Clinical trial NCT02732119
Conditions: Breast Cancer
Keywords: HR-positive HER2-negative Advanced breast cancer LEE011 ribociclib everolimus Afinitor exemestane Aromasin CDK CDK4 CDK6 CDK4/6 CDK4/6 inhibitor Phase I Phase II ER-positive PR-positive Postmenopausal adult
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-14; Completion date: 2020-02-25
Enrollment: 104 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is determine if the triplet combination of ribociclib, everolimus and exemastane is safe and effective in the treatment of locally advanced/metastatic breast cancer following treatment with a CDK 4/6 inhibitor

Detailed description:
This trial had two phases. The purpose of Phase I dose escalation and dose de-escalation was to determine the maximum tolerated doses (MTDs) and/or identify the recommended Phase II dose (RP2D) of the combination treatment of ribociclib+ everolimus + exemestane. The dosing was continuous in adult men and postmenopausal women with HR+ HER2-negative advanced breast cancer which was resistant to the non-steroidal aromatase inhibitors, fulvestrant or tamoxifen.

The purpose of the phase II portion of this trial was to evaluate the anti-tumor activity of exemestane, everolimus and ribociclib combination therapy following progression on a CDK 4/6 inhibitor.

The planned duration of the study was 30 months.

Arms: arm 1: Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B arm 2: Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally arm 3: Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally arm 4: Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally arm 5: Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally
Interventions: intervention 1: Ribociclib intervention 2: Everolimus intervention 3: Exemestane
Intervention descriptions: intervention 1: supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle intervention 2: supplied in 2.5 mg tablets taken orally, daily for 28 day cycle intervention 3: supplied in 25 mg tablets taken orally, daily for 28 day cycle

Protocol documents:
Prot_000.pdf: 
Oncology Clinical Development
Ribociclib (LEE011)
Protocol CLEE011XUS29 / NCT02732119  
TRINITI-1: A Phase I/II, single arm, open-label study of 
Ribociclib in Combination with Everolimus + Exemestane 
in the Treatment of Men and Postmenopausal Women with 
HR+, HER2- Locally Advanced or Metastatic Breast Cancer 
Following Progression on a CDK 4/6 Inhibitor
Triplet with Ribociclib, AfINitor® and AI posT CDK 4/6 Inhibitor
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Authors
Document type
Amended Protocol Version
Version number
03 (Clean)
Development phase
I/II
Document status
Final
Release date
15-Feb-2019


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Table of contents
Table of contents..................................................................................................................................... 2
List of tables............................................................................................................................................ 8
List of figures........................................................................................................................................ 10
List of abbreviations ............................................................................................................................. 11
Glossary of terms.................................................................................................................................. 14
Amendment 3........................................................................................................................................ 16
Amendment 2........................................................................................................................................ 18
Amendment 1........................................................................................................................................ 21
Synopsis................................................................................................................................................ 24
1
Background........................................................................................................................................... 35
1.1
Overview of current treatment................................................................................................. 35
1.1.1
Epidemiology of breast cancer ............................................................................. 35
1.1.2
Treatment options for hormone receptor positive advanced breast cancer........... 35
1.2
Introduction to investigational treatment(s) and other study treatment(s)............................... 39
1.2.1
Overview of ribociclib (LEE011)......................................................................... 39
1.2.2
Summary of results from patients treated with the combination of ribociclib 
600 mg and letrozole 2.5 mg daily from study CLEE011A2301 
(MONALEESA-2)................................................................................................ 45
1.2.3
Overview of everolimus (RAD001/ Afinitor®) .................................................... 49
1.2.4
Overview of exemestane....................................................................................... 52
1.2.5
Ribociclib in combination with everolimus.......................................................... 53
2
Rationale............................................................................................................................................... 59
2.1
Study rationale and purpose .................................................................................................... 59
2.1.1
Rationale for Continuous Dosing- Phase I-Dose Escalation ................................ 60
2.1.2
Rational for stomatitis prevention mouthwash ..................................................... 62
2.2
Risks and benefits.................................................................................................................... 62
2.2.1
Potential benefits to clinical trial participation..................................................... 63
2.2.2
Potential risks to clinical trial participants............................................................ 63
3
Study objectives and endpoints............................................................................................................. 63
3.1
Objectives and related endpoints-Phase I................................................................................ 63
3.2
Objectives and related endpoints-phase II............................................................................... 64
4
Study design.......................................................................................................................................... 66
4.1
Description of study design..................................................................................................... 66
4.1.1
Screening phase (Phase I and II) .......................................................................... 68
4.1.2
Treatment phase.................................................................................................... 69
4.1.3
Treatment discontinuation .................................................................................... 69
4.1.4
Safety follow-up ................................................................................................... 69


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4.2
Timing of interim analyses...................................................................................................... 69
4.3
Definition of end of study........................................................................................................ 70
4.4
Early study termination ........................................................................................................... 70
5
Population............................................................................................................................................. 70
5.1
Patient population.................................................................................................................... 70
5.1.1
Screening for Hepatitis B...................................................................................... 71
5.1.2
Screening for Hepatitis C...................................................................................... 71
5.2
Inclusion criteria...................................................................................................................... 72
5.3
Exclusion criteria..................................................................................................................... 74
6
Treatment.............................................................................................................................................. 77
6.1
Study treatment........................................................................................................................ 77
6.1.1
Dosing regimen..................................................................................................... 77
6.2
Dose escalation and de-escalation guidelines: Phase I Safety Run-in..................................... 78
6.2.1
Criteria for dose escalation and determination of MTD(s)/RP2D........................ 79
6.2.2
Definitions of dose limiting toxicities (DLTs) ..................................................... 80
6.2.3
Follow up for dose limiting toxicities................................................................... 81
6.2.4
Doses for Phase II................................................................................................. 82
6.3
Overview of Dexamethasone oral solution ............................................................................. 83
6.4
Dose modification ................................................................................................................... 84
6.4.1
Dose cohort modification ..................................................................................... 84
6.4.2
Anticipated Risks and safety considerations of the study drug combination........ 87
6.4.3
Dose modifications for ribociclib+everolimus+exemestane combination............ 87
6.4.4
Dose modification and management for everolimus specific toxicities ............... 95
6.4.5
Recommended actions to be taken for positive baseline hepatitis B test.............. 99
6.4.6
Guidance for all other adverse reactions............................................................. 100
6.5
Concomitant medications ...................................................................................................... 101
6.5.1
Permitted concomitant therapy for all treatment groups..................................... 101
6.5.2
Prohibited concomitant therapy during combined ribociclib + everolimus + 
exemestane.......................................................................................................... 102
6.5.3
Permitted concomitant therapy requiring caution and/or action while on 
study ................................................................................................................... 103
6.5.4
Drugs with QTc prolongation............................................................................. 103
6.6
Patient numbering, treatment assignment or randomization ................................................. 104
6.6.1
Patient numbering............................................................................................... 104
6.6.2
Treatment blinding ............................................................................................. 104
6.6.3
Study drug preparation and dispensation............................................................ 104
6.6.4
Study drug packaging and labeling..................................................................... 104
6.6.5
Drug supply and storage..................................................................................... 105
6.6.6
Study drug compliance and accountability......................................................... 105


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6.6.7
Handling of other study treatment ...................................................................... 105
6.6.8
Disposal and destruction..................................................................................... 105
7
Visit schedule and assessments........................................................................................................... 105
7.1
Study flow and visit schedule................................................................................................ 105
7.1.1
Screening............................................................................................................ 112
7.1.2
Treatment period................................................................................................. 113
7.1.3
End of study treatment visit including safety completion and study treatment 
discontinuation.................................................................................................... 114
7.1.4
Discontinuation of study treatment..................................................................... 114
7.1.5
Withdrawal of consent........................................................................................ 115
7.1.6
Safety Follow-up ................................................................................................ 115
7.1.7
Efficacy Follow-up............................................................................................. 116
7.1.8
Survival Follow-up............................................................................................. 116
7.1.9
Lost to Follow-up ............................................................................................... 116
7.2
Assessment types................................................................................................................... 116
7.2.1
Efficacy assessments .......................................................................................... 116
7.2.2
Safety and tolerability assessments..................................................................... 120
7.2.3
Pharmacokinetics................................................................................................ 125
127
129
130
8
Safety monitoring and reporting ......................................................................................................... 131
8.1
Adverse events ...................................................................................................................... 131
8.1.1
Definitions and reporting.................................................................................... 131
8.1.2
Laboratory test abnormalities ............................................................................. 132
8.2
Serious adverse events........................................................................................................... 133
8.2.1
Definitions .......................................................................................................... 133
8.2.2
Reporting............................................................................................................ 133
8.3
Pregnancy.............................................................................................................................. 134
8.4
Data Monitoring Committee.................................................................................................. 134
8.5
Steering committee................................................................................................................ 135
9
Data collection and management........................................................................................................ 135
9.1
Data confidentiality ............................................................................................................... 135
9.2
Site monitoring...................................................................................................................... 135
9.3
Data collection....................................................................................................................... 136
9.4
Data management and quality control................................................................................... 136
10
Statistical methods and data analysis.................................................................................................. 137
10.1
Analysis sets.......................................................................................................................... 138
10.1.1
Full analysis set .................................................................................................. 138


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10.1.2
Safety set ............................................................................................................ 138
10.1.3
DLT-determining analysis set............................................................................. 138
10.1.4
Pharmacokinetic analysis set .............................................................................. 138
10.1.5
Per-protocol set................................................................................................... 138
10.2
Patient demographics/other baseline characteristics ............................................................. 138
10.3
Treatments (study treatment, concomitant therapies, compliance) ....................................... 139
10.3.1
Study treatment................................................................................................... 139
10.3.2
Concomitant therapies ........................................................................................ 139
10.3.3
Compliance......................................................................................................... 139
10.4
Statistical hypothesis, model, and method of analysis .......................................................... 139
10.4.1
Study Design ...................................................................................................... 139
10.4.2
Sample size and accrual...................................................................................... 139
10.5
Objectives.............................................................................................................................. 140
10.5.1
Primary objectives .............................................................................................. 140
10.5.2
Secondary objective(s)........................................................................................ 140
10.5.3
Pharmacokinetics................................................................................................ 142
143
143
144
10.7
Interim analysis ..................................................................................................................... 145
11
Ethical considerations and administrative procedures........................................................................ 145
11.1
Regulatory and ethical compliance........................................................................................ 145
11.2
Responsibilities of the investigator and IRB/IEC/REB......................................................... 145
11.3
Informed consent procedures ................................................................................................ 145
11.4
Discontinuation of the study.................................................................................................. 146
11.5
Publication of study protocol and results .............................................................................. 146
11.6
Study documentation, record keeping and retention of documents....................................... 146
11.7
Confidentiality of study documents and patient records ....................................................... 147
11.8
Audits and inspections........................................................................................................... 147
11.9
Financial disclosures ............................................................................................................. 147
12
Protocol adherence.............................................................................................................................. 147
12.1
Amendments to the protocol ................................................................................................. 147
13
References (available upon request) ................................................................................................... 147
14
Appendices.......................................................................................................................................... 154
14.1
Appendix 1- Concomitant medication................................................................................... 154
14.2
Appendix 2 - Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1)................................ 157
14.2.1
Introduction ........................................................................................................ 158
14.2.2
Efficacy assessments .......................................................................................... 158


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14.2.3
Definitions .......................................................................................................... 159
14.2.4
Disease measurability......................................................................................... 159
14.2.5
Eligibility based on measurable disease ............................................................. 160
14.2.6
Methods of tumor measurement - general guidelines......................................... 160
14.2.7
Baseline documentation of target and non-target lesions ................................... 161
14.2.8
Follow-up evaluation of target and non-target lesions ....................................... 162
14.2.9
Follow-up and recording of lesions .................................................................... 162
14.2.10
Non-nodal lesions............................................................................................... 162
14.2.11
Nodal lesions ...................................................................................................... 163
14.2.12
Determination of target lesion response ............................................................. 163
14.2.13
Determination of non-target lesion response...................................................... 165
14.2.14
New lesions......................................................................................................... 166
14.2.15
Evaluation of overall lesion response................................................................. 166
14.2.16
Efficacy definitions............................................................................................. 167
14.2.17
Best overall response.......................................................................................... 167
14.2.18
Time to event variables....................................................................................... 169
14.2.19
Progression-free survival.................................................................................... 169
14.2.20
Overall survival .................................................................................................. 169
14.2.21
Time to progression............................................................................................ 169
14.2.22
Time to treatment failure .................................................................................... 170
14.2.23
Duration of response........................................................................................... 170
14.2.24
Time to response................................................................................................. 171
14.2.25
Definition of start and end dates for time to event variables.............................. 171
14.2.26
Handling of patients with non-measurable disease only at baseline................... 172
14.2.27
Sensitivity analyses............................................................................................. 173
14.2.28
Data handling and programming rules................................................................ 175
14.2.29
Study/project specific decisions ......................................................................... 175
14.2.30
End of treatment phase completion .................................................................... 175
14.2.31
End of post-treatment follow-up (study phase completion)................................ 176
14.2.32
Medical validation of programmed overall lesion response............................... 176
14.2.33
Programming rules ............................................................................................. 177
14.2.34
Calculation of ‘time to event’ variables.............................................................. 177
14.2.35
Incomplete assessment dates .............................................................................. 177
14.2.36
Incomplete dates for last known date patient alive or death............................... 177
14.2.37
Non-target lesion response ................................................................................. 177
14.2.38
Study/project specific programming................................................................... 177
14.2.39
Censoring reason ................................................................................................ 177
14.2.40
References (available upon request)................................................................... 178


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14.3
Appendix 3 - Bone Marrow Reserve in Adults ..................................................................... 179


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List of tables
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal BC patients..... 37
Table 1-2
Serious adverse events with a suspected causal relationship with ribociclib 
single agent........................................................................................................... 43
Table 1-3
Patient Demographic and baseline characteristics in study (CLEE011A2301).... 46
Table 1-4
Adverse events with suspected relationship to study treatment in study 
(CLEE011A2301)................................................................................................. 47
Table 1-5
Pharmacokinetic Parameters of Ribociclib and Everolimus at Steady State 
(Cycle 1, Day 15).................................................................................................. 55
Table 1-6
LEE011X2106: Adverse Events (All-grade greater than or equal to 15% in 
All Patients Receiving Triplet Therapy) Suspected to Be Related to 
Treatments ............................................................................................................ 56
Table 1-7
LEE011XUS29: Adverse Events (cohort A and B) Suspected to Be Related 
to Treatments........................................................................................................ 58
Table 3-1
Objectives and related endpoints-Phase I............................................................. 63
Table 3-2
Objectives and related endpoints-phase II............................................................ 64
Table 6-1
Dose and treatment schedule for the following combination: ribociclib + 
everolimus +exemestane (Phase II)...................................................................... 77
Table 6-2
Dose levels for ribociclib, everolimus and exemestane in Phase I dose 
escalation (cohort A and B).................................................................................. 78
Table 6-3
Dose levels for ribociclib, everolimus and exemestane in Phase I dose de-
escalation (cohort C)............................................................................................. 78
Table 6-4
Criteria for defining Dose Limiting Toxicities..................................................... 80
Table 6-5
Phase I dose escalation (cohort A and B) and Phase II group 1: Dose 
modification guidelines for Ribociclib + everolimus + exemestane..................... 85
Table 6-6
Phase I dose de-escalation (cohort C) and Phase II cohort 2: Dose 
modification guidelines for Ribociclib + everolimus + exemestane..................... 85
Table 6-7
Dose modification guidelines for ribociclib (if everolimus is held longer than 
3 weeks for pneumonitis)...................................................................................... 86
Table 6-8
Dose modifications and management recommendations for hematologic 
adverse reactions................................................................................................... 87
Table 6-9
Ribociclib/everolimus dose modification and management for QTcF 
prolongation.......................................................................................................... 89
Table 6-10
Ribociclib/everolimus dose modification and management for cardiac 
dysfunction ........................................................................................................... 92
Table 6-11
Ribociclib/everolimus dose modification and management for hepatotoxicity.... 92
Table 6-12
Everolimus specific toxicities management and recommendations ..................... 95
Table 6-13
Management of Pneumonitis ................................................................................ 97
Table 6-14
Recommendations for positive baseline hepatitis B test....................................... 99
Table 6-15
Guidelines for management of hepatitis B ........................................................... 99
Table 6-16
Ribociclib/everolimus dose adjustment and management recommendation 
for all other adverse reactions............................................................................. 100


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Table 7-1
Visit evaluation schedule.................................................................................... 107
Table 7-2
Imaging assessments........................................................................................... 118
Table 7-3
ECOG performance status.................................................................................. 121
Table 7-4
Local Clinical Laboratory Parameters Collection Plan ...................................... 122
Table 7-5
Central ECG Collection Plan.............................................................................. 124
Table 7-6
Schedule of blood sample collection for PK in phase I and II............................ 126
128
Table 10-1
Non-compartmental pharmacokinetic parameters.............................................. 143
Table 14-1
List of prohibited medications during study drug treatment............................... 154
Table 14-2
List of medications to be used with caution during study drug treatment .......... 155
Table 14-3
Response criteria for target lesions..................................................................... 163
Table 14-4
Response criteria for non-target lesions.............................................................. 165
Table 14-5
Overall lesion response at each assessment........................................................ 166
Table 14-6
Overall lesion response at each assessment: patients with non-target disease 
only..................................................................................................................... 173
Table 14-7
Options for event dates used in PFS, TTP, duration of response........................ 174
Table 14-8
Marrow distribution of the adult......................................................................... 179


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List of figures
Figure 1-1
Kaplan-Meier plot of PFS based on Investigator assessment (Full Analysis 
Set)........................................................................................................................ 49
Figure 1-2
LEE011 and everolimus in MCF 7 xenograft....................................................... 54
Figure 1-3
Triplet combination of LEE011, everolimus and fulvestrant in ZR and KPL-
1 xenograft models ............................................................................................... 54
Figure 4-1
Study design ......................................................................................................... 68


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List of abbreviations
aBC
AE
Advanced Breast Cancer
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BC
Breast Cancer
BCRP
Breast Cancer Resistance Protein
IRC
Independent Review Committee
BSEP
Bile Salt Export Pump
BUN
Blood Urea Nitrogen
CBR
Clinical Benefit Rate
CCND1
Cyclin D1
CDK4/6
Cyclin-Dependent Kinases 4 and 6
Cmax
Peak blood concentration
Cmin
Minimum concentration
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR 
Duration of Response
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EOT
End of Treatment
ER
Estrogen Receptor
FAS
Full Analysis Set
FFPE
Formalin-Fixed, Paraffin-Embedded
FIH
First-in-human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
HDL
High Density Lipoprotein
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus


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HR+
Hormone Receptor Positive
IB
Investigator Brochure
IC50
Inhibitory Concentration, where 50% inhibition is observed
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
LVEF
Left Ventricular Ejection Fraction
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MBC
Metastatic Breast Cancer
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition
NCRNPD
Non-Complete Response Non-Progressive Disease
NSAI
Nonsteroidal Aromatase Inhibitors
NSCLC
Non-Small Cell Lung Cancer
ORR 
Overall Response Rate
OS
Overall survival
PAS
Pharmacokinetic Analysis Set
Pd
Pharmacodynamics
PD
Progressive Disease
PFS
Progression free survival
P-gP
Permeability-glycoprotein
PgR
Progesterone receptor
PHI
Protected Health Information
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Partial Response
pRb
Retinoblastoma Protein
PS
Performance Status
PT
Prothrombin time
QD
Quaque Die (every day)
RAP
Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RDE
Recommended dose of expansion


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REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
R Value
ALT/ALP in x ULN
SAE
Serious Adverse Event
SC
Steering Committee
SD
Stable Disease
SEC
Safety Event Categories
SERM
Selective ER Modulators
S-ICF
Study ICF
SMT
Novartis Safety Management Team
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time).
TBIL
Total Bilirubin
ULN
Upper Limit of Normal


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of 
the investigational drug
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)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new 
drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated placebo 
and active treatment controls (when applicable). This also includes approved drugs used 
outside of their indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study treatments administered 
as concomitant background therapy required or allowed by the protocol when used in 
within approved indication/dosage
Medication 
number
A unique identifier on the label of each study treatment package which is linked to one of 
the treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study procedures that was not 
included in the investigational treatment
Subject Number
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Randomization 
number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to 
study timeline
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the original 
site to other parts of the body
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study treatment 
was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug run-
ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case refers to 
the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when a patient permanently discontinues study treatment for any reason
Supportive 
treatment
Refers to any treatment required by the exposure to a study treatment, e.g. premedication 
of vitamin supplementation and corticosteroid for pemetrexed disodium.


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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 time points
Withdrawal of 
Consent 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
any longer, and does not want any further visits or assessments, and does not want any 
further study related contact


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Amendment 3 
Study CLEE011XUS29 (TRINITI-1) was initiated in June 2016. As of 14-Nov-18, a total of 
104 patients have been enrolled in the study (25 patients in Phase I, 79 patients in Phase II).
The purpose of this amendment is to:
(i) Update the dose adjustment and management recommendations for QTcF prolongation.
Analyses of preclinical and clinical data with ribociclib have demonstrated that ribociclib
prolongs the QT interval in a concentration-dependent manner. Moreover, based on the
ribociclib exposure-ΔQTcF relationship and the clinical experience in studies CLEE011A2301 
(MONALEESA-2), 
CLEE011F2301 
(MONALEESA-3) 
and
CLEE011E2301 
(MONALEESA-7), ribociclib dose reduction is an effective strategy for managing ribociclib 
therapy in patients experiencing QTcF prolongation. Therefore, in order to reduce the risk of 
subsequent QTcF prolongation in patients experiencing a QTcF between 481-500 msec, 
ribociclib dosing should be reduced by 1 dose level with the first occurrence of QTcF ≥ 481 
msec. As a result, this amendment includes an update to the dosage management guidance for 
patients who experience QTcF prolongation.
(ii) Update the prohibited concomitant medications based on drug-drug interaction and 
comedication considerations.
(iii). Update End of Study to be defined as 15 months follow up from the last patient enrolled 
in the study
(iv). Minor additional updates as summarized below
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Section 4.1 and 6.2.4: RP2D for Phase II Group 2 was added

Section 4.1.3: Updated treatment discontinuation to follow patients through 
progression or follow up for up to 15 months after last patient enrolled in the study

Section 4.3: Updated definition of end of study to follow up for at least 15 months after 
last patient enrolled in the study

Section 4.4: updated the language regarding the reasons why the study may be 
terminated early by the sponsor and what actions are needed in that case

Section 5.1: updated inclusion criteria to add estimated glomerular filtration rate

Section 6.2.4.1 and 6.5.2: updated to clarify that herbal or dietary supplements with a 
known risk of QT prolongation are not permitted

Section 6.5.1.4: added to include guidance on use of antiemetic medications


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
Section 6.5.3: clarified the information provided regarding renal transporters MATE1, 
OCT2 and BCRP.

Section 6.5.3.1: added to include guidance on use of corticosteroids with caution

Section 7.1.5: updated language regarding actions needed when a patient withdraws 
their consent to participate in the trial

Section 7.1.7 and 7.1.8: updated to define end of follow up 

Table 6-4: updated with instructions on how to define hepato-biliary criteria for Dose 
Limiting Toxicities

Table 6-9: updated with instructions on how to manage QTcF prolongation

Table 14-1: updated with the most current prohibited medications

Table 14-2: updated with the most current medications to be used with caution
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 2
Amendment 2 rationale
Study CLEE011XUS29 (TRINITI-1) was initiated in June 2016. As of 22-May-17, a total of 
63 patients have been enrolled in the study (18 patients in Phase I, 45 patients in Phase II). 
The current amendment is intended to update the trial design to remove the Simon Two-Stage 
analysis of the phase II since cohort A, of Phase 1 demonstrated a CBR of 50% at 6 months in 
the patients that progressed on a CDK 4/6 inhibitor and a CBR of 100% at 6 months in those 
patients that were CDK 4/6 naïve (based on local assessment).  One interim analysis was done 
after the completion of the phase I portion of this trial, and one final analysis will be done after 
the completion of the phase II portion. 
Additionally this amendment will re-open the phase I portion of this trial to introduce a dose 
de-escalation in efforts to explore a new dosing regimen that would be safe and better tolerated 
with maximum exposure of everolimus. This will be referred to as Cohort C. Cohort C will be 
a 3+3 design to determine safety and tolerability. If proven safe and tolerable, an expansion 
phase will be added to phase II, referred to as Group 2 to look at Clinical Benefit Rate at 24 
weeks. 
The current phase II expansion phase (300mg qd + 2.5mg qd +25mg qd, will be referred to as 
Group 1).
A summary of the key changes proposed in this amendment is listed below:

Removed the Simon Two-stage design from the phase II portion of this trial. 
o
The phase II will now move forward with a standard phase II design and analysis.
o
The initial study design required approximately 39 evaluable patients for this 
Phase of the study. Now retaining the same assumptions using a one-sided alpha 
level of 0.05% to detect a power of at least 80%, a minimum of approximately 
60 evaluable patients are required for the study, (30 evaluable patients per group, 
Group 1 & Group 2)

Phase II sample size increased to 60 evaluable patients. Accounting for 10% drop out 
rate, approximately 66 patients will be enrolled, (33 patients per group, group 1 & group 
2)
o
8 or more patients need to show clinical benefit at 24 weeks for group 1 and 8 
patients in group 2 of the phase II part of this study to be considered a success 
based on the statistical changes.

Removed the term “key” from secondary endpoints for the phase II portion of this trial

Inclusion criteria #15 was updated to allow any endocrine therapy for up to 28 days 
prior to enrollment, rather than only allowing exemestane, so long as the patient does 
not progress on this therapy.


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
Exclusion Criteria #9 was updated to further clarify drugs with overlapping toxicities 
and better define the washout period.

Exclusion Criteria #16 was updated to remove: “Clinically and radiographically stable 
CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing 
anti-epileptic medications for brain metastases.” This change was based on supporting 
preclinical data demonstrating that ribociclib crosses the blood brain barrier.
Amendment 02 also includes minor editorial changes and additional clarifications to address
investigators’ questions as described in the list of changes below.  
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Throughout the document: Language stating, or relating to the Simon Two-Stage design 
was removed.

Section 1.2.5.1.1: Safety data from the interim analysis of TRINITI-1 was added

Section 3.2: Removed the term “Key” from Secondary Endpoints so all Secondary 
endpoints are looked at equally.

Section 4.1: Updated to reflect new trial design

Figure 4.1: Updated to reflect new trial design

Section 5.2: Inclusion Criteria #15 was updated to allow any endocrine therapy for up 
to 28 days prior to enrollment, rather than only allowing exemestane.

Section 5.3: Exclusion Criteria #9 was updated to further clarify drugs with overlapping 
toxicities to include CDK 4/6 inhibitors and to better define the washout period.

Section 5.3: Exclusion Criteria #16 was updated to allow patient with clinically and 
radiographically unstable CNS tumor at the time of screening and not receiving steroids 
and/or enzyme inducing anti-epileptic medications for brain metastases.

Section 5.3: Exclusion Criteria #25 was updated to exclude medication that cannot be 
discontinued within five half-lives.

Section 6.1: Updated to include cohort C treatment regimen. 

Table 6-3: Added to explain dose de-escalation dosing levels.

Section 6.2.1: Updated to include dose de-escalation guidelines. 

Table 6-4: Modified to explain dose escalation dose modifications.


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
Table 6-5: Modified to explain dose de-escalation dose modifications.

Table 6-6: Updated to state: If toxicity recurs at grade 3: temporary dose interruption of 
ribociclib and everolimus until recovery to grade ≤1 and reduce to the next lower dose 
level, or continue at same dose with growth-factor support at the discretion of the 
treating investigator.

Table 6-6: Modified to explain dose modifications if everolimus held more than 3 weeks.

Section 10.1.5: updated to state “A subset of Full Analysis Set (FAS) excluding major 
protocol violations”.

Section 10.4.1: Updated to reflect new statistical analysis plan for the phase II portion 
of the trial.

Section 10.5.1: Updated to reflect new statistical analysis plan for the phase II portion 
of the trial.


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Amendment 1 
Amendment 1 rationale
Study CLEE011XUS29 (TRINITI-1) was initiated in June 2016. As of 4-Jan-17, a total of 18
Patients have been enrolled in the study. 
The current amendment is intended to update the existing information about ribociclib, clarify 
specific aspects of the original protocol and remove inclusion criteria number 4 which required 
evaluation of total RB1. In addition the recommended phase II dose (RP2D) for this study has 
been determined to be 300mg Ribociclib (daily) + 2.5mg Everolimus (daily) + 25mg 
Exemestane (daily). 
A summary of the key changes proposed in this amendment is listed below:

Ribociclib information was updated based on the data available in the current IB version 
(v10, release date: Oct-10-2016; safety cut-off date: Jul-5-2016)

Detailed information from the pivotal study CLEE011A2301 (MONALEESA-2) 
supporting the use of ribociclib + letrozole in aBC has been included to strengthen the 
study rationale.

Remove inclusion criteria #4: Intact retinoblastoma protein (pRB). Confirmation of 
RB1status by IHC or an equivalent test required based on most recent tumor biopsy 
following progression on a CDK 4/6 inhibitor. If no tissue is available, most recent 
archival tissue should be tested for RB staining from metastatic site. This tissue sample 
should be tested locally for RB1 status.

After central evaluation of total RB1of patients enrolled into the phase I, dose 
escalation portion on the trial, it was determined by Novartis, and the Steering 
Committee that the inclusion criteria could be removed.
 
Amendment 01 also includes minor editorial changes and additional clarifications to address 
investigators’ questions as described in the list of changes below.  
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Throughout the document: Addition of language to refer to most recent version of the 
LEE011 Investigator’s  Brochure and minor text editorial changes

Throughout the document: Typographical and grammatical corrections


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
Throughout the document: the term “randomization” was replaced with “start of/starting 
study treatment” as this is an open label trial that is not randomized

Section 1.1.2: Updated to include data on clinical benefit of AIs in combination with 
ovarian function suppression (OFS) in premenopausal patients with breast cancer in 
neoadjuvant, adjuvant and advanced settings; Rationale for inclusion of male patients is 
further clarified.

Section 1.2.1.4 Updated based on new data from ongoing and completed trials with 
LEE011

Section 1.2.2: Added to provide CLEE011A2301 (MONALEESA-2) trial key efficacy 
and safety results of pre-planned interim analysis. 

Section 4.1: Updated to include the RP2D determined from the phase I dose escalation 
portion of the trial. (300mg ribociclib (daily) + 2.5mg everolimus (daily) + 25mg 
exemestane (daily)

Section 5.2: Inclusion Criteria #4 was removed based on the finding from data generated 
in the phase I dose escalation portion of the trial

Section 5.2: Inclusion Criteria #9 corrected to say patients must have progressed on only 
one CDK 4/6 inhibitor

Section 5.2: Inclusion Criteria #12 was updated to define bone disease as “Evaluable 
disease”, for clarity

Section 5.2: Inclusion Criteria #13 was updated to include alanine aminotransferase (ALT) 
limits

Section 5.3: Exclusion Criteria #8 was updated to exclude patients who have progressed 
more than once on the same CDK 4/6 inhibitor

Section 5.3: Exclusion Criteria #25 was updated to remove exclusion of the use of 
corticosteroids.

Table 6-1: Updated to remove the 1mg and 5mg doses of everolimus as they are not being 
used or provided. The size of the dexamethasone bottle (500mL) was also added for 
clarity

Table 6-2: Updated to provide clarity on what the dose levels of each cohort is

Section 6.2.1: Updated to state the RP2D to be used if unable to be determined in the 
phase I dose escalation

Section 6.2.4: Updated to state the RP2D for the phase II portion of this trial

Section 6.3: Updated for clarity around dexamethasone use

Section 6.4: Updated language to clearly state there are no dose reductions permitted for 
everolimus

Table 6-4: Updated for clarity and to state the RP2D for the phase II portion of this trial

Table 6-11: Added consideration of using flovent for pneumonitis 

Section 8.4: Updated as there was/is no interim analysis planed


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


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Synopsis
Title
A
Phase I/II, single arm, open-label study of Ribociclib in 
Combination with Everolimus + Exemestane in the Treatment of Men 
and Postmenopausal Women with HR+, HER2 Negative Locally 
Advanced or Metastatic Breast Cancer Following Progression on a 
CDK 4/6 Inhibitor
Sponsor and Clinical 
Novartis- Region US
Phase
Phase I run in followed by Phase II
Investigation/Study Type
Drug/Interventional
Purpose 
To assess safety, tolerability and efficacy of ribociclib+ everolimus + 
exemestane in patients that progressed on CDK4/6 inhibitor based 
therapy.
Number of Subjects
Phase I: 9-24; Phase II : approximately 60 evaluable
Estimated time of Enrollment
Phase 1: 4 months, Phase 2 :12 months 
Estimated Duration
Estimated 30 months
Number of sites
Approximately 30 sites (total Phase I and II)
Rationale
Hormone receptor-positive breast cancer is the most common form 
of breast cancer with endocrine therapy being the cornerstone of 
treatment. Unfortunately, endocrine resistance eventually develops 
resulting in the progression of disease and ultimately death for these 
patients.
Disruption 
of 
the
phosphatidylinositol 
3-kinase 
(PI3K)/mammalian target of rapamycin (mTOR) pathway and cyclin 
D–CDK4/6–INK4–Rb pathway has been implicated in resistance to 
endocrine therapy and disease progression. Activation of this 
pathway can result in increased levels of CCND1 leading to 
upregulation of this pathway. Cyclin-dependent kinase (CDK) 4/6 
inhibitors are believed to be critical mediators of this pathway as it 
acts downstream of the PIK3CA/Protein Kinase B (AKT)/mTOR axis.
The addition of everolimus to exemestane significantly improves 
progression-free survival of patients with endocrine resistant HR+ 
HER2- advanced breast cancer (Baselga J 2012) but eventually 
patients progress. Studies demonstrate that resistance to hormonal 
therapy, mTOR inhibition, and cytotoxic chemotherapy are at least in 
part mediated by upregulation of CDK4/6-cyclin D activity in breast 
cancer, suggesting that there might be a role for CDK4/6 inhibition + 
mTOR inhibition in patients who have progressed on these therapies.
The effect of combining ribociclib with the mTORC1-inhibitor 
everolimus (RAD001; Afinitor®) in the ER+, PIK3CA mutant MCF-7 
xenograft model was examined (RD-2013-50141). While single 
agent treatments with ribociclib and everolimus resulted in modest 
tumor regressions of -9% and -21%, respectively, combination of 
ribociclib with everolimus increased tumor regressions to -49%. Data 
from in vivo studies showed that ribociclib, when combined with the 
mTOR inhibitor, everolimus (RAD001; Afinitor®), induced synergistic 
growth inhibitions in multiple tumor models, including cell lines 
derived from MCL, ER+ breast cancer, and MRT.


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There is a role for continuing targeted therapies in patients with 
breast cancer, even beyond the point of disease progression. 
Everolimus appears to restore sensitivity to anti-estrogens by 
inhibiting resistance mediated by the PI3K/Akt/mTOR pathway. 
Currently, there is no clinical data available that reports the efficacy 
of further treatments after prior CDK4/6 inhibitor failure, which 
represents an unmet medical need and requires further exploration. 
Potential reasons for progression on CDK4/6 inhibitor include loss of 
the retinoblastoma protein (pRb) (the direct target of CDK4/6 
inhibitors), alterations in the estrogen receptor pathway as a 
consequence of endocrine therapy resistance, or activation of other 
signaling pathways including the PI3K/AKT/mTOR pathway. The 
heterogeneity of the anticipated mechanism of resistance requires 
further exploration since some patients may still benefit from a 
sustained inhibition of the CDK4/6 pathway. Anecdotal observations 
of a small subset of patients treated on 1st line therapy trials with 
CDK 4/6 inhibitors + aromatase inhibitors have suggested that some 
patients who discontinue therapy with the CDK 4/6 inhibitors develop 
an impressively rapid disease progression at initial imaging 
assessment to second line therapy. This lends the question of 
maintaining CDK 4/6 inhibition as a backbone therapy to keep the 
cell cycle arrested in G1 while adding mTOR inhibition to overcome 
resistance.
The CLEE011X2106 Phase-1b clinical trial tested a combination of 
exemestane + everolimus + ribociclib. The recommended dose for 
expansion was declared as exemestane 25 mg daily, everolimus 2.5 
mg daily and ribociclib 300 mg 3 weeks on/1 week off. This 
combination appeared to be safe and demonstrated clinical activity. 
Clinical activity was seen in a heavily pre-treated population (median 
number of 4 prior therapies) with 25.7% pts receiving prior 
PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. The 
clinical benefit rate in these patients was 26% in 74 evaluable 
patients and disease control rate was noted to be 73%. Furthermore, 
there was a trend towards longer duration of treatment in the CCND1 
amplified group (n=10; median 166 days) than in the non-amplified 
group (n=22; median 60 days), something which was not appreciated 
with the treatment of everolimus + exemestane in BOLERO-2 (Bardia 
A 2015). PK analysis suggested that ribociclib increased dose-
dependent exposure of everolimus during the time that both 
everolimus + ribociclib were dosed concurrently (Bardia A 2014), 
however, dose exposure of everolimus decreased during the week 
off of ribociclib therapy. By dosing ribociclib at a lower and continuous 
dose when combined with everolimus, both safety and efficacy could 
potentially be improved by lowering the Cmax concentration and 
continuously inhibiting both CDK 4 and 6, while maximizing 
everolimus’ dose exposure. 
Thus, triplet combination of endocrine therapy with mTOR and 
CDK4/6 inhibition is tolerable, and shows preliminary signs of clinical 
activity, including in patients with prior exposure to PI3K/AKT/mTOR 


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or CDK4/6 inhibitors, suggesting that triplet therapy could potentially 
overcome resistance to doublet therapy in a subset of patients. 
Therefore, this study proposes to examine continuous dosing of 
ribociclib when administered concurrently with everolimus (Phase I) 
and to test whether the addition of everolimus + exemestane to 
ribociclib can reverse resistance to a CDK 4/6 inhibitor and ultimately 
improve the efficacy of the approved combination regimen 
(everolimus + exemestane) in patients that progressed on CDK 4/6 
inhibitors (Phase II).
Phase I
Primary Objective(s)
To determine the Maximum Tolerated Dose (MTD) and/or the 
Recommended Phase II dose (RP2D) for the triplet combination of 
ribociclib 
+ 
everolimus 
+ 
exemestane 
when 
administered 
continuously 
in 
subjects 
with 
HR+ 
HER2-negative 
advanced/metastatic breast cancer
Secondary Objectives
Characterize the safety and tolerability of the triplet combination of 
ribociclib + everolimus + exemestane when all drugs
are 
administered continuously
Determine the PK profile of the combination of ribociclib + everolimus 
+ exemestane when administered continuously; evaluate the DDI 
potential (effect of ribociclib on the PK profile of everolimus)
Determine the overall response rate (ORR) by RECIST 1.1 on 
treatment with combination of ribociclib + everolimus +exemestane 
when administered continuously
Phase II
Primary Objective(s)
Determine the Clinical Benefit Rate (CBR) at 24 weeks among 
subjects receiving triple therapy with ribociclib + everolimus + 
exemestane for HR+, HER2-negative, advanced/metastatic breast 
cancer following progression on CDK 4/6 inhibitor.
Secondary Objectives
Secondary:

Progression Free Survival (PFS)

Overall Response Rate (ORR)

Duration of overall response (DOR)

Overall Survival (OS)

Time to deterioration of ECOG performance status

Safety and tolerability

Determine the PK profile of ribociclib and everolimus when 
administered continuously.


