or sooner if there is clinical evidence of disease progression. Tumor 
evaluations will also be performed at EOT. If the last prior tumor evaluation was within 28 
days of EOT or objective evidence of progressive disease has already been documented, then 
tumor evaluations do not need to be repeated at EOT.
Tumor evaluations after the screening assessment will include evaluation of all sites of 
disease identified at baseline, using the same technique that was used at screening. If there 
was no evidence of disease in a body region at screening, that region does not need to be 
imaged at subsequent assessments, unless there is clinical concern for a new lesion in that 
body region. Bone marrow aspirate and/or biopsies and MIBG scans are not required after 
baseline if they were negative at screening.
The CSF test is required for primary CNS tumors (including MRT) patients at screening and 
is performed per institutional standards. If sampling is not feasible, patients may still enroll in 
study after discussion with Novartis and the investigator. Information will be collected if 
performed. CSF will be performed at Screening and if positive at screening, subsequent 
measurements are performed only for confirmation of CR as needed on Day 22 (±7 days) of 
cycles 2, 4 and 6. After cycle 6 tumor evaluations, CSF test will be performed as needed on 
Day 22 (±7 days) of every 4th cycle (e.g., C10, C14, C18), or sooner if there is clinical 
evidence of disease progression. Only 2 negative sequential CSF cytology are required for 
establishing CR.
All radiological assessments obtained for all patients enrolled during the study 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.
7.2.2
Safety and tolerability
Safety and tolerability assessments will include adverse event reporting and changes from 
baseline in laboratory measures and vital signs. Tolerability will be assessed by the incidence 
of AEs leading to study drug delay or discontinuation. For details on AE collection and 
reporting, refer to Section 8.
7.2.2.1
Physical examination
A full physical examination (PE) that evaluates all major organ systems will be performed at 
screening. This should include a complete neurological exam. Subsequent PEs should be 
focused on sites of disease, and clinical signs and symptoms. Patients with CNS disease and 
baseline neurologic findings should have a complete neurologic exam performed at all 
subsequent visits.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s eCRF.
PEs to be performed are outlined in Table 7-1.
 


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7.2.2.2
Vital signs
Vital signs (heart rate, blood pressure and temperature) will be obtained in the same position, 
either sitting or supine, as appropriate prior to any blood collection.
Vital signs to be obtained are outlined in Table 7-1.
7.2.2.3
Height, weight and body surface area (BSA)
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Sitting height should be measured when 
appropriate. BSA will be measured using the patient’s weight and height, in accordance with 
local site procedure. For the purpose of BSA calculations and potential dose readjustment at 
subsequent cycles, it is acceptable for the BSA to be calculated up to 7 days in advance of 
Day 1.
Assessments to be obtained are outlined in Table 7-1.
7.2.2.4
Performance status
Performance status will be scored using the Karnofsky (for patients greater than 16 years old) 
or Lansky (for patients less than or equal to 16 years old) performance scales, depending on 
the patient’s age (see Appendix 4 and Appendix 5).
Performance status to be obtained are outlined in Table 7-1.
For patients that have their 17th birthday during the study, performance status will continue to 
be assessed by the Lansky scale, in order to preserve continuity.
7.2.2.5
Laboratory evaluations
Laboratory tests will be collected and analyzed by the study site’s local laboratory. More 
frequent examinations may be performed at the investigator’s discretion if medically indicated 
and should be recorded on the Unscheduled Visit eCRFs.
At any time during the study, abnormal laboratory parameters which are clinically relevant 
(e.g., require dose modification and/or interruption of study drug, lead to clinical symptoms or 
signs, or require therapeutic intervention), whether specifically requested in the protocol or 
not, must be recorded in the AE eCRF.
Novartis will be provided with a copy of the laboratory certification and tabulation of the 
normal ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, 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 of C1D1 do not need to be repeated.
7.2.2.5.1 Hematology
Please refer to Table 7-2 for a list of tests to be performed.
For timing of assessments, refer to Table 7-1.
 


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7.2.2.5.2 Clinical chemistry
Please refer to Table 7-2 for a list of tests to be performed.
For timing of assessments, refer to Table 7-1.
7.2.2.5.3 Thyroid
Please refer to Table 7-2 for a list of tests to be performed. TSH is required at all required 
timepoints. If TSH is abnormal, T3 and free T4 should be performed.
For timing of assessments, refer to Table 7-1.
Table 7-2
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Complete blood count (CBC) with differential - white blood cell (WBC) count, absolute 
neutrophil count [including bands], lymphocyte, monocyte, eosinophil, and basophil counts, 
hemoglobin, hematocrit, and platelet count.
Chemistry
Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, AST (SGOT), 
ALT (SGPT), total bilirubin (if a total bilirubin elevation ≥ grade 2 occurs then direct and indirect 
bilirubin should be measured), LDH, albumin, calcium, magnesium, alkaline phosphatase 
(ALP), and phosphate.
Thyroid
TSH. If TSH abnormal, T3 and free T4 to be performed.
7.2.2.5.4 Pregnancy assessments
When effective contraception is required pregnancy testing is required at screening and at the 
end of the trial. At screening a serum pregnancy test should be performed, while at the end of 
trial urinary pregnancy tests are sufficient.
Pregnancy test to be performed:

Screening (serum)

End of treatment (urine or serum)
A positive pregnancy test is cause for immediate withdrawal.
For females to be considered “of non-childbearing potential”, patient should meet one of the 
following:

Prior to onset of menarche (pre-menarche)

Surgically sterile for at least 6 months (hysterectomy with bilateral oophorectomy or tubal 
ligation). Documentation of sterilization method must be provided. The date of 
sterilization will be recorded.
To ensure patient safety, each pregnancy in a patient on study drug 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 local Novartis Drug Safety and Epidemiology (DS&E) follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
 


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the Novartis study drug of any pregnancy outcome. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form.
7.2.2.5.5 Electrocardiogram (ECG)
A standard 12-lead ECG in triplicate will be performed after the patient has been resting for 5-
10 min prior to each time point indicated in Table 7-3.  Each ECG recording must be taken at 
a minimum of 2-minute intervals. The combined QTc values from these 3 ECGs will be 
averaged to provide a single value for each patient.
If an abnormal ECG is obtained at any time, patient’s electrolytes must be reviewed and 
repeat ECG measurements must be done after correction of electrolyte abnormalities.
All ECGs will be transmitted to a central laboratory and will be centrally reviewed by an 
independent reviewer.
In the event that a QTc value of ≥ 501 ms is observed, a blood sample for PK will be collected 
to determine plasma levels of LEE011 and any other identified metabolites.
Each ECG tracing should be labeled with the study number, patient initials, patient number,
date, and kept in the source documents at the study site. Clinically significant abnormalities at 
screening should be recorded on the relevant medical history/current medical conditions 
eCRF page. Only clinically significant abnormalities will be recorded in the AE eCRF page.
Table 7-3
Central ECG collection plan
Cycle
Day
Time
Screening
Anytime during the screening period
1
1
pre-dose 
1
1
1h post-dose (± 15 min)
1
1
2h post-dose (± 15 min)
1
1
4h post-dose (± 30 min)
1
8
pre-dose
1
8
2h post-dose (± 15 min)
1
8
4h post-dose (± 30 min)
1
8
6h post-dose (± 30 min)
1
15
pre-dose
1
15
2h post-dose (± 15 min)
1
15
4h post-dose (± 30 min)
1
15
6h post-dose (± 30 min)
1
22
Anytime during visit
2
1
pre-dose
2
15
Anytime during visit
3-6
1
Anytime during visit
Unscheduled
As clinically indicated
EOT
Within 14 days of last dose
7.2.2.5.6 Cardiac imaging - echocardiogram (ECHO)
Cardiac imaging by ECHO to be performed are outlined in Table 7-1.
 