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Study design
Phase I:
A Phase I dose escalation (cohort A and B) and dose de-escalation
(cohort C) will be initiated to ensure the safety and tolerability of
daily dosing of ribociclib + everolimus + exemestane in patients with
HR+, HER2-negative advanced/metastatic breast cancer. Once the 
recommended Phase II dose is confirmed and safety and tolerability 
are established, the trial will commence into a Phase II study. 
Phase II:
This portion of the trial will be an open label, Phase II study to 
evaluate the antitumor activity of the ribociclib + everolimus + 
exemestane combination in patients that have progressed on 
CDK4/6 inhibitor based therapy. 
Patients with advanced/metastatic HR+, HER2-negative, breast
cancer will receive one of two RP2D determined by Phase 1, both 
Group 1 and Group 2.. All subjects that participate in Phase 2 must 
have progressed on a CDK 4/6 inhibitor. Prior CDK 4/6 inhibitor will 
be defined as disease progression while on, or within 30 days of 
discontinuing any CDK 4/6 inhibitor therapy (i.e. palbociclib, 
ribociclib, or abemaciclib).
Dose adjustment (reduction, interruption or dose re-escalation) 
according to safety findings will be allowed. Safety reviews by an 
Independent Data Monitoring Committee (IDMC) will be performed. 
Tumor assessments will be performed every 8 weeks starting from 
the date of first dose of study treatment, and as clinically indicated, 
until the first 12 months of treatment are completed or disease 
progression. If no progression, tumor assessments will occur every 
12 weeks, and as clinically indicated until disease progression. 
Every 28 days will be considered one cycle. Clinical visits will be 
twice per cycle for the 1st two cycles, then once per cycle from there 
on. The therapy on clinical trial will continue until disease progression 
(radiological), or intolerable adverse effects, or subject’s wish to 
withdraw consent. 
Follow up:
Subjects will be followed for safety until 30 days after study treatment 
discontinuation.
After treatment discontinuation for any reason other than 
progression, tumor assessments will continue every 8 weeks for up 
to 12 months after the first dose of study treatment. 


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Population
For both Phase I and Phase II: Men and postmenopausal women 
with HR+, HER2-negative, locally advanced or metastatic breast 
cancer whose disease is refractory to at least one endocrine therapy. 
Refractory disease to endocrine therapy is defined as:

Recurrence while on, or within 12 months of end of 
adjuvant treatment with letrozole, anastrozole, tamoxifen, 
exemestane or fulvestrant

Progression while on, or within one month of end of 
letrozole, anastrozole, tamoxifen or fulvestrant treatment 
for locally advanced or metastatic breast cancer.
For Phase II only: Patients must have a documented recurrence or 
progression while on a CDK 4/6 inhibitor. Documented radiological
recurrence or progression on a CDK 4/6 inhibitor is defined as:

Remained on a CDK 4/6 inhibitor ≥4 months prior to 
disease progression, AND

Progressed while on or within 30 days of discontinuing
treatment with a CDK 4/6 inhibitor, AND 

CDK 4/6 inhibitor must have been the last treatment
regimen prior to starting study treatment.
*Note: Phase I does not require prior CDK 4/6 inhibitor exposure.
Key Inclusion criteria
(see protocol for detailed list)
Patients eligible for inclusion in this study have to meet all of the 
following criteria:
1.
Adult men and women (≥18 years of age) with metastatic 
or locally advanced breast cancer not amenable to curative 
treatment by surgery or radiotherapy.
2.
Histological or cytological confirmation of hormone-
receptor positive (ER+ and/or PR+) breast cancer per local 
laboratory testing
3.
Patient has HER2-negative breast cancer (based on most 
recently analyzed biopsy) defined as a negative in situ 
hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 
2+, a negative in situ hybridization (FISH, CISH, or SISH) 
test is required by local laboratory testing.
5.
A representative tumor specimen must be available for 
molecular testing. Newly obtained tumor biopsy specimen is 
required if accessible prior to entry on trial. If tissue is not 
accessible based on surgical evaluation, an archival tumor 
sample from metastatic site may be submitted. 
6.
Women must be postmenopausal. Postmenopausal status 
is defined either by: 

Amenorrhea for at least 12 months and both follicle-
stimulating hormone (FSH) and estradiol levels are in 
postmenopausal range (according to the local 
laboratory) OR

History of bilateral oophorectomy (with or without 
hysterectomy) OR


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
History of partial hysterectomy with FSH and/or
estradiol within post-menopausal range OR

Ovarian function suppressed with a GnRH agonists 
(negative HCG required) with estradiol levels in the 
postmenopausal range (according to the local 
laboratory)
7.
Disease refractory to either, AI, tamoxifen or fulvestrant 
defined as:

Recurrence while on, or within 12 months of end of 
adjuvant treatment with letrozole, anastrozole, 
exemestane, tamoxifen or fulvestrant OR

Progression while on, or within one month of 
discontinuing letrozole, anastrozole, tamoxifen or 
fulvestrant for the treatment of locally advanced or 
metastatic breast cancer.
*Note: There are no restrictions as to which endocrine therapy 
the patients received as their last line of therapy just prior to 
study treatment.
8.
Patients who received up to 3 lines of therapy for 
advanced breast cancer are allowed. This includes a 
maximum of 1 line of chemotherapy and a maximum of 3 
lines of endocrine therapy in the advanced setting so long 
as the patient has not received more than a total of 3 lines 
of therapy. Patients must have recovered to grade 1 or 
better from any adverse events (except alopecia and or 
neuropathy) related to previous therapy prior to starting 
study treatment.
* Note: If patient relapsed with documented evidence of 
progression on/or within 12 months from completion of 
adjuvant endocrine therapy, then this is considered one line of 
therapy
9.
Patients previously treated on any CDK 4/6 inhibitor (i.e. 
ribociclib, abemaciclib OR palbociclib) must have:

Remained on treatment for ≥4 months for advanced 
breast cancer or metastatic disease prior to 
progression, AND

Progressed on, or within 30 days following the 
discontinuation of a CDK 4/6 inhibitor.
Phase II Only:

Patients must have progressed on only one CDK 4/6 
inhibitor. A CDK 4/6 inhibitor must have been the last 
treatment prior to starting study treatment.
*Note: Phase I does not mandate prior CDK 4/6 inhibitor 
exposure.
**Note: For patients who received prior CDK4/6 inhibition as part 
of a clinical trial, patients must be unblinded in order to verify 
that the patient did receive a CDK4/6 inhibitor. 


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10. ECOG Performance Status 0 – 1.
11. Radiological evidence of recurrence or progression on or 
after the last endocrine therapy prior to starting study 
treatment.
12. Patients must have:

Measurable disease: defined as at least one lesion 
that can be accurately measured in at least one 
dimension ≥20 mm with conventional imaging 
techniques or ≥10 mm with spiral CT or MRI
OR

Evaluable disease: bone lesions- lytic or mixed (lytic + 
sclerotic) in the absence of measurable disease 
13. Patient has adequate bone marrow and organ function as 
defined by the following LOCAL laboratory values at 
screening: 

Absolute neutrophil count ≥1.5 × 109/L

Platelets ≥100 × 109/L 

Hemoglobin ≥9.0 g/dL 

Potassium within normal limits, total calcium 
(corrected for serum albumin), magnesium and 
sodium within normal limits as per local lab’s normal 
range or corrected to normal limits with supplements 
before first dose of study medication 

INR ≤1.5 or ≤2.5 while on anti-coagulant

Serum creatinine <1.5 mg/dL or creatinine clearance 
≥50 mL/min 

Total bilirubin <ULN except for patients with Gilbert’s 
syndrome who may only be included if the total 
bilirubin is ≤3.0 × ULN or direct bilirubin ≤1.5 × ULN.

Alanine aminotransferase (ALT) and aspartate 
transaminase (AST) <2.5 × ULN, except for patients 
with liver metastasis, who are only included if the AST
and ALT are <5 × ULN
14. Must be able to swallow ribociclib, everolimus and 
exemestane capsules/tablets
15. Patients with metastatic disease are allowed to receive 
≤28 days of endocrine therapy prior to starting study 
treatment 
Key Exclusion criteria
(see protocol for detailed list)
Patients eligible for this study must not meet any of the following 
criteria:
1.
Patients with visceral crisis or any disease burden that 
makes the patient ineligible for this study per the 
investigator’s best judgment.
2.
Patients who received more than one line of chemotherapy 
for advanced breast cancer.
3.
HER2 overexpression by local laboratory testing (IHC 3+ 
staining or in situ hybridization positive).


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4.
Patient has received prior treatment with anthracyclines at 
cumulative doses of 450 mg/m² or more for doxorubicin or 
900 mg/m² or more for epirubicin.
5.
Patient with a known hypersensitivity to any of the 
excipients of ribociclib, mTOR inhibitors, e.g. sirolimus 
(rapamycin), or exemestane.
6.
Previous treatment with mTOR inhibitors
7.
Previous treatment with exemestane for advanced disease 
(except patients who received ≤28 days of exemestane for 
advanced breast cancer) 
8.
Disease progression on more than one CDK 4/6 inhibitor, 
or have progressed more than once on the same CDK 4/6 
inhibitor.
9.
Patient is concurrently using other anti-cancer therapy. All 
anti-cancer therapy must be discontinued at least 7 days
prior to study treatment (C1D1). Drugs with overlapping 
toxicities with either everolimus or ribociclib must also be 
discontinued at least 7 days prior to C1D1. All AEs related 
to prior treatment should have resolved to CTCAE version 
4.03 Grade ≤1 prior to study treatment (including any CDK 
4/6 inhibitor).”
10. Patient has had major surgery within 14 days prior to 
starting study drug or has not recovered from major side 
effects due to surgery.
11. Patients with Child Pugh score B or C.
12. Active, bleeding diathesis, or on oral anti-vitamin K 
medication (except low dose warfarin, LMWH and 
acetylsalicylic acid or equivalent, as long as the INR is 
≤2.5 while on anti-coagulant). Fondaparinux is allowed.
13. Radiotherapy < 2 weeks prior to starting study treatment. 
Patients must have recovered from radiotherapy toxicities 
prior to starting study treatment, and recovered to grade 1 
or better from related side effects of such therapy (with the 
exception of alopecia). Radiotherapy is not allowed at 
target site following screening.
14. Another malignancy within 3 years prior to starting study 
treatment, with the exception of adequately treated in-situ 
carcinoma of the cervix, uteri, basal or squamous cell skin 
carcinoma.
15. Patients with central nervous system (CNS) involvement 
unless they are at least 4 weeks out from prior therapy 
completion (including radiation and/or surgery) to starting 
the study treatment.
16. Patient has impairment of gastrointestinal (GI) function or 
GI disease that may significantly alter the absorption of the 
study drugs (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or 
small bowel resection).
17. Patient has a known history of HIV infection (testing not 
mandatory) 


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18. Patient has any other concurrent severe and/or 
uncontrolled medical condition that would, in the 
investigator’s judgment, cause unacceptable safety risks, 
contraindicate patient’s participation in the clinical study or 
compromise compliance with the protocol such as: 

chronic pancreatitis 

active untreated or uncontrolled fungal, bacterial or 
viral infections, sepsis etc.

Uncontrolled diabetes as defined by fasting serum 
glucose >1.5 × ULN

Acute and chronic, active infectious disorders 
including viral and nonmalignant medical illnesses 
that are uncontrolled or whose control may be 
jeopardized by the complications of this study therapy
19. Fasting serum cholesterol >300 mg/dl or 7.75 mmol/L and 
fasting triglycerides >2.5 × ULN. In case one or both of 
these thresholds are exceeded, the patient can only be 
included after initiation of statin therapy and when the 
above mentioned values have been achieved.
20. Significant symptomatic deterioration of lung function. If 
clinically indicated, pulmonary function tests including 
measures of predicted lung volumes, DLco, O2 saturation 
at rest on room air should be considered to exclude 
restrictive pulmonary disease, pneumonitis or pulmonary 
infiltrates.

Clinically significant, uncontrolled heart disease 
and/or cardiac repolarization abnormality including 
any of the following:

History of angina pectoris, symptomatic pericarditis, 
coronary artery bypass graft (CABG) or myocardial 
infarction within 6 months prior to study entry

Documented cardiomyopathy

Left Ventricular Ejection Fraction (LVEF) <50% as 
determined by Multiple Gated acquisition (MUGA) 
scan or echocardiogram (ECHO) detected during 
screening

History of cardiac failure or significant/symptomatic 
bradycardia Long QT syndrome or family history of 
idiopathic sudden death or congenital long QT 
syndrome or any of the following:

Known risk to prolong the QT interval or induce 
Torsade’s de Pointes.

Uncorrected hypomagnesemia or hypokalemia

Systolic Blood Pressure (SBP) >160 mmHg or 
<90 mmHg

Bradycardia (heart rate <50 at rest), by ECG or pulse.

On screening, inability to determine the QTcF interval 
on the ECG (i.e.: unreadable or not interpretable) or 


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QTcF >450 msec for men and >470 msec for women 
(using Frederica’s correction). All as determined by 
screening ECG (based on a mean of 3 ECGs).
21. Patient is currently receiving any of the following 
substances and cannot be discontinued 7 days prior to 
Cycle 1 Day 1:

That have a known risk to prolong the QT interval or 
induce Torsade’s de Pointes.

Known strong inducers or inhibitors of CYP3A4/5, 
including grapefruit, grapefruit hybrids, pummelos, 
star-fruit, and Seville oranges.

Medications that have a narrow therapeutic window 
and are predominantly metabolized through 
CYP3A4/5.

Herbal preparations/medications, (except for 
vitamins).
.
22. Not able to understand and to comply with study 
instructions and requirements.
23. 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.
24. Sexually active males unless they use a condom during 
intercourse while taking drug and for 21 days after 
stopping medication and should not father a child in this 
period. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug 
via seminal fluid.
Safety Assessments

Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 
(Phase I only)

Adverse Events (AEs), serious AE (SAEs), changes in 
hematology and chemistry values, vital signs, 
electrocardiograms (ECGs), dose interruptions, reductions 
and dose intensity 
Efficacy Assessments
CT/ MRI every 8 weeks for the first 12 months, then every 12 weeks 
thereafter until disease progression, death, withdrawal of consent, 
loss to follow-up, or subject/guardian decision.

Brain CT or MRI as clinically indicated.

Whole body bone scan at screening and as clinical 
indicated

Bone x-ray, CT or MRI (if bone lesion at screening) every 8 
weeks for the first 12 months and then every 12 weeks 
thereafter until disease progression

Skin color photography (if skin lesions at screening) every 
8 weeks during the first 12 months and then every 12 
weeks thereafter.


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
CT/ MRI for any disease outside of the chest, abdomen, 
pelvis (if lesion identified at baseline) every 8 weeks for the 
first 12 months and then every 12 weeks thereafter.

Survival status
Other Assessments
Pharmacokinetic: 
Ribociclib, 
everolimus 
and 
exemestane 
pharmacokinetic (PK) evaluations. PK parameters, including but not 
limited to AUC 0-6hrs, Cmax, Ctrough.
Investigational and reference 
therapy
The investigational or study drug refers to ribociclib. Investigational 
treatment/arm refers to the triple combination of ribociclib + 
everolimus + exemestane (R-E-E).
IDMC and SSC
An Independent Data Monitoring Committee (IDMC) will be 
constituted. 
A Study Steering Committee (SSC) will also be constituted for 
overseeing the clinical trial
Dose, regimen
Every 28 days will be considered one cycle. Everolimus, exemestane 
and ribociclib will be administered daily. 
Statistical methods 
Phase I:
The primary purpose of the Phase I is to estimate the MTD(s) and/or 
identify the RP2D of the combination treatment of ribociclib+ 
everolimus + exemestane when dosed continuously in adult men and 
postmenopausal women with HR+ HER2-negative advanced breast 
cancer resistant to the non-steroidal aromatase inhibitors (letrozole 
or anastrozole), fulvestrant or tamoxifen. The corresponding primary 
endpoint is the incidence of DLTs in the first cycle.
A patient is considered to have met the minimum exposure
requirement if having received at least
75% of the
planned 
combination doses for all compounds administered together (in the 
same day) for one cycle. The length of a cycle is 28 days.
Phase II:
Open label, Phase II trial will evaluate the anti-tumor activity of 
exemestane, everolimus and ribociclib triplet. This part of the study 
will be continued after the MTD/RP2D is determined in the Phase I. 


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A minimum of approximately 60 evaluable patients (30 per group
(group 1, and group 2) are required for Phase II of this study to 
evaluate clinical benefit rate at 24 weeks. 
The sample size is based on an exact test for single proportion to 
test the null hypothesis H0: p ≤ 0.10, where p is the clinical benefit 
rate in 24 weeks.  If the true rate is p ≥ 30%, then with one-sided 
alpha level of 0.05% and a power of 80%, a minimum of 
approximately 30 evaluable patients for each group are required for 
the study. Including dropout rate of 10%, to get at least 30 
evaluable patients, a total of approximately 33 patients for each 
group (group 1 and group 2) will be enrolled. 
If 8 or more patients show clinical benefit at 24 weeks then the null 
hypothesis will be rejected and significant clinical benefit will be 
demonstrated.  (See Section 10)
Details of the statistical analysis and data reporting will be provided 
in the RAP.
1
Background
1.1
Overview of current treatment
1.1.1
Epidemiology of breast cancer
There was an estimated 231,840 o f  new cases of invasive breast cancer diagnosed amongst
women in the US in 2015; excluding cancers of the skin, breast cancer is the most frequently 
diagnosed cancer in women. An estimated 40,730 breast cancer deaths (40,290 women) were
expected in 2015. Breast cancer ranks second as a cause of cancer death in women after
lung cancer (Cancer facts & figures 2015). Subtypes of BC are classified by the presence of
estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor
2 (HER2) antigens as well as by distinct gene expression profiles (Perou et al 2000; Sotiriou 
and Pusztai 2009; Sotiriou and Pusztai 2009) and other features for prognostic and treatment
purposes. Seventy percent of invasive breast cancers in women >45 years of age, express
ER and/or PgR, but not HER2, and are termed hormone receptor positive (HR+, HER2-negative)
(Huang 2005).
1.1.2
Treatment options for hormone receptor positive advanced breast 
cancer
Expression of the estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the 
most important prognostic factors in invasive breast cancer and is detected in approximately 
70% of cases. Estrogen deprivation therapy is the core treatment modality in patients with 
hormone receptor positive (HR+) advanced breast cancer. Endocrine therapy options for 
postmenopausal women with HR+ advanced breast cancer (locally advanced, recurrent, or 
metastatic breast cancer) include selective estrogen receptor modulators (SERM; tamoxifen), 
estrogen receptor antagonists (fulvestrant), selective nonsteroidal aromatase inhibitors (NSAI; 
anastrozole and letrozole) and steroidal aromatase inhibitors (exemestane). Tamoxifen is 


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indicated for the treatment across the whole continuum of HR+ breast cancer in premenopausal 
women, ranging from risk reduction in women at high risk of developing breast cancer to 
treatment of metastatic disease. In postmenopausal women, aromatase inhibitors (AI) reduce
peripheral estrogen synthesis by blocking the conversion of androgens to estrogens in non-
ovarian tissues; synthesis in these tissues is the primary source of estrogens in postmenopausal
women. Aromatase inhibitors are generally used as the first line of therapy for women with
ER+ breast cancer (Beslija 2009, Cardoso 2011, NCCN Guidelines 2016). 
Despite the broad spectrum of available options for patients with HR+ advanced breast cancer, 
most eventually develop resistance to hormonal deprivation. One mechanism of endocrine 
resistance is aberrant signaling via phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target
of rapamycin (mTOR) (Burstein 2011, Johnston 2006, Schiff 2004). Hyperactivation of 
PI3K/mTOR is observed in endocrine-resistant breast cancer cells, and treatment with mTOR 
inhibitors, including rapamycin analogs, reverses this resistance (Miller 2010). Growing 
evidence also supports a close interaction of the mTOR pathway with ER signaling. S6 kinase-
1 (S6K1), a substrate of mTOR Complex 1 (mTORC1), phosphorylates the activation domain
AF-1 of the ER, and stimulates ligand-independent activation of the receptor (Yamnik 2009; 
Yamnik 2010; Yamnik 2010).
Everolimus is a rapamycin derivative that inhibits mTORC1 through allosteric binding; it 
does not inhibit mTORC2 (Efeyan 2010). In the clinic, everolimus active in combination with 
exemestane in patients with ER+ advanced breast cancer resistant to previous hormonal 
deprivation therapy (BOLERO-2 study; Baselga 2012; Baselga 2012).
Recently, the United States Food and Drug Administration (FDA) approved palbociclib 
(Ibrance®) in combination with letrozole for the treatment of postmenopausal women with HR-
positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their
metastatic disease and fulvestrant in premenopausal, perimenopausal and postmenopausal 
women with AI refractory HR+ HER2- negative advanced breast cancer. For additional 
information, please refer to the Ibrance® Prescribing Information.
In premenopausal women who received a prior endocrine therapy within 12 months, the 
preferred therapy involves ovarian ablation or suppression + endocrine therapy - such as 
aromatase inhibitors (AIs) - as for post-menopausal patients. (NCCN Breast Cancer Guidelines, 
version 2.2016). 
Based on the clinical benefit shown in postmenopausal patients, AIs in combination with 
ovarian function suppression (OFS) have been investigated in premenopausal patients with 
breast cancer in neoadjuvant, adjuvant and advanced settings. Results from the randomized 
phase III trials SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and 
EXemestane Trial) showed that adjuvant treatment with exemestane+OFS as compared with 
tamoxifen+OFS, significantly reduced recurrence in premenopausal women with HR+ early 
breast cancer. Results from both trials (N=5,738) showed statistically significant differences in 
disease free survival (DFS) at 5 years (91.1% in exemestane + OFS vs 87.3% in tamoxifen + 
OFS) and rate of freedom from breast cancer at 5 years (92.8% in exemestane+OFS vs 88.8% 
in tamoxifen+OFS) (Pagani 2014). Studies exploring the combination of third generation AIs 


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and goserelin in metastatic premenopausal BC patients are shown below in Table 1-1.
(Montagna 2013)
Table 1-1
Goserelin and third generation AIs in metastatic premenopausal BC 
patients
Study
N
AI+goserelin (G)
ORR 
(CR+PR) (%)
CB 
(CR+PR+SD) 
(%)
TTP 
(months)
First line 
endocrine 
therapy
Forward (2014)
16
Anastrozole+G
6.2
75
N/R
No
Cheung (2010)
36
13
Anastrozole+G
Exemestane+G*
36
N/R
67
38
12
N/R
Yes
No
Carlson (2010)
35
Anastrozole+G
37
72
8.3
Yes
Park (2011)
35
Letrozole+G
46
77
9.5
Yes
Roche (2009)
52
Letrozole+G
21
71
10
Yes/No
Nishimura (2012)
33
Anastrozole+G
55
64
13
Yes
Forward (2014)
37
Anastrozole+G
19
62
7.2
Yes/No
ORR=Objective response rate, CR=Complete response, PR=Partial response, CB=Clinical benefit, SD=Stable 
disease, PD=Progressive disease, TTP=Time to progression, N/R=Not reported
*In study by Cheung et al, patients received treatment with exemestane after they received treatment with 
anastrozole.
Although data are limited (Montagna 2013), clinical benefit of the combination of AIs and OFS 
in premenopausal women with advanced ER+ breast cancer has been shown in small phase II 
studies with letrozole and anastrozole. In one study (Cheung 2010), patients received 
exemestane, but only after they had received anastrozole, so the effect of single–agent 
exemestane has not been well characterized. Lastly, novel therapeutic approaches targeting 
promising pathways should be explored to further improve efficacy in premenopausal women 
with advanced HR+ breast cancer.
Male breast cancer is rare, with less than 1% of all breast carcinomas occurring in men 
(Giordano 2005). The pathology is similar to that of female breast cancer, and infiltrating ductal 
cancer is the most common tumor type. Male breast cancers have high rates of hormone-
receptor expression, with approximately 90% of male breast cancers expressing estrogen 
receptor, and 81% expressing progesterone receptor.
In general, the approach to the treatment of metastatic breast cancer is similar in male and 
female patients with breast cancer, with hormonal therapy being the often the first approach. 
Although, historically, surgical ablative therapies such as orchiectomy, adrenalectomy, and 
hypophysectomy have been used effectively to control metastatic breast cancer in male patients, 
these surgical procedures are rarely used today and have been supplanted by additive hormonal 
therapies. Tamoxifen has established efficacy in metastatic male breast cancer, with an 
approximate 50% response rate, and is considered an acceptable treatment option. Luteinizing 
hormone–releasing hormone agonists, with or without antiandrogens, have also been reported 
to be effective in male breast cancer. There have been case reports of responses to a wide variety 


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of hormonal therapies including progestins, androgens, steroids, aminoglutethamide, estrogens, 
and letrozole. 
Since the hormonal environment in male patients differs from that observed in female patients, 
the role of AIs in male patients may be different (Doyen, J 2010). In men, 80% of circulating 
estrogens are derived from peripheral aromatization of testicular and adrenal androgens, with 
direct production from the testes accounting for the remaining 20%. Studies in men patients had 
demonstrated that non-steroidal AIs lead to a decrease in plasma E2 levels, but these levels can 
still be detectable in some patients, potentially because of the baseline levels of peripheral 
androgens (with are subtracts for aromatization) and the testicular production of estrogens, 
which is not inhibited by NSAIs. Additionally, the use of NSAIs can be associated with 
feedback loop leading to increase of LH and FSH, which can lead of additional production of 
androgens, with increased availability of subtracts for aromatization. All these elements 
converge to a suboptimal suppression of estrogen production in male patients submitted to 
treatment with monotherapy AI, and create a rational for the combined use of these agents 
together with targeted therapy.
The use of aromatase inhibitors together with LHRH was studied as first- or second-line therapy 
for male patients with HR+ metastatic breast cancer (Giordano SH 2005); 19 patients were 
evaluated with promising results: 2 patients (10.5 %) had complete response, 7 patients (36.8 %) 
experienced a partial response, 7 patients (36.8 %) had stable disease lasting ≥6 months, and 3 
patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median 
progression-free survival was 12.5 months (95 % CI 8.2–16.9), median overall survival was 
35.8 months (95 % CI 24.4–49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. 
Safety profile was expected and manageable, with no grade 3/4 adverse events.Cyclin-
dependent kinases in breast cancer
Cell cycle progression is directly regulated by cyclin-dependent serine-threonine protein 
kinases. The cyclin D proteins are important in cancer, as their abundance and functions are 
regulated by extracellular growth factor and adhesion signaling. The cyclin D proteins act 
through the cyclin-dependent kinases 4 (CDK4) and cyclin-dependent kinases 6 (CDK6)
protein kinases to promote G1 progression (Musgrove 2011). CDK4 and CDK6, in turn,
hyperphosphorylate and activate the retinoblastoma protein Rb to promote cell cycle entry and
cell proliferation. Consistent with their having an important role in human cancer, focal copy 
number abnormalities that result in increased CDK activity are among the most commonly 
described mutations observed in diverse tumor types; these mutations include amplifications of 
the genes that encode cyclin D1 or CDK4, and deletions affecting the CDKN2 locus, which 
encodes the p16INK4a inhibitor of CDK activity (Beroukhim 2010). In a mouse model of HER2+
breast cancer, deletion of either the CCND1 or CDK4 gene prevented breast cancer formation 
(Yu 2006).
Data from The Cancer Genome Atlas highlight the importance of the Cyclin/CDK/Rb pathway 
in luminal breast cancer (Beroukhim 2010). Abnormalities that result in CDK activation are
highly enriched in the luminal A and B molecularly defined subgroups, ~85% of which were
ER+/HER2−. Cyclin D1 amplifications were observed in 29% and 58% of the luminal A and
B subtypes, respectively, and CDK4 amplifications were observed in 14% and 25% of luminal


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A and B subtypes, respectively. Luminal A subtype tumors also have loss of CDKN2. The 
luminal subtypes also maintain expression of Rb (Beroukhim 2010), which would be essential 
for benefit from treatment with a CDK4/6 inhibitor.
Recent clinical data showed that inhibitors of CDK4/6 are active in advanced HR+ breast cancer.
Palbociclib is an oral, potent, selective inhibitor of CDK4/6 that when used in combination with
the non-steroidal aromatase inhibitor letrozole significantly prolonged progression-free
survival in postmenopausal women with locally recurrent or advanced ER+, HER2− breast
cancer (Finn et al 2012, Finn et al 2015). Among patients with HR+, HER2- negative metastatic
breast cancer who had progression of disease during prior endocrine therapy, palbociclib
combined with fulvestrant resulted in significant longer progression-free survival than
fulvestrant alone (Turner et al 2015). These encouraging data warrant further clinical 
investigation of CDK inhibitors in breast and other cancers. In anticipation of the imminent 
shift of treatment paradigms for HR+ HER2-negative advanced breast cancer, additional study
in the post-CDK4/6 inhibitor settings would be valuable.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of ribociclib (LEE011)
In the mammalian cell cycle, entry into S phase is achieved by CDK4/6.Ribociclib is an orally 
bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-
micro molar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib has 
proven efficacious when combined with other targeted therapies in vitro and in vivo in cancers 
driven by a variety of oncogenic signaling pathways. Ribociclib may therefore be an effective 
anti-cancer agent in a variety of pRb-positive human neoplasms, especially in those that contain 
activated CDK4/6-pRb pathway. Ribociclib is currently being developed in phase III for the 
treatment of hormone receptor positive breast cancer patients; several other phase I or II clinical 
studies are being conducted and presented below.
1.2.1.1
Pharmacology of ribociclib (LEE011)
Ribociclib inhibits the CDK4/CCND1 and CDK6/cyclin-D3 enzyme complexes with
concentration resulting in 50% inhibition (IC50) values of 0.01 and 0.039 μM in biochemical
assays, respectively. In Jeko-1 cells, the compound inhibits CDK4/6-dependent pRb
phosphorylation with an average IC50 of 0.06 μM. Consistent with the observed inhibition of
pRb phosphorylation, ribociclib also inhibited G1 to S phase cell cycle progression in Jeko-1
cells as judged by both the inhibition of bromodeoxyuridine (BrdU) uptake (IC50 of 0.1 μM) and 
fluorescence activated cell sorting (FACS) analysis (half-maximal increase in cells in G1 at 
0.11 μM).
The effect of ribociclib on pRb phosphorylation, BrdU uptake and cell cycle progression has
been assessed in more than 40 cell lines derived from hematological, esophageal, liposarcoma
and breast cancers. In pRb+ cell lines, ribociclib inhibits pRb phosphorylation with a median 
IC50 value of 0.275 μM (range: 0.06 to 8.8 μM). Similarly, ribociclib interferes with G1 to 


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S phase cell cycle progression in these cells as determined by either BrdU uptake or FACS 
analysis with a median IC50 value of 0.46 μM. In contrast, in lineage-matched pRb- cell lines no 
effect of ribociclib on either pRb phosphorylation or cell cycle progression is observed.
Thus, ribociclib is able to impact cell cycle progression in cell lines derived from a variety of 
tumor types that harbor a diversity of genetic alterations in a manner dependent on intact pRb.
1.2.1.1.1 In vivo pharmacology
Ribociclib was well-tolerated in mice and rats with body weight loss not exceeding 12.5% at
doses up to 250 mg mg/kg qd po or 150 mg/kg qd po, respectively, for up to 28 days. However,
myelosuppression was observed and correlated with pRb phosphorylation inhibition. Treatment 
with ribociclib resulted in tumor regression in the Jeko-1 MCL xenograft model at doses greater 
than or equal to 75 mg/kg, qd po. In vivo pharmacokinetics (PK)/pharmacodynamics (PD) 
studies demonstrated dose-related inhibition of pRb phosphorylation in tumors, with continuous 
dosing over at least 3-5 days being required to achieve optimal target inhibition. 
Ribociclib has demonstrated in vivo anti-tumor activity in subsets of tumor xenograft models.
Consistent with the compound mechanism of action, efficacy was only observed in tumor 
expressing pRb. Tumor types where ribociclib has demonstrated robust anti-tumor activities
include but are not limited to breast, melanoma, neuroblastoma, malignant rhabdoid, lung,
pancreas and hematological malignancies.
In addition, ribociclib has shown anti-tumor activity when combined with targeted agents which 
inhibit signaling pathways known to regulate D-cyclin levels, including inhibitors of the 
RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), 
phosphoinositide 3-kinase (PIK3) and mTOR pathways.
1.2.1.2
Nonclinical pharmacokinetics (PK) and metabolism of LEE011 
(ribociclib)
The PK of ribociclib was investigated in mouse, rat, dog and monkey. Ribociclib showed high 
clearance (CL) in the mouse, rat, dog and monkey. The volume of distribution was large across 
species and the terminal elimination half-life (T1/2) was moderate in rodents and monkey (~2 to 
5 h) and longer in dog (18 h). Bioavailability was low to moderate in rat (37%) and cynomolgus 
monkey (17%); moderate in mouse (65%) and dog (64%). Following oral administration, time 
to reach maximal plasma concentrations (Tmax) occurred between 2 to 4 h across species. Gender 
dependent toxicokinetics were observed in rats with higher exposure to ribociclib in males as 
compared to females and higher exposure to the metabolite, LEQ803. Plasma protein binding 
was moderate in all species (unbound fraction (fu) in human: 30%).
In a rat ADME (absorption, distribution, metabolism and excretion) study, extensive
distribution of [3H]LEE011 and its metabolites was observed. In pigmented rats, radioactivity
was specifically found in melanin-containing structures; the highest exposure to total
radiolabeled components was observed in eye ciliary body, eye choroid, meninges, tactile hair
and hair follicles. Radioactivity was not detected in the brain. LEQ803 (N-demethylation) was
a prominent metabolite found in mouse, rat, dog, monkey and human hepatocytes. This


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metabolite retains some pharmacologic activity and interacts with human Ether-a-go-go Related 
Gene (hERG) channels in vitro.
Results from the ADME (male rats) study showed that 3H-components were predominantly
excreted with bile (61.4% of dose). Minor urinary excretion was observed (5.9% of dose after 
p.o.). The majority of the administered dose (87.3%) was excreted within 24 h via urine, feces
(enteric secretion) and bile.
In vitro, ribociclib was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2,
CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. Ribociclib may inhibit
CYP3A4 under therapeutic conditions. No induction of CYP1A2, CYP2B6 or CYP3A4 was
observed. The in vitro inhibitory potency of ribociclib observed for the transporters organic 
anion transporting polypeptide 1B1 (OATP1B1), breast cancer resistance protein (BCRP), 
organic cation transporter 1 (OCT1), OCT2, multidrug and toxin extrusion protein 1 (MATE1), 
MATE2K and bile salt export pump (BSEP) may translate into clinically relevant inhibition at 
therapeutic doses. Elimination of ribociclib is dominated by oxidative metabolism mainly via 
CYP3A4 with a minor contribution by flavin-containing monooxygenase 3 (FMO3). The 
elimination of ribociclib may be affected by co-administered drugs that inhibit or induce 
CYP3A4. Although ribociclib is a substrate of the P-glycoprotein (P-gp) efflux transporter, this 
process is likely not clinically relevant due to the high passive permeability of ribociclib.
1.2.1.3
Safety pharmacology and toxicology of ribociclib (LEE011)
In vivo cardiac safety studies demonstrated a signal for QT prolongation with the potential to
induce incidences of premature ventricular contractions (PVCs) at higher exposure levels.
The effects of ribociclib on the bone marrow (hypocellularity), lymphoid system (lymphoid
depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) and
testes (atrophy) are considered to be related to the pharmacological inhibition of cell replication 
in these tissues due to CDK4/6 inhibition.
An increased number of ovarian corpora luteal was observed in a single female dog in the 
4-week toxicity study at the highest dose tested (20 mg/kg/day) and this effect could also be
related to the pharmacology of ribociclib (arrest of estrous cycle).
The liver, bile system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder 
calculi and inspissated bile) and the kidney (concurrent degeneration and regeneration of 
tubular epithelial cells) were identified as additional target organs of toxicity which are not 
likely related to the primary pharmacology of ribociclib.
Inflammatory changes in the lungs of dogs were considered secondary to aspiration of test
article and are indicative of the irritant potential of the formulated test-article in the respiratory 
tract. Correlating hematological and/or biochemistry changes were seen for the effects 
described in the bone marrow, lymphoid system and liver.
Generally all changes demonstrated either reversibility or a clear tendency towards reversibility. 
Data from a rabbit embryofetal development study, shows that ribociclib is teratogenic in the 
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Based on its mechanism of action and preclinical toxicology studies, the major potential 
toxicities for ribociclib 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 or other combination treatments.
Please refer to (LEE011 Investigator’s Brochure) for additional details.
1.2.1.4
Clinical experience with ribociclib (LEE011)
As of 5-July-2016, ribociclib is being investigated in patients as a single agent in 3 phase I
studies, in 1 phase II study and in combination in 15 studies: 12 phase Ib/II studies and 3 
randomized phase III studies. Five studies were closed to enrollment: (CLEE011A2201), a 
randomized phase II study; (CLEE011A2112C), a phase I dose finding study; 
(CLEE011X2102), a phase I study in malignant rhabdoid tumors and neuroblastomas; and 
(CLEE011X2105), a phase Ib/II study in BRAF mutant melanoma; and (CLEE011X2201), a 
phase II study of relapsed refractory unresectable teratoma. Ribociclib is also being investigated
in 2 clinical pharmacology studies. Five clinical pharmacology studies in healthy patients have 
been completed.
Refer to latest edition of (LEE011 Investigator’s Brochure) for more details.
1.2.1.4.1 Clinical safety of ribociclib (LEE011) as single agent
As of 18-Sep-2015, 153 patients have been treated with single agent ribociclib in the first-in-
human (FIH) phase I study (CLEE011X2101); 134 patients have been treated in the initial dose 
escalation part for the 3 week on/1 week off regimen and 47 patients in the dose expansion part 
of the study; 19 patients were enrolled for the continuous dosing regimen with ribociclib and, 8 
patients were enrolled in the liquid formulation cohort.
Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
ribociclib orally, once daily (qd) for 21 days followed by a 1-week rest (28-day cycle). Doses 
ranging from 50 mg to 1200 mg were evaluated on this schedule. Treatment has been 
discontinued in 127 (95%) patients; the primary reasons for treatment discontinuation were: 
disease progression (111 [83%] patients); adverse events (AEs) (9 [7%] patients); death (1.5%] 
patients); withdrawal of consent (4 [3%] patient); and loss to follow up (1 [1%] patient).
The most frequently reported AEs (≥10%), regardless of grade, causality and ribociclib dose 
Were (50mg-1200mg): nausea (51.5%); fatigue (42.5%); diarrhea (36.6%); vomiting (35.8 %); 
neutropenia (35.1%);  anemia  (33.6%);  decreased  appetite  (23.1%);  constipation  (22.4%);  
leukopenia (21.6   %);   dyspnea   (20.1%);   asthenia   (19.4%);  cough   (17.9%);   headache   
(17.9%); 
hyperglycemia and hypoalbuminemia (17.2% for each); AST increase, electrocardiogram 
QT prolongation (15.7% for each); abdominal pain (14.9%); lymphopenia (14.9%); blood 
creatinine increased, 
dizziness, pyrexia (14.2% for each); neutrophil count decreased, 
peripheral edema (13.4 %); ALT increase (12.7%); Pain in extremity (11.9%); hypocalcemia 
(11.2%) and blood alkaline phosphatase increase (10.4%).


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For either continuous or intermittent dosing, the onset of neutropenia (most frequently Grade 
2) occurs by Day 15, reaching a nadir in the third or fourth week with recovery during the week 
of drug holiday for the three weeks on/one week off schedule. Some patients require additional 
time for recovery (7 to 14 days). QT changes become evident in the first cycle by Day 8 and 
later (once steady state is reached), are associated with the maximum drug levels between 1 to 
8 h post-dose, and remain stable or improve in subsequent cycles.
There have been no deaths related to study drug reported on study (CLEE011X2101).The 
following serious adverse events shown in Table 1-2 have been reported with a suspected causal 
relationship in study (CLEE011X2101) as of 18-Sep-2015. For a complete list of AEs, all 
grades and Grade 3/4 that are suspected to be related to ribociclib refer to the (LEE011 
Investigator’s Brochure).
Table 1-2
Serious adverse events with a suspected causal relationship with 
ribociclib single agent
Serious suspected adverse events which have occurred with ribociclib ( single agent)
System Organ Class Preferred Term
Preferred Term
Blood and lymphatic system disorders
Anemia, Febrile neutropenia,
Neutropenia,Thrombocytopenia
Gastrointestinal disorders
Diarrhea, Nausea, Pancreatitis
General disorders and administration site conditions
Generalized edema
Infections and infestations
Herpes simplex
Investigations
Blood creatinine increased, Electrocardiogram QT 
prolonged
Events in italic font indicate those events which are newly included since the previous edition of the reference 
safety information.
1.2.1.4.2 Clinical efficacy with ribociclib as single agent
Preliminary anti-tumor activity of ribociclib from trial (CLEE011X2101) was assessed across 
all dose levels (50 mg – 1200 mg). Out of 134 evaluable patients as of 18-Sep-2015, 4 partial 
responses were observed at the 600 mg dose level; one each in BRAF/NRAS wild type with 
CCND1 amplified melanoma, and head and neck acinar carcinoma with CDKN2A loss (both 
on the 3 weeks on/1 week off regimen), and ER+/HER2-, PIK3CA mutant, CCND1 amplified 
breast cancer (on the continuous daily dosing regimen). Stable disease (SD) was the best 
overall response in 47 (35%) patients. Enrollment in this study is completed. Stable disease ≥4 
cycles and ≥6 cycles was observed in 30 (22%) and 21 (16%) patients, respectively. Six 
patients with SD ≥4 cycles received treatment for >1 year, of these 2 patients were on study 
for >2 years (Infante, JR ASCO 2014 abstract 2528).
Refer to (LEE011 Investigator’s Brochure) for more details.
1.2.1.4.3 Clinical Experience with Continuous Dosing of Ribociclib In Combination
CLEE011X2108 study is an ongoing Phase Ib/II study of ribociclib in combination with 
fulvestrant and alpelisib or buparlisib in postmenopausal women with hormone receptor 


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positive, HER2 negative, locally recurrent or advanced metastatic breast cancer. Patients were 
enrolled to one of the following dose combinations: (1) ribociclib (600 mg) + fulvestrant 
(500 mg), n=13, (2) ribociclib (400 mg) [continuous] + fulvestrant (500 mg), n=9, (3) ribociclib 
(200 mg) + alpelisib (200 mg) + fulvestrant (500 mg), n=3, (4) ribociclib (400 mg) + alpelisib 
(150 mg) + fulvestrant (500 mg), n=6, (5) ribociclib (400 mg) + alpelisib (200 mg mg) + 
fulvestrant (500 mg), n=9, (6) ribociclib (400 mg) + buparlisib (30 mg) + fulvestrant (500 mg), 
n=9, (7) ribociclib (400 mg) + buparlisib (40 mg) + fulvestrant (500 mg), n=6, (8) ribociclib 
(600 mg) + buparlisib (30 mg) + fulvestrant (500 mg), n=8. In the cohort with continuous 
ribociclib dosing at 400mg (n = 9), one DLT was reported, a Grade 3 AST elevation. The most 
frequently reported (≥10%) adverse events suspected to be related to study drug in the 
continuous ribociclib dosing cohort were: nausea (55.6%), neutropenia (44.4%), fatigue 
(33.3%), diarrhea, ALT increase, stomatitis, headache (22.2%), AST increase, decreased 
appetite, rash, vomiting, and pruritus (11.1%), Grade 3/4 adverse events in this group were 
neutropenia (22.2%) and AST increase (11.1%).
1.2.1.4.4 Clinical pharmacokinetics of ribociclib (LEE011)
As of 18-Sep-2015 preliminary PK data were available from approximately 153 patients from 
the FIH study CLEE011X2101 across the dose range of 50 to 1200 mg. Following oral dosing, 
ribociclib was rapidly absorbed with median Tmax ranging from 1 to 4 h. Ribociclib plasma 
exposure exhibited slightly over-proportional increases in exposure.
Steady-state was generally reached by Day 8 and the mean effective T1/2 based on accumulation
ratio (i.e., T1/2, acc) ranged from 12.0 to 33.1 h. The accumulation ratio based on area under 
the curve (AUC) obtained in a dosing interval (Racc) ranged from 1.34 to 2.5.
In a food effect study CLEE011A2111 in 24 healthy subjects, a single dose of ribociclib (600 
mg) was administered as drug-in-capsule (DiC) with a high-fat, high-calorie meal and under 
fasted conditions. Compared to the fasted state, oral administration of a single 600 mg dose of 
ribociclib DiC with a high-fat, high-calorie meal decreased the rate of absorption of ribociclib 
resulting in a 23% decrease in Cmax (geometric mean ratio: 0.775; 90% confidence interval 
[CI]: 0.700, 0.858) and a median difference in Tmax of 2 hours. However, there was no effect 
on the extent of absorption of ribociclib as the overall exposure (AUCinf) was unaffected under 
fed conditions (geometric mean ratio: 0.994; 90% CI: 0.925, 1.070). A similar trend was 
observed for LEQ803, an active metabolite of ribociclib, with a decrease in Cmax (32%), a 
delay in median Tmax, and no substantial effect on overall exposure. Based on these data, 
ribociclib DiC can be taken without regard to meals.
In the human ADME study CLEE011A2102, a single oral dose of 600 mg [14C] LEE011 was 
administered to 6 healthy male subjects. The majority of the administered dose was excreted in 
feces (69.1%), with a minor amount excreted in urine (22.6%). Absorption was estimated to be 
approximately 58.8%. Ribociclib accounted for approximately 23% of the total radioactivity in 
plasma, based on AUCinf. Metabolites M1 (glucuronidation of M15), M4 (LEQ803, N-
demethylation) and M13 (CCI284, N-hydroxylation) were the most abundant metabolites in 
plasma, representing an estimated 7.78%, 8.60% and 9.39% of total [14C]AUC0-48h, and 17.9%, 
19.8% and 21.6% of ribociclib AUC0-48h, based on metabolite profiles.


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A drug-drug interaction (DDI) study with ritonavir (a strong CYP3A4 inhibitor) and rifampicin 
(a strong CYP3A4 inducer) was conducted in 48 healthy subjects (CLEE011A2101). Compared 
to ribociclib alone, ritonavir (100 mg bid for 14 days) increased ribociclib Cmax and AUCinf 
by 1.7-fold and 3.2-fold, respectively, following a single oral dose of 400 mg ribociclib. Cmax 
and AUClast for LEQ803 decreased by 96% and 98%, respectively. These results demonstrated 
that concurrent use of strong CYP3A4 inhibitors may markedly increase ribociclib exposure 
and are prohibited.
Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib Cmax 
and AUCinf by 81% and 89%, respectively, following a single oral dose of 600 mg ribociclib. 
LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. These results 
demonstrated that concurrent use of strong CYP3A4 inducers may markedly decrease ribociclib 
exposure and are prohibited.
A DDI cocktail study with midazolam (a sensitive CYP3A4 substrate) and caffeine (a sensitive 
CYP1A2 substrate) conducted in 25 healthy subjects (CLEE011A2106) indicated that 
ribociclib (400 mg) is a moderate inhibitor of CYP3A4, but did not have a substantial effect on 
CYP1A2 substrates in humans. PK data indicated that compared to midazolam and caffeine 
alone, multiple doses of ribociclib (400 mg qd for 8 days) increased midazolam Cmax and 
AUCinf by 2.1-fold and 3.8-fold, respectively. The effect of multiple doses of ribociclib on 
caffeine was minimal, with Cmax decreased by approximately 10% and AUCinf increased 
slightly by 20%. Based on these data, ribociclib (400 mg) is a moderate CYP3A4 inhibitor (≥ 
2- fold but < 5-fold increase in AUC). Concurrent use of sensitive CYP3A4 substrates with a 
narrow therapeutic index is prohibited.
Ribociclib (400 mg) did not have a substantial effect on CYP1A2 in humans; therefore 
concurrent use of CYP1A2 substrates is not expected to lead to clinically significant DDIs.
Refer to the (LEE011 Investigator’s Brochure) for more details.
1.2.2
Summary of results from patients treated with the combination of 
ribociclib 600 mg and letrozole 2.5 mg daily from study CLEE011A2301 
(MONALEESA-2) 
MONALEESA-2 – (CLEE011A2301); a randomized, double blind, placebo controlled, 
multicenter global Phase III trial evaluated the safety and efficacy of ribociclib in combination 
with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- aBC 
who received no prior therapy for their advanced disease. See Table 1-3.
The study met its primary objective at the pre-planned interim analysis; ribociclib in 
combination with letrozole demonstrated statistically significant benefit over placebo in 
combination with letrozole in prolonging PFS based on Investigator assessment. Clinical 
benefit was evident relative to placebo plus letrozole with a 44.4% estimated risk reduction in 
the primary PFS endpoint as per Investigator assessment (HR=0.556, 95% CI: 0.429, 0.720; 
p=3.29×10-6).
Six hundred, sixty eight patients were randomized; 334 patients each to the ribociclib plus 
letrozole arm and the placebo plus letrozole arm. The median study follow-up was 15.3 months, 


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as of the 29-Jan-2016 data cut-off date, and the proportion of patients continuing to receive 
treatment in the ribociclib plus letrozole arm was higher than in placebo plus letrozole arm (58.4% 
vs 46.1%, respectively). Disease progression was the primary reason for treatment 
discontinuation and was more frequent in the placebo plus letrozole arm compared to the 
ribociclib plus letrozole arm (43.7% vs. 26%). Adverse events led to the discontinuation of 
study treatment in 32 patients (4.8%): 25 patients (7.5%) in ribociclib plus letrozole arm and 7 
patients (2.1%) in placebo plus letrozole arm.
The median age of patients was 62 years (range: 23-91) and 44.2% were ≥ 65 years old. The 
majority of the patients were Caucasian (82.2%). All patients had ECOG performance status of 
either 0 or 1. Approximately one-third (34.0%) of the patients in this study were de novo
metastatic breast cancer patients. Nearly two-thirds (58.8%) of patients had visceral disease 
(19.8% with liver and 45.4% with lung involvement) and 22.0% had bone only metastases at 
study entry. All except four patients had stage IV disease at the time of study entry (other four 
had stage III disease). One-third (34.0%) of the patients had ≥ 3 metastatic sites.
Table 1-3
Patient Demographic and baseline characteristics in study 
(CLEE011A2301)
Characteristic
Ribociclib + Letrozole
n=334
Placebo + Letrozole
n=334
Median age, years (range)
62 (23–91)
63 (29–88)
Race, n (%)
Caucasian
269 (80.5)
280 (83.8)
Asian
28 (8.4)
23 (6.9)
Black
10 (3.0)
7 (2.1)
Other/unknown
27 (8.1)
24 (7.2)
ECOG performance status, n (%)
0
205 (61.4) 
202 (60.5)
1
129 (38.6) 
132 (39.5)
Metastatic sites, n (%)
Visceral disease (lung and/or liver metastases)
197 (59.0)
196 (58.7)
Bone-only disease
69 (20.7)
78 (23.4)
De novo metastatic disease, n (%)
114 (34.1)
113 (33.8)
Disease-free interval, n (%)
≤12 months
4 (1.2)
10 (3.0)
>12 months
216 (64.7)
210 (62.9)
Prior (neo)adjuvant therapy, n (%)
Chemotherapy and endocrine therapy
123 (36.8)
120 (36.0)
Endocrine therapy only
52 (15.6)
51 (15.3)
As of 29-Jan-2016 (cutoff date), the median duration of exposure to study treatment was 13.0 
months in the ribociclib arm and 12.4 months in the placebo arm. The median duration of 
exposure to ribociclib/ placebo was 12.2 months in the ribociclib arm and 12.4 months in the 
placebo arm; 240 patients (71.9%) were exposed to ribociclib plus letrozole therapy for ≥ 9 


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months. Median relative dose intensity was 87.5% for ribociclib and 100% for placebo. 
Ribociclib dose interruptions occurred in 257 (76.9%) patients, and letrozole was interrupted in 
132 (39.5%) patients in the ribociclib arm. Placebo was interrupted in 134 (40.6%) patients and 
letrozole was interrupted in 107 (32.4%) patients in the placebo arm. Dose reductions occurred 
in 53.9% and 7.0% of patients in the ribociclib and placebo arms, respectively, most commonly 
for adverse events (169 [50.6%] vs. 14 [4.2%] patients; ribociclib vs. placebo arm). Dose 
reduction due to neutropenia occurred in 65% of patients who had a dose reduction due to AEs 
in the ribociclib arm.
The majority of the patients experienced at least one AE in both treatment groups (98.5% vs. 
97%); the most commonly (≥ 30%) reported AEs in ribociclib plus letrozole group irrespective 
of causality were: neutropenia (60.8%), nausea (51.5%), fatigue (36.5%), diarrhea (35%), and 
alopecia (33.2%) AEs where a higher proportion of ribociclib plus letrozole-treated patients 
reported events (and where there was a ≥ 10% difference to the placebo plus letrozole group) 
included neutropenia (+56.6%), nausea (+23%), decreased neutrophil count (+18%), alopecia 
(+17.7%), decreased white blood cell count (+17.4%), vomiting (+13.8%), anemia (+13.8%), 
diarrhea (+12.9%), leukopenia (+12.9%), increased ALT (+11.7%), and increased AST 
(+11.4%). The incidence of SAEs was 21.3% and 11.8% in the ribociclib plus letrozole and 
placebo plus letrozole arms, respectively. Twenty-five patients (7.5%) from the ribociclib plus 
letrozole group experienced SAEs that were considered by the Investigator to be related to study 
treatment. Febrile neutropenia was the only suspected SAE reported in >1% of patients (1.2%). 
Permanent discontinuations due to adverse events were reported in 7.5% of patients receiving 
ribociclib plus letrozole and in 2.1% of patients receiving placebo plus letrozole. The most 
common AEs leading to treatment discontinuation of both ribociclib and letrozole were ALT 
increased (2.7%), AST increased (2.4%) and vomiting (1.5%) (Table 1-4).
Table 1-4
Adverse events with suspected relationship to study treatment in 
study (CLEE011A2301)
Adverse events with suspected 
relationship to study treatment 
by preferred term and maximum 
grade (greater than 5% in either 
arm) (Safety set)
Ribociclib + Letrozole
n=334
Placebo + Letrozole
n=330
Preferred Term
All grades n 
(%)
Grade 3 n 
(%)
Grade 4 n 
(%)
All grades n 
(%)
Grade 3 n 
(%)
Grade 4 n 
(%)
Total
319 (95.5)
199 (59.6)
43 (12.9)
249 (75.5)
27 (8.2)
1 (0.3)
Neutropenia
199 (59.6)
130 (38.9)
29 (8.7)
13 (3.9)
2 (0.6)
0
Nausea
144 (43.1)
6 (1.8)
0
54 (16.4)
0
0
Alopecia
95 (28.4)
0
0
44 (13.3)
0
0
Fatigue
92 (27.5)
5 (1.5)
1 (0.3)
64 (19.4)
2 (0.6)
0
Diarrhoea
72 (21.6)
3 (0.9)
0
39 (11.8)
0
0
Neutrophil count decreased
63 (18.9)
44 (13.2)
3 (0.9)
3 (0.9)
1 (0.3)
0
Vomiting
62 (18.6)
6 (1.8)
0
22 (6.7)
1 (0.3)
0


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Adverse events with suspected 
relationship to study treatment 
by preferred term and maximum 
grade (greater than 5% in either 
arm) (Safety set)
Ribociclib + Letrozole
n=334
Placebo + Letrozole
n=330
Preferred Term
All grades n 
(%)
Grade 3 n 
(%)
Grade 4 n 
(%)
All grades n 
(%)
Grade 3 n 
(%)
Grade 4 n 
(%)
Total
319 (95.5)
199 (59.6)
43 (12.9)
249 (75.5)
27 (8.2)
1 (0.3)
White blood cell count
Decreased
57 (17.1)
37 (11.1)
2 (0.6)
5 (1.5)
1 (0.3)
0
Hot flush
51 (15.3)
1 (0.3)
0
63 (19.1)
0
0
Arthralgia
48 (14.4)
1 (0.3)
0
52 (15.8)
1 (0.3)
0
Leukopenia
48 (14.4)
25 (7.5)
1 (0.3)
9 (2.7)
1 (0.3)
0
Anaemia
46 (13.8)
2 (0.6)
0
9 (2.7)
3 (0.9)
0
Rash
45 (13.5)
2 (0.6)
0
10 (3.0)
0
0
Alanine aminotransferase
Increased
42 (12.6)
22 (6.6)
5 (1.5)
8 (2.4)
1 (0.3)
0
Constipation
40 (12.0)
0
0
20 (6.1)
0
0
Decreased appetite
39 (11.7)
3 (0.9)
0
18 (5.5)
0
0
Aspartate 
aminotransferase increased
36 (10.8)
12 (3.6)
2 (0.6)
8 (2.4)
3 (0.9)
0
Stomatitis
33 (9.9)
1 (0.3)
0
15 (4.5)
0
0
Pruritus
30 (9.0)
1 (0.3)
0
3 (0.9)
0
0
Asthenia
27 (8.1)
1 (0.3)
0
23 (7.0)
1 (0.3)
0
Headache
27 (8.1)
1 (0.3)
0
24 (7.3)
0
0
Dyspepsia
23 (6.9)
0
0
12 (3.6)
0
0
Dry mouth
21 (6.3)
1 (0.3)
0
14 (4.2)
0
0
Dizziness
19 (5.7)
0
0
21 (6.4)
0
0
Thrombocytopenia
19 (5.7)
1 (0.3)
0
0
0
0
Lymphocyte count decreased
18 (5.4)
12 (3.6)
0
3 (0.9)
2 (0.6)
0
For additional information about the safety profile of ribociclib (as monotherapy or in 
combination with letrozole), please refer to [ribociclib Investigator’s Brochure] (Section 6 
Reference Safety Information).
Key efficacy results
Study CLEE011A2301 met its primary objective at the primary analysis, with statistically 
significant clinical benefit in the treatment arm versus control arm. A 44.4% estimated risk 
reduction in ribociclib plus letrozole treated patients was evident in the primary PFS endpoint 
as per investigator assessment (HR=0.556, 95% CI: 0.429, 0.720; one sided p value=3.29×10-
6). Updated analysis resulted in a PFS of 25.3 months in the treatment arm and 16 months in the 
control arm. Results were consistent across the subgroups of age, race, prior adjuvant or neo-
adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone only 
metastatic disease (See Figure 1-3).


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Overall survival data were immature at the time of this interim analysis with 43 deaths being 
reported (23 patients [6.9%] and 20 patients [6.0%], respectively), from the ribociclib plus 
letrozole and placebo plus letrozole treatment arms.
There was an ORR of 52.7% vs. 37.1% and CBR of 80.1% vs. 71.8% in patients with 
measurable disease. See Figure 1-1.
Figure 1-1
Kaplan-Meier plot of PFS based on Investigator assessment (Full 
Analysis Set)
1.2.3
Overview of everolimus (RAD001/ Afinitor®)
Everolimus (RAD001; Afinitor®) is a derivative of rapamycin and has been in clinical 
development since 1996 as an immunosuppressant in solid organ transplantation. Everolimus 
is approved in Europe and other global markets for cardiac and renal transplantation, and in 
the United States for the prevention of organ rejection of kidney transplantation. In July 2012,
everolimus in combination with exemestane was approved for advanced breast cancer in the 
US, EU and other countries.
The following is a brief summary of the main characteristics of everolimus. More detailed 
information can be obtained from the (everolimus Investigator’s Brochure).
Everolimus
is
a
selective
mTOR
inhibitor, specifically targeting the mTOR-raptor 
(regulatory-associated protein of mTOR, Raptor) signal transduction complex 1 (mTORC1). 
Everolimus potently inhibits proliferation of endothelial cells (Yu 1999, Lane 2009) and has 
antiangiogenic activity in vivo (Guba 2002, Tsutsumi 2004, Mabuchi 2007, Lane 2009).


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1.2.3.1
Nonclinical experience 
Everolimus inhibits the proliferation of a wide range of human tumor cell lines in vitro at 
IC50s ranging from sub/low nM to μM.
The antitumor efficacy of everolimus was compared to other compounds in a panel of six breast 
cancer xenograft models established after direct transplantation of patients’ tumors onto nude
mice (Report RD-2011-50492). This panel included an ER + model, HBCx-3 (XTS-181), 
(Marangoni et al 2007). Everolimus given daily by oral gavage for 21 to 35 days at 20 mg/kg 
was well tolerated with no significant mean body weight loss. In all breast cancer models tested,
tumor growth was significantly inhibited, and was particularly evident in the HBCx-3 (XTS-
181) model with nine partial regressions in ten mice tested (-13.5% mean tumor volume 
regression, p<0.001).
All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an 
antiproliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes.
Based on data generated using human liver microsomes and microsomes from cells expressing
single human cytochrome P450s enzymes, CYP3A4 was identified as the major enzyme 
involved in
the microsomal biotransformation of everolimus. Everolimus inhibited 
competitively the metabolism of the CYP3A4 substrate cyclosporine with a Ki value of
2.3 μMol/L (2204 ng/mL) under in vitro conditions.
Further details can be found in the (everolimus Investigator’s Brochure).
1.2.3.2
Clinical experience
1.2.3.2.1 Everolimus pharmacokinetics
Everolimus is rapidly absorbed with a median tmax of one to two hours. The steady-state 
AUC0-τ is dose-proportional over the dose range between 5 to 70 mg when given weekly and 
5 and 10 mg when given daily. Steady-state was achieved within two weeks with the daily 
dosing regimen. Cmax is dose-proportional between 5 and 10 mg for both the weekly and daily 
regimens.
In healthy subjects, high fat meals reduced systemic exposure of a 10 mg dose of everolimus 
(as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat 
meals reduced AUC by 32% and Cmax by 42%. Food had no apparent effect on the post 
absorption phase concentration-time profile (Study RAD001C2120).
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 
5 to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is 
approximately 20% at blood concentrations observed in cancer patients given everolimus


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10 mg/day [DMPK R303044]. Plasma protein binding is similar in healthy patients and in 
subjects with moderate hepatic impairment (approximately 74%, (Study RAD001A2303)).
The major and nearly exclusive enzyme responsible for the metabolism of everolimus in man 
was CYP3A4 (DMPK(US)1998/005; DMPK(CH) R99-2448), (Kuhn 2001). Other CYP 
isoenzymes either do not metabolize everolimus or do so at very low rates. Everolimus is a 
moderate inhibitor of P-glycoprotein-like mediated efflux systems, although the compound 
has a high intrinsic permeability when P-glycoprotein is inhibited (Crowe 1998, Laplante 
2002, DMPK(CH) 1997/417). Following oral administration, everolimus is the main circulating
component in human blood and contributes the majority of the overall pharmacologic activity
(Study W107). Everolimus was also shown to increase exposure of exemestane: In (Study 
RAD001Y2301), average exemestane Cmin and C2h were 45% and 71% higher, respectively,
when co-administered with everolimus.
No specific excretion studies have been undertaken in cancer patients; however, data available 
from the transplantation setting found the drug to be mainly eliminated through the feces.
1.2.3.2.2 Everolimus in combination with endocrine therapy in HR+ breast cancer
The combination of everolimus with hormonal therapy has been assessed in different disease 
settings in HR+ breast cancer and showed evidence of efficacy of everolimus in this patient 
population (Bachelot et al 2012; Baselga et al 2012; Piccart et al 2012).
In newly diagnosed patients with ER+ breast cancer, a neoadjuvant randomized 270-patient 
Phase II study compared the combination of everolimus 10 mg QD and letrozole 2.5 mg QD 
to letrozole alone for 16 weeks of therapy prior to surgery. The overall response rate in the 
investigational everolimus + letrozole arm was higher than that with letrozole alone: 68%
vs.59% based on palpation (p = 0.062) and 58% vs. 47% based on ultrasound (p = 0.021) 
respectively, meeting the predetermined endpoint for efficacy. Additionally, there was a greater
antiproliferative response in the investigational arm, with a decrease of the Ki67 proliferation
index to <1 in 57% of patients in the everolimus arm compared to 30% of patients in the 
placebo arm (p<0.01) (Baselga 2009). A randomized Phase III, double-blind, placebo-
controlled study (BOLERO-2 Study) demonstrated very significant improvements in treatment 
of HR+ breast cancer that had recurred or progressed on letrozole or anastrozole. Response rate, 
progression-free survival (PFS), and clinical benefit rate were all significantly improved 
relative to exemestane monotherapy. The median PFS by local assessment was 7.8 months for
everolimus + exemestane versus 3.2 months for exemestane (HR = 0.45; 95% CI: 0.38-0.54; 
p<.0001). Overall response rate (12.6% vs 1.7%; p<.0001) and clinical benefit rate (51.3% vs 
26.4%; p<.0001) were superior in the everolimus + exemestane arm versus exemestane + 
placebo. Analyses by central assessment showed a median progression-free survival of 11 
months with everolimus versus 4.1 months with placebo (HR = 0.38; 95% CI: 0.31 – 0.48; 
p<.0001) confirming the results of the primary PFS analysis (Piccart 2012, Baselga 2012).


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1.2.3.3
Safety profile of everolimus
The following AEs are considered to be class-effects of mTOR inhibitors: stomatitis/oral 
mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, hemorrhages, 
non-infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal events, and 
thromboembolism. The more common metabolic side effects reported with mTOR inhibitors 
result from inhibitory effects on mTOR-regulated lipid and glucose pathways, while infections
stem from the immunosuppressive properties of these agents. Virtually all of the side effects
associated with mTOR inhibitors can be managed effectively with dose modification and/or 
supportive intervention.
The safety profile of everolimus observed in the Phase III BOLERO-2 study is consistent with 
prior experience in the oncology setting; events are predominantly low grade (grade 1 or 2). 
An increased risk of non-infectious pneumonitis, infection, and stomatitis in the everolimus 
plus exemestane arm relative to the control arm [exemestane + placebo] was observed, although 
each of these events can be effectively managed in this setting.
The most common adverse events (AEs) suspected to be related to treatment, with an incidence
≥10%, reported in association with everolimus plus exemestane therapy were consistent with
what was previously reported: stomatitis, rash, fatigue, decreased appetite, diarrhea, dysgeusia,
nausea, pneumonitis, weight loss, anemia, epistaxis, hyperglycemia, thrombocytopenia, and 
pruritus. The most common grade 3-4 AEs suspected to be related to treatment with an
incidence of ≥2% were: stomatitis, hyperglycemia, anemia, pneumonitis, fatigue, elevated 
alanine
and
aspartate transaminase
concentrations,
elevated γ-
glutamyltransferase
concentrations, dyspnea, neutropenia, and thrombocytopenia (Piccart et al 2012; Baselga et al 
2012). No new safety concerns have emerged compared to previous experience with everolimus 
monotherapy or combination therapy.
Further details related to everolimus safety can be found in the (everolimus Investigator’s 
Brochure) and package insert of the local supply of everolimus (if available) for more details.
1.2.4
Overview of exemestane
Exemestane is an irreversible steroidal aromatase inhibitor that has demonstrated efficacy in 
the treatment of postmenopausal patients with advanced breast cancer. It is indicated for 
adjuvant treatment of postmenopausal women with ER+ early breast cancer who have received
two to three years of tamoxifen and are switched to exemestane for completion of a total of five
consecutive years of adjuvant hormonal therapy. It is also indicated for the treatment of 
advanced breast cancer in postmenopausal women whose disease has progressed following 
tamoxifen therapy (in the USA) or following anti-estrogen therapy (in Europe).
Exemestane is initially recognized by the aromatase enzyme as a false substrate and is then 
transformed through an NADPH-dependent mechanism to an intermediate that binds 
irreversibly to the enzyme, causing inactivation. Exemestane significantly lowers circulating 
estrogen concentrations (estradiol, estrone and estrone sulfate) but has no detectable effect on 


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adrenal biosynthesis of corticosteroids or aldosterone (Aromasin prescribing information 
Pfizer-Pharmacia 2005).
The recommended daily dose of exemestane is 25 mg via oral administration. Exemestane is 
rapidly absorbed from the gastrointestinal tract. Its bioavailability is limited by first-pass 
metabolism, but is increased when taken with food. Exemestane is widely distributed, and is 
extensively bound to plasma proteins. The terminal half-life for exemestane is 18-24 hours. 
The time needed to reach maximal E2 suppression is 7 days (Demers 1993, Plourde 1995, 
Buzdar 2003). Exemestane is metabolized by CYP3A4 and aldoketoreductases. It does not 
inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1 and 3A4. 
Although no formal drug-drug interaction studies have been conducted, significant effects on 
exemestane clearance by CYP isoenzyme inhibitors appear  unlikely (Aromasin prescribing 
information Pfizer-Pharmacia 2011, Hutson 2005, Buzdar 2003). As noted in Section 1.2.3.2.1, 
everolimus increases exposure of exemestane.
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, 
hot flushes, arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects include 
headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and peripheral
and leg edema. Thrombocytopenia and leukopenia have been reported occasionally. 
Reductions in bone mineral density can occur with long-term use of exemestane. A total of
1058 patients were treated with exemestane 25 mg once daily in the clinical trials program.
Exemestane was generally well tolerated, and adverse events were usually mild to moderate. 
Adverse events occurring in greater than 10% of patients include hot flushes (14%), nausea
(11.9%), insomnia, headache, increased sweating, joint and musculoskeletal pain, and fatigue
(USPI Aromasin SmPC August 2008 (UK as RMS for EU MRP)). Androgenic effects were 
reported in a limited number of patients (4.3%) (Buzdar 2003).
Refer to the prescribing information of the local supply of exemestane for more details.
1.2.5
Ribociclib in combination with everolimus 
1.2.5.1
Synergy with everolimus and ribociclib (LEE011)
The effect of combining ribociclib with the mTORC1-inhibitor RAD001 (everolimus; Afinitor®) 
in the ER+, PIK3CA-mutant MCF-7 xenograft model was examined. As demonstrated in
Figure 1-2 single agent treatments with ribociclib and RAD001 resulted in modest tumor
regressions of -9% and -21%, respectively. When ribociclib was combined with RAD001 tumor 
regression increased to -49%. Moreover, single agent and combination treatments were well
tolerated as judged by body weight loss (not shown). In addition, the triplet combination of 
ribociclib plus everolimus plus the endocrine therapy, fulvestrant, was evaluated in the ER+, 
PIK3CA-mutant KPL-1 and PTEN-null XR751 xenograft models. The triplet combination
demonstrated superior tumor regression compared to single agent LEE011 or LEE011 plus
fulvestrant (see Figure 1-3) or compared to single agent everolimus or everolimus combined
with fulvestrant. These data suggest that combining inhibitors that target the mTOR pathway
with LEE011 may be an effective therapeutic strategy in ER+/PIK3CA-mutant tumors.


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Figure 1-2
LEE011 and everolimus in MCF 7 xenograft
Figure 1-3
Triplet combination of LEE011, everolimus and fulvestrant in ZR and 
KPL-1 xenograft models
Mice treated with vehicle, LEE011 (LEE011;75 mg/kg qd x 28), fulvestrant (Fulv; 5 mg qwk x 4) and/or everolimus 
(RAD; 10 mg/kd qd x 28). 
1.2.5.1.1 Drug interaction (ribociclib and everolimus)
In vitro experiments observed time-dependent inhibition of CYP3A4 by ribociclib with a KI 
value of 5 μM and a kinact value of 0.0245 min-1; a clinical DDI confirmed these in vitro results. 
Everolimus is a sensitive CYP3A4 substrate. Therefore, a PK DDI was possible with the 
combination of everolimus and ribociclib (LEE011 Investigator Brochure).
As of March 2, 2015, 84 patients have been treated with the combination of ribociclib + 
everolimus + exemestane in a Phase Ib study (CLEE011X2106). Everolimus (RAD001) was 


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administered at 2.5 mg (qd) concurrently with 200 mg, 250 mg and 300 mg of ribociclib (qd, 3 
weeks on/1 week off) with or without food. Additionally 350 mg of ribociclib was administered 
with 1 mg of everolimus without food or 2.5 mg everolimus with food and 200 mg of ribociclib 
was administered with 5 mg of everolimus with food. A fixed dose of 25 mg of exemestane (qd) 
was administered in each combination (Bardia A et al 2015).
Preliminary PK data for Cmax and AUC0-24h for ribociclib and everolimus were available on Day 
1 and after multiple doses on Day 15. Everolimus (2.5 mg qd) exposure (AUC0-24h) was 
increased in the presence of ribociclib (200-350 mg) to levels of 5 to 10 mg when compared to 
historical single agent data (Kovarik et al 2002; Kovarik et al 2005a; Urva et al 2013; 
Everolimus Investigator’s Brochure). In general, mean steady state exposure for ribociclib and 
everolimus appeared to be lower in the presence of food at the same dose level; however,
individual Cmax and AUC0-24h values with food were within the range of values observed without 
food. Further evaluation of 2.5 mg of everolimus (RAD001) (qd) with 300 mg ribociclib (qd, 3 
weeks on/1 week off) with food is ongoing in CLEE011X2106 dose expansion (Bardia A et al 
2015). See Table 1-5 for full PK parameters.
Table 1-5
Pharmacokinetic Parameters of Ribociclib and Everolimus at Steady 
State (Cycle 1, Day 15)
Analyte
Dose (ribociclib + 
EVE + EXE, mg
Fasted/Fed
N
Cmax (ng/mL), 
Mean (SD) [n]
AUC0-24h (h*ng/mL), 
mean (SD) [n]
Ribociclib
200 + 2.5 + 25
Fasted
6
473 (305) [6]
5200 (3540) [5]
200 + 2.5 + 25
Fed
3
315 (163) [3]
4330 (3920) [3]
250 + 2.5 + 25
Fasted
16
818 (549) [14]
9460 (6280) [11]
250 + 2.5 + 25
Fed
5
720 (301) [2]
10 000 (4960) [2]
300 + 2.5 + 25
Fasted
11
1250 (690) [8]
14 800 (9390) [8]
300 + 2.5 + 25
Fed
12
924 (505) [11]
13 500 (7680) [8]
350 + 1 + 25
Fasted
6
989 (362) [5]
11 900 (3390) [4]
350 + 2.5 + 25
Fed
5
896 (376) [5]
12 700 (5640) [5]
200 + 5 + 25
Fed
6
580 (216) [5]
6860 (2470) [5]
EVE
200 + 2.5 + 25
Fasted
6
20 (5) [5]
170 (47) [5]
200 + 2.5 + 25
Fed
3
8 (2) [3]
1120 (32) [3]
250 + 2.5 + 25
Fasted
16
33 (14) [13]
327 (161) [10]
250 + 2.5 + 25
Fed
5
24 (17) [2]
257 (182) [2]
300 + 2.5 + 25
Fasted
11
35 (18) [7]
365 (197) [7]
300 + 2.5 + 25
Fed
12
26 (9) [11]
305 (135) [9]
350 + 1 + 25
Fasted
6
13 (3) [4]
106 (30) [3]
350 + 2.5 + 25
Fed
5
26 (8) [5]
287 (103) [5]
200 + 5 + 25
Fed
6
40 (12) [5]
403 (124) [5]
Historical single-agent data (steady state)
EVE
5 mg13
4
32 (9) [4]
223 (74) [4]
10 mg13
7
60 (17) [7]
560 (283) [7]


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Analyte
Dose (ribociclib + 
EVE + EXE, mg
Fasted/Fed
N
Cmax (ng/mL), 
Mean (SD) [n]
AUC0-24h (h*ng/mL), 
mean (SD) [n]
5 mg14
23
54 (12) [23]
418 (87) [23]
AUC0-24h, area under the curve from time zero to 24 h;   Cmax maximum plasma concentration; EVE, 
everolimus; EXE, exemestane; SD, standard deviation
1.2.5.1.2 Clinical safety of ribociclib when combined with everolimus and exemestane
In the ongoing Phase Ib/II clinical trial (CLEE011X2106), out of 70 patients treated with the 
triplet combination, ribociclib (200–350 mg 3 weeks on, 1 week off), everolimus (most at 
2.5 mg), and exemestane (25 mg), the median number of prior regimens was 4, and 18 (25.7%) 
pts had received prior PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. Grade 
3/4 treatment-related AEs (≥5% patients) were neutropenia (45.7%), leukopenia (8.6%), and 
thrombocytopenia (5.7%). Two (2.9%) patients discontinued due to AEs. Grade 3 AST/ALT 
AEs were appreciated in 2 patients, febrile neutropenia and hypophosphatemia (1 patient), oral 
mucositis (1 patient), rash and thrombocytopenia (1 patient), and thrombocytopenia with 
bleeding (1 patient). MTD and RDE were declared at ribociclib 300 mg 3 weeks on, 1 week off, 
everolimus 2.5 mg daily and exemestane 25 mg daily. This combination dose appeared to be 
tolerable and safe. (Bardia A et al 2015). See Table 1-6 for full AE listing
Table 1-6
LEE011X2106: Adverse Events (All-grade greater than or equal to 15% 
in All Patients Receiving Triplet Therapy) Suspected to Be Related to 
Treatments
Adverse 
Event
Grade
R 200 mg + 
E 2.5 mg
R 250 mg + 
E 2.5 mg
R 300 mg + 
E 2.5 mg
R 350 
mg + E 
1 mg
R 350 
mg + E 
2.5 mg
R 200 
mg + E 
5 mg
All Patients 
With Triplet 
Therapy
Fasted /
Fed N
Fast
ed 
n=6
Fed 
n=3
Fast
ed 
n=18
Fed 
n=6
Fast
ed 
n=11
Fed 
n=12
Fasted 
n=6
Fed 
n=9
Fed 
n=6
N/A 
N=77
Total
All
6 
(100)
3 
(100)
17 
(94)
5 
(83)
11 
(100)
12 
(100)
6 (100)
9 (100)
6 (100)
75 (97)
G3/4
2 
(33)
0
11 
(61)
1 
(17)
10 
(91)
10 
(83)
2 (33)
8 (89)
4 (67)
48 (62)
Stomatitis
All
4(67)
3 
(100)
8 
(44)
5 
(83)
7 
(64)
6 
(50)
2 (33)
5 (56)
2 (33)
42 (55)
G3/4
0
0
0
0
0
1 (8)
0
0
0
1 (1)
Anemia
All
3 
(50)
1 
(33)
9 
(50)
2 
(33)
7 
(64)
6 
(50)
2 (33)
3 (33)
3 (50)
36 (47)
G3/4
0
0
2 
(11)
1 
(17)
1 (9)
0
0
0
1 (17)
5 (7)
Neutropeni
a
All
4 
(67)
0
5 
(28)
1 
(17)
6 
(55)
6 
(50)
3 (50)
8 (89)
3 (50)
36 (47)
G3/4
2 
(33)
0
2 
(11)
1 
(17)
6 
(55)
4 
(33)
0
7 (78)
2 (33)
24 (31)


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Adverse 
Event
Grade
R 200 mg + 
E 2.5 mg
R 250 mg + 
E 2.5 mg
R 300 mg + 
E 2.5 mg
R 350 
mg + E 
1 mg
R 350 
mg + E 
2.5 mg
R 200 
mg + E 
5 mg
All Patients 
With Triplet 
Therapy
Neutrophil 
count 
decreased
All
0
1 
(33)
10 
(56)
1 
(17)
5 
(46)
5 
(42)
1 (17)
2 (22)
2 (33)
27 (35)
G3/4
0
0
6 
(33)
0
3 
(27)
4 
(33)
0
0
1 (17)
14 (18)
White 
blood cell 
count 
decreased
All
1 
(17)
2 
(67)
5 
(28)
1 
(17)
7 
(64)
3 
(25)
4 (67)
1 (11)
1 (17)
25 (33)
G3/4
0
0
2 
(11)
0
3 
(27)
2 
(17)
1 (17)
1 (11)
0
9 (12)
Thrombocy
topenia
All
1 
(17)
0
6 
(33)
1 
(17)
5 
(46)
6 
(50)
1 (17)
4 (44)
1 (17)
25 (33)
G3/4
0
0
0
1 
(17)
2 
(18)
1 (8)
0
1 (11)
0
5 (7)
AST 
increase
All
2 
(33)
1 
(33)
5 
(28)
0
4 
(36)
4 
(33)
1 (17)
2 (22)
2 (33)
21 (27)
G3/4
0
0
0
0
2 
(18)
0
0
1 (11)
0
3 (4)
ALT 
increase
All
3 
(50)
0
2 
(11)
1 
(17)
6 
(55)
5 
(42)
0
1 (11)
3 (50)
21 (27)
G3/4
0
0
0
0
2 
(18)
1 (8)
0
0
1 (17)
4 (5)
Nausea
All
1 
(17)
1 
(33)
6 
(33)
1 
(17)
3 
(27)
3 
(25)
1 (17)
2 (22)
1 (17)
19 (25)
G3/4
0
0
0
0
0
0
0
0
0
0
Rash
All
1 
(17)
1 
(33)
2 
(11)
1 
(17)
5 
(46)
2 
(17)
0
2 (22)
2 (33)
16 (21)
G3/4
0
0
0
0
1 (9)
0
0
0
0
1 (1)
Platelet 
count 
decrease
All
2 
(33)
0
3 
(17)
1 
(17)
3 
(27)
2 
(17)
0
2 (22)
2 (33)
15 (20)
G3/4
1 
(17)
0
0
0
0
0
0
0
0
1 (1)
Diarrhea
All
1 
(17)
1 
(33)
4 
(22)
0
2 
(18)
2 
(17)
0
1 (11)
3 (50)
14 (18)
G3/4
0
0
0
0
0
0
0
0
0
0
Lymphope
nia
All
3 
(50)
1 
(33)
4 
(22)
0
1 (9)
2 
(17)
2 (33)
0
1 (17)
14 (18)
G3/4
1 
(17)
0
3 
(17)
0
0
1 (8)
0
0
0
5 (7)
Fatigue
All
0
1
(33)
3 
(17)
1 
(17)
2 
(18)
2 
(17)
2 (33)
1 (11)
1 (17)
13 (17)
G3/4
0
0
0
0
0
0
0
0
0
0
Lymphocyt
e count 
decreased
All
0
0
5 
(28)
1 
(17)
4 
(36)
1 (8)
1 (17)
0
1 (17)
13 (17)
G3/4
0
0
3 
(17)
0
0
0
0
0
0
3 (4)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; E, everolimus; G, Grade; R, ribociclib.