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7.2.3
Pharmacokinetics
7.2.3.1
PK blood sample collection and handling
All blood samples will be taken either by direct venipuncture or through an indwelling 
cannula (eg, inserted in a forearm vein, or central venous line) according to the dose 
escalation schedule described in Table 7-4 and, for the dose expansion schedule Table 7-5. 
Residual plasma samples after the PK concentration analysis may be used for drug 
metabolism investigations.
At the specified time points, 1 mL of blood will be collected in tubes containing K3 EDTA. 
Refer to the Laboratory Manual for detailed instructions for the collection, handling and 
shipping of samples.
Patients may switch between the different methods of drug administration/formulation
depending on clinical status and swallowing abilities.  If changes in methods of drug
administration/formulation are made during the course of the study and not previously 
provided to patient, PK will be collected as outlined in Tables 7-4 or 7-5.  These subjects 
should have one set of PK blood samples collected at pre-dose, 2 hours post-dose and 4 hours 
post-dose at the time of the first dose using the new method of administration or formulation.  
PK and safety will be monitored to ensure that there are no major changes related to methods 
of LEE011 administration.
Table 7-4
Pharmacokinetic blood collection log – dose escalation part
Cycle
Day
Scheduled time points* (hours)
1
1
pre-dose
1
1
1h post-dose (± 15 min)
1
1
2h post-dose (± 15 min)
1
1
4h post-dose (± 30 min)
1
1
8h post-dose (± 30 min)
1
2
24h post dose (± 1 h, pre-dose for the next dose)
1
8
pre-dose
1
8
2h post-dose (± 15 min)
1
15
pre-dose
1
15
1h post-dose (± 15 min)
1
15
2h post-dose (± 15 min)
1
15
4h post-dose (± 30 min)
1
15
8h post-dose (± 30 min)
1
22
24h post day 21 dose (± 1 h)
2
1
pre-dose
2
1
4h post-dose (± 30 min)
3
1
pre-dose
Unscheduled
PK samples related to a QTc >= 501 ms
Unscheduleda
When CSF is collected
Not applicable (NA)
NA
pre-doseb
Not applicable
NA
2h post-dose (± 15 min)b
Not applicable
NA
4h post-dose (± 30 min)b
Unscheduled
Anytime
 


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Cycle
Day
Scheduled time points* (hours)
*All measurement times are relative to dose of LEE011 unless otherwise specified.
a. A PK blood sample (1 mL) should be obtained at the same time point a CSF sample is obtained.
b. For drug administration/ formulation switch not previously provided to patient, one set of PK blood samples 
should be collected at the time of the first dose using the new administration or formulation.
Table 7-5
Pharmacokinetic blood collection log – dose expansion part
Cycle
Day
Scheduled time points* (hours)
1
1
pre-dose
1
1
4h post-dose (± 30 min)
1
8
pre-dose
1
15
pre-dose
1
22
24h post day 21 dose (± 1 h)
2
1
pre-dose
3
1
pre-dose
Unscheduled
PK samples related to a QTc >= 501 ms
Unscheduleda.
When CSF is collected
NA
NA
pre-doseb
NA
NA
4h post-dose (± 30 min)b
Unscheduled
Anytime
*All measurement times are relative to dose of LEE011 unless otherwise specified.
a. A PK blood sample (1 mL) should be obtained at the same time point a CSF sample is obtained.
b. For drug administration/ formulation switch not previously provided to patient, one set of PK blood samples 
should be collected at the time of the first dose using the new administration or formulation. 
7.2.3.2
PK cerebrospinal fluid (CSF) sample collection and handling
If CSF is collected as part of efficacy assessment or routine/standard care at any time after 
patient has received first dose of LEE011, a sample will be requested for assaying LEE011 
concentration levels (maximum 2 mL volume). As the timing of this procedure may vary 
depending on clinical condition of the patient, there is no set time point(s) for this 
measurement.
CSF samples should be processed, labeled, and stored as specified in the Laboratory Manual. 
The actual sample collection date and time should be entered on the appropriate eCRF.
When CSF is obtained, a PK blood sample (1 mL) is required at the same time point for 
plasma concentration analysis. Tmax for LEE011 is around 2-4 hours and SS is reached in 
about 8 days. Therefore, recommended timing for CSF and PK sampling is after 8 days of 
continuous treatment and within 2-5 hours after dosing with LEE011.
7.2.3.3
Analytical method
The plasma and CSF samples from all patients will be assayed for concentrations of LEE011 
and if needed, any clinically significant identified metabolites using a validated liquid 
chromatography-tandem mass spectrometry assay (LC/MS/MS). Residual samples may be 
used for drug metabolism investigations. Values below the lower limit of quantification 
(LLOQ) of approximately 5.00 ng/mL or lower will be reported as 0 ng/mL. Missing values 
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7.2.4
Biomarker assessments
7.2.4.1
Potential predictive biomarkers
All patients will be required to provide archival tumor samples (at diagnosis or relapse) unless 
otherwise agreed upon by Novartis and the investigator. The accompanying pathology report 
should also be included. 
 
 
7.2.4.2
Pharmacodynamic biomarkers
Patients with bone marrow involvement at study entry will provide pre- and post-treatment 
bone marrow samples (BMA and/or biopsy) for efficacy assessments.  Remaining samples 
will be analyzed for changes in key pharmacodynamic markers e.g. 
 and 
. If bone marrow aspirate/biopsy is being collected on a day when LEE011 is 
administered, every effort should be made to obtain BMA/biopsy sample around 4 hours post 
dose.
Additional markers may be analyzed if indicated by new findings from the literature as well 
as from Novartis internal data.
Detailed instructions for the collection, handling, and shipping of biomarker samples are 
outlined in the Laboratory Manual.
Table 7-6
Biomarker sample collection plan
Sample Type
Visit
Biomarker Analysis
Purpose
Archival Tumor
(at diagnosis or relapse)
Screening
(Anytime)
 
Potential 
predictive 
markers
Bone Marrow Aspirate 
(neuroblastoma patients only, 
if feasible)
Screening, C2D22, additional 
samples from other cycles, if 
feasible
PD analysis
Bone Marrow Biopsy
(neuroblastoma patients only, 
if feasible)
Screening, C2D22, additional 
samples from other cycles, if 
feasible
PD analysis
7.2.4.3
Storage of remaining biomarkers samples and additional analyses
The remaining biomarker samples (tumor, bone marrow aspirate or biopsy) may be stored for 
up to 15 years and further analyzed to address scientific questions related to the LEE011 
and/or cancer and/or the development of biological tests. The storage of these biomarker 
samples for additional analyses is optional. A decision to perform such exploratory biomarker 
research studies would be based on outcome data from this study or from new scientific 
findings related to the drug class or disease, as well as reagent and assay availability.
 


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Samples will only be stored and additional analyses will only be performed on samples from 
patients who agree to participate in this biomarker component by agreeing to this option in the 
main informed consent form.
7.2.5
Total blood volume
The total volume of blood that will be drawn from each patient in this study during the first 2 
cycles (8 weeks) of treatment is shown in Table 7-7.
Table 7-7
Maximum total blood volume (pediatric patients)
Maximum 
Sample 
Volume
24 hr (Cycle 1 Day 1)
Cycle 1 (4 weeks)
Cycle 1 + 2 (8 weeks)
No. 
samples
Total 
volume
No. 
samples
Total 
volume
No. 
samples
Total 
volume
Hematology
1 mL
1
1 mL
4
4 mL
6
6 mL
Chemistry
1 mL
1
1 mL
4
4 mL
6
6 mL
Thyroid
1 mL
0
0 mL
0
0 mL
1
1 mL
PK
1 mL
5
5 mL
14
14 mL
16
16 mL
Total
7 mL
22 mL
22 mL
32
32 mL
For younger and/or smaller patients where collection of these samples may compromise local blood volume limits, 
priority for blood samples will be (1) safety, followed by (2) PK
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events CRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current 
Medical Conditions page of the patient’s CRF. Adverse event monitoring should be continued 
for at least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible,
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4, will be 
 


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used. CTCAE grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through the End of Treatment or Study Evaluation Forms.
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. Whether it is serious, where a SAE is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per INRC and RECIST for neuroblastoma, RANO and RECIST for 
primary CNS (including MRT) and RECIST criteria for all solid tumors), should not be 
reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
SAE is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period 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 
 


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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 DS&E department.
The telephone and telefax number of the contact persons in the local department of 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 (CRF) 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 (IB) or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis 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 requirements in 
participating countries.
8.3
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 DS&E. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the investigational 
treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between 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.
 


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9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
patient experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO [Contract Research Organization]) will review the protocol and 
CRFs with the investigators and their staff. During the study, the field monitor will visit the 
site regularly to check the completeness of patient records, the accuracy of entries on the 
CRFs, the adherence to the protocol to Good Clinical Practice, the progress of enrollment, and 
to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
 


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9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol including biomarker and PK data 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.
In addition to data entered into eCRFs, requisition forms may also need to be completed for 
biomarker and PK sample collection. Imaging data from the patients enrolled in the study 
will be collected from the Investigator sites, sent to a specialty CRO, and held centrally.
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).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. The data will be summarized 
with respect to demographic and baseline characteristics, efficacy observations and 
measurements, safety observations and measurements, and all relevant PK and PD 
measurements using descriptive statistics (quantitative data) and contingency tables 
(qualitative data).
The study data will be analyzed and reported based on all patients’ data of the dose escalation 
and expansion parts up to the time when all patients have potentially completed at least six 
cycles of treatment or discontinued the study. Any additional data for patients continuing to 
 


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receive study treatment past the data cutoff date for the primary CSR, as allowed by the 
protocol, will be reported once all patients have discontinued the study.
Unless otherwise specified, cohorts treated during the dose escalation/dose expansion with the 
same dose levels of LEE011 will be pooled into a single treatment group and all summaries, 
listings, figures and analyses will be performed by treatment group.
10.1
Analysis sets
10.1.1
Full analysis set
The FAS includes all patients who received at least one dose of LEE011. Patients will be 
classified according to the planned treatment. The FAS will be used for all listings of raw data. 
Unless otherwise specified the FAS will be the default analysis set used for all analyses.
10.1.2
Safety set
The safety set includes all patients who received at least one dose of LEE011, and have at 
least one valid post-baseline safety assessment. The statement that a patient had no AEs (on 
the AE eCRF) constitutes a valid safety assessment. Patients will be classified according to 
treatment received, where treatment received is defined as:
1. The treatment assigned if it was received at least once, or
2. The first treatment received in the study if the assigned treatment was never received.
10.1.3
Dose-determining analysis set
The dose-determining set consists of all patients from the safety set who either meet the 
following minimum exposure criterion and have scheduled safety evaluations, or experience a 
DLT. A patient is considered to have met the minimum exposure criterion if he received at 
least 16 out of the 21 planned daily doses (3 weeks on, 1 week of schedule) of LEE011 in the 
first 28 days of dosing.
Patients who do not experience DLT during the first cycle are considered to have sufficient 
safety evaluations if they have been observed for ≥ 28 days following the first dose, and are
considered by both the Sponsor and Investigators to have enough safety data to conclude that 
a DLT did not occur.
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the DDS.
10.1.4
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable drug concentration data. The PAS will be used for summaries of 
PK data (Tables and Figures) as well as for listings of derived parameters.
Note: Patients will be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of the analyses and prior database lock.
 