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At the time of the completion of cohort A, and cohort B in the phase I portion of TRINTI-1 
(LEE011XUS29) an interim analysis was done on 16 evaluable patients (8 patients in cohort 
A [250mg qd Ribociclib + 2.5mg qd Everolimus + 25mg qd Exemestane], and 8 patient in 
cohort B [300mg qd Ribociclib + 2.5mg qd Everolimus + 25mg qd Exemestane]). The most 
common all-grade AEs (>20% in either cohort) were neutropenia (Cohort A, 4 patients 
[50.0%]; Cohort B, 4 patients [50.0%]), fatigue (Cohort A, 3 patients [37.5%]; Cohort B, 0 
patients), thrombocytopenia (Cohort A, 2 patients [25.0%]; Cohort B, 2 patients [25.0%]), and 
mucositis (Cohort A, 0 patients; Cohort B, 2 patients [25.0%]). The most common Grade 3/4 
AE (>20% in either cohort) was neutropenia (Cohort A, 3 patients [37.5%]; Cohort B,
3 patients [37.5%]). 2 patients (12.5%) experienced Grade 3/4 febrile neutropenia, 1 in each 
cohort. There were no cases of QT interval prolongation, abnormal liver function tests, or 
pneumonitis in either cohort. (Hurvitz S et al 2017). See Table 1-7 for full AE listing.
Table 1-7
LEE011XUS29: Adverse Events (cohort A and B) Suspected to Be 
Related to Treatments
Patients, n (%)
Ribociclib 250 mg
+ EVE 2.5 mg
+ EXE 25 mg
(n=8)
Ribociclib 300 mg
+ EVE 2.5 mg
+ EXE 25 mg
(n=8)
All patients
(n=16)
Adverse event, n (%)
All grade
Grade 3/4
All grade
Grade 3/4
All grade
Grade 3/4
Total
7 (87.5)
6 (75.0)
7 (87.5)
6 (75.0)
14 (87.5)
12 (75.0)
Neutropeniaa
4 (50.0)
3 (37.5)
4 (50.0)
3 (37.5)
8 (50.0)
6 (37.5)
Thrombocytopeniab
2 (25.0)
0
2 (25.0)
1 (12.5)
4 (25.0)
1 (6.3)
Fatigue
3 (37.5)
0
0
0
3 (18.8)
0
Anemia
1 (12.5)
1 (12.5)
1 (12.5)
1 (12.5)
2 (12.5)
2 (12.5)
Febrile neutropenia
1 (12.5)
1 (12.5)
1 (12.5)
1 (12.5)
2 (12.5)
2 (12.5)
Mucositis
0
0
2 (25.0)
0
2 (12.5)
0
Urticaria
1 (12.5)
1 (12.5)
1 (12.5)
0
2 (12.5)
1 (6.3)
AKI
1 (12.5)
1 (12.5)
0
0
1 (6.3)
1 (6.3)
Diarrhea
0
0
1 (12.5)
0
1 (6.3)
0
Dry mouth
0
0
1 (12.5)
0
1 (6.3)
0
Dyspepsia
0
0
1 (12.5)
0
1 (6.3)
0
GGT increased
0
0
1 (12.5)
0
1 (6.3)
0
Hyperglycemia
0
0
1 (12.5)
1 (12.5)
1 (6.3)
1 (6.3)
Leukopenia
0
0
1 (12.5)
1 (12.5)
1 (6.3)
1 (6.3)
Lymphopenia
0
0
1 (12.5)
0
1 (6.3)
0
Muscle spasm
0
0
1 (12.5)
0
1 (6.3)
0
Nausea
0
0
1 (12.5)
0
1 (6.3)
0
Pruritus
1 (12.5)
0
0
0
1 (6.3)
0
Vomiting
0
0
1 (12.5)
0
1 (6.3)
0
Weight decreased
1 (12.5)
0
0
0
1 (6.3)
0
AKI, acute kidney injury; EVE, everolimus; EXE, exemestane; GGT, gamma-glutamyltransferase. a Includes neutropenia, 
neutrophil count decreased, and white blood cell count decreased. bIncludes thrombocytopenia and platelet count 
decreased. 


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2
Rationale
2.1
Study rationale and purpose
Hormone receptor-positive breast cancer is the most common form of breast cancer. Resistance
to hormonal-deprivation therapy is the leading cause of death for women with this diagnosis.
Disruption of the PI3K/mTOR pathway and cyclin D-CDK4/6–INK4–Rb pathway has been 
implicated in resistance to endocrine therapy and disease progression. Activating mutations in 
the mTOR, AKT, PIK3CA genes are oncogenic drivers in a variety of cancer types, including
ER+ breast cancer. The addition of everolimus to exemestane significantly improves 
progression-free survival of women with disease resistant to hormonal deprivation (Baselga J 
2012); however, this too ultimately results in disease progression. Studies demonstrate that 
resistance to hormonal therapy, mTOR inhibition, and cytotoxic chemotherapy are at least in 
part mediated by upregulation of CDK4/6-cyclin D activity in breast cancer, suggesting that 
there might be a role for CDK4/6 inhibition + mTOR inhibition in patients who have progressed 
on these therapies. Cyclin-dependent kinase (CDK) 4/6 inhibitors are believed to be critical
mediators of this pathway as they act downstream of the PIK3CA/Protein Kinase B 
(AKT)/mTOR axis. The effect of combining ribociclib with the mTORC1-inhibitor everolimus
(RAD001; Afinitor®) in the ER+, PIK3CA mutant MCF-7 xenograft model was examined 
(RD-2013-50141). While single agent treatments with ribociclib, and everolimus resulted in 
modest tumor regressions of -9% and -21%, respectively, combination of ribociclib with 
everolimus increased tumor regressions to -49%. Data from in vivo studies showed that 
ribociclib, when combined with the mTOR inhibitor, everolimus (RAD001; Afinitor®), induced 
synergistic growth inhibitions in multiple tumor models, including cell lines derived from MCL, 
ER+ breast cancer, and MRT (LEE011 Investigator’s Brochure).
There is a role for continuing targeted therapies in patients with breast cancer, even beyond the 
point of disease progression. Inhibition of CDK 4/6 has been associated with autophagy-
senescence transition (AST) in stromal fibroblasts, which leads to mitochondrial dysfunction 
and catabolism, a process that releases high-energy mitochondrial fuels into the stroma where 
they drive anabolic tumor growth and cancer metastasis (Capparelli C, 2012). When fibroblasts 
with induced senescence were co-cultured with the MDA-MB-231 breast cancer cell line, a 
near 2-fold increase in tumor growth was noted compared to control (Capparelli C, 2012).
Release of CDK inhibition in a primed microenvironment could have the potential to cause 
rapid tumor progression, although this is still not well understood. Additional preclinical 
experiments have also suggested that inhibition of cyclin D1 or CDK 4/6 enhances mobility in 
both breast and pancreatic cancer cell lines, predominately through activation of TGF-, which 
induces Akt-TOR signaling (Tobin NP, 2011) As such, treatment with the mTOR inhibitor 
everolimus may overcome a potential pathway of drug resistance to CDK 4/6/Cyclin D 
inhibition.
Everolimus appears to restore sensitivity to anti-estrogens by inhibiting resistance mediated by 
the PI3K/AKT/mTOR pathway. Currently, there is no clinical data available reporting the
efficacy of further treatments after prior CDK4/6 inhibitor failure, which represents an unmet
medical need and requires further exploration. Potential reasons for progression on CDK4/6


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inhibitor include loss of the retinoblastoma protein (pRb) (the direct target of CDK4/6
inhibitors), alterations in the estrogen receptor pathway as a consequence of endocrine therapy 
resistance, or activation of other signaling pathways including the PI3K/AKT/mTOR pathway.
Anecdotal observations of a small subset of patients treated on 1st line therapy trials with CDK 
4/6 inhibitors + aromatase inhibitors have suggested that some patients who discontinue therapy 
with the CDK 4/6 inhibitors develop rapid disease progression at initial imaging assessment to 
second line therapy. This lends the question of maintaining CDK 4/6 inhibition as a backbone 
therapy to keep the cell cycle arrested in G1 while adding mTOR inhibition to overcome 
secondary resistance.
The heterogeneity of the anticipated mechanism of resistance requires further exploration in 
identifying the subset of patients that may still benefit from a sustained inhibition of the
CDK4/6 pathway. Therefore, the analysis of newly acquired tumor biopsy at progression after
CDK4/6 inhibitor based therapy will be a preferred way to identify potential mechanisms of 
resistance in such patients.
The LEE011X2106 Phase-1b clinical trial tested a combination of exemestane + everolimus + 
ribociclib. This combination appeared to be safe and demonstrated clinical activity at the RDE 
of ribociclib 300 mg (3weeks on/1 week off), everolimus 2.5 mg daily, and exemestane 25 mg
daily. PK analysis indicated that ribociclib (200 mg-350 mg) increased exposure of everolimus
(2.5 mg) due to CYP3A4 inhibition by ribociclib. At steady-state, everolimus exposure was 
largely within the exposures achieved with multiple doses of 5 and 10 mg of single agent 
everolimus. (Bardia A 2015). Clinical activity was seen in a heavily pre-treated population with 
median number of prior regimens being 4, and 25.7% pts had received prior PI3K/AKT/mTOR 
or CDK4/6 inhibitors for metastatic disease. The clinical benefit rate (confirmed CR + PR + SD 
≥24 weeks + NCRNPD ≥24 weeks) was 26% in 74 evaluable patients (n=19; 95% CI: 16–37%)
and a disease control rate (CR + PR + SD + NCRNPD) of 73% (n=56; 95% CI: 61–82%). 
Furthermore, there was a trend towards longer duration of treatment in the CCND1 amplified 
group (n=10; median 166 days) than in the non-amplified group (n=22; median 60 days), 
something which was not seen in BOLERO-2 (Bardia A 2015). Thus, triplet combination of 
endocrine therapy with mTOR and CDK4/6 inhibition is feasible, permits lower dosing of 
everolimus with acceptable dose exposure levels, and shows encouraging signs of clinical 
activity, including in patients with prior exposure to PI3K/AKT/mTOR or CDK4/6 inhibitors, 
suggesting that triplet therapy might overcome resistance to doublet therapy in a subset of 
patients.
Therefore, this study proposes to test whether the addition of everolimus + exemestane to 
ribociclib can reverse resistance to a CDK 4/6 inhibitor and ultimately improve the efficacy of 
the approved combination regimen (everolimus + exemestane) in patients that progressed on
CDK 4/6 inhibitors.
2.1.1
Rationale for Continuous Dosing- Phase I-Dose Escalation
The RDE for the Phase I CLEE011X2106 dose escalation study, was declared at ribociclib 
(300 mg 3 weeks on/ 1 week off), everolimus 2.5 mg daily, and exemestane 25 mg daily. Based 
on the PK data from CLEE011X2106 study, when ribociclib (300 mg) and everolimus (2.5 mg) 


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were dosed concurrently, steady state exposure of ribociclib was generally within the range of 
exposures observed for single agent ribociclib at similar doses (Bardia A 2015). However, 
ribociclib increased the exposure of everolimus by approximately 2 and 4 fold (5 and 10 mg 
respectively) when ribociclib was dosed 21/28 days at 200 mg and 300 mg respectively (see
Section 1.2.5.1.1). During the week of rest for ribociclib (days 22-28), levels of everolimus 
decreased below the single agent recommended dose levels of everolimus. 
Continuous dosing of ribociclib has been evaluated in both X2108 (400 mg ribociclib daily + 
fulvestrant) and X2101 300 mg and 400 mg single agent ribociclib. Both studies demonstrate 
acceptable tolerability. In X2108, when compared to 600 mg 3 weeks on/1 week, daily dosing 
of ribociclib at 400 mg resulted in a decrease in neutropenia, ALT elevation, QTc prolongation
and fatigue (Section 1.2.1). 
The design of the Phase I, open label, dose finding part of the study was chosen in order to 
establish the MTD(s)/RP2D of continuous dosing of ribociclib at 250 mg starting dose in
combination with a fixed, dose of everolimus (2.5 mg) based on the CLEE011X2106 Phase I 
study and standard dose of exemestane (25 mg) in men and postmenopausal women with HR+
HER2 negative advanced breast cancer. Based on the decreased levels of everolimus during the 
rest week of ribociclib and the improved safety data demonstrated with the continuous dosing 
of ribociclib in both the CLEE011X2101 study and CLEEX2108 study, it is believed that dosing 
ribociclib continuously with daily everolimus and exemestane may lead to improved safety and 
efficacy. Because the exposure of ribociclib does not change when administered concurrently 
with everolimus, we believe that 250 mg of ribociclib will be safe to administer with 2.5 mg of 
everolimus daily.
The decisions on new dose combinations are made by the Investigators and Novartis study 
personnel and will be based upon a synthesis of the recommendations made by the independent 
data monitoring committee (IDMC), patient tolerability
and safety, PK and efficacy
information available at the time of the decision. The discussion and decisions will be 
documented in the dose escalation meeting minutes.
The dose escalation part of this study will also assess the PK of everolimus and ribociclib in 
HR+ HER2-negative advanced breast cancer patients receiving the triplet combination 
(ribociclib + everolimus + exemestane) with continuous dosing and will compare the
findings with historical data for the approved combination of everolimus + exemestane as well 
as the data from the ongoing CLEE011X2106 study. This comparison will be done in order to
determine the optimal dosing of the triplet combination when all drugs are dosed continuously.
Each cycle was determined to be 28 days. In the initial cohort(s) of subjects, if therapy is well
tolerated after two cycles and have no evidence of grade 3 or 4 clinically significant AEs,
subjects may undergo intra-patient dose escalation(s) to ensure that they receive a therapeutic
dose of everolimus and ribociclib. See Section 6.2 for details on starting dose and escalation 
guidelines.


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2.1.2
Rational for stomatitis prevention mouthwash
2.1.2.1
Overview of stomatitis and current treatment
Stomatitis, the inflammation of mucous membranes lining the mouth and throat, has been 
observed in approximately 44-86% of everolimus-treated patients (Afinitor® prescribing 
information Novartis 2013). In the BOLERO-2 trial, patients who received everolimus 
+exemestane had a 67% overall reported incidence of stomatitis (Afinitor® prescribing 
information Novartis 2013) including 33% incidence grade ≥2 (Data on file). The median time 
to first onset of stomatitis (Gr≥2) in the BOLERO-2 trial was 15.5 days (Perez et al 2013) and 
the incidence of new stomatitis (Gr≥2) plateaued at 6 weeks (Rugo et al 2013). Reports from 
clinicians indicate that in routine practice, everolimus treated advanced breast cancer patients 
who develop stomatitis tend to develop it within the first month of therapy. Clinicians also 
report that once resolved the stomatitis typically either doesn’t recur or recurs at lower grade, 
even in patients who have been maintained or re-escalated to full-dose everolimus.
Specific strategies to prevent and/or ameliorate the severity of everolimus-associated stomatitis 
are still ongoing. One recent study evaluated the clinical presentation and management of 
stomatitis in 17 patients treated with an mTOR inhibitor. The majority of patients were treated 
with topical corticosteroids including an oral dexamethasone solution which was rinsed and 
expectorated. Clinical improvement was noted in over 85% of topical corticosteroid-treated 
patients (de Oliveira et al 2011). Another recent study prospectively evaluated the presentation 
and management of oral stomatitis in advanced breast cancer patients being treated with 
everolimus combined with exemestane. Seven out of 15 women (46.6%) developed stomatitis 
grade ≥2. All (100%) ulcers were treated with topical dexamethasone solution and healed after 
a median of 2 weeks.
Four patients (57.1%) required a temporary interruption of their everolimus, and two patients 
(28.6%) required an everolimus dose reduction (Nicolatou-Galitis et al 2013). 
Anecdotal reports from clinicians indicate that prophylactic use of a steroid-based oral 
mouthwash may help to prevent stomatitis in patients treated with everolimus. Texas
Oncology–Baylor Charles A. Sammons Cancer Center in Dallas, Texas reported overwhelming 
success in preventing Gr≥2 stomatitis since they began prescribing a prophylactic mouthwash 
(hydrocortisone, tetracycline, nystatin, and diphenhydramine) to their advanced breast cancer 
patients on everolimus (Divers et al 2013). A Phase II single arm stomatitis prevention trial 
(SWISH) with Dexamethasone mouthwash administered QID for 56 days is currently ongoing 
and interim results will be reported at American Society of Clinical Oncology (ASCO) in June 
2016.
2.2
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria,
study procedures and close clinical monitoring.


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2.2.1
Potential benefits to clinical trial participation
All subjects enrolled in this trial will receive an active and valid endocrine therapy for second 
or later line treatment of men and post-menopausal women (see Section 1.1.2). They will
receive triplet (ribociclib + everolimus + exemestane) combination to evaluate their effect on
delaying the emergence of resistance to endocrine therapy and CDK 4/6 inhibitors. Based 
on preclinical and clinical data (Section 1.2.5), treatment with ribociclib in combination
everolimus + exemestane is expected to be well tolerated and it is hypothesized that it will result 
in delayed disease progression by inhibiting proliferation of endocrine-resistant and CDK 4 and 
6 resistant breast cancer cells.
2.2.2
Potential risks to clinical trial participants
Subjects in this study will be carefully monitored for key toxicities that have been observed 
with ribociclib (Section 1.2.1), everolimus (Section1.2.3), and exemestane (Section1.2.4) with
the following assessments (Section 7): periodic laboratory, renal and liver function, urinalysis
and ECG. Risk will be further minimized by adherence to inclusion/exclusion selection criteria
(Section 5), avoidance of prohibited medication (Section 6.5.2), close safety monitoring
(Section 8) and dose adjustment guidelines (Section 6.4 and current everolimus and 
exemestane prescribing information). PK sampling will be conducted in patients to assess
plasma concentration of the study drug to further evaluate the drug-drug interaction when 
ribociclib is dosed continuously. An independent data monitoring committee (IDMC) will be 
constituted and will monitor safety, efficacy and available PK data as comprising of 
investigators and Novartis personnel participating in the trial to ensure transparent management 
of the trial according to the protocol. A Novartis Safety Management Team (SMT) periodically 
reviews and evaluates all emerging data across the ribociclib program for potential safety signal 
assessment in a timely manner.
3
Study objectives and endpoints
3.1
Objectives and related endpoints-Phase I
Table 3-1
Objectives and related endpoints-Phase I
Objective
Endpoint
PHASE I
Primary
To determine the maximum 
tolerated dose (MTD) and/or 
recommended Phase II dose 
(RP2D) for the combination of 
ribociclib + everolimus 
+exemestane when dosed 
continuously
Incidence of Dose Limiting 
Toxicities (DLTs) in Cycle 1 (28 
day cycle)
Secondary
To determine the safety and 
tolerability based on NCI 
Incidence and severity of
adverse events(AE) and serious 


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Objective
Endpoint
Common Terminology for 
Adverse Events Version 4 when 
treated with ribociclib + 
everolimus + exemestane
continuously in subjects with 
HR+ HER2- negative advanced 
breast cancer.
adverse events (SAE), clinical 
laboratory values, vital signs 
and electrocardiogram (ECGs), 
dose interruptions, reductions 
and dose intensity.
To determine the 
pharmacokinetic (PK) profile of 
everolimus and ribociclib when
dosed continuously in the triplet
combination.
PK parameters including, but 
not limited to, AUC 0-4h, Ctrough, 
Cmax, accumulation ratio (Racc).
To assess the preliminary anti-
tumor activity of the triplet 
combination of ribociclib + 
everolimus + exemestane when 
combination is given 
continuously.
Overall response rate (ORR), 
Disease Control Rate (DCR),
Clinical benefit rate (CBR)
based on central assessment
per RECIST v1.1, CBR is 
defined as CR, PR,SD or Non-
CR, Non-PD (NCRNPD) lasting 
24 weeks or longer.
3.2
Objectives and related endpoints-phase II 
Table 3-2
Objectives and related endpoints-phase II 
Objective
Endpoint
PHASE II
Primary
Determine the Clinical Benefit 
Rate (CBR) at 24 weeks
amongst patients receiving triple 
therapy with ribociclib +
everolimus + exemestane, for 
advanced/metastatic HR+, 
HER2-negative breast cancer 
following progression on CDK 
4/6 inhibitor.
Clinical Benefit Rate (CBR) 
defined as the proportion of 
patients with a complete (CR) or 
partial response (PR), or with 
stable disease (SD) at 24 weeks 
as per RECIST 1.1 or Non-CR 
Non-PD (NCRNPD) at week 24.
Secondary
To determine centrally assessed 
progression Free Survival (PFS) 
in HR+ HER2-negative 
advanced breast cancer.
Progression-free survival (PFS), 
defined as the time from date of 
treatment to the date of first 
documented progression or 
death due to any cause. If a 


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Objective
Endpoint
subject has not had an event, 
PFS will be censored at the date 
of last adequate tumor 
assessment. Disease 
progression for primary efficacy 
endpoint derivation will be 
based on the central 
radiologist’s tumor assessment.
To determine overall response 
rate (ORR)
Overall response rate (ORR) 
defined as the proportion of 
patients whose best overall 
response is either complete 
response (CR) or partial 
response (PR) according to 
RECIST 1.1.
To determine Overall Survival 
(OS)
To determine Duration of 
Overall Response (DOR)
To evaluate time to deterioration 
or ECOG performance status
This is defined as the time from 
treatment initiation with study 
treatment until death as a result 
of any cause.
Duration of Overall Response 
defined as the time between the 
initial response to the treatment 
with the combination of 
ribociclib+everolimus+ 
exemestane, and subsequent 
disease progression or 
recurrence.
Time to definitive deterioration 
of ECOG performance status 
from baseline.
To determine safety and 
tolerability
Adverse Events (AEs), serious 
AE (SAEs), changes in 
hematology and chemistry 
values, vital signs, dose 
interruptions, reductions and 
dose intensity.
To determine the PK profile of 
ribociclib and everolimus in the 
triplet combination 
PK parameters including, but 
not limited to, AUC 0-4h, Ctrough, 
Cmax, accumulation ratio (Racc) 


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4
Study design
4.1
Description of study design
This is a multi-center, open-label, Phase I/II study consisting of two phases: Phase I and Phase 
II. The Phase I will be conducted in men and postmenopausal women with HR+, HER2-
negative advanced breast cancer that is endocrine resistant, and a Phase II part in men and 
postmenopausal women with HR+, HER2 negative advanced breast cancer that is resistant to
at least one endocrine therapy and who have progressed on a CDK 4/6 inhibitor. 
Phase I: The dose escalation part of the study is designed to estimate the MTD and/or RP2D
for the combination of ribociclib when dosed continuously with everolimus and exemestane. It 
will consist of 3 cohorts (A and B, and C). Each cohort will enroll 3-6 evaluable patients,
including at least 6 patients at the RP2D level. Between 9-24 patients are expected to be treated 
in the phase I part of this study. Once an optimal safety dose is determined based on tolerability, 
AEs, serious AE (SAEs), changes in hematology and chemistry values, vital signs, dose 
interruptions, reductions and dose intensity, this study will commence to a phase II design.
The study will initiate with a 2 cohort dose escalation design. Cohort A: ribociclib (250 mg
daily), everolimus (2.5 mg daily) and exemestane (25 mg daily). If no DLTs are appreciated
after 1 cycle, patients will then be enrolled in Cohort B: ribociclib (300 mg daily), everolimus 
(2.5 mg daily) and exemestane (25 mg daily). The optimal dose will then be selected and 
expanded in Group 1 of the Phase II part of the study.
An additional cohort, Cohort C, will be explored as a dose de-escalation cohort. A starting 
dose of: Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily)
will we explored. If DLT’s are appreciated, a lower dose of: Ribociclib (200 mg daily), 
everolimus (2.5 mg daily) and exemestane (25 mg daily) will be explored. For further details 
about DLT criteria reference section 6.2.1. 


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Phase II: This is a multi-center open label study to evaluate the antitumor activity of the 
ribociclib (LEE011) + everolimus + exemestane combination in patients with 
advanced/metastatic HR+, HER 2 negative breast cancer that have progressed on CDK4/6 
inhibitor based therapy. This part of the study will be continued after the MTD/RP2D is 
determined in the Phase I. 
A minimum of approximately 60 evaluable patients ( 30 per group(Group 1 and Group 2)) are 
required for Phase II of this study to evaluate clinical benefit rate at 24 weeks. 
In each phase II group (1 and 2), if 8  or more patients show clinical benefit at 24 weeks then 
the null hypothesis will be rejected and the study will demonstrate significant clinical benefit.
RP2D: 
Following completion of the phase I, dose escalation portion of this trial, it was determined that 
the RP2D to be explored in group 1 of phase II is as follows:
300mg ribociclib (daily) + 2.5mg everolimus (daily) + 25mg exemestane (daily)
RP2D for group 2 of phase II was determined after completion of cohort C, of phase I, as follows:
         200mg ribociclib (daily) + 5mg everolimus (daily) + 25mg exemestane (daily)During 
Phase II, all patients must have progressed on any CDK 4/6 inhibitor. Prior CDK 4/6 inhibitor 
will be defined as disease progression while on, or within one month of discontinuing any CDK 
4/6 inhibitor (i.e. palbociclib, ribociclib, or abemaciclib).


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Figure 4-1
Study design
4.1.1
Screening phase (Phase I and II)
Men and postmenopausal women with HR+, HER2-negative advanced breast cancer will be
screened for eligibility within a 21 day screening window prior to starting study treatment of 
ribociclib + everolimus + exemestane . During this time, the inclusion and exclusion criteria
will be assessed and all screening assessments, laboratory tests, and procedures will be
performed.
.
Results of all screening/baseline eligibility criteria must be reviewed by the investigator or
his/her designee prior to patient enrollment into the study in order to assure that all inclusion
and exclusion criteria have been satisfied.
All study patients must be thoroughly informed about all aspects of the study, including the 
study agents, visit schedule, required evaluations, and all regulatory requirements for informed 
consent. The signed informed consent must be obtained to participate in this study prior to the
performance of any study-related activities. If the patient is unable to read, an impartial 
witness must be present during the entire informed consent discussion. Eligibility will be
determined according to the inclusion/exclusion criteria as described in Section 5.2. A list of
procedures to be performed at the time of screening is summarized in Table 7-1. Patients 
must meet all eligibility criteria to be considered for enrollment in the study.


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4.1.2
Treatment phase
Patient eligibility will be checked once all screening procedures are completed. An eligibility 
review and confirmation will be embedded in the Interactive Response Technology (IRT) 
system. Please refer to and comply with detailed guidelines in the IRT manual.
Subjects may continue study treatment until disease progression, occurrence of unacceptable 
toxicity, withdrawal of consent by the patient, patient is lost to follow-up, or the sponsor 
terminates the study.
Dose adjustment (reduction, interruption or dose re-escalation) according to safety findings will 
be allowed. Regular safety reviews by an IDMC will be performed. 
Tumor assessments will be performed every 8 weeks (+/- 1 week) starting from the first date of 
study treatment, and as clinically indicated, until the first 12 months of treatment are complete, 
or disease progression. Following 12 months if no disease progression, tumor assessments will 
occur every 12 weeks (+/- 2 weeks), and as clinically indicated until disease progression. Scans 
could be obtained earlier if there is concern of disease progression. If additional tumor 
assessments are performed prior to starting further anticancer therapy, the corresponding tumor 
assessments should also be sent for central review. Additional evaluation should be performed 
to confirm response at least 4 weeks after it was first observed. 
Every 28 days will be considered one cycle. All the medications will be given with food. 
Clinical visits will be twice a cycle for the 1st two cycles, then once a cycle from there on. 
The therapy on clinical trial will continue until disease progression (radiological), or intolerable 
adverse effects, or patient wishes to withdraw consent.
4.1.3
Treatment discontinuation
Subjects will continue to be followed for response until progression, or for up to 15 months 
after last patient enrolled in the study, whichever occurs first. If treatment discontinuation for 
any reason, other than progression, tumor assessments will continue every 8 weeks +/-1 week 
for at least 12 months after their first dose of study treatment.
The study evaluation completion (SEC) eCRF page records the end of study for every individual 
subject. 
4.1.4
Safety follow-up
After the permanent discontinuation of study drug, all patients must complete End of Treatment 
assessments within 15 days and the safety follow-up assessments for 30 days after the last dose 
of the study treatment.
4.2
Timing of interim analyses 
Not applicable.


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4.3
Definition of end of study
The end of the study for a given patient is defined as when the patient permanently discontinues
study treatment with ribociclib + everolimus + exemestane (Phase 1 and 2) and all the end of 
trial procedures are completed.
End of study (Last Patient Last Visit [LPLV]) will be upon completion of the follow up period 
for the last patient treated in the study. This will be after all patients have been on study for at 
least 15 months after last patient enrolled.
4.4
Early study termination
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
5
Population
5.1
Patient population
Men and postmenopausal women with hormonal receptor positive (HR+), HER2-negative, 
locally advanced or metastatic breast cancer whose disease is refractory to at least one endocrine 
therapy and have a documented recurrence or progression on their last therapy for breast cancer.
Refractory disease to endocrine therapy is defined as (Phase I and Phase II):

Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, 
anastrozole, tamoxifen, exemestane or Fulvestrant

Progression while on, or within one month of end of letrozole, anastrozole, tamoxifen or 
fulvestrant treatment for locally advanced or metastatic breast cancer.
Phase II will require that patients with HR+, HER2-negative advanced/metastatic breast cancer 
have documented progression on a CDK 4/6 inhibitor. 
Documented progression on a CDK 4/6 inhibitor is defined as:

Treatment duration while on a CDK 4/6 inhibitor must have been for >4 months prior to 
progression, AND

Progressed while on or within 30 days of discontinuing CDK 4/6 inhibitor for locally 
advanced or metastatic disease, AND

CDK 4/6 inhibitor must have been the last treatment prior to starting study treatment.


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Of note, Phase I does not require prior CDK 4/6 inhibitor exposure.
Patients must have documented radiological evidence of recurrence or progression on last 
therapy prior to starting study treatment. No more than 1 line of chemotherapy with a maximum 
of 3 lines of therapy (including endocrine therapy and chemotherapy) is allowed in the advanced 
setting.
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation 
and associated HBV morbidity and mortality (Loomba et al. 2008).
5.1.1
Screening for Hepatitis B
Prior to enrollment, the following three categories of patients should be tested for hepatitis B 
viral load and serologic markers, that is HBV-DNA, HBsAg, HBs Ab, and HBc Ab:
1. All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal, and/or Greece.
2. Patients with any of the following risk factors:

known or suspected past hepatitis B infection

blood transfusion(s) prior to 1990

current or prior IV drug users

current or prior dialysis

household contact with hepatitis B infected patient(s)

current or prior high-risk sexual activity

body piercing or tattoos

mother known to have hepatitis B

history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain.
3. Additional patients at the discretion of the investigator.
The management guidelines for patients in dose escalation, in Section 6.4 are provided 
according to the results of the baseline assessment of viral load and serological markers for 
hepatitis B.
5.1.2
Screening for Hepatitis C
Patients with any of the following risk factors for hepatitis C should be tested using quantitative 
RNA-PCR:

known or suspected past hepatitis C infection (including patients with past interferon
‘curative’ treatment)

blood transfusions prior to 1990

current or prior IV drug users

current or prior dialysis


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
household contact of hepatitis C infected patient(s)

current or prior high-risk sexual activity

body piercing or tattoos
At the discretion of the investigator, additional patients may also be tested for hepatitis C.
5.2
Inclusion criteria
Written informed consent must be obtained prior to study entry. Patients eligible for inclusion 
in this study have to meet all of the following criteria:
1. Adult men and women (≥18 years of age) with metastatic or locally advanced breast 
cancer not amenable to curative treatment by surgery or radiotherapy.
*Note: sexually active males should use a condom during intercourse while taking study 
treatment and for 21 days after stopping medication and should not father a child in this 
period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via seminal fluid.
2. Histological or cytological confirmation of hormone-receptor positive (ER+ and/or PR+) 
breast cancer by local laboratory testing per local laboratory testing.
3. Patient has HER2-negative breast cancer (based on most recently analyzed biopsy) 
defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 
2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local 
laboratory testing.
5. A representative tumor specimen must be available for molecular testing. Newly obtained 
tumor biopsy specimen is required if accessible prior to entry on trial. If tissue is not 
accessible based on surgical evaluation, an archival tumor sample from metastatic site 
may be submitted. 
6. Women must be postmenopausal. Postmenopausal status is defined either by: 

Amenorrhea for at least 12 months and both follicle-stimulating hormone (FSH) 
and/or estradiol levels are in postmenopausal range (according to the local laboratory) 
OR

History of bilateral oophorectomy (with or without hysterectomy) OR

History of partial hysterectomy with FSH and/or estradiol within post-menopausal 
range OR

Ovarian function suppressed with a GnRH agonists (negative HCG required) with 
estradiol levels in the postmenopausal range (according to the local laboratory)
7. Disease refractory to either, AI, tamoxifen or fulvestrant defined as:


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
Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, 
anastrozole, exemestane, tamoxifen or fulvestrant OR

Progression while on, or within one month of discontinuing letrozole, anastrozole, 
tamoxifen or fulvestrant for the treatment of locally advanced or metastatic breast 
cancer.
*Note: There are no restrictions as to which endocrine therapy patients received as their last 
line of therapy just prior to randomization.
8. Patients who received up 3 lines of therapy for advanced breast cancer are allowed. This 
includes a maximum of 1 line of chemotherapy and a maximum of 3 lines of endocrine 
therapy in the advanced setting so long as the patient has not received more than a total of 
3 lines of therapy. Patients must have recovered to grade 1 or better from any adverse 
events (except alopecia and/or neuropathy) related to previous therapy prior to starting 
study treatment.
Note: If patient relapsed with documented evidence of progression on/or within 12 months 
from completion of adjuvant endocrine therapy, then this is considered one line of therapy.
9. Patients previously treated on any CDK 4/6 inhibitor (i.e. ribociclib, abemaciclib OR 
palbociclib) must have:

Remained on treatment for >4 months for advanced breast cancer or metastatic 
disease prior to progression, AND

Progressed on, or within 30 days following the discontinuation of a CDK 4/6 
inhibitor.
Phase II Only:

Patients must have progressed on only one CDK 4/6 inhibitor. A CDK 4/6 inhibitor 
must have been the last treatment regimen prior to starting study treatment.
*Note: Phase I does not require prior CDK 4/6 inhibitor exposure
*Note: For patients who received prior CDK4/6 inhibition as part of a clinical trial, patients 
must be unblinded in order to verify that the patient did receive a CDK4/6 inhibitor. 
10. ECOG Performance Status 0 – 1.
11. Radiological evidence of recurrence or progression on or after the last therapy prior to 
starting study treatment.
12. Patients must have:

Measurable disease (based on RECIST 1.1): defined as at least one lesion that can be 
accurately measured in at least one dimension ≥20 mm with conventional imaging 
techniques or ≥10 mm with spiral CT or MRI,
OR

Evaluable disease: bone lesions- lytic or mixed (lytic + sclerotic) in the absence of 
measurable disease 
13. Patient has adequate bone marrow and organ function as defined by the following LOCAL 
laboratory values at screening: 


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
Absolute neutrophil count ≥1.5 × 109/L.

Platelets ≥100 × 109/L.

Hemoglobin ≥9.0 g/dL.

Potassium, total calcium (corrected for serum albumin), magnesium and sodium
within normal limits for the institution or corrected to within normal limits with 
supplements before first dose of study medication.

INR ≤1.5 or ≤2.5 while on anti-coagulant.

Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the 
Modification of Diet in Renal Disease (MDRD) formula

Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min.

Total bilirubin <ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤3.0 × ULN or direct bilirubin ≤1.5 × ULN.

Alanine aminotransferase (ALT) and aspartate transaminase (AST) <2.5 × ULN, 
except for patients with liver metastasis, who are only included if the AST is <5 ×
ULN.
14. Must be able to swallow ribociclib, everolimus and exemestane capsules/tablets.
15. Patients with metastatic disease are allowed to receive <28 days of endocrine therapy prior 
to starting study treatment.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient with visceral crisis or any disease burden that makes the patient ineligible for this 
study per the investigator’s best judgment.
2. Patients who received more than one line of chemotherapy for advanced breast cancer.
*Note: A chemotherapy line in advanced disease is an anticancer regimen(s) that contains at 
least 1 cytotoxic chemotherapy agent and given for greater 21 days or longer. If a cytotoxic 
chemotherapy regimen was discontinued for a reason other than disease progression and 
lasted 21 days or less, then this regimen does not count as a "prior line of chemotherapy"
3. HER2 overexpression by local laboratory testing (IHC 3+ staining or in situ hybridization 
positive).
4. Patient has received prior treatment with anthracyclines at cumulative doses of 450mg/m² 
or more for doxorubicin or 900 mg/m² or more for epirubicin.
5. Patient with a known hypersensitivity to any of the excipients of ribociclib, mTOR 
inhibitors, e.g. sirolimus (rapamycin), exemestane.
6. Previous treatment with mTOR inhibitors.
7. Previous treatment with exemestane for metastatic disease (except patients who received ≤
28 days of exemestane for advanced breast cancer and did not progress).


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8. Disease progression on more than one CDK 4/6 inhibitor, or have progressed more than 
once on the same CDK 4/6 inhibitor.
9. Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be 
discontinued atleast 7 days to study treatment (C1D1). Drugs with overlapping toxicities 
with either everolimus or ribociclib must also be discontinued at least 7 days prior to 
C1D1. All AEs related to prior treatment should have resolved to CTCAE version 4.03 
Grade ≤1 prior to study treatment (including any CDK 4/6 inhibitor).”.
10. Patient has not recovered from all toxicities related to prior anticancer therapies to Grade 
≤1 (based on NCI CTCAE version 4.03). Exception to this criterion: patients with any 
grade of alopecia and or neuropathy are allowed to enter the study.
11. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects.
12. Patients with Child Pugh score B or C.
13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose 
warfarin, Low molecular weight heparin (LMWH) and acetylsalicylic acid or equivalent, 
as long as the INR is ≤2.5 while on anti-coagulant). Fondaparinux is allowed.
14. Radiotherapy <2 weeks prior to starting study treatment. Patients must have recovered 
from radiotherapy toxicities prior to starting study treatment, and recovered to grade 1 or 
better from related side effects of such therapy (with the exception of alopecia). 
Radiotherapy is not allowed at target site following screening.
15. Another malignancy within 3 years prior to starting study treatment, with the exception of 
adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell skin 
carcinoma.
16. Patients with central nervous system (CNS) involvement unless they are at least 4 weeks 
from prior therapy completion (including radiation and/or surgery) to starting the study 
treatment.
17. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
18. Patient has a known history of HIV infection (testing not mandatory).
19. Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient’s 
participation in the clinical study or compromise compliance with the protocol such as: 

chronic pancreatitis.

active untreated or uncontrolled fungal, bacterial or viral infections, sepsis etc.

Uncontrolled diabetes as defined by fasting serum glucose >1.5 × ULN.

Acute and chronic, active infectious disorders including viral and nonmalignant 
medical illnesses that are uncontrolled or whose control may be jeopardized by the 
complications of this study therapy.


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20. Fasting serum cholesterol >300 mg/dl or 7.75 mmol/L and fasting triglycerides >2.5 × 
ULN. In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of statin therapy and when the above mentioned values have been 
achieved.
21. Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary 
function tests including measures of predicted lung volumes, DLco, O2 saturation at rest 
on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or 
pulmonary infiltrates.
22. Active skin, mucosa, ocular or GI disorders of Grade >1.
23. Bilateral diffuse lymphangitic carcinomatosis.
24. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality 
including any of the following:

History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft 
(CABG) or myocardial infarction within 6 months prior to study entry.

Documented cardiomyopathy.

Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO) detected during screening.

History of cardiac failure, significant/symptomatic bradycardia, Long QT syndrome, 
family history of idiopathic sudden death or congenital long QT syndrome or any of 
the following:

Known risk to prolong the QT interval or induce Torsade’s de Pointes.

Uncorrected hypomagnesemia or hypokalemia.

Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.

Bradycardia (heart rate <50 at rest), by ECG or pulse.

On screening, inability to determine the QTcF interval on the ECG (i.e.: 
unreadable or not interpretable) or QTcF >450 msec for men and >470 msec for 
women (using Frederica’s correction). All as determined by screening ECG 
(based on a mean of 3 ECGs).
25. Patient is currently receiving any of the following substances and cannot be discontinued 5 
half-lives prior to Cycle 1 Day 1:

That have a known risk to prolong the QT interval or induce Torsade’s de Pointes.

Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges.

Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5.
26. Not able to understand and to comply with study instructions and requirements.
27. 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.


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28. Sexually active males unless they use a condom during intercourse while taking drug and 
for 21 days after stopping medication and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
6
Treatment
6.1
Study treatment
For this study, the terms “investigational drug” or “study drug” refer to ribociclib (LEE011). 
“Investigational treatment”, or “study treatment/group” refers to the triplet combination of 
ribociclib, everolimus and exemestane. “Study treatment” refers to all drug combinations given 
during the course of the trial. All dosages prescribed and dispensed to the patient and all dose 
changes during the study must be recorded on the Dosage Administration Record eCRF.
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). Drug accountability must be performed on a regular basis. 
Patients will be instructed to return unused study drugs to the site at the end of each cycle. The 
site personnel will ensure that the appropriate dose of each study drug is administered at each 
visit and will provide the patient with the correct amount of drugs for subsequent dosing.
In phase I dose escalation (cohort A and B) the subjects will receive everolimus 2.5 mg orally, 
once daily, and exemestane 25 mg orally, once daily and an increasing/decreasing doses of 
ribociclib to establish MTD and/or RP2D for Phase II Group 1.
In phase I dose de-escalation (cohort C) the subjects will receive ribociclib 200mg orally, once 
daily, and exemestane 25 mg orally, once daily and an increasing/decreasing doses of 
everolimus to establish MTD and/or RP2D for Phase II Group 2.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule for the following combination: ribociclib 
+ everolimus +exemestane (Phase II)
Study 
treatments
Form and route of administration
Dose
Frequency/regimen
Ribociclib
Capsules/tablets - 50 mg, 200 mg
For oral use
RP2D Group 1 or
RP2D Group 2
Days 1–28 of each 
cycle
Continuous – no rest 
days
Everolimus
Tablet - 2.5 mg
For oral use
RP2D Group 1 or 
PR2D Group 2
Days 1–28 of each cycle
Continuous – no rest 
days
Exemestane
Tablet - 25 mg
25 mg
Days 1–28 of each cycle


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For oral use
Continuous – no rest 
days
Dexamethasone mouthwash (500mL bottle): TID swish and spit (NPO X1 h) for 2 cycles (56 days)
The study drugs will be administered as a flat-fixed dose, and not by body weight or body 
surface area. Everolimus and exemestane will be taken orally, once a day every day. Ribociclib 
will be administered based on RP2D.
6.2
Dose escalation and de-escalation guidelines: Phase I Safety 
Run-in
The starting doses for the ribociclib + everolimus + exemestane (R-E-E) combination in the 
dose escalation (cohort A and B) is 250 mg QD for ribociclib, 2.5 mg QD for everolimus, and
exemestane at the approved dose of 25 mg QD. The doses of everolimus and exemestane 
for all patients in this portion will be fixed at 2.5 mg and 25 mg respectively. 
The starting doses for the ribociclib + everolimus + exemestane (R-E-E) combination in the 
dose de-escalation (Cohort C) is 200 mg QD for ribociclib, 5 mg QD for everolimus, and
exemestane at the approved dose of 25 mg QD. The doses of ribociclib and exemestane for
all patients in this portion will be fixed at 200 mg and 25 mg respectively. 
The starting doses of ribociclib and everolimus are based upon a review of the safety,
tolerability, and PK observed in the clinical studies outlined in Section 1.2. Because of the
potential drug interaction between ribociclib and everolimus that may inhibit the metabolism
of everolimus and increase drug exposure by approximately 3-5-fold, the dose of everolimus
will be reduced to 2.5mg or 5mg (based on CLEE011X2106 RDE) from the standard dose
recommended in the treatment of breast cancer of 10 mg QD (Section 1.2.2). The starting dose
of ribociclib is supported by a recommendation from the CLEE011X2106 study (Section 1.2.4), 
CLEE011X2101 study and CLEEX2108 study (Section 1.2.1.4).
Table 6-2
Dose levels for ribociclib, everolimus and exemestane in Phase I dose 
escalation (cohort A and B)
Dose Level
Ribociclib
Everolimus
Exemestane
+1 Cohort B
300 mg PO daily
2.5 mg PO daily
25 mg PO daily
1 Cohort A (Start)
250 mg PO daily
2.5 mg PO daily
25 mg PO daily
Table 6-3
Dose levels for ribociclib, everolimus and exemestane in Phase I dose 
de-escalation (cohort C)
Dose Level
Ribociclib
Everolimus
Exemestane
0 (start)
200 mg PO daily
5 mg PO daily
25 mg PO daily
-1 
200 mg PO daily
2.5 mg PO daily
25 mg PO daily


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6.2.1
Criteria for dose escalation and determination of MTD(s)/RP2D
6.2.1.1
MTD definition
The MTD is defined as the highest combination drug dosage not causing medically 
unacceptable DLTs in more than 33% of the treated patients in the first cycle of treatment.
AEs and laboratory abnormalities considered to be DLTs are defined in Table 6-4. Only one
RP2D will be tested in the Phase II.
In the dose escalation a total of 6 patients will be treated at dose-level 1 (cohort A). Patients
must complete a minimum of one cycle of treatment with the minimum safety evaluation and
drug exposure or have had a DLT within the first cycle of treatment to be considered evaluable
for dose escalation decisions. 

If ≤33% of patients experience a DLT in cohort A (dose level 1), the dose will be 
escalated to the next level cohort B (dose level +1) where 3 patients will be enrolled.

If ≤33% patients experience DLTs in cohort B, an additional 3 patients will be treated at 
the same dose level. 

If ≤33% patients experience a DLT in both cohorts, then the optimal treatment dose based 
on tolerability and safety profile after two cycles will move into Phase II.

If >33% patients experience DLTs in both cohorts, the dose will be de-escalated to the 
next level down .
Dose escalation and R2PD decisions will be/were made jointly by the independent Data 
Monitoring Committee, Steering Committee, and Novartis study personnel.
In the dose de-escalation (cohort C), the starting dose of ribociclib and everolimus are based
upon a review of the safety, tolerability, and PK observed in the clinical studies outlined in
Section 1.2. Because of the potential drug interaction between ribociclib and everolimus that
may inhibit the metabolism of everolimus and increase drug exposure by approximately 2-
fold, if ribociclib is dosed at 200mg (based on CLEE011X2106) from the standard dose
recommended in the treatment of breast cancer of 10 mg QD (Section 1.2.2). The starting
dose of ribociclib is supported by a recommendation from the CLEE011X2106 study (Section 
1.2.4)
The MTD is defined as the highest combination drug dosage not causing medically 
unacceptable DLTs in more than 33% of the treated patients in the first cycle of treatment. AEs 
and laboratory abnormalities considered to be DLTs are defined in Table 6-4. Only one RP2D 
will be tested in the Phase II.
Three patients will be treated at dose-level 0 (cohort C). Patients must complete a minimum
of one cycle of treatment with the minimum safety evaluation and drug exposure or have had


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a DLT within the first cycle of treatment to be considered evaluable for dose escalation 
decisions. 

If ≤33% of patients experience a DLT in cohort C (dose level 0), then an additional 3 
patients will be added. 

If ≤33% of patients experience a DLT then an expansion phase will be initiated
pending approval from DMC.

If >33% patients experience a DLT in Dose level 0, the dose will be de-escalated to 
the next level down (-1).  A total of 6 patients with ≤33% of patients experience a 
DLT will be needed in order for dose to be considered for expansion
6.2.2
Definitions of dose limiting toxicities (DLTs)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as having a reasonably possible relationship to the study medication(s) and is 
unrelated to disease, disease progression, inter-current illness, or concomitant medications 
that occurs within the first 28 days of treatment (cycle 1) with ribociclib + everolimus + 
exemestane and meets any of the criteria included in Table 6-4. National Cancer Institute 
Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used 
for all grading.
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the 
study drug combination will be interrupted and the toxicity will be followed up as described 
in Section 6.2.3. For the purposes of dose escalation and determination of the MTD(s), DLTs 
that occur during cycle 1 will be necessarily considered, including those in which the event 
started in Cycle 1 and the confirmation of the DLT occurs in a subsequent cycle. The 
investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥3 adverse
events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE 
grade ≥2 adverse events will be reviewed for all patients at the current dose level.
Patients must have completed ≥75% of ribociclib + everolimus + exemestane in cycle 1 (≥21 
days out of 28 days) to be considered for DLT evaluation. Patients not evaluable for DLT could 
be replaced after discussing with the steering committee. 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study 
drug induced adverse events are provided in Table 6-5 and Table 6-6.
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. These changes must be 
recorded on the Dosage Administration Record eCRF.
Table 6-4
Criteria for defining Dose Limiting Toxicities 
TOXICITY
DLT CRITERIA
CTCAE grade 3 thrombocytopenia with bleeding


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Hematology
Febrile neutropenia (decrease in neutrophils associated with fever ≥38.5°C, ANC
<1.0 x 109/L)
CTCAE grade 4 neutropenia lasting more than 7 consecutive days
CTCAE grade 4 thrombocytopenia
Gastro-intestinal
CTCAE grade ≥3 vomiting ≥48 hrs. despite optimal anti-emetic therapy
CTCAE grade ≥3 diarrhea ≥48 hrs. despite optimal anti-diarrhea treatment
Hepato-biliary
CTCAE grade ≥3 total bilirubin
CTCAE grade ≥2 ALT or AST with total bilirubin >2.0 x ULN without evidence of 
cholestasis***
OR
For subjects with abnormal baseline AST or ALT or total bilirubin value:
[AST or ALT>2x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], 
whichever is lower, combined with [total bilirubin > 2 x baseline AND > 2.0 x ULN]
≥ CTCAE grade 3 ALT for more than 4 consecutive days
Cardiac
Cardiac toxicity ≥CTCAE grade 3
Clinical signs of cardiac disease, such as unstable angina or myocardial infarction,
or Troponin ≥CTCAE grade 3
ECG QT Interval
QTcF interval ≥501 ms on at least two separate ECGs
Renal
CTCAE grade ≥3 serum creatinine
Stomatitis
CTCAE grade ≥4 stomatitis
Hyperglycemia
CTCAE grade ≥4 hyperglycemia
Events not 
CTCAE grade ≥3, except for the exclusions noted below
Exceptions to DLT 
criteria
<7 days of CTCAE grade 3 fatigue
<48 hours of CTCAE grade 3 edema
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant
*** “Cholestasis” defined as ALP elevation [>2.0 xULN and R value < 2] in subjects without bone 
metastasis, or elevation of ALP liver fraction in subjects with bone metastasis)
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both 
values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), 
hepatocellular ( R ≥ 5), or mixed (R >2 and < 5) liver injury)
CTCAE version 4.03 will be used for all grading.
Optimal therapy for vomiting or diarrhea will be based on institutional guidelines, with consideration of
the prohibited medications listed in this protocol.
6.2.3
Follow up for dose limiting toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value must be followed up at least once every 7 days (or more frequently
if required by institutional practices, or if clinically indicated) for 30 days, and subsequently


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at approximately 30 day intervals, until resolution or stabilization of the event, whichever 
comes first.
Appropriate clinical experts should be consulted as deemed necessary.
6.2.4
Doses for Phase II
The dose used in Phase II, group 1 recommended by the dose escalation part of this study (Phase 
I), was determined to be 300mg ribociclib (daily) + 2.5mg everolimus (daily) + 25mg exemestane 
(daily).
The dose used for phase II, group 2 recommended by the dose escalation part of this study 
(Phase I), was determined to be 200mg ribociclib (daily) + 5mg everolimus (daily) + 25mg 
exemestane (daily).
6.2.4.1
Ribociclib, everolimus and exemestane administration
Detailed instructions regarding administration of ribociclib capsules/tablets will be supplied to 
Investigator sites in a separate document from this protocol.
Complete guidelines for management and administration of exemestane can be found in 
(Section 6.4) and the package insert.
Ribociclib, everolimus and exemestane should be taken as follows:

Patients should be instructed to take the study drug combination of one or more 
capsules/tablets of ribociclib with one tablet of everolimus and one tablet of exemestane 
with a large glass of water (~250 mL) daily approximately the same time every day.

Patients should be instructed to swallow the ribociclib capsules/tablets and everolimus and 
exemestane tablets whole and not to chew, crush or open them.

Patients should take all three drugs after eating a light low fat meal

On days when PK collection/ECG is scheduled at the clinic, patients will take ribociclib,
everolimus and exemestane in the clinic under the supervision of the investigator or 
designee. On all other days patients will take the ribociclib, everolimus and exemestane 
combination at home.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increase stool frequency) during a treatment cycle must be noted in the 
adverse events section of the eCRF. 

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 must avoid consumption of grapefruit, Seville oranges, grapefruit hybrids, 
pomelos, star fruit 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.


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
Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or 
those with a known risk of QT prolongation are not permitted. Multivitamins are 
permitted. If the potential for interactions are unknown, then the herbal / dietary
supplements should be avoided.
6.2.4.2
Additional dosing guidelines for scheduled visit days
On days with PK, ECG sampling, chemistry and/or lipid profile sampling as outlined in Table 7-
1, the following additional guidelines should be followed:

On a day when PK blood collection is scheduled at the clinic, patients must take study 
treatment in the clinic under the supervision of the Investigator or designee. On all other 
days patients may take the study treatment at home.

The patient must be fasting for at least 8 hours prior to cycle visits that include fasting 
glucose and lipid profile samples. Coffee, tea and water without milk and sugar (or 
artificial sweeteners) are allowed. 

If a pre-dose ECG measurement should be collected, then the ECG measurement should 
occur before dosing of the study treatment.

When both PK and ECG are required, please complete the ECG prior to PK draw.

Post-dose ECGs and PKs should be collected after dosing of the study treatment. ECG 
will be performed according to Section 7.2.2.6 and Table 7-5.

Pre-dose samples should be drawn prior to dosing. The sampling time of the PK samples 
and the dosing time must be precisely recorded in the eCRF.

Post-dose PK samples should be collected after dosing of the study treatment. PK sample 
collection will be performed according to Table 7-6.
6.3
Overview of Dexamethasone oral solution
Dexamethasone steroid-based oral solution comprised of 0.5 milligrams per 5mL of alcohol 
free dexamethasone. The oral solution contains citric acid, disodium edentate, flavoring, 
glycerin, methylparaben, propylene glycol, propylparaben, sorbitol and water. 
6.3.1.1
Dexamethasone administration
All patients will be given 0.5 mg/5 mL dexamethasone steroid mouthwash. The patient will 
initiate the dexamethasone steroid mouthwash on the same day that they initiate the study 
treatment (C1D1). The alcohol-free, 0.5 mg/5 mL dexamethasone steroid mouthwash should be 
administered based on the following instructions:

10 mL of mouthwash swish and spit 3 times daily (TID). The mouthwash is to be held in 
mouth and swished around mouth to come in contact with entire buccal mucosa surface 
for a minimum of two minutes, and then spit out. 

Patient should remain NPO (no food, no drinks, nothing in mouth) for at least an hour 
after administering mouthwash, with the exception of Nystatin (or another topical 
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6.3.1.2
Dexamethasone treatment regimen
Cycle 1 Day 1 (C1D1) is the day the patient initiates the mouthwash regimen and study drugs. 
A treatment cycle consists of 28 days. Patients should use mouthwash regimen for two 
consecutive treatment cycles (56 days).
All patients will be instructed to perform routine “good oral care” each day during the trial. 
Good oral care will consist of: brushing teeth at least twice daily with soft bristled toothbrush 
continue current daily flossing routine (if patients were not already flossing daily, they should
not be instructed to start flossing as this could cause oral trauma), and continue routine dental 
care/maintenance with their dentist, if they have one. 
Salt water mouth rinse and the steroid mouthwash should be administered based on the 
following instructions:

The Salt water mouth rinse will only be administered once the onset of Grade 1 stomatitis 
has been noted.
If the salt water (0.9%) mouth rinse is needed, it will be administered as 10mL swish and spit 
TID and must be done prior to the dexamethasone mouthwash. The patient should administer 
the salt water (0.9%) mouth rinse (swish and spit) and wait for 10-15 minutes before 
administering the dexamethasone mouthwash.
The alcohol-free, 0.5mg/5mL dexamethasone steroid mouthwash should be administered based 
on the following instructions:

10 mL of mouthwash swish and spit TID. The mouthwash is to be held in mouth and 
swished around mouth to come in contact with entire buccal mucosa surface for a 
minimum of two minutes, and then spit out.

Patient should remain NPO (no food, no drinks, nothing in mouth) for at least an hour
after administering mouthwash, with the exception of Nystatin (or another topical 
antifungal).
6.4
Dose modification
6.4.1
Dose cohort modification
For patients who do not tolerate the protocol-specified dosing schedule, ribociclib adjustments 
are recommended in order to allow the patient to continue the study treatment. 
Dose reductions are not permitted for everolimus, exemestane or GnRH agonists (if 
patient is currently taking). Any changes to the dose or interruption of dosing must be 
recorded on the Dosage Administration Record eCRF. Patients who require a study treatment 
hold of more than 28 days will be discontinued from the study unless discussed and approved 
by the sponsor (Section 7.1.2). Once dose-reduced the dose may be re-escalated once discussed 
and approved by the sponsor. All patients will be followed for AEs and for SAEs for 30 days 
following the last dose of study drug.


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6.4.1.1
Ribociclib (LEE011)
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of ribociclib therapy. Each patient is allowed a maximum 
of two dose reductions for ribociclib. After this, the patient will be discontinued from the study 
treatment. For each patient, once a dose level reduction for ribociclib has occurred, the dose 
level may be re-escalated during subsequent treatment cycles once discussed and approved by 
the sponsor. If a dose reduction is required, ribociclib should be reduced one dose level. Dose
levels for ribociclib are provided in Table 6-5.
A dose-dependent DDI was observed between ribociclib and everolimus based on clinical PK 
analyses in a separate dose escalation trial, where everolimus exposure increased 2- to 4-fold in 
the presence of ribociclib. If a dose adjustment of both ribociclib and everolimus are required, 
a dose reduction in ribociclib is considered as a method to reduce exposure to both drugs since 
everolimus exposure is increased with increased ribociclib doses through a DDI. After 
permanent discontinuation of either ribociclib, everolimus or exemestane, patients should be 
discontinued from study treatment The dose modification guidelines for study treatment are 
found in Table 6-5 and Table 6-6.
Table 6-5
Phase I dose escalation (cohort A and B) and Phase II group 1: Dose 
modification guidelines for Ribociclib + everolimus + exemestane 
Ribociclib
Everolimus
Exemestane
Dose
Dose
Dose
Starting dose
Phase I: refer to 
cohort A, or B.
Phase II cohort 1: 
300mg (daily)
2.5 mg daily
25 mg
First dose reduction
Reduced by 50mg
2.5 mg daily
Second dose reduction
Change current dose
to 21days out of 28
2.5 mg daily
Table 6-6
Phase I dose de-escalation (cohort C) and Phase II cohort 2: Dose 
modification guidelines for Ribociclib + everolimus + exemestane
Ribociclib
Everolimus
Exemestane
Dose
Dose
Dose
Starting dose
200mg daily
If starting at dose 
level 0: 5mg daily
25 mg


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If starting at dose 
level -1: 2.5mg 
daily
First dose reduction
200mg daily
If starting at dose 
level 0: 2.5mg 
daily
If starting at dose 
level -1: 2.5mg 
every other day
Second dose reduction
200mg daily
If starting at dose 
level 0: 2.5mg 
every other day
If starting at dose 
level -1: 
discontinue from 
trial
Management of everolimus specific adverse reactions may require temporary dose reduction 
and/or interruption of everolimus therapy longer than 3 weeks. Recommendations for dose 
interruption of everolimus longer than 3 weeks in the management of everolimus specific 
adverse reactions are summarized in Table 6-7. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment 
(USA Afinitor® PI 2012). 
Table 6-7
Dose modification guidelines for ribociclib (if everolimus is held 
longer than 3 weeks for pneumonitis)
Ribociclib
Exemestane
Dose
Dose
Starting dose
400 mg daily
25 mg
First dose reduction
200mg daily
Second dose reduction
200mg 3 weeks on, 1 week 
off
6.4.1.2
Exemestane
No specific dose modifications are recommended for exemestane. Toxicities attributed to
exemestane should be managed in a manner consistent with the investigator’s usual clinical 
practice. Per (exemestane package insert).


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6.4.2
Anticipated Risks and safety considerations of the study drug 
combination
Preclinical and Phase I clinical data available from ongoing studies with ribociclib and 
everolimus with exemestane separately suggest few overlapping toxicities for the proposed 
combinations. Special attention will be paid to blood counts (cytopenias), mucositis, liver 
function test abnormalities and QTc prolongation. Clinical data from the [CLEE011X2101]
study do not show marked accumulation in ribociclib with time, suggesting that it does not
substantially inhibit its own metabolism or clearance. Based on the known properties of
exemestane and ribociclib, a clinically significant drug-drug interaction that would increase the
toxicities of either drug is not anticipated.
Everolimus and ribociclib are in vitro inhibitors and substrates of CYP3A4, and the latter
is also a time-dependent CYP3A4 inactivator. The available preclinical and clinical data 
therefore suggest the possibility of a drug interaction, specifically one that may increase 
exposure to everolimus. Based on simulation using Simcyp software (Simcyp Version 12, 
release 1), the projected increase in the AUCleac 0-6h of everolimus was 3.5-fold following the 
starting daily dose of 200 mg ribociclib co-administered with 2.5 mg of everolimus for 14
days. No significant effect on ribociclib metabolism was predicted when co-administered with 
everolimus. Appropriate eligibility criteria, dose modification guidelines and stopping rules are 
included in this protocol.
6.4.3
Dose modifications for ribociclib+everolimus+exemestane 
combination
6.4.3.1
Dose modifications and management recommendations for 
hematologic adverse reactions
Table 6-8
Dose modifications and management recommendations for 
hematologic adverse reactions
(see Table 6-5 and Table 6-6 for dose reduction guide)
Toxicity
Grade
Dose Adjustment and 
Management 
Recommendations
Thrombocytopenia
Thrombocytopenia
Grade 1(≥75 x 109/L)
No dose adjustment required.
Grade 2 (≥50 x 109/L – <75 x 
109/L)
Dose interruption of ribociclib 
and everolimus until recovery to 
grade 1.
Re-initiate study treatment at 
the same dose.
Grade 3 (≥25 x 109/L - <50 x 
109/L)
Dose interruption of ribociclib 
and everolimus until recovery to 
grade 1.


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Toxicity
Grade
Dose Adjustment and 
Management 
Recommendations
Re-initiate study treatment at 
the same dose level.
If toxicity recurs at grade 3: 
temporary dose interruption of 
ribociclib and everolimus until 
recovery to grade 1 and 
reduce to the next lower dose 
level. Maintain everolimus at 
same dose
Grade 4(<25 x 109/L)
Dose interruption of ribociclib 
and everolimus until recovery to 
grade 1.
Re-initiate study treatment at 
the next lower dose level. If 
toxicity recurs at grade 4: 
discontinue study treatment
Neutropenia
Absolute neutrophil count (ANC)
Grade 1 (≥1.5 x 109/L)
No dose adjustment required.
Grade 2 (≥1.0 - <1.5 x 109/L)
No dose adjustment required.
Grade 3 (≥0.5 - <1.0 x 109/L)
Dose interruption of ribociclib 
and everolimus until recovery to 
≥1.0 x 109/L.
Re-initiate study treatment at 
the same dose level.
If toxicity recurs at grade 3: 
temporary dose interruption of 
ribociclib and everolimus until 
recovery to grade ≤1 and 
reduce to the next lower dose 
level, or continue at same dose 
with growth-factor support at the 
discretion of the treating 
investigator.
Grade 4 (<0.5 x 109/L)
Dose interruption of ribociclib 
and everolimus until recovery to 
≥1.0 x 109/L.
Re-initiate ribociclib at the next 
lower dose level (first dose 
reduction level). Maintain 
everolimus at same dose
If toxicity recurs at grade 4: 
temporary dose interruption of 
ribociclib and everolimus until 
recovery to ≥1.0 x 109/L and 
reduce at the next lower dose 


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Toxicity
Grade
Dose Adjustment and 
Management 
Recommendations
level. Maintain everolimus at 
same dose 
Febrile Neutropenia
Grade 3: ANC<1.0 x 109/L with 
[a single temperature of >38.3 
degrees C (101 degrees F) or a 
sustained temperature of >=38 
degrees C (100.4 degrees F)
for more than one hour]
.
Dose interruption of both 
ribociclib and everolimus until 
improvement of ANC ≥1.0 x 
109/L and no fever. Restart at 
the next lower dose level.
If febrile neutropenia recurs, 
discontinue study treatment.
Colony Stimulating Factors 
should be considered in patients 
with fever and profound 
neutropenia (<1.0 x 109/L)
Grade 4 Life-threatening
consequences; urgent 
intervention indicated
Discontinue study treatment
Anemia (Hemoglobin)
Grade 1: ≥10.0 – LLN g/dL
No dose adjustment required
Grade 2: ≥8.0 – <10.0 g/dL
No dose adjustment required.
Grade 3: <8.0 g/dL
Dose interruption of ribociclib 
and everolimus recovery to 
grade 1.
Re-initiate study treatment at 
the same dose.
Grade 4: Life-threatening
consequences;
urgent intervention
indicated
Discontinue study treatment
PRBC transfusion to be 
considered per NCCN 
guidelines
6.4.3.2
Ribociclib/everolimus dose modification and management for QTcF 
prolongation
Table 6-9
Ribociclib/everolimus dose modification and management for QTcF 
prolongation
(see Table 6-5 and Table 6-6 for dose reduction guide)
Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
QTcF prolongation
For All Grades
Check the quality of the ECG 
and the QT value and repeat if 
needed.


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Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
Perform analysis of serum 
electrolytes (K+, Ca++,
Phosphorus, Mg++). If outside 
of normal range, hold ribociclib 
and everolimus, correct with 
supplements or appropriate 
therapy as soon as possible, 
and repeat electrolytes until 
documented as normal.
Review concomitant medication 
usage for the potential to inhibit 
CYP3A4 and/or to prolong the 
QT interval.
Check compliance with correct 
dose and administration of study 
treatment
Consider collecting a time 
matched PK sample; record 
date and time of last study drug 
intake.
Grade 1
QTc 450-480 ms
Perform steps 1-4 as directed in 
“For All Grades.” No dose 
adjustment required.
Grade 2
QTc 481-500 ms
Hold ribociclib and everolimus.
Perform steps 1-4 as directed in 
“For All Grades.”  
Repeat ECG as clinically 
indicated until the QTcF returns 
to <481 ms. Restart ribociclib 
withdose reduced
by 1 dose level.
If QTcF ≥ 481 ms recurs, 
ribociclib should be reduced 
again by 1 dose level.
Repeat ECGs 7 days and 14 
days after doseresumption of 
study treatment (then as 
clinically indicated ) for any 
patients who had therapy 
interrupted due to QTcF ≥481 
ms.
Grade 3
QTc ≥501 ms on at least two 
separate ECGs
Hold ribociclib and everolimus. 
Perform steps 1-4 as directed in 
“For All Grades.”  
Transmit ECG immediately and 
confirm prolongation/


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Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
abnormalities with central 
assessment. Perform a repeat 
ECG within one hour of the first 
QTcF of ≥501 ms.
If QTcF remains ≥501 ms,
consult with a cardiologist (or 
qualified specialist) and repeat 
cardiac monitoring as indicated 
until the QTcF returns to <481 
ms.
If QTcF returns to <481 ms, 
study treatment will be reduced
by 1 dose level; 
If QTcF remains ≥ 481 ms after 
performing steps 1-4 as directed 
in “For All Grades,” discontinue 
ribociclib.
Repeat ECGs 7 days and 14 
days after dose resumption 
(then as clinically indicated) for 
any patients who had therapy 
interrupted due to QTcF 
≥501ms
If QTcF of ≥501 ms recurs, 
discontinue study treatment. 
Perform frequent ECGs until the 
QTcF is <500 msec. Address 
electrolyte, calcium and 
magnesium abnormalities. 
Grade 4
QT/QTc ≥501 or >60 ms change 
from baseline and
Torsade’s de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms
of serious arrhythmia
Discontinue study treatment. 
Perform steps 1-4 as directed in 
“For All Grades.”  
Transmit ECG immediately and 
confirm prolongation/
abnormalities with central 
assessment. Obtain local 
cardiologist (or qualified 
specialist) consultation and 
repeat cardiac monitoring as 
indicated until the QTcF returns 
to <481 ms.


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6.4.3.3
Ribociclib/everolimus dose modification and management for 
cardiac dysfunction
Table 6-10
Ribociclib/everolimus dose modification and management for cardiac 
dysfunction
(see Table 6-5 and Table 6-6 for dose reduction guide)
Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
Cardiac - Left Ventricular 
Systolic Dysfunction
Asymptomatic,
resting ejection fraction 40-50%;
or 10-20% drop from baseline
Maintain dose level, and 
continue ribociclib and 
everolimus with caution.
Repeat LVEF within 4 weeks or 
as clinically appropriate.
Symptomatic,
responsive to intervention, 
ejection fraction 20-39%
or >20% drop from baseline
Hold ribociclib and everolimus 
until resolved, then reduce study 
treatment by one dose level;
LVEF measurement to be 
repeated, if not resolved within 
28 days permanently 
discontinue ribociclib and 
everolimus if applicable.
6.4.3.4
Ribociclib/everolimus dose modification and management for 
hepatotoxicity’s
Table 6-11
Ribociclib/everolimus dose modification and management for 
hepatotoxicity
(see Table 6-5 and Table 6-6 for dose reduction guide)
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48 to 72hrs later)
If confirmed, maintain dose level with LFTs monitored bi-weekly until 
normalizes.
Grade 2 (>1.5 – 3.0 x ULN)
Dose interruption of ribociclib and everolimus
If resolved to ≤grade 1 in ≤21 days, then maintain dose level
If resolved to ≤grade 1 in >21 days or toxicity recurs, lower 1 dose 
level,.Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks after dose resumption
If toxicity recurs after two dose reductions, discontinue study 
treatment


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HEPATOTOXICITY (AST or ALT)
AST or ALT without bilirubin elevation >2 x ULN
Same grade as baseline or 
increase from
baseline grade 0 to grade 1
No dose adjustment required with LFTs monitored per protocol if 
same grade as baseline or bi-weekly in case of increase from 
baseline grade 0 to 1
Increase from baseline grade 0 
or 1 to
grade 2 (>3.0 – 5.0 x ULN)
Dose interruption of ribociclib and everolimus until recovery to 
≤baseline
If resolved to ≤baseline in ≤21 days, then maintain dose level
If resolved to ≤baseline in >21 days or toxicity recurs, then reduce 1 
dose level. Repeat liver enzyme and bilirubin tests twice weekly for 
2 weeks after dose resumption
If toxicity recurs after two dose reductions or recovery to ≤baseline 
grade is >28 days, discontinue study treatment
Increase from baseline grade 0 
or 1 to
grade 3 (>5.0 – 20.0 x ULN)
Dose interruption of ribociclib and everolimus until resolved to 
≤baseline grade, then lower 1 dose level of study treatment. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks 
after dose resumption
If recovery to ≤baseline grade is >28 days, discontinue study 
treatment
If toxicity recurs after two dose reductions or recovery to
baseline is > 28 days, discontinue study treatment
Increase from baseline grade 2 
to grade 3
(>5.0 – 20.0 x ULN)
Dose interruption of ribociclib and everolimus until resolved to 
baseline, then lower 1 dose level of study treatment
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks 
after dose resumption
If toxicity recurs after two dose reductions or recovery to ≤baseline 
grade is >28 days, discontinue study treatment
Grade 4 (>10.0 x ULN)
Discontinue study treatment
Grade 3 (>3.0 – 10.0 x ULN)
Dose interruption of ribociclib and everolimus
If resolved to ≤Grade 1 in ≤21 days, lower 1 dose level.
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks 
after dose resumption
If resolved to ≤grade 1 in >21 days or toxicity recurs, discontinue 
study treatment
Grade 4 (>10.0 x ULN)
Discontinue ribociclib
Confounding  factors  and/or  alternative  causes  for  increase  of total  bilirubin  should  be excluded  
before dose interruption/reduction. They include but are not limited to: evidence of obstruction, such as 
elevated ALP and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due to the 
indirect component only (i.e. direct bilirubin component ≤1 x ULN) due to hemolysis or Gilbert’s
Syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other 
hepatotoxic drugs. For patients with Gilbert’s Syndrome, these dose modifications apply to changes in 
direct bilirubin only. Bilirubin will be fractionated if elevated.