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including age, gender, height, weight, medical condition, 
disease characteristics, etc. will be summarized descriptively for all patients in the FAS. 
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.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
The actual dose and duration in days of LEE011 treatment as well as the dose intensity 
(computed as the ratio of actual dose received and actual duration) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose received/planned duration), 
will be listed and summarized.
The summary data will be presented for each treatment cycle individually, as well as for all 
study days as a single category.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC term by means of 
contingency tables.
10.3.3
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized.
10.4
Primary objective
The primary objective of the study is to estimate the MTD and/or the RDE of LEE011 when 
administered as a single agent orally in patients. The corresponding primary analysis method 
is an adaptive BLRM guided by the EWOC principle (Neuenschwander et al 2008).
10.4.1
Variable
The primary endpoint is the incidence of DLTs in cycle 1. Estimation of the MTD of the 
treatment will be based upon the estimation of the probability of DLT in Cycle 1 for patients 
in the DDS. This probability is estimated by the model in Section 10.4.2.
10.4.2
Statistical hypothesis, model, and method of analysis
An adaptive BLRM with 2 parameters, guided by the EWOC principle, will be used to make 
dose recommendations and estimate the MTD/ RDE during the study. The use of Bayesian 
response adaptive models for Phase I studies has been advocated by the EMEA guideline on 
 


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small populations 2006 and by Rogatko et al (2007) and is one of the key elements of the 
FDA’s Critical Path Initiative.
The adaptive BLRM model will be fitted on the dose-limiting data (i.e. absence or presence of 
DLT) accumulated in cycle 1 throughout the dose escalation part (and possibly during the 
dose expansion part), for modeling the dose-DLT relationship of LEE011.
The DLT relationship in the escalation part of the study will be described by the following 
Bayesian logistic regression model:
logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0
where logit(π(d))= ln ((d)/(1-(d))), and π(d) is the probability of a DLT at dose d. Doses are 
rescaled as d/d* with reference dose of d*= 580 mg/m2. As a consequence α is equal to the 
odds of the probability of toxicity at d*. Note that for a dose equal to zero, the probability of 
toxicity is zero.
If a different dosing schedule will be considered, a Bayesian Meta-analytic approach will be 
used to take into account historical data collected for the initially planned schedule in the 
actual study, in order to derive an informative prior estimation of the dose-toxicity 
relationship for the new dosing regimen. This informative prior will be combined with DLT 
data for the new dosing regimen using a 2-parameter BLRM.
For further details of the statistical model including specification of prior distribution for the 
BLRM parameters, implementation and results under a variety of data scenarios please refer 
to Appendix 7.
Dose recommendation
Dose escalation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose-level will lie within each of the 
following intervals:

[0, 0.166) under-dosing

[0.166, 0.333) targeted toxicity

[0.333, 1.00] excessive toxicity
The overdose control criterion mandates that any dose of LEE011 for which the DLT rate has 
more than a 25% chance of being excessively toxic, i.e. exceeding 0.333, will not be 
considered for the next dose cohort. The final estimate of the MTD/RDE before the start of 
the expansion will also satisfy this condition.
Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion 
if the amount of data is insufficient. If vague prior information is used for the probabilities of 
DLT, in the early stages of the study this escalation procedure will reflect a conservative 
strategy.
 


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Details of the criteria for dose escalation and the determination of the MTD are provided in 
Section 6.2.2.
Dose expansion
Upon completion of the first cycle of treatment for at least 10 patients within the dose 
expansion part, if the observed DLT rate exceeds 33%, the BLRM will be re-run to confirm 
that the estimated MTD/RDE still satisfies the overdose criterion. If the dose fails to satisfy 
the criterion a change to the dose under study may be made according to the Bayesian model 
recommendation, after review of the clinical data.
Listing/ summary of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade based on the CTCAE version 4.03, type of adverse event, and by treatment group. The 
dose-determining set will be used for these summaries.
10.4.3
Handling of missing values/censoring/discontinuations
Continuing events (e.g. AEs, concomitant medication, etc.) will be summarized using the data 
cut-off date as the date of completion, with an indication within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event with the appropriate censoring as 
described in the above paragraph.
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient.
Other missing data will simply be noted as missing on appropriate tables/listings.
10.4.4
Supportive analyses
Supportive analyses may be performed to incorporate later cycle DLT data to provide 
additional guidance for dose escalation within the escalation part of the study.
Additional exploratory and supportive analyses will be conducted if appropriate and defined 
in the reporting and analysis plan (RAP).
10.5
Secondary objectives
Refer to Section 3 for secondary objectives of dose escalation part and dose expansion part.
10.5.1
Population and grouping for the analyses
For all safety analyses, the safety population will be used. All other secondary analyses will 
use the population specified in the relevant section below. All listings and tables will be 
presented by treatment group (or study arm for efficacy analysis in the expansion part with 
patients classified to treatment group as described in Section 10.
 


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10.5.2
Safety evaluation
10.5.2.1 Analysis set and grouping for the analyses
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication.
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication.
3. Post-treatment period: starting at day 31 after last dose of study medication.
10.5.2.2 Adverse events (AEs)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by primary 
system organ class, severity based on the CTCAE version 4.03, type of adverse event, and 
relationship to the study drug by treatment group. Deaths reportable as SAEs and non-fatal 
serious adverse events will be listed by patient and tabulated by primary system organ class, 
type of adverse event, and by treatment group.
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.
10.5.2.3 Laboratory abnormalities
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using CTCAE, version 4.03. Parameters for which a grading does not exist will be 
classified into low/normal/high group by means of laboratory normal ranges.
For each laboratory test (e.g. hematology, biochemistry, etc.) a listing of laboratory values 
will be provided by laboratory parameter, patient and treatment group. The frequency of 
notable lab abnormalities will be displayed by parameter, cycle and treatment group. Similarly, 
the frequency of all laboratory abnormalities will be displayed by parameter, worst CTCAE 
version 4.03 grade experienced and treatment group. A separate listing will display notable 
laboratory abnormalities (i.e., newly occurring CTC grade 3 or 4 laboratory toxicities).
Laboratory data will be summarized by presenting grade shift tables for those parameters for 
which CTCAE version 4.03 allows classification. All remaining data will be summarized by 
presenting shift tables based on normal ranges.
Laboratory data will also be displayed by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges).
10.5.2.4 Electrocardiograms
Data from electrocardiograms will be listed, notable values will be flagged and any other 
information collected will be listed as appropriate. Furthermore, combined QTc values from 
the triplicate ECGs will be averaged to provide a single value for each patient and to be used 
in the summary tables.
 


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Change from baseline in QT intervals by treatment will be summarized for each visit. 
Moreover change from baseline in all ECG parameters for the worst change from baseline 
will be summarized. The frequency and percentage of patients with notable ECGs and newly 
occurring qualitative ECG abnormalities will be tabulated by treatment group and mutually 
exclusive categories of QTcF, QTcB, QT, HR, PR, QRS (see Table 10-1).
In the listings of baseline cardiac imaging results subjects with a notable post-dose QTc 
abnormality will be identified.
Table 10-1
ECG parameters and abnormal values
ECG Parameter
Abnormal values
QT, QTcF and QTcB
New absolute values >450, >480 and >500
Changes from baseline >30 and >60
HR
Decrease from baseline >25% and to a HR < 50
Increase from baseline >25% and to a HR > 100
PR
Increase from baseline >25% and to a value >200
QRS
Increase from baseline >25% and to a value >110
QT or QTc values will also be also considered notable when >450 msec, >480 msec and >
500 msec. They will be flagged as such in listings.
The difference between baseline and maximum post-QTcF values will also be summarized.
Post-baseline values will also be presented in the following categories: an increase from 
baseline of > 30 msec or > 60 msec, or new absolute values > 450 msec, > 480 msec, or > 500 
msec. A frequency table for such categories will be summarized by treatment.
A listing of QT prolonging concomitant medications will be produced. 
Additional outputs and details will be fully specified in the RAP.
10.5.2.5 Other safety data
Data from other tests (e.g., vital signs) will be listed, notable values will be flagged, and any 
other information collected will be listed as appropriate. Any statistical tests performed to 
explore the data will be used only to highlight any interesting comparisons that may warrant 
further consideration.
10.5.2.6 Supportive analyses for secondary objectives
Additional exploratory and supportive analysis will be conducted if necessary and specified in 
the RAP.
10.5.3
Tolerability
Tolerability of study drug LEE011 will be assessed by summarizing the number of dose 
interruptions and dose reductions. Reasons for dose interruption and dose reductions will be 
listed by patient and summarized. Cumulative dose, dose intensity and relative dose intensity 
of LEE011 will be listed by patient and summarized. Categories for relative dose intensity of 
LEE011 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75- < 0.9, ≥ 0.9-< 1.1, ≥1.1. The number 
and proportion of patients within each category will be presented.
 