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AST or ALT and concurrent Bilirubin
For patients with normal ALT 
and AST and total
bilirubin at baseline: AST or 
ALT > 3 x ULN combined
with total bilirubin > 2 x ULN 
without evidence of cholestasis
or
For patient with elevated AST or 
ALT or total bilirubin at baseline: 
baseline : [AST or ALT >2 x 
baseline AND >3.0x ULN] OR 
[AST or ALT 8.0 x ULN]-
whichever is lower- combined 
with [total bilirubin 2 x
baseline AND >2.0 x ULN]
Discontinue study treatment
Confounding factors and/or alternative causes for increased transaminases should be excluded before 
dose interruption/reduction. They include but are not limited to: concomitant medications, herbal 
preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new or 
progressive liver metastasis, and alcohol intake.
6.4.3.4.1 Additional follow-up for hepatic toxicities
Hepatic toxicity monitoring includes assessment of the following liver function tests (LFTs): 
albumin, ALT, AST, total bilirubin, direct and indirect bilirubin alkaline phosphatase 
(fractionated if alkaline phosphatase is grade 2 or higher), creatinine kinase, prothrombin time 
(PT)/(PTT), international normalized ratio (INR) and Gamma-glutamyl transpeptidase (GGT). 
For patients with Gilbert’s Syndrome: total and direct bilirubin must be monitored, intensified 
monitoring applies to changes in direct bilirubin only. Close observation is recommended in
case of AST, ALT, and/or bilirubin increase requiring dose interruption, which involves:
Repeating liver enzyme and serum bilirubin tests approx. two times weekly. Frequency of re-
testing can decrease to once a week or less if abnormalities stabilize or return to normal values.

Obtaining a more detailed history of current symptoms.

Obtaining a more detailed history of prior and/or concurrent diseases including history of 
any pre-existing liver conditions or risk factors.

Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets.

Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
cytomegalovirus (CMV), Epstein-Barr virus (EBV), or herpes simplex virus (HSV); 
autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary 
tract disease.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).

Considering gastroenterology or hepatology consultations.


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
Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction.

Obtaining a PK sample, as close as possible to last dose of study drug.

Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury.
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of 
drug-induced liver injury (DILI), and should be considered as clinically important events. The 
threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; 
patients meeting any of the following criteria will require further follow-up as outlined below:

For patients with normal ALT AND AST AND TBIL value at baseline: AST or ALT >3.0 
x ULN combined with TBIL >2.0 x ULN.

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT >2 x 
baseline AND >3.0 x ULN] OR [AST or ALT >8.0 x ULN], whichever is lower, 
combined with [TBIL >2 x baseline AND >2.0 x ULN].
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: Alkaline phosphatase (ALP) elevation >2.0 x ULN with R value <2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values [R value = ALT/ULN)/(ALP/ULN)]. It denotes the relative pattern of ALT 
and/or ALP elevation is due to cholesteric or hepatocellular liver injury or mixed type injury.
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, thus met the definition of SAE (Section 8.2), and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.4.4
Dose modification and management for everolimus specific toxicities
Table 6-12
Everolimus specific toxicities management and recommendations
(Refer to dose modification Table 6-5 and Table 6-6)
Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
Stomatitis
Grade 1 
No dose adjustment required.


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Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
Minimal symptoms, normal diet
Manage with non-alcoholic 
steroid mouthwash and salt 
water (0.9%) mouth wash four 
times a day.
Grade 2
Symptomatic but can eat and 
swallow modified diet
Interrupt everolimus and 
ribociclib until recovery to grade
1.
Re-initiate study treatment at 
the same dose.
If stomatitis recurs, interrupt 
ribociclib and everolimus until 
recovery to grade 1. Re-initiate 
study treatment at a one dose 
lower. 
Manage with topical analgesic 
mouth treatments (e.g. 
benzocaine,butyl minobenzoate, 
tetracaine hydrochloride, 
menthol or phenol) with or 
without topical corticosteroids 
(i.e. triamcinolone oral paste).
Grade 3
Symptomatic and unable to 
adequately aliment or hydrate 
orally
Interrupt everolimus and 
ribociclib until recovery to grade
≤1.Re-initiate study treatment at 
a reduced dose; 
If reoccurs, interrupt ribociclib 
and everolimus until recovery to 
grade ≤1.Re-initiate study 
treatment at second dose level.
Manage with topical analgesic 
mouth treatments (i.e. 
benzocaine, butyl 
aminobenzoate, tetracaine 
hydrochloride, menthol or 
phenol) with or without topical 
corticosteroids (i.e. 
triamcinolone oral paste).
Grade 4
Symptoms associated with life-
threatening consequences
Hold ribociclib and everolimus 
and provide appropriate medical 
therapy. If recovered to ≤grade 
1 within 3 weeks, Re-initiate 
study treatment at a reduced 
dose. If >3 weeks, then 
discontinue study treatment. 
Serum creatinine
Grade 1
No dose adjustment required. 
Initiate appropriate monitoring.


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Adverse drug reaction
Severity
Dose adjustment and 
management 
recommendations
Grade 2
Hold ribociclib and everolimus 
until resolved to grade ≤1, then
re-initiate study treatment at the 
same dose level.
If toxicity recurs at Grade 2, 
interrupt ribociclib and 
everolimus until recovery to
grade ≤1, re-initiate and study 
treatment by one dose level. 
Grade 3
Hold ribociclib and everolimus 
until resolved to grade ≤1, then 
reduce study treatment by 1 
dose level. If toxicity recurs after 
two dose reductions, 
discontinue study treatment
Grade 4
Discontinue study treatment and 
manage appropriately.
Metabolic events (e.g. 
hyperglycemia, dyslipidemia)
Grade 1
No dose adjustment required.
Initiate appropriate medical 
therapy and closely monitor. 
Consider metformin for 
hyperglycemia
Grade 2
No dose adjustment required.
Manage with appropriate 
medical therapy and monitor. 
For hyperglycemia, consider 
metformin and follow up with 
endocrinologist
Grade 3
Hold ribociclib and everolimus 
until resolved to grade ≤1, then 
reduce study treatment by 1 
dose level;.
Manage with appropriate 
medical therapy and monitor.
Grade 4
Hold ribociclib and everolimus 
until resolved to grade ≤1 then 
discontinue study treatment
6.4.4.1
Pneumonitis
Table 6-13
Management of Pneumonitis
(refer to Table 6-5 and Table 6-6 for dose reduction guide)


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Worst Grade
Pneumonitis
Required 
Investigations
Management of
Pneumonitis
Dose Adjustment
Grade 1
Asymptomatic
radiographic
findings only
CT scans with lung 
windows
Repeat at least every
8-12 weeks until return 
to within normal limits.
No specific therapy is 
required
Consider flovent until 
resolution
Administer 100% of 
study treatment
dose.
Grade 2
Symptomatic,
not interfering
with ADL
CT scan with lung
windows.
Consider pulmonary 
function
testing includes: 
spirometry,
DLCO, and room air O2
Saturation at rest
Repeat at least every
8-12 weeks until return 
to within normal limits.
Consider a 
bronchoscopy with 
biopsy and / or BAL
Symptomatic only.
Consider flovent and 
corticosteroids if
symptoms are
troublesome.
Reduce study 
treatment by one level 
until recovery to 
≤Grade 1. 
Ribociclib and 
everolimus may also be 
interrupted if symptoms 
are troublesome.
If failure to recover to 
≤Grade 1 within 3 
weeks, subjects can 
resume ribociclib at full 
treatment dose (Table 
6-5 and Table 6-6)
until recovery to Grade 
≤1. Once recovered, to 
Grade ≤1, reinitiate 
study treatment and 
reduce study treatment 
(ribociclib+everolimus+
exemestane)by one 
dose level. 
Grade 3
Symptomatic,
interfering with
ADL; O2
indicated
CT scan with lung 
windows
and pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation 
at rest.
Repeat at least every 6 
weeks until return to 
within normal limits. 
Bronchoscopy with
biopsy and / or BAL is
recommended.
Consider 
corticosteroids if
infective origin is ruled
out. 
Taper as
medically indicated.
Hold study treatment 
until recovery to Grade 
≤1. May restart study 
treatment within 3
weeks at a reduced
dose (by one level) if 
evidence of clinical
benefit.
Grade 4
Life threatening;
ventilatory
support
CT scan with lung 
windows
and required 
pulmonary
Consider
corticosteroids if
infective origin is ruled
out. Taper as
Discontinue study 
treatment


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Worst Grade
Pneumonitis
Required 
Investigations
Management of
Pneumonitis
Dose Adjustment
indicated
function testing, if 
possible,
includes: spirometry, 
DLCO, and room air 
O2 saturation at rest.
Repeat at least every 6 
weeks until return to 
within normal limits. 
Bronchoscopy with 
biopsy and / or BAL is 
recommended if 
possible.
medically indicated.
6.4.5
Recommended actions to be taken for positive baseline hepatitis B 
test
Table 6-14
Recommendations for positive baseline hepatitis B test
Test
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HBsAg
+ or -
+
-
-
-
HBs Ab
+ or -
+ or -
+
and no prior HBV 
vaccination
+ or -
-
or + with 
prior HBV 
vaccination
HBc Ab
+ or -
+ or -
+ or -
+
-
Recommendation
Prophylaxis treatment should be started 
1-2 weeks prior to first dose of study 
drug
Monitor HBV-DNA approximately every 
6 weeks
No prophylaxis Monitor HBV-
DNA approximately every 4 
weeks at the end of treatment 
and until EOT + 30 days
No specific 
action
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug. For hepatitis B reactivation, definition and management guidelines see Table 6-15
Guidelines for management of hepatitis B.
Table 6-15
Guidelines for management of hepatitis B
Reactivation is Defined 
as:
Treatment
Increase of 1 log in HBV-
DNA relative to baseline 
HBV- DNA value OR new 
Start appropriate antiviral therapy
AND
Interrupt ribociclib and everolimus administration until resolution:


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appearance of measurable 
HBV-DNA
AND
ALT elevation x 5 ULN
≤grade 1 ALT (or baseline ALT, if >grade 1) and
≤baseline HBV-DNA levels
If resolution occurs within ≤21 days study treatment should be re-
started at one dose lower, if applicable. If the patient is already 
receiving the lowest dose of study drug according to the protocol, the 
patient should restart at the same dose after resolution. Both antiviral 
therapies should continue at least 4 weeks after last dose of study 
drug.
If resolution occurs >21 days Patients should discontinue study 
treatment but continue both antiviral therapies at least 4 weeks after 
last dose of study treatment
6.4.6
Guidance for all other adverse reactions
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium for 
all adverse reactions, if indicated. If electrolyte values are outside of the normal range, interrupt 
ribociclib/everolimus administration, correct electrolytes with supplements or appropriate 
therapy as soon as possible, and repeat electrolyte testing until documented normalization of 
the electrolytes.
Table 6-16
Ribociclib/everolimus dose adjustment and management 
recommendation for all other adverse reactions
(see Table 6-5 and Table 6-6for dose reduction guide)
Grade/Severity
Dose adjustment and management recommendations
Grade 1
No dose adjustment- maximize AE management
Grade 2
Dose interruption of ribociclib/everolimus until recovery to 
Grade ≤1
Initiate appropriate medical therapy and monitor
Re-initiate study treatment at the same dose
If the same toxicity recurs at Grade 2, interrupt 
ribociclib/everolimus until recovery to Grade ≤1. Re-initiate 
study treatment at the next lower dose level.
Grade 3
Hold both everolimus and ribociclib until it resolves to ≤Grade 
1.
Initiate appropriate medical management and monitor
Re-initiate study treatment at the next lower dose level 
If toxicity recurs at grade 3, discontinue study treatment
Grade 4
Discontinue study treatment
Additional recommendations (see supplementary management brochure for further 
recommendations):
Nausea: Ensure adequate hydration or fluid repletion. Consider performing an analysis of serum 
potassium, calcium, phosphorus and magnesium, if indicated. If electrolyte values are below LLN, 
interrupt ribociclib, correct electrolytes with supplements as soon as possible, and repeat electrolyte 
testing until documented normalization. 


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Diarrhea: At the first sign of loose stools (Grade 1), initiate loperamide. Patient should remain well 
hydrated. Fluids and electrolytes should be replaced as needed. Consider performing an analysis of 
serum potassium, calcium, phosphorus and magnesium, if indicated. If electrolyte values are below 
LLN, interrupt ribociclib, correct electrolytes with supplements as soon as possible, and repeat 
electrolyte testing until documented normalization. 
6.5
Concomitant medications
6.5.1
Permitted concomitant therapy for all treatment groups
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as packed red blood cells (PRBCs), pain medications, anti-
emetics, short courses of steroids, chronic use of a low dose steroid for physiologic replacement, 
topical treatments for stomatitis and anti-diarrheal are allowed. The use of any other potential 
new concomitant medications may be discussed between the investigator and the sponsor on a 
case by case basis.
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug combination. All medications (other than study drugs) 
and significant non-drug therapies (including vitamins, herbal medicines, physical therapy and 
blood transfusions) administered within 30 days of study entry and during the study must be 
listed on the Concomitant medications/Significant non-drug therapies eCRF.
Patients taking concomitant medication chronically should be maintained on the same dose 
and dose schedule throughout the study period, as medically feasible.
Refer to the (LEE011 Investigator’s Brochure), (everolimus Investigator’s Brochure), 
(aromasin package insert) and (Appendix 1 for concomitant medications).
6.5.1.1
Hematopoietic growth factors
The use of Transfusions or Hematopoietic growth factor support (e.g. erythropoietins, G-CSF
and GM-CSF) should be according to ASCO guidelines.
6.5.1.2
Bisphosphonates and denosumab
Bisphosphonates and denosumab are generally allowed with the following comments:

Bisphosphonate/denosumab therapy for the treatment of osteoporosis is permitted.

Bisphosphonate/denosumab therapy for the prevention of skeletal related events for 
patients with existing bone metastases is permitted.

If bisphosphonate therapy is to be started after the first dose of study drug, prior 
consultation and approval by Novartis is required and the reason for its use must be clearly 
documented.


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6.5.1.3
Palliative radiotherapy
Palliative radiation is permitted while on study after discussion with sponsor. It should not
be delivered to a target lesion and it should not encompass more than 25% of irradiated bone 
marrow.
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use 
must be clearly documented and progression as per RECIST 1.1 must be ruled out.
No dose modification of study treatment is needed during palliative radiotherapy.
6.5.1.4
Use of antiemetic medications
Ribociclib has low to minimal emetogenic potential according to a the definition of 
antineoplastic agent emetogenicity (Grunberg et al 2010). Antiemetic therapy can be used 
according to clinical guidelines for antineoplastic medications with low to minimal emetogenic 
potential for treatment and/or prevention of nausea and vomiting as a result of study treatment 
(NCCN Clinical Practice Guidelines in Oncology. Antiemesis, 2017; Roila F et al 2016).
Potential drug interaction between ribociclib and antiemetic medications should always be taken into 
consideration. Example of a prohibited antiemetic medication is ondansetron that in combination 
with ribociclib may precipitate TdP. Refer to Appendix 1 for list of medications that are prohibited 
or allowed to be used with ribociclib.
6.5.2
Prohibited concomitant therapy during combined ribociclib + 
everolimus + exemestane
The following medications are prohibited during study treatment in the study (see Table 14-1 
in Appendix 1, this list is not comprehensive and is only meant to be used as a guide. Please 
contact the medical monitor with any questions):

Strong and moderate inhibitors or inducers of CYP3A4/5.

Substrates of CYP3A4/5 with a narrow therapeutic index.

Medications with a known risk for QT prolongation.

Other investigational and anti-neoplastic therapies, including chemotherapy, 
immunotherapy, target therapy, biological response modifiers, or endocrine therapy other 
than exemestane.

Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. 
raloxifene).

Prolonged systemic corticosteroid treatment (≥2 weeks), except for topical applications 
(e.g. rash), inhaled sprays (e.g. obstructive airways diseases), dexamethasone mouthwash 
(provided by Novartis), eye drops or local injections (e.g. intraarticular) should not be 
given. A short duration of systemic corticosteroids is allowed (e.g. chronic obstructive 
pulmonary disease, LFT abnormality).

Herbal preparations/medications (except for vitamins) or dietary supplements that are 
strong inhibitors or inducers of CYP3A4/5 or those with a known risk of QT prolongation,


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including, but not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 
Patients should stop using these preparations at least 7 days prior to first dose of study
treatment.
6.5.3
Permitted concomitant therapy requiring caution and/or action while 
on study
Permitted medications to be used with caution combined ribociclib + everolimus + exemestane 
treatment in this study (Appendix 1, Table 14-2) are listed below. These medications should 
be excluded from patient use if possible. If they must be given based on the investigator’s 
judgment, then use with caution and consider a ribociclib interruption if the concomitant 
medication is only needed for a short time:

Moderate inhibitors or inducers of CYP3A4/5.

Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index.

Strong inhibitors of BSEP.

Medications that carry a possible risk for QT prolongation.

Sensitive substrates of the renal transporters, MATE1 and OCT2.

Sensitive substrates of BCRP (has a potential to increase exposure to substrates of these 
transporters, although no animal or clinical data are available to support these statements)
6.5.3.1   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)
6.5.4
Drugs with QTc prolongation
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with 
the potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI 
that increases the exposure of ribociclib or the exposure of the QT prolonging drug). A 
definitive list of drugs with a known risk, possible risk, or conditional risk of QT prolongation 
and/or Torsades de Pointes (TdP) is available online at www.qtdrug.org.and in Appendix 1.
Medications with a known risk for QT prolongation are prohibited during study treatment.


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6.6
Patient numbering, treatment assignment or randomization
6.6.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening (signs consent) and is retained as the primary identifier 
for the patient throughout his/her entire participation in the trial. The Patient No. consists of a 
4 digit Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential 3 digit patient number, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next sequential 
Patient No. available to the investigator.
6.6.2
Treatment blinding
This study is open-label.
6.6.3
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
Ribociclib will be supplied as capsules or tablets for oral use. The capsules or tablets will be 
packaged in bottles. Everolimus and exemestane will be supplied as tablets for oral use. Refer 
to Table 6-1 for ribociclib capsule/tablet and everolimus and exemestane tablet strengths. 
Ribociclib, everolimus and exemestane will be dosed on a flat scale of mg/day and not adjusted 
to body weight or body surface area. The dexamethasone mouthwash must be received by 
designated personnel at the study site, handled and stored safely and properly, and kept in a 
secured location to which only the investigator and designated site personnel have access. The 
dexamethasone mouthwash should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled 
Room Temperature]. Dispense in original, commercial container.
6.6.4
Study drug packaging and labeling
Ribociclib capsules/tablets are packaged in high density polyethylene (HDPE) bottles with child 
resistant closures. Everolimus tablets are packaged in blister packs (4 blisters per pack per 
strength). Exemestane tablets are packaged in high density polyethylene (HDPE) bottles with 
child resistant closures.
Medication labels will be in the local language and comply with the legal requirements of the 
United States. They will include storage conditions for the drug but no information about the 
patient. The medication will be supplied as open label supply to the sites in a way which allows 
the patient to take medication at home.
Ribociclib capsules/tablets, Everolimus and Exemestane tablets, and dexamethasone 
mouthwash will be supplied by Novartis.


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6.6.5
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels, and in the (Investigator’s Brochure for LEE011) and 
the package insert for everolimus,exemestane, and dexamethasone.
6.6.6
Study drug compliance and accountability 
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.
On days of PK sampling and scheduled ECG visits to the clinic, the patient will take their 
assigned combination of drugs at the clinic. For all other study days, the patient will take their 
assigned combination at home. The time of dose administrations taken in the clinic must be 
recorded in the Dosage Administration Record eCRF.
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 monitor or to the Novartis address provided in the investigator folder 
at each site.
6.6.7
Handling of other study treatment
Not applicable.
6.6.8
Disposal and destruction
The ribociclib, everolimus, exemestane and dexamethasone supply can be destroyed at the local 
Novartis facility, Drug Supply group or third party, as appropriate. If pre-arranged between 
Novartis and study site, destruction of used and unused ribociclib, everolimus, exemestane and 
dexamethasone will be performed at the study site if permitted by local regulations. 
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Below is a list all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 


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documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column).
The following are based on local lab results. Allowed visit windows are specified as follows:

Screening assessments, apart from those listed below, must occur within 21 days before 
first dose of study treatment as per Table 7-1.

Vital signs, physical exam, laboratory assessments and ECOG performance status that
were completed within 3 days prior to Day 1 of each cycle (e.g. C1D1) do not need to be
repeated on day 1 of that respective cycle.

For all other visits, a ±3 day window is permitted on assessments to take into account 
scheduling, if not explicitly specified otherwise. For efficacy assessments there is a ±7
day window for those done within 12 months of C1D1. After 12 months, there is a ±14 
day window, refer to Section 7.2
Radiological assessments must be performed as outlined in Table 7-2.


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Table 7-1
Visit evaluation schedule
Category
Reference to 
protocol 
section
Screening phaseTreatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-21 to -1
1
15
1
15 1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 6 
months
Screening
Study Informed Consent D
7.1.1
X
IRT Screening (after ICF 
signature)
S
7.1.1.1
X
Disposition Assessment
End of Phase Disposition D
7.1.1.2
X
X
X
Patient history
Demography
D
7.1.1.3
X
Inclusion/exclusion 
criteria
D
5.2 
X
Medical history and 
current medical 
conditions
D
7.2.2.1
X
HER2 status
D
7.2.2.1 
X
Pregnancy test (if GnRH 
antagonist required)
D
5.3
X 


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Category
Reference to 
protocol 
section
Screening phaseTreatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-21 to -1
1
15
1
15 1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 6 
months
Diagnosis and extent of 
cancer
D
7.1.1.3
X
Prior antineoplastic 
therapy
D
7.1.1.3 
X
Prior / concomitant 
medications
D
6.5
Continuous – up to 30 days after last dose
Assessments
Physical examination
S
7.2.2.1
X
X1
X
X
X
X
Performance status
D
7.2.2.3
X
X1
X
X
X
X
Height 
D
7.2.2.4
X
Weight
D
7.2.2.4
X
X1
X
X
X
X
Vital signs
D
7.2.2.2 
X
X1
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.5.1
X
X1
X
X
X
X
X
X
Chemistry 
D
7.2.2.5.2
X
X1
X
X
X
X
X
X
Fasting Lipid Panel
D
7.2.2.5.2
X
X
Every 3rd 
cycle
X


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Category
Reference to 
protocol 
section
Screening phaseTreatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-21 to -1
1
15
1
15 1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 6 
months
Coagulation
D
7.2.2.5 
X
As clinically indicated
X
Urinalysis
D
7.2.2.5.3
X
X1
X
X
Tumor assessment
Tumor evaluation 
(RECIST 1.1)
D
7.2.1.1 
X
CT/MRI Chest, Abdomen, Pelvis +/- whole body bone scan +/- X-ray
Every 8 weeks first day of study treatment for the first 12 months, and then every 
12 weeks thereafter until disease progression
Cardiac assessment
ECG (standard 12-lead)
D
7.2.2.6.1 X (Must be
completed 
between days -7 
to -1)
X
X
X
X
X
X
For all 
cycles up 
to Cycle 6
As clinically indicated
ECHO or MUGA
D
7.2.2.6.2 X
As clinically indicated
Safety
Adverse events
D
8.1 
X
Continuous
X
X
Pharmacokinetics
PK
D
7.2.3
X
X
X
X
X


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Category
Reference to 
protocol 
section
Screening phaseTreatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-21 to -1
1
15
1
15 1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 6 
months
Study Drug administration
ribociclib
D
6.2.4.1
Daily
everolimus
D
6.2.4.1 
Daily
exemestane 
D
6.2.4.1
Daily
dexamethasone
D
6.3.1.1
TID through Cycle 2
Discontinuation
New antineoplastic 
therapies after 
discontinuation
D
7.1.6
X
X


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Category
Reference to 
protocol 
section
Screening phaseTreatment phase
Post treatment follow-up phase
Survival 
phase
Visit name
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
End of 
study 
treatment 
(EOT) 
Safety 
follow-up 
Efficacy 
follow-up
End of 
post-
treatment 
follow-up
Survival 
follow-up 
Study days
-21 to -1
1
15
1
15 1
1
Within 15 
days from 
last dose
Last dose + 
30 days
Every 8 
weeks (if 
applicable) 
Every 6 
months
Survival follow-up (phone 
call)
D
7.1.8
X
1 If performed within 3 days prior to day 1 of study treatment, will not need to be repeated on first day of cycle. Use of the same value in 
screening and C1D1 is allowed if done within 3 days of cycle 1 day 1. 


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7.1.1
Screening
The Study IRB/IEC approved Informed Consent Form (ICF) must be signed and dated before 
any screening procedures are performed (procedures that are part of the clinical routine during 
the initial diagnostic work-up of the patient may be performed before signing the ICF). A 
copy of the ICF must be given to the patient or to the person signing the form. The Investigator
or designee must record the date when the study informed consent was signed in the medical 
records of the patient.
After signing the study Informed Consent Form, the screening assessments will be done within
21 days prior to day one of study treatment for selected assessments (Table 7-1 and Table 7-2)
for the list of assessments to be performed).
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to starting study treatment, including before signing the main study ICF can be 
considered as the baseline images for this study.
Re-screening of patients is allowed once per patient if the patient was not registered as entering
the treatment phase. In this case the Subject Number assigned to the patient initially will be
used and the patient will be identified with this number throughout his/her entire participation 
to the study.
For laboratory evaluations used to determine eligibility, repeated evaluation within the 
screening window are permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. In case
rescreening occurs, all evaluations re-assessed should meet the eligibility criteria
7.1.1.1
Eligibility screening
Following registration in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to start treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (Section 8.2 for SAE 
reporting details).
7.1.1.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Date of birth and initials, sex, race, ethnicity, source of patient referral)

Diagnosis and extent of cancer (including staging at study entry and histology/cytology)


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
Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History eCRF should include the toxicity grade.

ER, PgR and HER2 status

Rb status

All prior antineoplastic therapies including surgical interventions and chemotherapy,
biologic, immunologic and radiation therapies provided as treatment for cancer prior to the 
administration of study drug.

All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded in the Prior and Concomitant medication or 
Surgical and medical procedures eCRF page and updated on a continual basis if there are 
any new changes to the medications.
Furthermore the following assessments will be performed:

Vital signs

Height, weight

Physical examination

Performance status (ECOG)

Laboratory evaluations (hematology, PT/PTT, INR, chemistry (including LFTs), lipid 
panel, HBV-DNA, HBsAg, HB Ag, HBc Ab, HCV-RNA-PDC, urinalysis, and FSH, LH 
and/or estradiol (if necessary) 

ECG

ECHO/MUGA

Radiological assessments (e.g. CT /MRI/bone scan)

PK 
7.1.2
Treatment period
During the treatment period, the patient must follow the Investigator’s instructions with regards 
to contraception, concomitant medications, and dosing regimen (see Section 6). Patients will be 
treated with ribociclib + everolimus + exemestane until disease progression, unacceptable
toxicity, withdrawal of consent by the patient, patient is lost to follow up, death, discontinuation
from the study treatment due to any other reason or the sponsor terminates the study. For details 
of assessments, refer to Table 7-2, and Table 7-3.
If a patient remains on study after a dose interruption of >28 days, or after disease progression
because the patient had experienced objective evidence of clinical benefit and in the opinion
of the investigator it is in the best interest of the patient to remain on study, then this decision
and report of a discussion with the sponsor must be reported in the source documentation and 
in a comment in the eCRF.


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7.1.3
End of study treatment visit including safety completion and study 
treatment discontinuation
Patients who discontinue study treatment should be scheduled for an End of Treatment (EOT) 
visit within 15 days following the date study treatment is permanently discontinued, at which 
time all of the assessments listed for the EOT visit will be performed. For details of assessments, 
refer to Table 7-1. If the decision to withdraw the patient occurs at a regularly scheduled visit, 
that visit may become the EOT visit rather than having the patient return for an additional visit.
An End of phase disposition eCRF page should be completed, giving the date and reason for 
stopping the study treatment. If a withdrawal occurs, or if the patient fails to return for visits, 
the investigator must determine the primary reason for a patient’s premature withdrawal from 
the study and record this information on the EOT eCRF page. The EOT visit is not considered 
the end of the study.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of study treatment.
If a patient discontinues study treatment, but continues study assessments, the patient remains
on study until such time as he/she completes protocol criteria for ending study assessments. At
that time, the reason for study completion should be recorded on the End of Post Treatment
Phase Disposition CRF page.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every effort 
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate eCRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, on balance, he/she
believes that continuation would be detrimental to the patient’s well-being.
Patients may be withdrawn from the study treatment if any of the following occur:

Adverse Event 

Lost to follow-up

Physician decision

Progressive Disease

Protocol deviation

Study terminated by sponsor

Technical problems
Patients must be withdrawn from the study treatment if any of the following occur:

Pregnancy


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
Death

Subject/Guardian decision
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation:

Adjustments to study treatment that result in discontinuation. Please refer to Section 6.4.

Use of prohibited medication. Please refer to Section 6.5 and Appendix 1.
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Table 7-1. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact them as specified in Section 7.1.8. 
Patients who discontinue study treatment should undergo an End of Treatment (EOT) visit 
followed by a 30 day safety follow-up.
7.1.5
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. Novartis will continue to keep and use collected study information (including 
any data resulting from the analysis of a patient’s samples until their time of withdrawal) 
according to applicable law.
7.1.6
Safety Follow-up
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Information related to AEs (including concomitant medication taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected for 30 days after the last dose of study 
drug. All AEs suspected to be related to study treatment should be followed up as clinically 
indicated, until resolution or stabilization. Data collected should be added to the Adverse Events 
CRF, Concomitant Medications CRF, and Anti-neoplastic treatment CRF.


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7.1.7
Efficacy Follow-up
Patients enrolled in this study who discontinue study treatment for any reason other than disease
progression will be followed up every 8 (±1 weeks) weeks via a phone call and CT/MRI scans 
as detailed in Table 7-1 and Section 7.2, until disease progression or until 15 months after last 
patient enrolled into the study, whichever comes first. Antineoplastic therapies beginning
during this F/U period must be recorded on the Antineoplastic Therapies Since Discontinuation 
of Study Drug eCRF.
7.1.8
Survival Follow-up
All patients will be follow for survival status every 24 weeks, until death, lost to follow up or 
withdrawal of consent, for at least 15 months after last patient enrolled into the study. Survival 
information can be obtained via phone, and information will be documented in the source 
documents and relevant eCRFs.
7.1.9
Lost to Follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Imaging tumor assessments
Tumor response will be assessed locally and centrally according to RECIST Version 1.1
(Eisenhauer et al 2009). The decision regarding patient management will remain with the local 
investigator. Patients should have at least one documented measurable lesion (per RECIST v1.1) 
or in the absence of measurable disease, have at least one lytic or mixed (blastic/lytic) bone 
lesion at study entry.
Imaging assessments will be performed at screening within 21 days prior to first dose 
of study treatment and subsequently every 8 weeks (+/- 1 week) from day one of study 
treatment during the first 12 months and every 12 weeks (+/- 2 weeks) thereafter. See Table 7-
2 for details of assessments. The 8-week (or 12 week) interval should be respected regardless 
of whether study treatment is temporarily withheld or modified.
After baseline, selected assessments should be performed on cycle 1 day 1(will not need to be 
repeated on day of treatment if performed within 3 days of C1D1) see Table 7-1.
If a patient discontinues treatment for reasons other than radiological documentation of 
progression of disease, an efficacy assessment should be performed at the time of End of 
Treatment unless a CT/MRI for tumor measurement was performed within 21 days. Efficacy 


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assessments should continue as per the scheduled visit per Table 7-1 and Table 7-2, Table 7-3, 
and Table 7-4.
To the extent possible, each lesion should be assessed using the same imaging method 
throughout the study.
All patients will undergo CT, PET CT or MRI of the chest, abdomen and pelvis at baseline and 
subsequent scheduled visits per Table 7-2. The preferred imaging methodology is CT with 
intravenous (i.v.) contrast. However, if at baseline, a patient is known to have a contraindication
to CT i.v. contrast media or develops a contraindication during the trial, a non-contrast CT
or PET CT is allowed. MRI plus contrast is allowed, however not recommended of the chest 
due to respiratory artifacts. 
A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole 
body bone MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET) must
be acquired at screening for all patients. Skeletal lesions identified on the whole body bone
scan at baseline, which are not visible on the chest, abdomen and pelvis CT (or MRI) scan must
be imaged at baseline and followed at scheduled visits using localized CT, MRI or x-ray. If 
multiple bone lesions are identified, bone scans can be used to follow lesions throughout the 
study instead of localized CT, MRI or x-ray. They should be repeated every 8 weeks from 
C1D1 for the first 12 months, then every 12 weeks thereafter. If a new bone lesion is identified
on bone scan, confirm with CT, MRI or X-ray. If previous lesion is no longer appreciated, 
confirm response with CT, MRI or X-ray. If no bone lesions are identified at baseline or if bone 
lesions can be followed with X-ray, CT or MRI, then bone scan need not be repeated unless 
clinically indicated.
Positron Emission Tomography (PET)/CT may be used in place of bone scan and CT only if 
the CT component is of similar diagnostic quality as a CT performed without PET. At the
discretion of the Investigators, FDG-PET scans may be performed to document progressive 
disease per RECIST 1.1
Color photography, including a metric ruler to estimate the size of the lesion, must be acquired 
for all skin lesions present at baseline per instructions provided in the manual from the
designated vendor. These should be followed throughout the study according to the schedule 
outlined in Table 7-2.
Other metastatic disease sites will be followed by CT or MRI, as clinically indicated. Chest X-
ray or ultrasound should not be used to assess tumor lesions.
Partial Response (PR) and Complete Response (CR) must be confirmed by repeat assessments 
performed no less than 4 weeks and after the criteria for objective response are first met. In case 
tumor assessment is performed <8 weeks from the first assessment of an objective response to
confirm PR/CR, subsequent tumor assessments should revert back to the protocol schedule 
outlined in Table 7-2 .
If possible, a single radiologist should perform all tumor response evaluations for an individual
patient. Any lesions in previously irradiated areas should not be considered measurable unless
they have experienced progression since the radiotherapy. Any pre-existing radiographic
findings which may mimic metastatic disease and any prior radiotherapy should be recorded in 
the eCRF.