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10.5.4
Efficacy evaluation
Assessment of preliminary efficacy for all patients will be based on RECIST v1.1 (Appendix 
1). In addition, patients with primary CNS tumors (including MRT) will have response 
assessment per RANO criteria (Appendix 3) whenever possible. Disease response in 
Neuroblastoma patients will additionally be assessed per INRC (Appendix 2).
TTP and DOR per RECIST v1.1 will be presented descriptively for the neuroblastoma and the 
MRT arms in the expansion phase using a Kaplan-Meier curve. Summary statistics from the 
Kaplan-Meier distribution will be determined, including the median and estimates at 4 and 8 
months, for TTP and DOR respectively. These statistics will be provided as point estimates 
with 95% confidence intervals.
ORR as per RECIST v1.1 will be presented at the MTD/RDE as point estimate and 
corresponding 95% exact confidence interval according to Clopper-Pearson for the 
neuroblastoma and the MRT population separately.
The same analysis will also be presented as per RANO in MRT patients and as per INRC in 
Neuroblastoma patients.
Moreover, preliminary efficacy response as per RECIST 1.1 will be listed for all patients as 
well as preliminary efficacy response per RANO and INRC for patients with Primary CNS 
and with Neuroblastoma, respectively.
Any other additional analysis will be fully specified in the RAP.
10.5.5
Pharmacokinetics
All patients in PAS will be included in the PK data analysis.
Pharmacokinetic variables:
The PK parameters listed in Table 10-2 for LEE011 will be estimated and reported as 
appropriate from the individual plasma concentration versus time profiles using a non-
compartmental approach within Phoenix® (Pharsight, Mountain View, CA). Exploratory PK 
analysis will be conducted using compartmental modeling as required.
Table 10-2
Non-compartmental pharmacokinetic parameters
AUCtau
The AUC calculated to the end of a dosing interval (tau) following single dose or at steady-state 
(amount x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after 
single dose administration or at steady-state (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration or at steady-state (time)
CL/F
The apparent total body clearance of drug from the plasma (volume x time-1)
Racc
Accumulation ratio
T1/2,eff
Effective elimination half-life
 


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10.5.5.1 Data handling principles
All samples will be assayed for LEE011 concentrations by Novartis using methods that will 
be fully described in the CSR. Values below the assay LLOQ will be reported as 0.00 ng/mL. 
Missing values will be labeled accordingly.
10.5.5.2 Data analysis princplies
Analysis sets
Only PK blood samples with date and time and for which the last prior dose dates and times 
are adequately recorded will be included in the PK analyses. Samples taken from patients who 
vomited within 4 hours of dosing will be excluded from the analysis.
Basic tables, figures and listings
The individual plasma concentration versus time profiles and mean concentration versus time 
profile of LEE011 and analyzed metabolites (if any) will be listed, summarized and displayed 
graphically.
Descriptive statistics of all pharmacokinetic parameters will include arithmetic and geometric 
mean, median, standard deviation (SD), and Coefficient of Variation (CV), geometric CV, 
minimum and maximum. However, for Tmax, median values and ranges will be given. Zero 
concentrations will not be included in the geometric mean/CV calculation. Summaries by age 
group will also be provided as appropriate.
10.6
Exploratory objectives
For exploratory objectives, refer to Table 3-1.
10.6.1
Biomarkers
10.6.1.1 Outline of the data analysis
Since this clinical trial was not designed to address specific biomarkers-related hypotheses, 
the analysis of this data should be viewed as exploratory and hypotheses generating.
There may be circumstances when a decision is made to stop collection, or not to perform or 
discontinue the analysis of samples due to either practical or strategic reasons. Under such 
circumstances, the sample size number may be too small or the quality of the data not 
sufficient to perform any data analysis and the available data will be only listed.
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in a stand-alone analysis 
plan document, as appropriate.
 


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10.6.1.2 Data handling principles
All measurements below their respective LLOQs or missing data will be labeled as such in the 
data listings. Imputation rules for measurements below the LLOQ will be described in the 
RAP.
Details of the data handling principles will be specified in the RAP. These will include 
definition of MYCN mutation (neuroblastoma) and 
 amplification (MRT) cutoff 
for gene copy numbers.
10.6.1.3 Data analysis principles
10.6.1.3.1
Analysis sets
FAS will be used for biomarker related analysis
10.6.1.3.2
Basic tables, figures and listings
Relationship between MYCN (neuroblastoma), 
(MRT), other genetic alterations 
and anti-tumor activity at the MTD/RDE will be presented using two way tables of best 
overall response. Moreover, the panel of assessed genes known to be genetically altered at a 
frequency of at least 5% in our study population will also be listed.
Pharmacodynamic assessments of LEE011 will be evaluated by pre and post treatment bone 
marrow aspirate/biopsy samples analyzed for 
 and 
. Absolute and/or relative (%) 
changes from baseline will be listed by subject and summarized using descriptive statistics by 
treatment and by visit for each biomarker. Longitudinal plots showing patient level and mean 
changes may also be generated.
 collected from archival tumor samples will be listed.
10.6.1.3.3
Advanced analysis methods
Additional analyses of biomarker data may be performed as needed. These will be 
documented in the RAP or a stand-alone analysis plan document.
10.6.2
PK-QTc relationship
Matched PK and ECG data will be used to investigate any possible relationship between 
LEE011 exposure (as measured by PK assessments of LEE011 plasma concentration) and QT 
prolongation.
To investigate the possible relationship between LEE011 concentration and change from 
baseline in QTcF, hereafter denoted ΔQTcF, different mixed effect models will be fitted 
(Table 10-3). The initial model contains only two explanatory variables, baseline QTcF and 
LEE011 concentration. This allows a first assessment of any possible relationship between 
LEE011 concentration and ΔQTcF, but without controlling for the possible confounding 
effects of other factors. Model 2 will be augmented with Day and Day*LEE011 concentration 
interaction term. If the interaction term will be non-significant it will be removed from the 
model before proceeding to the subsequent exploratory model in which different number of 
covariates of interest will be considered for inclusion (details specified in the RAP). Moreover, 
 


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additional models such as mixed effect model with correlation and non-linear mixed model 
may be used if appropriate.
Central tendencies 
For each treatment group, mean ΔQTcF will be evaluated by time point, and the maximum 
mean ΔQTcF identified. A plot will be produced showing maximum mean ΔQTcF (with SD) 
versus dose group. This will make possible the review of the data for indication of a 
relationship between dose and maximum mean ΔQTcF.
A plot will be produced of mean ΔQTcF and standard error (SE) by scheduled time point 
representing each treatment group on the same axes. This allows the data to be reviewed for 
indication of a dose effect on the magnitude of mean ΔQTcF, or on the time of maximum 
mean ΔQTcF.
Investigation of lagged effect
The relationship between Tmax and the time of maximum ΔQTcF will be investigated 
graphically. For each treatment group, plots of mean LEE011 concentration by time and of 
mean ΔQTcF will be plotted on the same axes, using the matched ECG and PK concentration 
data. 
10.7
Interim analysis
No formal interim analyses are planned. However, the dose-escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose-escalation phase, the next dose will to be chosen depending on the 
observed data. Details of this procedure and the process for communication with investigators 
are provided in Section 6.2.2.
Additionally, upon completion of the first cycle of treatment for at least 10 patients within the 
dose expansion part, if the observed DLT rate exceeds 33%, the BLRM will be re-run to 
confirm that the estimated MTD/RDE still satisfies the overdose criteria of the model.
 


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10.8
Sample size calculation
Dose-escalation phase
Each cohort will enroll 3 to 6 evaluable patients, including at least six patients at the 
MTD/RDE level and a minimum of 12 patients in total (details in Section 6.2.2). Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 
patients may be enrolled at any dose level below the estimated MTD/RDE for further 
elaboration of safety and pharmacokinetic parameters as required. It is expected that 
approximately 10 patients may be enrolled and treated within this context. In all, it is 
anticipated that approximately 28 patients will be treated during the escalation phase for the 
model to have reasonable operating characteristics relating to its MTD recommendation.
Dose expansion part
During dose expansion a sample size of approximately 18 evaluable patients per arm 
(including those with MRT or neuroblastoma treated at the recommended MTD/RDE during 
dose-escalation) will be treated to gain more information about the overall safety and 
tolerability of LEE011, to provide additional PK and PD data to guide the selection of dosing 
for future studies with LEE011, and to provide an early opportunity to identify LEE011 anti-
tumor activity associated with neuroblastoma and MRT populations.
Assuming no differences in toxicity profile across the subpopulations enrolled in the 
expansion phase, 36 patients will result in 97% probability of detecting at least one adverse 
event with a true rate of 10%. This probability rises as the true adverse event rate increases.
To allow for dropouts and expansion of cohorts, it is estimated that approximately 64 patients 
may be treated in the entire study.
10.9
Power for analysis of key secondary variables
Not applicable
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
 


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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 or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a patient’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed ICF that is 
considered appropriate for this study and complies with the ICH GCP guideline and 
regulatory requirements. Any changes to this ICF suggested by the investigator must be 
agreed to by 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.
Additional consent form
Studies with an optional storage of remaining biomarkers samples and additional analyses 
component (Section 7.2.3.3) will have a separate consent form covering those studies. This 
form will be adapted for each Study based on a standard template used globally for all Studies. 
These informed consent forms will be submitted for ethical approval together with the Study 
Protocol and the main informed consent form of the Study. If a patient opts not to participate 
in the optional assessments, this in no way affects the patient’s ability to participate in the 
main research study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
 


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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 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 
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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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13
References (available upon request)
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stats Med; 17(10):1103-20.
Biegel JA (2006) Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus; 
20:E11.
Brodeur GM, Seeger RC, Schwab M, et al (1984) Amplification of N-myc in untreated human
neuroblastomas correlates with advanced disease stage. Science; 224:1121-4.
Chi SN, Zimmerman MA, Yao X, et al (2009) Intensive multimodality treatment for children 
with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol.; 27(3):385-9.
Cohn SL, Pearson AD, London WB, et al (2009) The International Neuroblastoma Risk 
Group (INRG) classification system: an INRG Task Force report. J Clin Oncol; 27:289-97.
Deeken JF, Loscher W (2007) The blood-brain barrier and cancer; transporters, treatment, and 
Trojan horses. Clin Cancer.Res; 12(6);1663-74.
EMA (2003) Note for guidance for evaluation of anticancer medicinal products in man, 
addendum to paediatric medicine. July 24, 2003: 1-7.
Fujisawa H (2005) Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with 
hSNF5/INI1 gene activationJ Neurooncol; 73(2): 117-24.
Kim A, Fox E, Warren K, et al (2008) Characteristics and outcome of pediatric patients 
enrolled in phase I oncology trials. Oncologist; 13(6):679-89.
Lee DP, Skolnik JM, Adamson PC (2005) Pediatric Phase I Trials in Oncology: An Analysis 
of Study Conduct Efficiency. JCO; 23(33):8431-8441.
London WB, Castleberry RP, Matthay KK, et al (2005) Evidence for an age cutoff greater 
than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J 
Clin Oncol; 23:6459-65.
Maris JM (2010) Recent Advances in Neuroblastoma. NEJM; 362(23):2202-2211.
McClellan KA, Slack RS (2006) Novel functions for cell cycle genes in nervous system 
development. Cell Cycle; 5:1506–13.
McKenna ES, Sansam CG, Cho YJ, et al (2008) Loss of the epigenetic tumor suppressor 
SNF5 leads to cancer without genomic instability. Mol Cell Biol; 28:6223–6233.
Molenaar JJ, Koster J, Ebus ME, et al (2012) Copy Number Defects of G1-Cell Cycle Genes 
in Neuroblastoma are Frequent and Correlate with High Expression of E2F Target Genes and 
a Poor Prognosis. Genes, Chromosomes & Cancer; 51:10–19.
Molenaar JJ, Ebus ME, Koster J, et al (2008) Cyclin D1 and CDK4 Activity Contribute to the 
Undifferentiated Phenotype in Neuroblastoma. Cancer Research; 68(8): 2599-2609.
Mosse YP, Laudenslager M, Longo L, et al (2008) Identification of ALK as a major familial 
neuroblastoma predisposition gene. Nature; 455:930-5.
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med; 27(13):2420-39.
 


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Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials; 7(1):5-18.
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 64(2):66-9.
Tekautz TM, Fuller CE, Blaney S, et al (2005) Atypical teratoid/rhabdoid tumors (AT/RT): 
Improved survival in children 3 years of age and older with radiation therapy and high-dose 
alkylator-based chemotherapy. J Clin Oncol; 23:1491–1499.
Tsikitis M, Zhang Z, Edelman, et al (2005) PNAS; 102(34);12129-12134.
Versteege I, Sevenet N, Lange J, et al (1998) Nature; 394:203–206.
Woehrer A, Slavc I, Waldhoer T, et al (2010) Cancer; OO:1-8.
 


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14
Appendices
14.1
Appendix 1: Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Guidelines for Response, Duration of Overall Response,
TTF, TTP, Progression-Free Survival and Overall Survival
(based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.1:
29-Nov-2011
Version 3:0:
19-Oct-2009
Version 2:0:
18-Jan-2007
Version 1:0:
13-Dec-2002
Release date:
29-Nov-2011
List of contributors
Authors 
:
 
Authors 
:
 
Authors 
:
Authors 
:
 


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


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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 2 and the definition of best response in 
Section 3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 3.2 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 4 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.
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.
2.1 Definitions
2.1.1 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 3.2.8.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.

Cystic lesions:
 


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
Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
2.1.2 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 3.2.8.
2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
 


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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 
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. 
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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.
2.3 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 2.1.1.

Nodal target: See Section 2.1.1.
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.
2.4 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 2-1) and non-target lesions (Table 2-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 2-3) as well as the presence or absence of new lesions.
 


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2.4.1 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.
2.4.1.1 Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
2.4.1.2 Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
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2.4.2 Determination of target lesion response
Table 2-1 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 2.2.
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 2-1 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 
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2.4.3 Determination of non-target lesion response
Table 2-2 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 2.4.2 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
2.4.4 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 2.5).

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 2.2.
2.5 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 2-3.
Table 2-3 Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1.
This overall lesion response also applies when there are no non-target lesions identified at baseline.
2.
Once confirmed PR was achieved, all these assessments are considered PR.
3.
As defined in Section 2.4.
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.
3 Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 3.2.8 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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3.1 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).
3.2 Time to event variables
3.2.1 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.
3.2.2 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.
3.2.3 Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
 


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a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
3.2.4 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.
3.2.5 Duration of response
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response 
rates… If an inferential comparison between treatments is required this should only be 
performed on all patients (i.e. not restricting to “responders” only) using appropriate statistical 
methods such as the techniques described in Ellis et al (2008). It should also be stated in the 
protocol if duration of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
 


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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.
3.2.6 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 3.2.5. 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.
3.2.7 Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
 


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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 3.2.8).
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.
3.2.8 Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
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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 3-1.
Table 3-1 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 2.4.
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.
3.2.9 Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
 


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Table 3-2 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 3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 3.2.7.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
 


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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 3-2 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.
4 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).
4.1 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).
4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment.
Patients may discontinue study treatment for any of the following reasons:
 


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
Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
4.4 Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at 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 
 


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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.
4.5 Programming rules
The following should be used for programming of efficacy results:
4.5.1 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.
4.5.2 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 3.2.7). 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.
4.5.3 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.
4.5.4 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)’.
 


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4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
4.5.6 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 3-2)

Death due to reason other than underlying cancer

Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 3.2.7. 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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5 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: International Neuroblastoma Response Criteria 
(INRC)
Table 14-1
INRC definition
RESPONSE
ANATOMICAL IMAGING + MIBG (PET)
CR
●
Complete resolution of non-primary measurable lesions
●
MIBG non-avid (no increased FDG-PET uptake for mIBG non-avid tumors) of non-
primary lesions
PR
●
30% decrease in size/sum of non-primary measurable disease (RECIST), or
●
≥50% reduction in MIBG score (Relative MIBG score ≥0.1 to ≤to 0.5)
PD
●
Any new lesion by CT/MRI or MIBG
●
>20% increase in size AND a minimum absolute increase of 5 mm in longest 
dimension in existing lesions
●
Relative mIBG (FDG-PET for mIBG non-avid tumors) score ≥1.2
SD
Neither sufficient shrinkage for MR or PR nor sufficient increase for PD
Table 14-1 describes Revised International Neuroblastoma Response Criteria written by Park 
J, Valteau-Couanet D, Baruchel S et al. (manuscript in preparation)
 


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14.3
Appendix 3: Revised Assessment in Neuro-Oncology (RANO) 
Criteria
Table 14-2
RANO definition
 