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Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to registration for treatment, including before signing the main study ICF can be 
considered as the baseline images for this study.
Results from tissue or body fluid collection should be recorded in the eCRF to complement 
radiographic findings.
All study imaging performed, (e.g., to fulfill a progression or response criterion), should
be submitted to the designated imaging CRO within 2 weeks. 
If an off-schedule imaging assessment is performed to confirm response or if progression is
suspected, subsequent imaging assessments should be performed in accordance with the 
original imaging schedule.
Physical exam tumor assessments, photography, pathology/histology and cytology results, as 
well as, information regarding prior interventions, pre-existing radiographic findings that mimic
metastatic disease at baseline/screening and on-study interventions should be captured in the
appropriate eCRF’s and will be transmitted to the imaging CRO for review by a medical 
oncologist.
Table 7-2
Imaging assessments
Procedure
Screening:
Day −21 to
Day 1
Treatment phase*
End of treatment*
Post-Treatment
Phase
CT or MRI 
(Chest, 
Abdomen, 
Pelvis)1
Mandated
Every 8 weeks (±1 
week) during the 
first 12 months and 
every 12 weeks 
thereafter (± 2 
weeks)
Mandated
Every 8 weeks (±1 week) 
during the first 12 months 
and every 12 weeks 
thereafter (± 2 weeks) until 
disease progression, 
withdrawal of consent, loss 
to follow-up, or 
subject/guardian decision
(±1 week). In the absence 
of disease progression, 
continue the assessment 
even if a new anti-
neoplastic therapy is started 
until disease progression, 
only in this case a ±14 days 
window is allowed
Brain CT or 
MRI
Mandated at 
screening if 
history of 
existing or 
suspected 
brain 
metastases
If brain lesion is 
present at 
screening: every 8 
weeks (±1 week)
during the first 12 
months and every 
12 weeks thereafter 
(± 2 weeks)
Mandated only if 
brain lesion at 
screening
If brain lesion at screening:
every 8 weeks (±1 week)
during the first 12 months 
and every 12 weeks 
thereafter (± 2 weeks) until 
disease progression, 
withdrawal of consent, loss 
to follow-up, or 
subject/guardian decision
(±1 week). In the absence 
of disease progression, 
continue the assessment 


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Procedure
Screening:
Day −21 to
Day 1
Treatment phase*
End of treatment*
Post-Treatment
Phase
even if a new anti-
neoplastic therapy is started 
until disease progression, 
only in this case a ±14 days 
window is allowed
Whole body 
bone scan1,2
Mandated 
If multiple bone 
lesions at 
screening and 
cannot be followed 
by X-ray, MRI or 
CT then bone 
scans should be 
done every 8 
weeks (±1 week)
during the first 12 
months and every 
12 weeks thereafter 
(± 2 weeks) If any 
new lesions are 
identified, then 
confirm with X-ray, 
CT or MRI
Mandated only if 
multiple bone 
lesions identified 
at screening
Or as clinically 
indicated. 
If multiple bone lesions at 
screening and cannot be 
followed by X-ray, MRI or 
CT then bone scans should 
be done every 8 weeks (±1 
week) during the first 12 
months and every 12 weeks 
thereafter (± 2 weeks) until 
disease progression, 
withdrawal of consent,
loss to follow-up, or 
subject/guardian
decision (±1 week). In the 
absence of disease 
progression, continue the 
assessment even if
a new anti-neoplastic 
therapy is started until 
disease progression, only 
as clinically indicated
Bone X-ray,
CT
or MRI1
Only if 
skeletal 
abnormalitie
s identified 
at screening 
or by bone 
scan and 
are not 
visible in the 
chest, 
abdomen, 
pelvis 
CT/MRI.
If new bone lesion 
is identified with 
bone scan, confirm 
metastasis with 
bone X-ray, CT or 
MRI, if not visible in 
the chest, 
abdomen, pelvis 
CT/MRI.
Mandated
only if bone
lesion at
screening
If bone lesion at screening, 
every 8 weeks (±1 week)
during the first 12 months 
and every 12 weeks 
thereafter (±2 weeks) until 
disease progression, 
withdrawal of consent, loss 
to follow-up, or
subject/guardian
decision (±1 week). In the 
absence of disease
progression, continue the 
assessment even if
a new anti-neoplastic
therapy is started until
disease progression,
only in this case a ±14 days 
window is allowed.
CT or MRI of 
any disease 
outside of 
Chest 
Abdomen 
Pelvis
Only if 
suspected 
lesion at 
screening
Every 8 weeks if 
lesion identified at 
screening.
Of note, If multiple 
bone lesions at 
screening and 
cannot be followed 
Mandated if lesion 
at screening
If lesion s are identified at 
screening, every 8 weeks 
(±1 week) during the first 12 
months and every 12 weeks 
thereafter (± 2 weeks) until 
disease progression, 
withdrawal of consent,


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Procedure
Screening:
Day −21 to
Day 1
Treatment phase*
End of treatment*
Post-Treatment
Phase
by X-ray, MRI or 
CT then bone 
scans should be 
done every 8 
weeks (±1 week)
during the first 12 
months and every 
12 weeks thereafter 
(± 2 weeks) If any 
new lesions are 
identified, then 
confirm with X-ray, 
CT or MRI
loss to follow-up, or 
subject/guardian
decision (±1 week). In the 
absence of disease 
progression, continue the 
assessment even if
a new anti-neoplastic 
therapy is started until 
disease progression, only 
as clinically indicated
Skin Color 
Photography
Only if
lesions at 
screening
Every 8 weeks if 
lesion at screening
Mandated if lesion 
at screening
If lesion s are identified at 
screening, every 8 weeks 
(±1 week) during the first 12 
months and every 12 weeks 
thereafter (± 2 weeks) until 
disease progression, 
withdrawal of consent,
loss to follow-up, or 
subject/guardian
decision (±1 week). In the 
absence of disease 
progression, continue the 
assessment even if
a new anti-neoplastic 
therapy is started until 
disease progression, only 
as clinically indicated
1 Positron Emission Tomography (PET)/CT may be used in place of bone scan and CT only if the CT 
component is of similar diagnostic quality as a CT performed without PET. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 1.1
2 A whole body bone scan according to institutional guidelines (e.g. Tc-99 bone scan, whole body 
bone MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET)
All scans will be acquired and analyzed locally. For primary endpoint, scans should be 
sent centrally to the CRO designated by Novartis for central imaging interpretation within 
2 weeks.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing the procedures listed below as well as collecting all
adverse events at every visit. All safety assessments should be performed pre-dose unless 
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7.2.2.1
Physical examination
A complete physical examination that evaluates all major organ systems will be performed at 
Screening/baseline. Subsequent physical exams may be limited and should be focused on sites 
of disease to explore clinical signs and symptoms.
Significant findings that were present prior to the signing of informed consent must be included
in the 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.
Physical exams to be performed are outlined in Table 7-1.
7.2.2.2
Vital signs
Vital signs (heart rate, blood pressure and temperature) will be obtained in the sitting position, 
or as appropriate prior to any blood collection.
Vital signs to be performed per Table 7-1.
7.2.2.3
Performance status
Assessment of ECOG Performance Status will be performed at screening and regularly 
throughout the whole study period irrespective of the time of dosing 
Performance status to be performed per Table 7-1 and Table 7-3.
Table 7-3
ECOG performance status
Grade ECOG status
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature e.g., light house work, office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about
more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 Dead
7.2.2.4
Height and Weight
Height in centimeters (cm) and body weight in kilogram (kg). Height and weight to be performed per
Table 7-1.
7.2.2.5
Laboratory evaluations
Sites will use their local laboratories for the analysis of all safety lab samples, collected at the
time points indicated as per Table 7-1. More frequent assessments may be performed if
clinically indicated, or at the investigator’s discretion and these should be recorded on the 
Unscheduled Visit eCRF’s.
Abnormal laboratory values that are clinically relevant (e.g., require an interruption or delay 
to study treatment, lead to clinical symptoms, or require therapeutic intervention) must be 
documented in the Adverse Event eCRF.


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Novartis will be provided with a copy of the site’s local laboratory certification and tabulation 
of the normal ranges for each parameter required at study start and should be kept up to date 
on an ongoing basis. In addition, if at any time a patient has laboratory parameters obtained 
from a different outside laboratory, Novartis must be provided with a copy of the certification 
and a tabulation of the normal ranges for that laboratory.
Table 7-4
Local Clinical Laboratory Parameters Collection Plan
Test Category
Test Name
Hematology
White blood cell count (WBC) with differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils ), hemoglobin (Hgb) 
and platelet count.
Biochemistry with fasting glucose
Sodium, potassium, urea or BUN, creatinine, 
fasting glucose, calcium (or corrected calcium), 
magnesium, phosphorous, total protein and 
albumin.
AST (SGOT), ALT (SGPT), total bilirubin, direct 
bilirubin, GGT and alkaline phosphatase, 
Amylase, lipase and LDH.
Fasting Lipid Panel
Total cholesterol, LDL-cholesterol, HDL-
cholesterol and triglycerides
Coagulation
PT/PTT, International normalized ratio [INR]
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, 
Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen)
If there are any significant findings on the dipstick 
then a microscopic evaluation should be 
measured: Microscopic Panel (WBC and RBC 
sediments, Casts, Crystals, Bacteria, Epithelial 
cells)
7.2.2.5.1 Hematology
Complete blood count (CBC) with differential - white blood count (WBC), neutrophil count 
(including bands], lymphocyte, monocyte, eosinophil, and basophil counts, hemoglobin, and 
platelet count. Hematology collections to be performed per Table 7-1. Hematology tests are to
be performed according to the Visit Schedules outlined in Table 7-1. For details of the 
Hematology panel refer to Table 7-4.
7.2.2.5.2 Clinical chemistry
Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, fasting glucose (at
least 2 hours fasting), AST (SGOT), ALT (SGPT), total bilirubin (if a total bilirubin elevation 


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≥Grade 2 occurs then direct and indirect bilirubin should be measured), LDH, albumin, calcium 
(corrected for serum albumin), magnesium, phosphate, alkaline phosphatase and fasting lipid 
panel (at least 8 hours). Clinical chemistry visit schedules are outlined in Table 7-1. For details 
of the Chemistry panel refer to Table 7-4.
7.2.2.5.3 Urinalysis
Urinalysis is to be performed according to the Visit Schedules outlined in Table 7-1. For 
details of the urinalysis panel refer to Table 7-4.
7.2.2.5.4 HBV testing
Prior to enrollment, the categories of patients listed in Section 5.1.1 should be tested for
hepatitis B serologic markers and viral load: HBV-DNA HBsAg, HBc Ab, and HBs Ab. 
HBV DNA monitoring should be done depending on results from serologic markers and viral 
load as listed in HCV testing.
Patients with hepatitis C risk factors and additional patients at the discretion of the investigator
should be tested for HCV RNA-PCR test at screening. For a list of hepatitis C risk factors,
refer to Section 5.1.2. Follow-up testing will be performed, as per the visit schedule, only if the
patient has a history or is positive at baseline, or both.
7.2.2.5.5 Hepatic safety markers
An additional blood sample is requested from patients in response to rise in ALT/AST or in 
total bilirubin (as described below) if this rise occurs outside of the scheduled collection dates:

In patients with normal AST and ALT and total bilirubin at baseline that present a rise of 
AST or ALT ≥grade 2 with total bilirubin >2 x ULN without evidence of cholestasis 
(defined as: ALP elevation >2.0 x ULN with R value [ALT/ALP in x ULN] <2 in patients 
without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis).
OR

For patients with elevated baseline AST or ALT or total bilirubin that present [AST or 
ALT >2 x baseline AND >3.0x ULN] OR [AST or ALT 8.0x ULN]- whichever is lower-
combined with [total bilirubin 2xbaseline AND >2.0 x ULN]
OR

ALT or AST >8 x ULN without bilirubin increase
Analysis of samples will be performed based on results of ALT/AST and total bilirubin, with 
the aim to better understand the underlying mechanism of any observed hepatotoxicity. 
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
Standard triplicate 12-lead ECGs will be performed after the patient has been resting for 5-10 
minutes prior to each time point indicated in Table 7-5.
Triplicate ECGs should be taken approximately 2-minutes apart. The combined QTcF values 
from these 3 ECGs will be averaged to provide a single value for each time point. Eligibility 


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will be based on the average of the triplicate ECG conducted at screening. In order for accurate 
evaluation of baseline QTcF, a total of three 12-lead ECGs will be performed within 7 days 
prior to registration (at screening between Day -7 and Day -1).
Note: All study ECGs, should be submitted to the designated CRO immediately.
Note: To ensure ECG evaluation is received for eligibility assessment, it is advisable to
perform the ECG at least 24 hours prior the scheduled enrollment date as it takes at least 24 
hours to receive central read.
If an abnormal ECG or QTcF value of ≥481 ms is obtained at any time after enrollment,
management guidelines detailed in Table 6-7 must be followed.
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected in triplicate.
Local cardiologist ECG assessment may be performed at any time during the study at the 
discretion of the investigator.
In the event that a QTcF value of ≥501 ms is observed or if an unscheduled ECG is 
performed for safety reasons, it is recommended to collect a time-matched blood sample for 
PK and record the time and date of the last study drug intake to determine plasma levels of 
ribociclib and any other identified metabolites.
Table 7-5
Central ECG Collection Plan
Cycle
Patients
Day
Sampling Timea, 
b
ECG Type
Screening
All
-7 to -1
Anytime
Triplicate 12 Lead
1
All
Day 15
pre-dosed
Triplicate 12 Lead
2 h post-dose (± 15 
min)
Triplicate 12 Lead
4 h post-dose (± 15 
min)
Triplicate 12 Lead
2
All
Day 1
pre-dosed
Triplicate 12 Lead
2 h post-dose (± 15 
min)
Triplicate 12 Lead
4 h post-dose (± 15 
min)
Triplicate 12 Lead
All
Day 15
pre-dosed
Triplicate 12 Lead
2 h post-dose (± 15 
min)
Triplicate 12 Lead
4 h post-dose (± 15 
min)
Triplicate 12 Lead
3
All
Day 1
pre-dosed
Triplicate 12 Lead
4
All
Day 1
pre-dosed
Triplicate 12 Lead
5
All
Day 1
pre-dosed
Triplicate 12 Lead
6
All
Day 1
pre-dosed
Triplicate 12 Lead
9th and every 3rd 
cyclec
For patients
with QTcF ≥481 ms 
at any time prior to 
cycle 7
Day 1
pre-dose
Single 12 Lead


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Cycle
Patients
Day
Sampling Timea, 
b
ECG Type
Unscheduled
As clinically 
indicated
Triplicate 12 Lead
End of Treatment
Within 15 days of 
last dose
Triplicate 12 Lead
a. All measurement times are relative to dose of ribociclib unless otherwise specified.
b. If both ECG and PK sample are scheduled at the same time, the PK sample should be taken immediately 
(within 1 hour) after ECG assessment
c. Pre-dose ECG on the first day of every cycle. Additionally, 2 h post-dose in every 3rd cycle (i.e. Cycle 9, 12, 15, 
18, etc.).
d. The exact date and time of dosing must be recorded on the appropriate eCRF.
All ECGs including unscheduled triplicate ECGs with clinically relevant findings, collected 
during the study should be transmitted to a central laboratory and will be centrally reviewed 
by an independent reviewer. Each ECG tracing should be labeled with the study number, patient
number, date, and kept in the source documents at the study site. Clinically significant ECG
abnormalities present at screening when the patient signs informed consent should be recorded
on the relevant medical history/current medical conditions eCRF page. New or worsened 
clinically significant findings occurring after informed consent must be recorded on the Adverse 
Events CRF page
7.2.2.6.2 Cardiac imaging - ECHO (echocardiogram) or MUGA (multiple gated 
acquisition) scan
The left ventricular heart function will be evaluated by ECHO or MUGA at Screening and if
clinically indicated during the study. The same procedure should be used throughout the study.
7.2.3
Pharmacokinetics
The blood sampling regimens for determining the PK of ribociclib (and its active metabolite, 
LEQ803) and everolimus after oral administration are given in the table below (Table 7-6).
An unscheduled PK blood sample may be collected at any time for measurement of plasma 
drug concentrations if clinically indicated or at the Investigator’s discretion. If a patient 
discontinues from the study treatment due to toxicities related to study treatment, an 
unscheduled PK blood sample may be obtained as soon as possible after the last dose and the 
date and time of last dose recorded. In addition, an unscheduled blood sample may be collected 
if additional ECG measurements are conducted.
 
 
 
 


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7.2.3.1
Pharmacokinetic blood sample collection and handling
7.2.3.1.1 Blood collection plan
Phase I and II: PK sampling will be performed in all subjects treated in the Phase I and Phase 
II parts of this study. Blood for PK profiling of ribociclib (and its metabolite) and everolimus
will be collected on Cycle1 Day 15, Cycle 2 Days 1 and Day 15 and Cycle 3 Day 1 (see Table 
7-6).
For subjects who were previously treated with a CDK 4/6 inhibitor within 30 days of starting 
study drug will require PK sample on Cycle 1 Day 1
Table 7-6
Schedule of blood sample collection for PK in phase I and II 
Cycle
Day
Scheduled Time Point Relative to Dosing
Blood Volume
(mL)
1
1
Pre-dose (if previously treated with a CDK 4/6 i)
3
15
Pre-dosea
3
2 h post-dose (± 30 min)
3
4 h post-dose (± 30 min)
3
2
1
Pre-dosea
3
15
Pre-dosea
3
2 h post-dose (± 15 min)
3
4 h post-dose (± 15 min)
3
3
1
Predose
3
Unscheduled
Anytime b
3
a. Collect Pre-dose PK sample immediately before drug administration (approximately 24-hrs after the 
last dose and immediately before the next dose)
b. Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, sequentially 
numbered.
7.2.3.1.2 Additional guidelines for PK sampling/ECG
On days with PK sampling and/or ECG testing (collection days are outlined in Table 7-6), the 
following additional guidelines must be followed:

Pre-dose ECGs and/or PK samples should be collected before dosing of the study 
treatment.

ECGs should be done prior to PK sampling.


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
The time of PK collection and the time the study medication was taken must be precisely
recorded in the eCRF.

Sites must record the precise date and time of the last study treatment prior to PK
collection in the eCRF.

Post-dose ECGs and/or PK samples should be collected after dosing of the study 
treatment.
The date and exact time of dosing on PK collection days, as well as the date and actual time of 
blood sampling must be recorded on the appropriate eCRF pages. In addition, the exact time 
of dosing on the previous day must be precisely recorded.
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed, and 
medication should resume on the next day. The occurrence and frequency of any vomiting 
must be noted in the adverse events section of the eCRF. In addition, the date and exact time 
of vomiting should only be recorded if it occurs within 4 hours of dosing on the days of PK 
sampling. If a vomiting episode occurs within the first 4 hours post-dosing during the day of 
the last dose prior to trough PK samples the exact time (whenever possible) must be noted on 
the eCRF.
PK parameters (eg. Cmax, Tmax, AUC0-6h, etc.) will be estimated (when feasible) from individual 
plasma concentration-time profiles using appropriate methods and software; a detailed 
description of the planned analyses is given in Table 7-6.
7.2.3.1  Pharmacokinetic blood sample collection and handling
Blood samples will be obtained from all patients either by direct venipuncture or through an 
indwelling cannula (e.g., inserted in a forearm vein, or central venous line) for the analysis of 
plasma concentrations of ribociclib (and any relevant metabolites such as LEQ803), when 
feasible. At the specified time points described in Table 7-1 and Table 7-5, one single 3mL 
blood draw will be collected into a tube containing EDTA and gently inverted several times to 
thoroughly mix the anticoagulant. The blood tube will be centrifuged to separate the plasma. 
Plasma will immediately be split and transferred into separate pre-labeled tubes for ribociclib. 
Plasma samples will be stored frozen in an upright position until shipment.
Any sampling problems (e.g., patient took study drug before blood sample, scheduled sampling 
time is missed, sample is not drawn according to the schedule) should be noted as a 
comment on the eCRF. Refer to the Laboratory Manual for detailed instructions for the 
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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).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
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)


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4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a SAE is defined as in Section 8.2.
If the event worsened the event should be reported a second time in the CRF noting the start
date when the even worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the CRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1 criteria), should not be reported as a serious adverse 
event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for adverse events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.


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8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening.

Results in persistent or significant disability/incapacity.

Constitutes a congenital anomaly/birth defect.

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:
1. Routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition
2. 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
3. Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given 
above is not a serious adverse event
8.2.2
Reporting
For all patients who sign the study ICF, SAE collection starts at time of study informed consent 
whether the patient is a screen failure or not. To ensure patient safety, every SAE, regardless of 
suspected causality, occurring after the patient has provided informed consent and until at least 
30 days after the patient has stopped study treatment must be reported to Novartis within 24 
hours of learning of its occurrence.
Any SAEs experienced after this 30 days period (or 5 half-lives, whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and fax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder provided to 


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each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
8.3
Pregnancy
This protocol will enroll only men and post-menopausal women (chemical ovarian suppression 
allowed).
If a female subject, or a female partner of a male subject should become pregnant, to ensure 
safety, each pregnancy occurring while the patient is on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E).
Pregnancy follow-up should be recorded on the same form and should include an assessment
of the possible relationship to the investigational treatment any pregnancy outcome. Any SAE
experienced during pregnancy must be reported on the SAE Report Form. 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’s 
Brochure for ribociclib and the approved package inserts for everolimus and exemestane.
Additional safety information collected between IB updates will be communicated in the form 
of INs. This information will be included in the patient informed consent and should be 
discussed with the patient during the study as needed.
8.4
Data Monitoring Committee
An independent data monitoring committee (IDMC) will be established to assess the safety 
efficacy of ribociclib. The IDMC will be responsible for reviewing the efficacy and safety data 


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accruing in the trial at regular intervals of approximately every three months or when 25%, 50%, 
75% and 100% of the patients are enrolled whichever occurs first. Also, if requested by the 
IDMC Chair, additional safety reviews may be performed.
The IDMC will consist of at least one oncologist, one hepatologist and one statistician and will 
be formed prior to the study treatment of the first patient. Detailed recruitment status and interim 
safety reports will be provided to the IDMC on a regular basis. Recruitment will not be 
interrupted during IDMC analysis. Details will be provided in the IDMC charter.
8.5
Steering committee
The SC will be established comprising investigators participating in the trial, and Novartis 
representatives from the Clinical Trial Team.
The SC will be an advisory board for the study according to the protocol through 
recommending modifications as circumstances require. The SC will be consulted for protocol 
amendments as appropriate. Together with the clinical trial team, the SC will also develop 
recommendations for publications of study results. The details of the role of the SC will be 
defined in a SC charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRF’s 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 eCRF’s, the adherence to the 


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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 eCRF’s must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency
with
the
eCRF
entries. 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 
eCRF’s are performed according to the study-specific monitoring plan.
9.3
Data collection
This study will use Electronic Data Capture (EDC). The designated investigator staff will enter
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRF’s
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 
eCRF’s 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.
Blood and tumor samples for  PK
assessments will be collected by sites and
sent to the Novartis designated central laboratory for processing. The laboratory results and
IRT data will be sent electronically to Novartis. Imaging and ECG data will be collected at the
sites and the data will be transmitted to a designated CRO for centralized analysis, as well as 
further processing and data reconciliation.
Designated investigational site staff will enter the information required by the protocol into 
the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
review the eCRF’s and laboratory paper requisition forms for accuracy and completeness and 
will instruct site personnel to make any required corrections or additions. One copy of the 
requisition form will be forwarded to each analytical laboratory with the respective sample(s) 
by the field monitor or by the designated investigational site staff, and one copy will be retained 
at the investigational site.
9.4
Data management and quality control
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 


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investigational site via the EDC system. Designated investigator site staff is 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 collected for all third party data such as ECG, PK
will be 
processed centrally and the results will be sent electronically to Novartis (or a designated CRO).
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and data made available for data analysis. Authorization is required prior to 
making any database changes to locked data, by joint written agreement between Novartis and 
the CRO biostatistician and database management. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site.
10
Statistical methods and data analysis
Data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 
respect to demographic and baseline characteristics, efficacy and safety observations and 
measurements using descriptive statistics (quantitative data) and contingency tables (qualitative 
data).
The study data will be analyzed and reported based on all patients’ data up to the time when 
all patients have potentially completed at least six cycles of treatment or discontinued the study.
Any additional data for patients continuing to receive study treatment past the data cutoff date 
for the primary Clinical Study Report will be reported once all patients have discontinued the 
study or at the end of the study, whichever occurs first.
Data will be summarized and listed by study group.
For safety endpoint, all patients will be analyzed for each phase and may be pooled for analysis.
The efficacy data that will be analyzed for Phase I and Phase II of this study separately 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected, will not be included in 
any analysis, but will be reported in the CSR as separate listings.


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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.
10.1
Analysis sets
10.1.1
Full analysis set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of the
assigned combination of study drugs (ribociclib+ everolimus + exemestane).
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of any of the components 
from the investigational treatment, and have at least one valid post-baseline safety assessment. 
Investigational
treatment/group
refers
to
the
triplet
combination
of
ribociclib
+
everolimus + exemestane. The statement that a patient had no AEs (on the AE eCRF)
constitutes a safety assessment.
10.1.3
DLT-determining analysis set
The DLT-determining set (DDS) includes all patients from the safety set in the dose escalation 
part who either completed a minimum exposure requirement and have sufficient safety 
evaluations in the first cycle or discontinued prematurely due to a dose limiting toxicity (DLT).
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% of the planned combination doses (i.e. 21 out of 28 planned daily doses) for all 
compounds administered together (same day): ribociclib, everolimus and exemestane. The 
length of a cycle is 28 days.
Patients who do not experience a DLT during the first cycle will be considered to have sufficient
safety evaluations if they have been observed for ≥28 days following the first dose, and are
considered by both the Sponsor and Investigators to have enough safety data to conclude that 
a DLT did not occur.
10.1.4
Pharmacokinetic analysis set
The PK analysis set (PAS) consists of all patients who have at least one blood sample providing 
evaluable PK data. The PAS will be used for summaries of PK data (tables and figures) as well 
as for listings of derived parameters.
10.1.5
Per-protocol set
A subset of Full Analysis Set (FAS) excluding major protocol violations
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including age, gender, height, weight, medical condition,
and disease characteristics will be summarized descriptively. Treatments (study treatment,
concomitant therapies, compliance).


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
The actual dose and duration in days of ribociclib, everolimus and exemestane as well as the 
dose intensity (based on actual dose received and actual duration) and the relative dose intensity
(computed as the ratio of dose intensity and planned dose intensity based on planned dose and 
planned duration), will be listed and summarized by means of descriptive statistics. The
summary data will be presented for each treatment cycle individually, as well as for all study 
days as a single category. The total daily doses of ribociclib, everolimus and exemestane for 
each patient will be summarized using descriptive statistics (e.g. mean, median, maximum and 
minimum doses).
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (Anatomical Therapeutic 
Chemical Classification System) term. These summaries will include medications starting on
or after the start of study treatment or medications starting prior to the start of study treatment
and continuing after the start of study treatment. Any prior concomitant medications or
significant non-drug therapies starting and ending prior to the start of study treatment will be 
listed.
10.3.3
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by treatment group/study arm. Compliance to the study drug will be assessed by 
the number of dose reductions and dose interruptions).
10.4
Statistical hypothesis, model, and method of analysis
10.4.1
Study Design
This is a multi-center, open-label, Phase I/II study consisting of both Phase I dose escalation
and dose de-escalation, and a Phase II. The dose escalation and de-escalation part of the trial
will be conducted in men and postmenopausal women with HR+ HER2-negative advanced
breast cancer that is endocrine resistant. Phase II will evaluate the antitumor activity of the
combination of ribociclib +everolimus + exemestane combination in men and postmenopausal 
women with HR+HER2- advanced breast cancer that progressed on a CDK4/6 inhibitor. 
10.4.2
Sample size and accrual
Phase I: In the phase I of the study, there will be 3-6 patients per dose level cohort (for a total 
of 3 cohorts). A RP2D will be based on safety profile of the dose escalation (cohort A&B) and 
the dose de-escalation (cohort C). RP2D will be defined as the optimal dose level at which 33% 
or less experience DLTs.  Thus, including confirmation, at least 3-6 patients will be required 
for Phase I for each cohort.


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Phase II:
The sample size is based on an exact test for single proportion to test the null hypothesis H0: p 
≤ 0.10 where p is the clinical benefit rate in 24 weeks. If the true rate is p ≥ 30%, then with 
one-sided alpha level of 0.05% and a power of 80%, a minimum of approximately 60 (30 per 
group) evaluable patients are required for the study.
Including drop out rate of 10%, to get 60 evaluable patients, a total of approximately 66 
pateints (33 patients per group) will be enrolled for the phase 2 of the study for each group
(group 1 and group 2). Thus, if fewer than 8 patients show clinical benefit at 24 weeks out of 
33 patients within each group then the study will not show significant clinical benefit. Thus,
approximately at least 66 patients (33 patients per group (group 1&2)) will be required to be 
enrolled for the Phase II of the study
10.5
Objectives
10.5.1
Primary objectives
Phase I: The primary objective of this dose escalation part of the study is to estimate the 
MTD(s) and/or RP2D of ribociclib in combination with everolimus and exemestane in 
postmenopausal women with HR+ HER2−advanced breast cancer.
Phase II: The primary objective is to evaluate efficacy measured by Clinical benefit rate 
(CBR) at 24 weeks for the triple combination of ribociclib + everolimus + exemestane among 
patients with HR+HER2- advanced breast cancer following the progression of CDK 4/6 
inhibitors.
Demonstration of significant Clinical Benefit Rate (CBR) will be based on this study with at 
least an 80% power to test the null hypothesis that the clinical benefit rate in 24 weeks is at least 
10% or less with an alternative hypothesis that this rate is above 10%.
The Clinical benefit rate will be presented together with an exact 95% Clopper-Pearson 
confidence interval. The null hypothesis will be rejected and successful clinical benefit will be 
demonstrated if the lower limit of the 95% confidence interval is greater than at least 0.10.
Thus, if 8  or more patients show clinical benefit at 24 weeks then the null hypothesis will be 
rejected and significant clinical benefit will be demonstrated. Primary efficacy analysis will be 
performed on the FAS. For primary efficacy variable, the analysis time point is when all 
patients who are enrolled complete 24 weeks or discontinue from the study earlier.  Phase 1 
patients who had received the RP2D and are post CDK 4/6 completing 24 weeks or 
discontinue early will also be included in the final phase II analysis.
10.5.2
Secondary objective(s)
Progression-free survival (PFS), defined as the time from date of treatment to the date of first 
documented progression or death due to any cause.
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Patients who do not 
progress will be censored at the last adequate assessment. Estimates of the 25th, median and 
75th percentile of the PFS and their 95% confidence intervals will be provided, if applicable. 


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Overall response rate (ORR) defined as the proportion of patients whose best overall response 
is either complete response (CR) or partial response (PR) according to RECIST 1.1. ORR will 
be calculated based on FAS according to the IIT principle; however, patients with only non-
measurable disease at baseline will be included in the numerator if they achieved a complete 
response. ORR will be summarized by frequency and percentage. Disease Control Rate (DCR)
in Phase I will be summarized by prior CDK 4/6 inhibitor treatment status with accompanying 
95% confidence intervals. 
Overall survival (OS) is defined as the time from date of first treatment to the date of death due 
to any cause. If a patient is not known to have died, survival will be censored at the last date of 
contact. OS will also be summarized by Kaplan-Meier Product-Limit method.
Duration of Overall Response (DOR) applies only to patients whose best overall response is 
CR or PR according to RECIST 1.1. The start date is the date of first documented response (CR 
or PR) and the end date is the date defined as first documented progression or death due to 
underlying cancer. In other words, the start date should be determined using the time that the 
response was first determined and not using the time the response was confirmed. If a patient 
had not had an event, duration will be censored at the date of the last adequate tumor assessment. 
DOR will be listed and summarized by treatment arm. 
ECOG performance scale as described in Table 7-3 will be used to assess physical health of 
patients. An analysis of time to definitive deterioration of the ECOG PS by one category of the 
score from baseline will be performed. Deterioration is considered definitive if no
improvements in ECOG PS status is observed at a subsequent time of measurement during 
treatment period following the time point where the deterioration is observed.
Adverse Events (AEs), serious AE (SAEs), changes in hematology and chemistry values, vital 
signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity 
To determine the PK profile of ribociclib and everolimus in the triplet combination. PK 
parameters including, but not limited to, AUC0-6h, Ctrough, Cmax, accumulation ratio (Racc) 
10.5.2.1 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and preferred term, severity (based on CTCAE grades), 
relation to study treatment by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
10.5.2.2 Laboratory abnormalities
For laboratory tests covered by CTCAE version 4.03, the study’s bio statistical and reporting 
team will grade laboratory data accordingly. For laboratory tests covered by CTCAE, a Grade
0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used.


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For laboratory tests where Grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by a clinical meaningful limit.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

Frequency table for newly occurring on-treatment Grades 3 or 4.

Shift tables using CTCAE Grades to compare baseline to the worst on-treatment value.

For laboratory tests where CTCAE Grades are not defined, shift tables using the 
low/normal/high/ (low and high) classification to compare baseline to the worst on-
treatment value.
Listing of all laboratory data with values flagged to show the corresponding CTCAE Grades 
and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other
analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the Report and Analysis Plan (RAP).
10.5.2.3 Other safety data
Vital sign and ECG data will be summarized descriptively.
All safety information collected will be listed and notable values will be flagged. Any statistical
tests performed to explore the data will be used only to highlight any interesting comparisons
that may warrant further consideration.
10.5.2.4 Supportive analysis for secondary objectives
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the RAP Module 3 prior to DBL.
10.5.2.5 Tolerability
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized. Cumulative dose, dose intensity and relative dose intensity 
of ribociclib, everolimus and exemestane will be listed by patient and summarized. Categories
for relative dose intensity for ribociclib, everolimus and exemestane will be specified as <0.5, 
≥0.5 - <0.75, ≥0.75 - <0.9, ≥0.9 - <1.1 and ≥1.1. The number and proportion of patients within 
each category will be presented.
10.5.3
Pharmacokinetics
Ribociclib and everolimus concentrations for all PK-evaluable patients will be summarized 
based on timepoints (listed in Table 7-6). The LLOQ for ribociclib (and LEQ803) in plasma
is approximately 1.00 ng/mL. The LLOQ for everolimus in whole blood is approximately 
0.3 ng/mL. The LLOQ for exemestane in plasma is approximately 0.0200 ng/mL. All
concentrations below the LLOQ or missing data will be labeled as such in the concentration 


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data listings.
 
Table 10-1
Non-compartmental pharmacokinetic parameters
Parameter
Definition
Cmax
Maximum observed drug concentration after drug administration (mass x volume-1 )
Ctrough
Minimum drug concentration at the end of a dosing interval (taken directly before next 
administration) (mass x volume-1)
Tmax
Time to reach maximum plasma/blood/serum drug concentration (time)
AUC 0-6h
Area under the drug concentration-time curve during a dosing interval (mass x time x 
volume-1)
Racc
Accumulation ratio calculated as AUC τ ,ss / AUC τ,sd
T1/2
Effective elimination half-life (time)
CL
Apparent total body clearance of drug (volume x time-1)
10.5.3.1
Data handling principals
10.5.3.1.1
Basic tables, figures amd listings
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented 
for all PK parameters by treatment group and study day. When a geometric mean is presented,
it will be stated as such. Only median values and ranges will be given for Tmax.
Descriptive graphical plots of individual plasma concentration by time will be generated, as 
will mean concentration-time profiles for ribociclib (and LEQ803) and everolimus. Details of 
PK analysis presented will be given in the Reporting and Analysis Plan (RAP).
 


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10.7
Interim analysis
No formal interim analysis is planned  One interim statistical analysis will be done after 
completing Phase I part of the study. The final analysis will be after completing Phase II of the 
study.
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. Prior to study start, the investigator is required
to sign a protocol signature page confirming his/her agreement to conduct the study in
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis
Clinical
Quality Assurance
representatives,
designated
agents
of
Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written, IRB/IEC/REB-
approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed Informed Consent 
Form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.


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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.
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 subjects. 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, subjects’ diaries or evaluation
checklists, pharmacy dispensing records, recorded data from automated instruments, copies
or transcriptions certified after verification as being accurate and complete, microfiches,
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility,
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source
documents or the discrepancies should be explained. All data requested on the CRF must
be recorded. Any missing data must be explained. Any change or correction to a paper CRF
should be dated, initialed, and explained (if necessary) and should not obscure the original
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.


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Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to 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 but not later than 10 working days.
13
References (available upon request)
Afinitor® (package insert). East Hanover, NJ : Novartis Pharmaceuticals Corp; 2012.
Aromasin (package insert). New York, NY : Pfizer-Pharmacia; 2013.


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Bachelot T, et al (2012). Randomized phase II trial of everolimus in combination with 
tamoxifen in patients with hormone receptor-positive, human epidermal growth factor 
receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a 
GINECO study. J Clin Invest. 30(22):2718-24. doi: 10.1200/JCO.2011.39.0708
Bardia A, et al (2015) Triplet therapy with ribociclib, everolimus, and exemestane in women 
with HR+/HER2– advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth 
Annual CTRC-AACR San Antonio Breast Cancer Symposium [poster]: 2015 Dec 8-12; San 
Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-01.
Baselga J, Campone M, Piccart M, Burris HA et al (2012) Everolimus in postmenopausal 
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14
Appendices
14.1
Appendix 1- Concomitant medication
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or ribociclib.
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
and Co-Medication Considerations (v05 release date: 2015), which was compiled from the 
Indiana 
University 
School 
of 
Medicine’s 
“Clinically 
Relevant” 
Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(February 
2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm292362.pdf), and the University of Washington’s Drug Interaction Database 
(.druginteractioninfo.org/). For current lists of medications that may cause QT prolongation 
and/or torsade’s de pointes (TdP), refer to the CredibleMeds® website (www.qtdrugs.org/).
These lists are not comprehensive and are only meant to be used as a guide. Please contact the 
medical monitor with any questions.
Table 14-1
List of prohibited medications during study drug treatment
Category
Drug Name
Strong CYP3A4/5 inhibitors
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, elvitegravir/ritonavir, grapefruit juice, indinavir/ritonavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, troleandomycin, voriconazole
Strong CYP3A4/5 inducers
Carbamazepine, lumacaftor, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampin (rifampicin)3, St. John's wort (hypericum perforatum)3, enzalutamide
CYP3A substrates with NTI1
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, lomitapide5, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, simvastatin, sirolimus, 
tacrolimus
Medications with a known risk 
for QT prolongation4
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin,bepridil
chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, levomethadyl, mesoridazine methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, probucol, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, 
terlipressin, terodiline, terfenadine, thioridazine, vandetanib,
Herbal preparations/ 
medications
Herbal preparations/medications known as strong inducers or inhibitors of
CYP3A4/5 or those with a known risk of QT prolongation are prohibited 
throughout the study. These herbal medications include, but are not limited 
to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 7 days prior to first dose 
of study drug.


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Category
Drug Name
Other investigational and 
antineoplastic therapies
Other investigational therapies must not be used while the patient is on the 
study. Anticancer therapy (chemotherapy, hormonal therapy, including but 
not limited to all SERMS [inclduing raloxifene], biologic or radiation therapy
[except for palliative radiotherapy as outlined in the protocol],and surgery) 
other than the study treatments must not be given to patients while the 
patient is on the study medication. If such agents are required for a patient 
then the patient must discontinue study drug.
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure 
levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de 
Pointes), or drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective
concentrations in the blood.
2 Herbal product
3 P-gp inducer
4 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for
the most updated list.
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of 
ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, 
or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at www.qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers.
Table 14-2
List of medications to be used with caution during study drug 
treatment
Category
Drug Name
Moderate CYP3A4/5 inhibitors
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine,
crizotinib, diltiazem, faldaprevir, imatinib, isavuconazole, netupitant, nilotinib, 
tofisopam, Schisandra sphenanthera (nan wu wei zi), verapamil
Moderate CYP3A4/5 inducers
Bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
telotristat, lopinavir5
Sensitive CYP3A4/5
substrates1
Alpha-dihydroergocryptine, apixaban, aprepitant, atorvastatin, avanafil,
bosutinib,brotizolam, budesonide, buspirone, cobimetinib, darifenacin, 
dasatininb, ebastine, eletriptan, eplerenone, everolimus, felodipine, 
fluticasone, grazoprevir, ibrutnib, isavuconazole, ivabradine, ivacaftor, 
lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, naloxegol, 
neratinib, perospirone, quetiapine, ridaforolimus, rivaroxaban, sildenafil, 
simeprevir, ticagrelor, tilidine, tolvaptan, triazolam, ulipristal, vardenafil, 
venetoclax, vicriviroc, voclosporin-
BSEP inhibitors
Alectinib, atorvastatin, bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, mifepristone, 
pioglitazone, reserpine, rifamycin, simeprevir, telmisartan, timcodar, 
troglitazone, valinomycin, velpatasvir


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Category
Drug Name
Medications that carry a 
possible risk for QT 
prolongation2
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine,
atazanavir, atomoxetine, bedaquiline, bendamustine, bortezomib, bosutinib, 
buprenorphine, cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib, 
clozapine, cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, 
epirubicin, eribulin mesylate, ezogabine(retigabine), famotidine, felbamate, 
fingolimod, flupentixol, gemifloxacin, granisetron, hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, ketanserin, lapatinib, 
lenvatinib, leuprolide, loperamide, lithium, melperone, midostaurin, 
mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, , 
nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, lanzapineosimertinib, 
oxytocin, paliperidone, palonosetron, panabinostat, pasireotide, pazopanib, 
perflutren lipid microspheres, perphenazine, pilsicainide, pimavanserin, 
pipamperone, promethazine, prothipendyl, quetiapine, ranolazine rilpivirine, 
risperidone, romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, 
telavancin,tetrabenazine, tipiracil/trifluridine, tizanidine, 
tolterodine,oremifene,trimipramine, tropisetron, vardenafil, vemurafenib, 
venlafaxine, vorinostat, ziprasidone
MATE1/2 substrates3
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium,
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline
OCT2 substrates4
Amantadine, 6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin,
cephradine, ipratropium, lamivudine, linagliptin, metformin, oxyplatin, 
oxybutynin, phenformin, picoplatin, pilsicainide, pindolol, ranitidine, sorafenib, 
tropisetron, trospium, umeclidinium,, and zidovudineAcyclovir,
BCRP substrates
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib,
methotrexate, mitoxantrone, pitavastatin, rosuvastatin, irinotecan,
ethinyl estradiol, sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax..
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor.
2 The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list
3MATE1 and MATE2 share considerable substrate specificity.
4OCT1 and OCT2 share considerable substrate specificity.
5 Lopinavir is prohibited when combined with ritonavir
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana University 
“Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction Database, and 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.2


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14.2
Appendix 2 - Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
14.2.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.2.2 and the definition of best response in
Section 14.2.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.28 of 
this guideline describes data handling and programming rules. This section is to be referred to
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.2.2
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.