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Table 14-3
Summary of RANO response criteria
Table 14-2 and Table 14-3 is described in Updated Response Assessment Criteria for High 
Grade Glioma: Response Assessment in Neuro-Oncology Working Group. Journal of Clinical 
Oncology, Vol 11, No 8 (August), 1993: pp 1466-1477.
14.4
Appendix 4: Karnofsky Performance Status Scale (for patients 
greater than 16 years old)
Table 14-4
Karnofsy Performance Status Scale
Able to carry on normal 
activity and work; no special 
care needed
100%
Normal; no complaints
90%
Able to carry on normal activity; minor signs or symptoms of disease
80%
Normal activity with effort; some signs or symptoms of disease
Unable to work; able to live at 
home and care for most 
personal needs; varying 
amount of assistance needed
70%
Cares for self; unable to carry on normal activity or work
60%
Requires occasional assistance; able to care for most personal needs
50%
Requires considerable assistance and frequent medical care
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly
40%
Disabled; requires special care and assistance
30%
Severely disabled; hospitalization is indicated though death not 
imminent
20%
Very sick; hospitalization necessary; active supportive treatment 
necessary
10%
Moribund; fatal processes progressing rapidly
0
Dead
 


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14.5
Appendix 5: Lansky Score (for patients less than or equal to 16 
years old)
Table 14-5
Lansky score
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of play and less time spent in play activity
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed but lies around much of the day; no active play but able to participate in all quiet play and 
activities
40
Mainly in bed; participates in quiet activities
30
Bed-bound; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive
14.6
Appendix 6: Medication and herbals to be excluded or to be used 
with caution
Any patient who requires a prohibited medication should not be enrolled on a trial for 
LEE011 until further information becomes available.
Note: This is not a comprehensive list of cytochrome P450 isoenzymes and QT prolongation 
medications. This is only meant to be used as a guide. Please contact the medical monitor with 
any questions.
CYP3A4/5
In order to avoid clinically significant drug-drug interactions, the co-administration of known 
CYP3A4/5 substrates with narrow therapeutic windows will be prohibited (Table 14-6). 
Additionally, considering LEE011 is a substrate of CYP3A4, strong inducers and inhibitors of 
CYP3A4 will also be contraindicated (Table 14-6). Medications that are moderate or weak 
inhibitors or inducers of CYP3A4/5, are permitted in this study, however they should be used 
with caution (Table 14-7). In addition, sensitive substrates of CYP3A4/5, that do not have a 
narrow therapeutic index are permitted, but should be used with caution (Table 14-7).
 


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Table 14-6
List of contraindicated CYP3A substrates, inducers or inhibitors
Category
Drug Name
Strong CYP3A Inhibitors – AUC substrate 
increased by ≥ 5 fold
Boceprevir, indinavir, lopinavir, nelfinavir, ritonavir, 
saquinavir, telaprevir, Clarithromycin, telithromycin, 
troleandomycin, itraconazole, ketoconazole, voriconazole, 
posaconazole, mibefradil, nefazodone, conivaptan, 
grapefruit juice
Strong CYP3A Inducers – AUC decreased by ≥ 
80%
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, 
Avasimibe,2St. John's wort
1 CYP3A substrates with narrow therapeutic index 
(NTI)
alfentanil, fentanyl, pimozide, astemizole, terfenadine, 
cyclosporine, sirolimus, tacrolimus, dihydroergotamine, 
ergotamine, quinidine, cisapride
1 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
This list of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table (http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx; accessed April 4th, 2012),from the FDA’s 
“Drug Interaction Studies —Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations, DRAFT GUIDANCE, February 2012 (For further information, please see the FDA’s website: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf 
(accessed April 04, 2012)”
Table 14-7
List1 of medications which are CYP3A substrates, inducers or 
inhibitors to be used with caution
Category
Drug Name
Sensitive CYP3A substrates2
brotizolam, midazolam, triazolam, ebastine, felodipine, 
nisoldipine, quetiapine, lovastatin, simvastatin, alpha-
dihydroergocryptine, budesonide, buspirone, darifenacin, 
dasatinib, dronedarone, eletriptan, eplerenone, fluticasone, 
lurasidone, perospirone, sildenafil, ticagrelor, vardenafil
Moderate CYP3A inhibitors – AUC substrate 
increased by 2 to 5 fold
Amprenavir, aprepitant, atazanavir, clozapine, cimetidine, 
ciprofloxacin, crizotinib, darunavir, diltiazem, domperidone, 
elvitegravir, erythromycin, fluconazole, fosamprenavir, 
imatinib, lapatinib, losartan, mianserin, mifepristone, 
naftidrofuryl, nicardipine, ondansetron, oxatomide, 
pazopanib, pirenzepine, raloxifene, sorafenib, ticlopidine, 
schisandra sphenanthera, tipranavir, tofisopam, verapamil
Moderate CYP3A Inducers - AUC decreased by 
50-80%
Bosentan, efavirenz, etravirine, modafinil, nafcillin, ritonavir, 
talviraline, tipranavir
1 Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria as specified in Section 5.3 of the Study Protocol
2 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor.
3 Herbal product
This list of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table (http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx; accessed April 4th, 2012),from the FDA’s 
“Drug Interaction Studies —Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations, DRAFT GUIDANCE, February 2012 (For further information, please see the FDA’s website: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf 
(accessed April 04, 2012))”
CYP1A2
The co-administration of known CYP1A2 substrates with a narrow therapeutic index and 
agents that are strong inhibitors of CYP1A2 are to be used with caution (Table 14-8).
 


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Table 14-8
List1 of medications which are CYP1A2 substrates with narrow 
therapeutic index (NTI) or strong inhibitors of CYP1A2
Category
Drug Name
Strong CYP1A2 Inhibitors – AUC substrate 
increased by ≥ 5 fold
enoxacin, fluvoxamine
2CYP1A2 substrates with narrow therapeutic 
index (NTI)
alosetron, clozapine, duloxetine, clinafloxacin, melatonin, 
olanzapine, ramelteon, rofecoxib, tacrine, theophylline, 
tizanidine, zafirlukast
1 Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria as specified in Section 5.3 of the Study Protocol
2 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor.
This list of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table (http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx; accessed April 4th, 2012),from the FDA’s 
“Drug Interaction Studies —Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations, DRAFT GUIDANCE, February 2012 (For further information, please see the FDA’s website: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf 
(accessed April 04, 2012))”,
and from the University of Washington’s Drug Interaction Database
BSEP transporter
In order to avoid clinically significant drug-drug interactions, the co-administration of known 
BSEP inhibitors causing further BSEP inhibition are to be used with caution (Table 14-9).
Table 14-9
BSEP transporter: List of medications causing inhibition to be used 
with caution
Drug Name
Drug Class
Bosentan
Antihypertensive
Cyclosporin A
Immunosuppressant
Fusidate
Antibiotic
Glibenclamide
Sulfonylurea
Lovastatin
Antihyperlipidemic
Nefazodone
Antidepressant
Rifampicin
Antitubercular
Ritonavir
Antiretroviral
Sulindac
Nonsteroidal anti-inflammatory
Troglitazone (TGZ-sulfate)
Anti-diabetic
QT prolongation
Due to the concern that LEE011 will cause QT prolongation, caution should be exercised with 
all medications that are known to produce this effect. Those known to have a strong signal 
will be prohibited (Table 14-10) and others are to be used with caution (Table 14-11).
 


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Table 14-10
QT prolongation: List of excluded medications
Drug Name
Drug Class
Amitriptyline, Desipramine, Imipramine
Antidepressants
Chloroquine
Antimalarials
Chlorpromazine, Mesoridazine, Risperidone
Antipsychotics
Itraconazole, Ketoconazole
Antifungals
Tacrolimus, Arsenic trioxide, Domperidone
Miscellaneous drugs
Table 14-11
QT prolongation: List of medications to be used with caution
Drug Name
Drug Class
Dolasetron, Ondansetron, Tropisetron
Anti-emetics
Doxepin, Maprotiline, Venlafaxine,
Antidepressants
Gatifloxacin, Moxifloxacin, Sparfloxacin
Quinolone antibiotics
Halofantrine
Antimalarials
Pentamidine, Droperidol, Methadone, Bepridil
Miscellaneous drugs
Thioridazine, Ziprasidone,
Antipsychotics
14.7
Appendix 7: Prior calibration and operating characteristics of the 
Bayesian logistic regression model (BLRM)
Statistical model and dose recommendation
An adaptive BLRM with 2 parameters, guided by the EWOC principle, will be used to make 
dose recommendations and estimate the MTD/ RDE during the study. The use of Bayesian 
response adaptive models for Phase I studies has been advocated by the EMEA guideline on 
small populations, 2006 and by Rogatko et al (2007) and is one of the key elements of the 
FDA’s Critical Path Initiative.
The adaptive BLRM will be fitted on the dose-limiting data (i.e. absence or presence of DLT) 
accumulated in cycle 1 throughout the dose escalation and the dose expansion parts of the 
study, for modeling the dose-DLT relationship of LEE011.
The DLT relationship in the escalation and escalation parts of the study will be described by 
the following Bayesian logistic regression model:
logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0
where logit(π(d))= ln ((d)/(1-(d))), and π(d) is the probability of a DLT at dose d. Doses are 
rescaled as d/d* with reference dose of d*= 580 mg/m2. As a consequence α is equal to the 
odds of the probability of toxicity at d*. Note that for a dose equal to zero, the probability of 
toxicity is zero.
If a different dosing schedule will be considered, a Bayesian Meta-analytic approach will be 
used to take into account historical data collected for the initially planned schedule in the 
actual study, in order to derive an informative prior estimation of the dose-toxicity 
relationship for the new dosing regimen.
 


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Prior specifications
The Bayesian approach requires the specification of prior distributions for the model 
parameters. All information currently available about the dose-DLT relationship of LEE011 
was summarized in a prior distribution. 
 
 
 

 

Estimation of the MTD/RDE in the dose-escalation part of the current study will take into 
account patients in the dose-determining set and will be based upon the estimation of the 
probability of DLT in the Cycle 1,
 by 28 days.


For the pediatric population subject to inclusion/exclusion criteria studied in the current 
trial, it is expected that the probability of DLT within cycle 1 at any given LEE011 doses 
administered in mg/m2 is similar to the probability of DLT within cycle 1 at the 
corresponding flat LEE011 dose administered in the adult population 
 
.

 

 
 


 
 

 

 

 
 
 


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




 
 
 
 
 

 

 

 
 
 

 

For the remaining doses, the prior 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Hypothetical dose escalation scenarios
In order to show how the Bayesian model reacts, different hypothetical dose escalation 
scenarios were investigated. The design should make reasonable dose-recommendations 
during the clinical trial based on the observed DLTs. During the study, the decision to dose 
escalate after completion of a given cohort and the actual dose chosen for the subsequent 
cohort will depend on the recommendation of the BLRM per EWOC principle and medical 
review of available clinical and laboratory data.
Note that the next dose level is selected in concordance with the provisional dose levels 
specified in Section 6.2.1 of the protocol, to mimic possible on-study escalation steps. For 
example, in scenario 1 (0/3 at 280 mg/m2), the next dose level is below the maximal increase 
allowed by the model and below the 100% increase limit. However, since this is one of the 
provisional dose levels suggested for the next cohort, it has been selected.
Additionally, for the scenarios in which a high toxicity rate is observed at the starting dose 
level (2/3 DLTs, scenario 3), a dose of 85 mg/m2 has been added in order to show cases in 
which future re-escalations of the compound may be recommended.
Some scenarios to illustrate the dose escalation up to the third dose cohort are listed in Table 
14-15. Some scenarios illustrate the ability for the model to handle cohorts of different size.
 


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Table 14-15
Scenarios
scenario
LEE011 dose
Npat
Ntox
Next dose 
level (NDL)
P(target) 
NDL
P(over) 
NDL
Median 
DLT rate
1
280 mg/m2
3
0
420 mg/m2
31.5%
7.5%
13.7%
2
280 mg/m2
3
1
280 mg/m2
43.3%
16.9%
19.5%
3
280 mg/m2
3
2
85 mg/m2
35.7%
25%
20.3%
4
280 mg/m2
420 mg/m2
3
3
0
0
630 mg/m2
31.8%
10.2%
14.1%
5
280 mg/m2
420 mg/m2
3
3
0
1
420 mg/m2
45.9%
10.8%
18.3%
6
280 mg/m2
420 mg/m2
3
3
0
2
280 mg/m2
48%
15.4%
20.1%
7
280 mg/m2
280 mg/m2
3
3
1
0
420 mg/m2
46%
13%
18.9%
8
280 mg/m2
85 mg/m2
3
3
2
0
210 mg/m2
45.6%
22.7%
22%
9
280 mg/m2
420 mg/m2
3
6
0
2
420 mg/m2
55.5%
13.9%
20.9%
10
280 mg/m2
420 mg/m2
3
6
0
3
280 mg/m2
53.7%
15.2%
21.4%
11
280 mg/m2
420 mg/m2
630 mg/m2
3
3
3
0
0
0
850 mg/m2
25.3%
7.2%
11.9%
12
280 mg/m2
420 mg/m2
630 mg/m2
3
3
3
0
0
1
630 mg/m2
43.9%
14.2%
18.7%
13
280 mg/m2
420 mg/m2
630 mg/m2
3
3
3
0
0
2
420 mg/m2
48.7%
10.1%
18.6%
14
280 mg/m2
420 mg/m2
630 mg/m2
3
3
6
0
0
2
630 mg/m2
52.1%
16.4%
21.2%
15
280 mg/m2
420 mg/m2
630 mg/m2
3
3
6
0
0
3
420 mg/m2
53.2%
9%
19.2%
16
280 mg/m2
420 mg/m2
630 mg/m2
420 mg/m2
3
3
3
6
0
0
2
0
* 420 mg/m2
31.3%
1.6%
13.2%
* the next dose level is selected in concordance with the provisional dose levels specified in Section 6.2.1 but in 
this case intermediate doses between 630 mg/m2
420 mg/m2 would be more appropriate and are allowed as per EWOC.
Within Table 14-14, it can be seen that the model leads to decisions that are in agreement with 
clinical sense: progressive increase of the LEE011 doses if no DLT is observed, enrolling of a 
new cohort at the same dose level when 1/3 or 2/6 DLT’s are reported, and decrease when 
more than 1 or 2 DLTs are reported in cohorts of 3 or 6 patients respectively.
 

SAP_001.pdf: 
Clinical Development
LEE011
CLEE011X2102 / NCT01747876
A phase I, multi-center, open-label study of LEE011 in 
patients with malignant rhabdoid tumors and 
neuroblastoma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final 
Release date:
02-Sep-2016
Number of pages:
13
Property of Novartis
For business use only
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)
02-
Sep-
2016
Prior 
to 
final 
DB 
lock
Creation of 
final 
version
N/A - First version
NA


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................6
2.1
Data analysis general information ...........................................................................6
2.1.1
General definitions..................................................................................6
2.2
Analysis sets ............................................................................................................6
2.2.1
Subgroup of interest ................................................................................6
2.3
Patient disposition, demographics and other baseline characteristics .....................7
2.3.1
Patient disposition...................................................................................7
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................7
2.4.1
Study treatment / compliance..................................................................7
2.4.2
Prior, concomitant and post therapies .....................................................8
2.5
Analysis of the primary objective............................................................................8
2.5.1
Primary endpoint.....................................................................................8
2.5.2
Statistical hypothesis, model, and method of analysis............................8
2.5.3
Handling of missing values/censoring/discontinuations.........................8
2.5.4
Supportive analyses.................................................................................8
2.6
Analysis of the key secondary objective .................................................................8
2.7
Analysis of secondary efficacy objective(s) ............................................................8
2.8
Safety analyses.........................................................................................................8
2.8.1
Adverse events (AEs)..............................................................................8
2.8.2
Deaths....................................................................................................10
2.8.3
Laboratory data .....................................................................................10
2.8.4
Other safety data ...................................................................................10
2.9
Pharmacokinetic endpoints....................................................................................10
2.10
PD and PK/PD analyses.........................................................................................10
2.11
Patient-reported outcomes .....................................................................................10
2.12
Biomarkers.............................................................................................................10
2.13
Other Exploratory analyses....................................................................................10
2.14
Interim analysis......................................................................................................10
3
Sample size calculation .....................................................................................................10


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4
Change to protocol specified analyses ..............................................................................11
5
Appendix ...........................................................................................................................11
5.1
Imputation rules.....................................................................................................11
5.1.1
Study drug .............................................................................................11
5.1.2
AE date imputation ...............................................................................11
5.1.3
Concomitant medication date imputation .............................................11
5.2
AEs coding/grading ...............................................................................................12
5.3
Laboratory parameters derivations ........................................................................12
5.4
Statistical models...................................................................................................12
5.4.1
Primary analysis ....................................................................................12
Prior specifications ................................................................................................13
5.4.2
Key secondary analysis .........................................................................13
6
Reference...........................................................................................................................13


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List of abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This document describes the detailed statistical analysis plan for final CSR for study 
LEE011X2102. The final CSR will be written after the final database lock.
The statistical analyses which are covered in the RAP Module 3 for the primary CSR are not 
repeated within this document. Refer to
 
 
 
 
 
 
 
 
 
 
All changes to the planned analysis described in this document required before or after 
database lock will be made through an amendment or addendum, respectively. Note that 
obvious corrections will be made at the time of analysis to address minor formatting or 
spelling mistakes present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of 
any outputs required outside of the CSR, e.g., PSUR/DSUR, MTD/RDE declaration, IB 
updates, abstracts, posters, presentations, manuscripts, health authority requests and 
management updates. 
1.1
Study design
See the primary CSR RAP Module 3.
1.2
Study objectives and endpoints
Please see the primary CSR RAP Module 3.
2
Statistical methods
2.1
Data analysis general information
See the primary CSR RAP Module 3.
2.1.1
General definitions
See the primary CSR RAP Module 3. 
2.2
Analysis sets
See the primary CSR RAP Module 3.
2.2.1
Subgroup of interest
See the primary CSR RAP Module 3.


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2.3
Patient disposition, demographics and other baseline 
characteristics
Background, baseline and demographic characteristics including age, gender, race, ethnicity, 
height, weight, body surface area (BSA), body mass index (BMI), Karnofsky/Lansky 
performance status, etc., are listed individually by patient and summarized by treatment for 
patients in the FAS.
BMI and BSA (Gehan and Georage formulae) are calculated using the following formulas:

BMI [kg/m2] = weight[kg] / (height[m]**2)

BSA [m2] = 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000
BMI may be summarized by categories as appropriate. It is acceptable for the BSA to be 
calculated up to 7 days in advance of Day 1. Dose adjustments for changes in BSA in 
subsequent cycles are made as per standard site practice (e.g., if the BSA changes by ± 10% 
from the previous dose calculation).
Performance status is scored using the Karnofsky (for patients > 16 years old) or Lansky (for 
patients≤ 16 years old) performance scales (Protocol Appendix 4 and 5).
For patients that have their 17th birthday during the study, performance status will continue to 
be assessed by the Lansky scale, in order to preserve continuity.
2.3.1
Patient disposition
The following patient disposition information are listed and summarized by treatment for all 
patients in FAS at the time of final database lock: 

Enrolled patients who remained on treatment or discontinued treatment

Primary reasons for EOT based on EOT CRF

Study evaluation completion after EOT:

Patients who are either no longer being followed up for study evaluation or who 
continued to be followed for study evaluation based on EOT CRF

Primary reason for study evaluation completion based on Study Evaluation 
Completion CRF.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure to study drug is categorized into time intervals in days (≤56, 57-≤84, 85-
≤140, and ≥ 141) and in cycles (≤1, 2 - ≤3, 4 - ≤5, ≥6), frequency counts and percentages are 
summarized for the number of patients in each interval.
Duration of exposure to study drug by treatment is listed.
The safety set is used for all summaries tables and listings of study drug.
See the primary CSR RAP Module 3 for more detailed definitions. 


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2.4.2
Prior, concomitant and post therapies
No analysis of prior, concomitant or post therapient will be performed for the final CSR.
2.5
Analysis of the primary objective
The primary objective of the dose-escalation part was to determine the MTD of LEE011 when 
administered as a single agent orally to patients aged 12 months to 21 years old with 
malignant rhabdoid tumors and neuroblastoma.The MTD/RDE of LEE011 was determined 
prior to halted enrollment.
No analysis related to MTD will be performed for the final CSR as this analysis was fully 
covered in the primary CSR.
2.5.1
Primary endpoint
See the primary CSR RAP Module 3. 
2.5.2
Statistical hypothesis, model, and method of analysis
See the primary CSR RAP Module 3. 
2.5.3
Handling of missing values/censoring/discontinuations
See the primary CSR RAP Module 3. 
2.5.4
Supportive analyses
The MTD was to be further evaluated for preliminary anti-tumor activity and overall 
tolerability during the dose-expansion part of the trial. Due to halted enrollment, this analysis 
will not be performed.
2.6
Analysis of the key secondary objective
No key secondary objective is defined.
2.7
Analysis of secondary efficacy objective(s)
No other secondary efficacy objectives will be analyzed for the final CSR.
2.8
Safety analyses
2.8.1
Adverse events (AEs)
AEs 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) is
not used since this information was collected at the “End of Treatment” and “Study evaluation 
completion” pages. 
Summary tables for AEs include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. AEs, SAEs, and all deaths (on treatment and post 
treatment) are tabulated by primary system organ class, preferred term, severity and treatment. 


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Additional summaries based on causality, study drug discontinuation or study drug 
interruptions are produced.
All AEs collected in the AE (e)CRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. 
Listing and summaries are produced according to the following rules: 

Patients reporting and experiencing multiple occurrences of a specific AE have 
occurrences listed but are counted only once in the appropriate event category/class 
and according to the worst observed grade within summary tables. 

AEs are summarized by presenting the number and percentage of patients having at 
least one AE sorted by descending frequency then alphabetically (by system organ 
class and preferred term.
Analysis for clinicaltrials.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
and equal to 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
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.). 


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A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
2.8.2
Deaths
Summary of all deaths will be produced by treatment, system organ class and preferred term. All 
deaths will be listed for the full analysis set, on-treatment deaths will be flagged. 
2.8.3
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 for the final CSR.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
No ECG and cardiac imaging data will be analyzed for the final CSR.
2.8.4.2
Vital signs
No vital signs data will be analyzed for the final CSR.
2.9
Pharmacokinetic endpoints
No Pharmacokinetic data will be analyzed for the final CSR.
2.10
PD and PK/PD analyses
No PD data will be analyzed for the final CSR.
2.11
Patient-reported outcomes
No patient-reported outcomes will be analyzed for the final CSR.
2.12
Biomarkers
No biomarker data will be analyzed for the final CSR.
2.13
Other Exploratory analyses
No other exploaratory analyses will be be executed for the the final CSR.
2.14
Interim analysis
See the primary CSR RAP Module 3. 
3
Sample size calculation
See the primary CSR RAP Module 3.


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4
Change to protocol specified analyses
-
Due to halted enrollment, all analyses are performed for the dose-escalation part only. 
-
The analysis of adverse events of special interest is added. 
-
For the final CSR only limited demographic, disposition, exposure and safety data will 
be analysed.  
5
Appendix
This appendix gives details about statistical methods in addition to the report text.
5.1
Imputation rules
As a general rule, when a date is recorded as a partial date, the missing day is imputed to the 
15th of the month (e.g., DEC2007 imputed to 15DEC2007), and if the day and month are both 
missing then to July 1st of that year (e.g., 2007 imputed to 01JUL2007). Such imputed data are 
flagged in the listings.
For computation of time intervals (e.g. elapse time between initial diagnosis to first 
recurrence/relapse), if the imputation rule leads to a negative value, time interval should be set
to missing.
Continuing events (e.g. AEs) are summarized using the data cut-off date as the date of 
completion, with an indication within listings that the event is continuing. For patients who 
discontinue the study with ongoing events, the discontinuation date is used as the completion 
date of the event with the appropriate censoring.
Other missing data will simply be noted as missing on appropriate tables/listings
5.1.1
Study drug
The study drug and study treatment refer to the Novartis investigational drug LEE011, an 
orally bioavailable small molecule inhibitor of CDK4/6. 
5.1.2
AE date imputation
See Section 5.1
5.1.3
Concomitant medication date imputation
See Section 5.1
5.1.3.1
Prior therapies date imputation
See Section 5.1
5.1.3.2
Post therapies date imputation
See Section 5.1


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5.1.3.3
Other imputations
5.2
AEs coding/grading
AEs 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) is
not used since this information was collected at the “End of Treatment” and “Study evaluation 
completion” pages. 
5.3
Laboratory parameters derivations
All laboratory values are converted into SI units when applicable and the severity grade 
calculated using CTCAE, version 4.03 unless otherwise indicated. A severity grade of 0 is
assigned when the value is within normal limits. In the case when a local laboratory normal 
range overlaps into the higher (i.e., non-zero) CTC grade, the laboratory value is still 
considered within normal limits and assigned a CTC grade of zero.
5.4
Statistical models
5.4.1
Primary analysis
See the primary CSR RAP Module 3.
An adaptive BLRM with two parameters guided by the EWOC principle is used to make dose 
recommendations and estimate the MTD/ RDE during the study. The model is fitted on the 
Cycle 1 DLT data (i.e. absence or presence of DLT).
The adaptive BLRM model is fitted on the dose-limiting data (i.e. absence or presence of 
DLT) accumulated in Cycle 1 throughout the dose-escalation part (and possibly during the 
dose-expansion part), for modeling the dose-DLT relationship of LEE011.
The DLT relationship in the dose-escalation part of the study is described by the following 
Bayesian logistic regression model:
logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0
where logit(π(d))= ln ((d)/(1-(d))), and π(d) is the probability of a DLT at dose d. 
Doses are rescaled as d/d* with reference dose of d*= 580 mg/m2. As a consequence α is equal 
to the odds of the probability of toxicity at d*. Note that for a dose equal to zero, the 
probability of toxicity is zero.
If a different dosing schedule is considered, a Bayesian Meta-analytic approach is used to take 
into account historical data collected for the initially planned schedule in the actual study, in 
order to derive an informative prior estimation of the dose-toxicity relationship for the new 
dosing regimen. This informative prior is combined with DLT data for the new dosing 
regimen using a two-parameter BLRM. After patients in each cohort have completed at least 
one cycle of LEE011 treatment, the prior distribution is updated with the cumulated DLT data 
from Cycle 1. Posterior probabilities for the rate of DLT are summarized; the 
recommendation for the next dose level is based on these probabilities.


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Prior specifications
The Bayesian approach requires the specification of prior distributions for the model 
parameters. All information currently available about the dose-DLT relationship of LEE011 
was summarized in a prior distribution. 
 
 
 
Operating characteristics of this model and the escalation recommendations for some 
particular situations are provided in Protocol Appendix 7.
5.4.2
Key secondary analysis
NA
6
Reference
NA