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14.2.3
Definitions
14.2.4
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.2.26.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to <15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.


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14.2.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
if she/he has bone only disease (if lytic or mixed) See section 5 eligibility criteria. Guidance on 
how patients with just non-measurable disease at baseline will be evaluated for response and 
also handled in the statistical analyses is given in Section 14.2.26.
14.2.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).


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
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. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.2.7
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).


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Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.2.4.

Nodal target: See Section 14.2.4.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.2.8
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-3) and non-target lesions (Table 14-4) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-5) as well as the presence or absence of new lesions.
14.2.9
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
14.2.10
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm,
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 


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should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
14.2.11
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.2.12
Determination of target lesion response
Table 14-3
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to <10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3. Methodology change See Section 14.2.6.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 


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and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-3 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.


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
Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.
14.2.13
Determination of non-target lesion response
Table 14-4
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (<10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. <10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.2.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.


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14.2.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.2.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.2.6.
14.2.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in
Table 14-5.
Table 14-5
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 14.2.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.


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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.2.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.2.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required


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
SD = at least one SD assessment (or better) >6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying for 
CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

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.


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Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
14.2.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.2.19
Progression-free survival
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.2.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.2.21
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.


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Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.2.22
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.2.23
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988)
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.


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The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.2.24
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.2.23. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.2.25
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.


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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 14.2.26).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.2.26
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.


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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 14-6.
Table 14-6
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.2.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.2.27
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned And should progression event be ignored if it occurred after a long period of 
a patient being lost to follow-up? It is important that the protocol and RAP specify the primary 
analysis in detail with respect to the definition of event and censoring dates and also include a
description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.2.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:


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Table 14-7
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.=Definitions can be found in Section 14.2.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.1.25.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.


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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-7 the
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.2.28
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.2.29
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and agreed 
with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.2.30
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 15 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision


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
Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
14.2.31
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.2.32
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the investigator or central reader’s response 
assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 


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RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.2.33
Programming rules
The following should be used for programming of efficacy results:
14.2.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.35
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.2.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.2.36
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.2.37
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.2.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.39
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.


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For survival the following censoring reasons are possible:

Alive

Lost to follow-up

For PFS and TTP (and therefore duration of responses) the following censoring reasons 
are possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-7)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.2.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:
This may be when there has been a definite decision to stop evaluation (e.g. reason=“Sponsor 
decision” on study evaluation completion page), when patients are not followed for progression 
after treatment completion or when only UNK assessments are available just prior to data cut-
off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.2.40
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18


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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
14.3
Appendix 3 - Bone Marrow Reserve in Adults
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol. 5, 255-258, 1961
Table 14-8
Marrow distribution of the adult
SITE
MARROW
wt. (g)
FRACTION 
RED MARROW 
AGE 40
RED MARROW 
wt. (g)
AGE 40
% TOTAL RED 
MARROW
CRANIUM 
AND
MANDIBLE
Head:
Cranium
Mandible
165.8
16.4
0.75
0.75
136.6
124.3
12.3
13.1
13.1
HUMERI, 
SCAPULAE, 
CLAVICLES
Upper Limb Girdle :
2 Humerus, head & 
neck
2 Scapulae
2 Clavicles
26.5
67.4
21.6
0.75
0.75
0.75
86.7
20.0
50.5
16.2
8.3
8.3
STERNUM AND
RIBS
Sternum
Ribs:
1 pair
2
3
4
5
6
7
8
9
10
11
12
39.0
10.2
12.6
16.0
18.6
23.8
23.6
25.0
24.0
21.2
16.0
11.2
4.6
0.6
All 0.4
23.4
82.6
4.1
5.0
6.4
7.4
9.5
9.4
10.0
9.6
8.5
6.4
4.5
1.8
2.3
7.9
10.2
PELVIC BONES
Sacrum
2 os coxae
194.0
310.6
0.75
0.75
145.6
233.0
13.9
22.3
36.2
FEMUR
2 Femoral head
and neck
53.0
0.75
40.0
3.8

SAP_001.pdf: 
Clinical Development
LEE011/ Ribociclib
CLEE011XUS29 / NCT02732119
TRINITI-1: A Phase I/II, single arm, open-label study of 
Ribociclib in Combination with Everolimus + Exemestane 
in the Treatment of Men and Postmenopausal Women with 
HR+, HER2- Locally Advanced or Metastatic Breast Cancer 
Following Progression on a CDK 4/6 Inhibitor 
Triplet with Ribociclib, AfINItor™ and AI posT CDK 4/6 Inhibitor 
Statistical Analysis Plan (SAP)
Author:
Statistician:
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
03-Jun-2020
Number of pages:
512
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
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Page 2
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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)
26-Sep-18
Prior to 
DB 
lock
Creation of final 
version
N/A - First version
NA
03-Jun-20
Prior to 
DB 
lock
Team decided  to 
remove PK 
parameter analysis
as it will be 
pulished outside 
of CSR
Removed PK 
parameter details from 
section 3.4 and added 
text that PK parameter 
will be summarized 
outside of CSR
Section 3.4


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Page 3
SAP
CLEE011XUS29
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
Figure 1-1 Study Design.............................................................................................................9
1.1.1
Timing of interim analyses....................................................................10
1.1.2
Definition of end of study .....................................................................10
1.1.3
Early study termination.........................................................................10
1.2
Study objectives and end points ............................................................................10
1.2.1
Phase I...................................................................................................10
1.2.2
Phase II..................................................................................................11
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................16
2.2.1
Full analysis set.....................................................................................16
2.2.2
Safety set ...............................................................................................16
2.2.3
DLT-determining analysis set...............................................................16
2.2.4
Pharmacokinetic analysis set.................................................................17
2.2.5
Per-protocol set .....................................................................................17
17
2.2.7
Subgroup of interest ..............................................................................17
2.3
Concomitant medications with specific impact on the analysis ............................17
2.3.1
Inducers, inhibitors and substrates of CYP3A......................................17
3
General Strategies for Data Presentation...........................................................................19
3.1
Patient disposition, demographics and other baseline characteristics ...................19
3.1.1
Patient disposition.................................................................................19
3.1.2
Demographic and baseline characteristics variables.............................20
3.1.3
Medical history......................................................................................22
3.1.4
Diagnosis and extent of cancer .............................................................22
3.1.5
Other baseline characteristics................................................................22
3.1.6
Prior, concomitant and post therapies...................................................22
3.1.7
Prior antineoplastic therapy...................................................................23
3.2
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
3.2.1
Study treatment exposure......................................................................23


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3.2.2
Study treatment .....................................................................................24
3.2.3
Dose change or interruptions ................................................................24
3.2.4
Compliance ...........................................................................................25
3.3
Efficacy Evaluations..............................................................................................25
3.3.1
Disease assessment................................................................................25
3.4
PK evaluations.......................................................................................................29
3.5
Analysis of the primary objective..........................................................................29
3.5.1
Primary end point..................................................................................29
3.5.2
Statistical hypothesis, model, and method of analysis..........................29
3.5.3
Handling of missing values/censoring/discontinuations.......................31
3.5.4
Supportive analyses...............................................................................31
3.6
Analysis of the key secondary objective ...............................................................31
3.7
Analysis of secondary efficacy objective(s)..........................................................31
3.7.1
Secondary end points ............................................................................32
3.7.2
Statistical hypothesis, model, and method of analysis..........................32
3.7.3
Handling of missing values/censoring/discontinuations.......................36
3.8
Safety analyses.......................................................................................................36
3.8.1
Adverse events (AEs)............................................................................36
3.8.2
Deaths....................................................................................................37
3.8.3
Laboratory data .....................................................................................37
3.8.4
Other safety data ...................................................................................38
3.9
Pharmacokinetic end points...................................................................................41
3.10
PD and PK/PD analyses.........................................................................................41
3.11
Patient-reported outcomes .....................................................................................41
41
44
44
44
3.15
Interim analysis......................................................................................................45
4
Sample size calculation .....................................................................................................45
5
Change to protocol specified analyses ..............................................................................46
6
Appendix ...........................................................................................................................46
6.1
Imputation rules.....................................................................................................46
6.1.1
Study drug.............................................................................................46
6.1.2
AE date imputation ...............................................................................47
6.1.3
Concomitant medication date imputation .............................................48


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6.2
AEs coding/grading ...............................................................................................50
6.3
Laboratory parameters derivations ........................................................................50
6.3.1
Differential Counts:...............................................................................50
6.4
Statistical models...................................................................................................50
6.4.1
Analysis of Response Rate....................................................................50
6.4.2
Time to event analysis...........................................................................51
6.5
Rule of exclusion criteria of analysis sets..............................................................51
7
Reference...........................................................................................................................51


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
BMI 
Body Mass Index
CBR 
Clinical Benefit Rate
CDK
Cyclin-Dependent Kinases
Cmax
Peak blood concentration
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization
CSR 
Clinical Study report
CT
Computed Tomography 
CTC 
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR 
Dose Administration Record
DCR
Disease Control Rate
DDS 
DLT-determining set 
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
FDG 
Fluorodeoxyglucose 
HER2
Human Epidermal Growth Factor Receptor 2
HR
Hormone receptor
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IVR
Interactive Voice Response
IWR
Interactive Web Response
LLOQ
Lower Limit of Quantification
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI 
Magnetic Resonance Imaging
MTD 
Maximum Tolerated Dose
NCI 
National Cancer Institute
NCRNPD
Non-CR Non-PD
o.d.
Once Daily
ORR
Objective Response Rate
OS
Overall Survival


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PAS 
Pharmacokinetic Analysis Set
PD
Progressive Disease
PET
Positron Emission Tomography 
PFS 
Progression-Free Survival
PK 
Pharmacokinetics
PPS 
Per-Protocol Set
PR
Partial Response
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 
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP 
Statistical Analysis Plan
SD
Stable Disease
SEC
Safety Event Categories
SOC
System Organ Class
TFLs
Tables, Figures, Listings
UNK
Unknown
WHO
World Health Organization


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1
Introduction
This document contains details of the statistical methods which will be used in the phase I/II  
clinical trial of the clinical study protocol CLEE011XUS29. This statistical analysis plan (SAP) 
module is prepared based on Original Protocol, CRF version 1.0. Mock tables and listing mocks 
are included in TFL Shell document. 
Data will be analyzed by Novartis and/or designated Contract Research Organization according 
to the data analysis Section 10 of the study protocol which is available in Appendix 16.1.1 of 
the Clinical Study Report (CSR). Important information is given in the following sections and 
details are provided, as applicable, in Appendix 16.1.9 of the CSR.
1.1
Study design
This is a multi-center, open-label, Phase I/II study consisting of two phases: Phase I and Phase 
II. The Phase I will be conducted in men and postmenopausal women with HR+, HER2-
negative advanced breast cancer that is endocrine resistant, and a Phase II part in men and 
postmenopausal women with HR+, HER2 negative advanced breast cancer that is resistant to 
at least one endocrine therapy and who have progressed on a CDK 4/6 inhibitor.
Phase I run-in: The dose escalation part of the study is designed to estimate the MTD and/or
RP2D for the combination of ribociclib when dosed continuously with everolimus and 
exemestane. It will consist of 3 cohorts (A and B, and C). Each cohort will enroll 3-6 evaluable 
patients, including at least 6 patients at the RP2D level. Between 9-24 patients are expected to 
be treated in the phase I part of this study. Once an optimal safety dose is determined based on 
tolerability, AEs, serious AE (SAEs), changes in hematology and chemistry values, vital signs, 
dose interruptions, reductions and dose intensity, this study will commence to a phase II design.
The study will initiate with a 2 cohort dose escalation design. Cohort A: ribociclib (250 mg 
daily), everolimus (2.5 mg daily) and exemestane (25 mg daily). If no DLTs are appreciated 
after 1 cycle, patients will then be enrolled in Cohort B: ribociclib (300 mg daily), everolimus 
(2.5 mg daily) and exemestane (25 mg daily). The optimal dose will then be selected and 
expanded in Group 1 of the Phase II part of the study. 
An additional cohort, Cohort C, will be explored as a dose de-escalation cohort. A starting dose 
of: Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) will we 
explored. If DLT’s are appreciated, a lower dose of: Ribociclib (200 mg daily), everolimus (2.5 
mg daily) and exemestane (25 mg daily) will be explored. For further details about DLT criteria 
reference section 6.2.1 of the CSP.
For phase I dose cohorts are as follow:
Cohort A: Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily).
Cohort B: Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily).
Cohort C: Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily)


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Phase II: This is a multi-center open label study to evaluate the antitumor activity of the 
ribociclib 
(LEE011) 
+everolimus 
+ 
exemestane 
combination 
in 
patients 
with 
advanced/metastatic HR+, HER2 negative breast cancer that have progressed on CDK4/6 
inhibitor based therapy. This part of the study will be continued after the MTD/RP2D is
determined in the Phase I.
A minimum of approximately 60 evaluable patients (30 per group (Group 1 and Group 2)) are
required for Phase II of this study to evaluate clinical benefit rate at 24 weeks.
In each phase II group (1 and 2), if 8 or more patients show clinical benefit at 24 weeks then
the null hypothesis will be rejected and the study will demonstrate significant clinical benefit.
RP2D:
Following completion of the phase I, dose escalation portion of this trial, it was determined that 
the RP2D to be explored in Group 1 and Group 2 of phase II  are as follows:
Group1: Ribociclib (300 mg daily) + everolimus (2.5 mg daily) + exemestane (25 mg daily).
Group 2:Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily)
During Phase II, all patients must have progressed on any CDK 4/6 inhibitor. Prior CDK 4/6 
inhibitor will be defined as disease progression while on, or within one month of discontinuing 
any CDK 4/6 inhibitor (i.e. palbociclib, ribociclib, or abemaciclib).
To show significant clinical benefit, currently atleast ≥ 8 patients will have to achieve CBR at 
24weeks.But if number of patients enrolled in study is higher than the planned number of 33
patients (approximately 44 to 46), then the requirement for number of patients to have achieved 
significant clinical benefit will also increase (upto >= 10 patients). 
Figure 1-1 Study Design


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1.1.1
Timing of interim analyses 
Not applicable.
1.1.2
Definition of end of study
The end of the study for a given patient is defined as when the patient permanently discontinues
study treatment with ribociclib + everolimus + exemestane (Phase 1 and 2) and all the end of 
trial procedures are completed.
End of study (Last Patient Last Visit [LPLV]) will be upon completion of the follow up period 
for the last patient treated in the study. This will be either upon SEC of the last patient treated 
or after all patients have completed SEC and have been followed for at least 12 months after 
their first dose of study treatment, have been lost to follow-up, or withdrew consent, whichever 
occurs first.
Patients continuing to derive clinical benefit from study treatment, at the end of the study, in 
the opinion of the investigator, will be able to continue receiving ribociclib + everolimus + 
exemestane on a separate protocol. Ribociclib, everolimus and exemestane will be supplied by 
sponsor and safety will continue to be monitored. 
1.1.3
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
patients should be seen as soon as possible and the same assessments should be performed as 
described in Table 7-1 of the CSP for a discontinued or 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 Institutional Review Board (IRB) and/or Independent Ethics 
Committee (IEC) of the early termination of the trial.
1.2
Study objectives and end points
1.2.1
Phase I
1.2.1.1
Primary objective(s) 
The primary objective of this dose escalation part of the study is to estimate the MTD(s) and/or 
RP2D of ribociclib in combination with everolimus and exemestane in postmenopausal women 
with HR+, HER2 negative advanced breast cancer.
1.2.1.1.1 End point(s) for primary objective(s)
The primary end point for the Phase I, dose escalation part of this study, is the incidence rate
of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 day cycle).
1.2.1.2
Secondary objective(s) 
The secondary objectives for the Phase I, dose escalation part of this study, are:


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
To determine the safety and tolerability based on NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03 when treated with ribociclib + everolimus 
+ exemestane continuously in subjects with HR+, HER2 negative advanced breast 
cancer.

To determine the pharmacokinetic (PK) profile of everolimus and ribociclib when dosed
continuously in the triplet combination.

To assess the preliminary anti-tumor activity of the triplet combination of ribociclib + 
everolimus + exemestane when combination is given continuously.
1.2.1.2.1 End point(s) for secondary objective(s)
The secondary end points for the study are:

Incidence and severity of adverse events (AE) and serious adverse events (SAE), 
clinical laboratory values, vital signs and electrocardiogram (ECGs), dose 
interruptions, reductions and dose intensity.

PK parameters including, but not limited to, AUC (0-4), Ctrough, Cmax, accumulation ratio 
(Racc).

Overall response rate (ORR), Disease Control Rate (DCR), Clinical benefit rate (CBR) 
based on the central assessment as per RECIST v1.1 (CBR is defined as CR, PR, SD 
or Non-CR-Non-PD (NCRNPD)  lasting 24 weeks or longer).
Refer to Section 3.7.2.1 for definitions of ORR,DCR, and CBR. ORR, DCR, and CBR will be 
assessed based on the responses provided by the Investigator on centrally and locally assessed 
data.
1.2.2
Phase II
1.2.2.1
Primary objective(s) 
The primary objective for Phase II part is to evaluate efficacy measured by Clinical benefit rate 
(CBR) at 24 weeks for the triple combination of ribociclib + everolimus + exemestane among 
patients with HR+, HER2 negative advanced breast cancer following the progression of CDK 
4/6 inhibitors. CBR will be assessed based on the responses provided by the Investigator on 
centrally assessed data. 
1.2.2.1.1 End point(s) for primary objective(s)
The primary end point of this Phase II part of this trial is CBR at week 24 (refer to Section 
3.5.2.2 for definition of CBR). CBR will be assessed based on the centrally assessed tumor 
responses provided by the Investigator according to RECIST Version 1.1
1.2.2.2
Secondary objective(s) 
The secondary objectives for the Phase II part of this trial, are:

To determine centrally assessed Progression Free Survival (PFS)

To determine Overall Response Rate (ORR)


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
To determine Overall Survival (OS)

To determine Duration of Overall Response (DOR)

To evaluate time to deterioration or ECOG performance status

To determine safety and tolerability

To determine the PK profile of ribociclib and everolimus in the triplet combination
1.2.2.2.1 End point(s) for secondary objective(s)
The secondary end points for the Phase II part of this trial, are:

PFS

ORR 

OS 

DOR 

Time to definitive deterioration of ECOG performance status from baseline.

Adverse Events (AEs), serious AE (SAEs), changes in hematology and chemistry 
values, vital signs, dose interruptions, reductions and dose intensity.

PK parameters including, but not limited to, AUC(0-4), Ctrough, Cmax, accumulation ratio 
(Racc). 
Refer to Section 3.7.2.2 for definitions of ORR, OS, PFS and DOR. ORR, PFS and DOR will 
be assessed based on the responses provided by the Investigator on centrally and locally
assessed data. Refer to Section 3.7.2.5 for definition of time to definitive deterioration. 


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis and/or the designated Contract Research Organization (CRO), 
according to the data analysis section of the study protocol. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation. Data from all participating centers will be combined so that an adequate number 
of patients are available for analysis.
All statistical analyses will be performed using SAS® Version 9.4.
The planned statistical analysis is described in Section 10 of the protocol (Appendix 16.1.1 of 
the CSR). Data will be summarized with respect to demographic and baseline characteristics, 
efficacy and safety observations.
The study data will be analyzed and reported based on all patients’ data up to the time when all 
patients have potentially completed at least six cycles of treatment or discontinued the study. 
Any additional data for patients continuing to receive study treatment past the data cutoff date 
for the primary CSR will be reported once all patients have discontinued the study or at the end 
of the study, whichever occurs first.
Data will be summarized and listed by dose groups. For safety end point, all patients will be 
analyzed for each phase and may be pooled for analysis. The efficacy data will be analyzed 
for Phase I and Phase II of this study separately.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected, will not be included in 
any analysis, but will be reported in the CSR as separate listings.
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.
Unless otherwise specified, all statistical tests will be performed at a two-sided significance 
level of 0.05 and confidence intervals will be calculated with 95% confidence.
2.1.1
General definitions
2.1.1.1
Study drug and study treatment

For this study, the terms “investigational or study drug” refers to Ribociclib (LEE011). 

“Study treatment” refers to the triplet combination of ribociclib, everolimus and 
exemestane given during the course of the trial.


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2.1.1.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug was administered and recorded on the Dose administration record (DAR) CRF. 
For the sake of simplicity, the date of first administration of study drug will also be referred as 
start date of study drug.
2.1.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on the DAR CRF.
2.1.1.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF. 
For example, if the 1st dose of study drug A is administered on 04JAN2010, and the 1st dose 
of its combination partner, drug B, is administered on 03JAN2010, the date of the first 
administration of study treatment is on 03JAN2010. For the sake of simplicity, the date of the 
first administration of study treatment will also be referred as the start date of study treatment.
2.1.1.5
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF. 
For example, if the last dose of study drug A is administered on 15APR2010, and the last dose 
of a combination partner, drug B is administered on 17MAY2010, the date of last administration 
of study treatment is then on 17MAY2010.
2.1.1.6
Study day
The study day for all assessments (both efficacy and safety) will be calculated as the difference 
between the date of the event (visit date, onset date of an event, assessment date, etc.) and the 
start date of study treatment plus one day. The first day of study treatment is therefore study 
day 1. The study day for all pre-treatment assessments will be calculated as the difference
between the date of the event and the start of study treatment. The last day prior to study 
treatment intake is therefore Study Day -1.
Unless specified otherwise, the study day will be displayed in the data listings.
2.1.1.7
Baseline
Baseline (e.g. for laboratory parameters), is considered as the last available assessment or value 
before start of the first treatment, unless otherwise stated under the related assessment. For all 
relevant parameters comparisons against baseline will be presented through the report. 
Baseline could be within 21 days before first treatment administration or on the same day as 
first treatment administration if specified pre-dose. Specific assessments may be performed 
more than 21 days prior to day 1 of dosing. Such cases will also be considered as baseline, if 
no other assessments are performed thereafter, prior to day 1 of dosing. Patients with no data 


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on a particular parameter before the first treatment administration have a missing baseline for 
this parameter. 
 
For ECGs, standard triplicate 12-lead ECGs will be performed after the patient has been resting
for 5-10 min prior to each time point. Triplicate ECGs should be taken approximately 2-minutes 
apart. The combined QTcF values from these 3 ECGs will be averaged to provide a single value 
for each time point.
General guidance for baseline definition:
Dependent on the variable, the baseline assessment will be done at screening (Day -21 to 1) or 
baseline (Cycle 1 Day 1 [C1D1]). Baseline assessments should be obtained before the first study 
treatment intake based on the variables. Any assessment which is obtained outside of the 
protocol-defined screening period will not be considered for baseline unless otherwise specified.
2.1.1.8
On-treatment assessment/event
Safety summaries and selected summaries of deaths will summarize only on-treatment 
assessments/events. On-treatment assessment/event is defined as any assessment/event 
obtained in the time interval:
Date of first administration of study treatment through the date of last administration of study 
treatment + 30 days, i.e. including the lower and upper limits. 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF.  
If the last date of study treatment is missing, on-treatment assessments/events include any 
assessment/event recorded in the database and which occur after the start date of study treatment.
Data listings will include all assessments/events, flagging those which are not on-treatment 
assessments/events.
2.1.1.9
Last contact date
The last contact date will be derived for patients not known to be dead at the analysis cut-off 
using the last complete date among the following:

All assessment dates (e.g. vital signs assessment, performance status). Note, only a true 
on study assessment date or patient contact date will be used. If there is a visit date 
without evidence of any actual assessment performed that date will not be used. No 
dates post cut-off will be used.

Medication dates including study medications, concomitant medications, and anti-
neoplastic therapies administered after study treatment discontinuation (with non-
missing medication/procedure term).

Adverse event dates (with non-missing verbatim AE term present).


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
Last known date patient alive collected on the ‘Survival information’ eCRF.

Date of discontinuation from end of treatment page and ‘End of post-treatment   follow-
up’ eCRF.
The last contact date is defined as the latest complete date from the above list or the cut-off date 
whichever comes first. The cut-off date will not be used for last contact date, unless an actual 
assessment or patient contact was performed.
Important note: imputed dates (e.g. the analysis cut-off date programmatically imputed to 
replace the missing end date of a dose administration record) will not be used to derive the last 
contact date, except for the following: partial date’s imputation is allowed to be used for event 
(death) and for censoring date only if coming from Survival Information page.
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Analysis sets
2.2.1
Full analysis set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of the
assigned combination of study drugs (ribociclib + everolimus + exemestane) i.e. a patient 
should have taken atleast one dose of each of the components from the study treatment. 
2.2.2
Safety set
The Safety Set includes all patients who received at least one dose of any of the components 
from the investigational treatment, and have at least one valid post-baseline safety assessment.
The statement that a patient had no AEs (on the AE eCRF) constitutes a safety assessment.
2.2.3
DLT-determining analysis set
The DLT-determining set (DDS) includes all patients from the safety set in the dose escalation 
part who either completed a minimum exposure requirement and have sufficient safety 
evaluations in the first cycle or discontinued prematurely due to a dose limiting toxicity (DLT).
A patient is considered to have met the minimum exposure requirement if having received at 
least 75% of the planned combination doses (i.e. 21 out of 28 planned daily doses) for all 
compounds administered together (same day): ribociclib, everolimus and exemestane. The 
length of a cycle is 28 days.
Patients who do not experience a DLT during the first cycle will be considered to have sufficient
safety evaluations if they have been observed for ≥28 days following the first dose, and are
considered by both the Sponsor and Investigators to have enough safety data to conclude that 
a DLT did not occur.
  Note: This analysis set will only use to display dose limiting toxicities for phase I.


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2.2.4
Pharmacokinetic analysis set
The PK analysis set (PAS) consists of all patients who have at least one blood sample providing 
evaluable PK data. The PAS will be used for summaries of PK data (tables and figures) as well 
as for listings of derived parameters.
2.2.5
Per-protocol set
A subset of Full Analysis Set (FAS) excluding major protocol violations.
Supportive analyses of the primary endpoint (i.e., CBR) may be performed using Per- protocol 
set (PPS).
2.2.7
Subgroup of interest
Not Applicable.
2.3
Concomitant medications with specific impact on the analysis
2.3.1
Inducers, inhibitors and substrates of CYP3A
According to the study protocol, treatment with substances which are strong inhibitors, or 
inducers of CYP3A4/5, or substrates of CYP3A4/5 with a narrow therapeutic window, or 
medications with a known risk of QT prolongation should be avoided. These substances are 
listed in the Table 2-1. A corresponding list for programming purposes will be saved in a 
separate document. 
However, some patients may take these substances during the treatment period so these 
concomitant medications will be selected via programming and tabulated and listed in the 
Clinical Study Report. If there is an update for the list of prohibited medications (e.g., in 
protocol amendment), the most up-to-date list shall be used for the Clinical Study Report.
Treatment with the prohibited substances mentioned above will be identified in the 
database as protocol deviations.


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Table 2-1
List of prohibited medications during study drug treatment
Category
Drug Name
Strong CYP3A4/5 
inhibitors
Boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, 
grapefruit juice, idelalisib, indinavir, indinavir/ritonavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, VIEKIRA PAK2, voriconazole
Strong CYP3A4/5 
inducers
Avasimibe2,3, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum 
perforatum)3
CYP3A4/5 substrates 
with NTI1
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, astemizole, 
cisapride, cyclosporine, diergotamine (dihydroergotamine), 
ergotamine, fentanyl, lomitapide, lovastatin, nicardipine, 
nisoldipine, pimozide, quinidine, rivaroxaban, simvastatin, 
sirolimus, tacrolimus, terfenadine, thioridazine
Medications with a 
known risk for QT 
prolongation4
Amiodarone, anagrelide, arsenic trioxide, astemizole, 
azithromycin, bepridil, chloroquine, cocaine, chlorpromazine, 
cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacine, grepafloxacin, halofantrine, haloperidol, ibutilide, 
levofloxacin, levomethadyl, mesoridazine, methadone, 
moxifloxacin, ondansetron (i.v. only), oxaliplatin, papayerine 
HCl, pentamidine, pimozide, probucol, procainamide, propofol, 
quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, 
sulpiride, terfenadine, thioridazine, vandetanib
Herbal 
preparations/medications
Herbal preparations/medications known as strong inducers or 
inhibitors of CYP3A4/5 or those with a known risk of QT 
prolongation are prohibited throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng. Patients should 
stop using these herbal medications 7 days prior to first dose of 
study drug
Other investigational and 
antineoplastic therapies
Other investigational therapies must not be used while the patient 
is on the study. Anticancer therapy (chemotherapy, biologic or 
radiation therapy, and surgery) other than the study treatments 
must not be given to patients while the patient is on the study 
medication. If such agents are required for a patient then the 
patient must be discontinued study drug.


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1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes).
2 Herbal product
3 P-gp inducer
4 Source: www.qtdrugs.org (as of August 23, 2017)
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with
the potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI 
that increases the exposure of ribociclib or the exposure of the QT prolonging drug). A 
definitive list of drugs with a known risk, possible risk, or conditional risk of QT prolongation 
and/or Torsades de Pointes (TdP) is available online at qtdrugs.org.
3
General Strategies for Data Presentation
All categorical data will be summarized by frequencies and percentages. Wherever categorical
data is missing, a ‘Missing’ row will be included at the bottom with frequencies and percentages 
presented for it.
Continuous data will be summarized with either standard descriptive statistics (i.e. the number 
of non-missing data points, arithmetic mean, 25th and 75th percentiles, standard deviation, 
minimum, median and maximum), or will be grouped into categorical data and summarized as 
categorical data. 
All collected data will be listed.
3.1
Patient disposition, demographics and other baseline 
characteristics
3.1.1
Patient disposition
3.1.1.1
End of treatment phase disposition
The number of patients who are enrolled and treated as well as those who discontinued the study 
(along with their reasons for premature discontinuation) or are still ongoing in the study at the 
time of the analysis will be summarized for FAS by dose cohorts of Phase I and by groups of
Phase II. 
A listing of study completion by dose cohorts of phase I and groups of phase II will be produced 
using the FAS. Patients are considered to be ongoing if they have not discontinued due to any 
reason.  
The possible reasons for discontinuation of study treatment are as follows:

Adverse events 

Lost to follow up

Physician decision

Pregnancy


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
Protocol Deviation 

Technical problems

Subject/Guardian decision

Death

Progressive disease

Study terminated by the sponsor
A listing for data on final status of the patient in the study will be provided. A data listing of 
screened patients who did not take study drug will be also provided with reasons for screening 
failure.
3.1.2
Demographic and baseline characteristics variables
Demographic and baseline characteristics data will be summarized using the FAS. All 
demographic and background data will also be listed. 
The following variables will be summarized by dose cohorts of Phase I and by groups of Phase 
II:

Age [years]

Age categories 
o
≤40 
o
>40 - ≤60
o
>60 - ≤75
o
>75
o
missing

Sex 
o
Male
o
Female
o
missing

Race 
o
Asian
o
Black
o
White/Caucasian
o
Native American
o
Pacific Islander
o
Unknown
o
Other
o
missing

Ethnicity 
o
Hispanic/latino
o
East Asian
o
Chinese
o
Japanese
o
Korean
o
Other East Asian


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o
South East Asian
o
Thai
o
Malay
o
Vietnamese
o
Cambodian
o
Laotian
o
Indonesian
o
Filipino
o
Other South East Asian
o
South Asian
o
Indian
o
Pakistani
o
Other South Asian
o
West Asian
o
Turkish
o
Arabian
o
Persian
o
Lebanese
o
Other West Asian
o
Russian
o
Mixed Ethnicity
o
Not Reported
o
Unknown
o
Other
o
Missing

Child bearing status for female patients 
o
Able to bear children
o
Premenarche
o
Post menopausal
o
Sterile-of child bearing age

ECOG PS 
o
0-Fully active, able to carry on all pre-disease performance without restriction
o
1- Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
o
2- Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
o
3- Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
o
4- Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair
o
5- Dead
o
Missing

Body weight [kg]

Body weight categories
o
<55


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o
55-75
o
≥75

Body height [cm]

Body Mass Index (BMI) [kg/m2]

BMI categories
o
<30
o
≥30
All categorical data will be summarized by frequencies and percentages. Continuous data will 
be summarized with standard descriptive statistics. 
3.1.3
Medical history
Medical history and current medical conditions will be summarized using FAS, by dose cohorts 
of Phase I and by group of Phase II and will also be listed. Separate summaries will be presented 
for current and past medical conditions; these summaries will be presented by primary system 
organ class and preferred term. Medical history/current medical conditions will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
3.1.4
Diagnosis and extent of cancer
For the patients in FAS, the summary statistics will be provided for the following variables for 
diagnosis and extent of cancer: Diagnosis of disease

Histological grades

Staging system used

Stage at initial diagnosis

Stage at study entry 

Histological grade 

Predominant histology/cytology

Number and type of metastatic sites involved.

Time since initial diagnosis
Time since initial diagnosis will be summarized in months. A month is defined as 
365.25/12=30.4375 days. This data will also be categorized into time intervals. Frequency 
counts and percentages will be presented for the number of patients in each interval. The 
summary will be by dose cohorts of Phase I and by group of Phase II.
3.1.5
Other baseline characteristics
ER, PgR and HER2, Rb status, prior line of endocrine therapy and chemotherapy prior CDK4/6 
inhibitor and duration of CDK4/6 inhibitor will also be summarized and listed using FAS, by 
dose cohorts of Phase I and by group of Phase II.
3.1.6
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies prior to (within 30 days prior to 
first dose) and after the start of the study drug treatment will be listed by patient and summarized 
by ATC (Anatomical Therapeutic Chemical Classification System) term. All prior and 


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concomitant medication/significant non-drug therapies entered into the database will be coded 
using the World Health Organization (WHO) Drug Reference List dictionary, which is supplied 
by Novartis and used by CRO at the time of coding.
These summaries will include medications starting on or after the start of study treatment or
medications starting prior to the start of study treatment and continuing after the start of
study treatment. Any prior concomitant medications or significant non-drug therapies starting 
and ending prior to the start of study treatment will be listed.
The number and percentage of patients taking such treatments will be summarized for patients 
in the Safety Set, by dose cohorts of Phase I and by group of Phase II.
3.1.7
Prior antineoplastic therapy
Prior anti-neoplastic therapy will be listed in three separate listings: (i) medications, (ii)
radiotherapy, and (iii) surgery. This summary will be provided for FAS patients by dose cohorts 
of Phase I and by group for Phase II.
The summary of prior anti-neoplastic medication will include the total number of regimens used 
at last therapy, setting of last medication, and also the time from last medication to progression, 
the best response at last therapy .Best Response is defined as the best recorded patient response 
during all previous treatment regimens, up to and including the last recorded. 
The last medication is defined taking into account the end date. 
All prior antineoplastic medications will also be tabulated by ATC code, preferred term by dose 
cohorts of Phase I and by group for Phase II.
The summary of prior anti-neoplastic radiotherapy will include a summary of radiotherapy 
locations, including all locations recorded for each patients. Setting, method and prior 
radiotherapy of bone marrow (Y/N) at last radiotherapy will also be summarized. 
The summary of prior anti-neoplastic surgeries will include the time between the last surgery 
to start of treatment, procedure applied in last surgery and residual disease at last surgery.
A summary of post discontinuation antineoplastic medications, surgeries and radiotherapies 
will also be provided with recorded details. 
3.2
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
3.2.1
Study treatment exposure
The following algorithm will be used to calculate the duration of study treatment exposure (in 
cycles and in days) for patients who takes at least 1 dose of the study treatment:

Duration of exposure (days) to investigational drug = date of last administration of the 
study drug – date of first administration of the study drug + 1.


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
Duration of exposure (days) to study treatment = (latest of last dates of exposure to study 
treatment (ribociclib, everolimus and exemestane)) – (date of first administration of 
study treatment (ribociclib, everolimus and exemestane)) + 1.
For patients who did not take any drug, the duration of drug exposure is by definition equal to 
zero.

Cumulative Dose: Cumulative dose is defined as the total dose given to a patient during 
the study treatment. For patients who did not take any drug the actual cumulative dose 
is by definition equal to zero.

Average Daily Dose: It is defined cumulative dose divided by the number of days the 
patients took the drug (excludes the no-dose period)

Dose Intensity (DI): DI is defined as the ratio of cumulative dose and the number of 
days the patient should have taken the drug (includes the no-dose period). 

Planned dose intensity (PDI): PDI is defined as the ratio of total planned dose and the 
number of days the patient should have taken the drug [(planned dose * (last dose date 
– first dose date+1)].

Relative Dose Intensity (RDI): RDI is defined as the ratio of dose intensity (DI) and
planned dose intensity (PDI) based on planned dose and planned duration, expressed as 
percentage.
Cumulative Dose, average daily dose, DI, PDI and RDI will be calculated separately for each 
of the component of study treatment.
Additionally, prior duration of CDK4/6 against the duration of CDK4/6 during the study will 
be summarized by 25th ,50th (median) and 75th Percentiles of duration.
3.2.2
Study treatment
The actual dose and duration (days) of ribociclib, everolimus and exemestane will be
summarized by means of descriptive statistics. The summary data will be presented by dose 
cohorts of Phase I and by group of Phase II. The total daily doses of ribociclib, everolimus and
exemestane for each patient will be summarized using descriptive statistics (e.g. mean, median, 
maximum and minimum doses). The exposure data for all the patients will be provided based 
on the Safety Set.
3.2.3
Dose change or interruptions
The number of patients who have dose change or interruptions and the reasons for such change 
/interruptions will be summarized by study treatment component using Safety Set. This 
summary will be provided by dose cohorts of Phase I and by group of Phase II.
If a patient moves from a protocol-studied dose down to a lower-than-protocol-studied dose or 
to the dose level being studied under the protocol but on a less frequent regimen, such changes 
will then be counted as reductions.


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3.2.4
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations for all patients in FAS. These will be identified prior to database lock and
will be listed and summarized by dose cohorts of Phase I and by group for Phase II. 
Compliance to the study drug will be assessed by the number of dose reductions and dose 
interruptions for all patients in FAS.
3.3
Efficacy Evaluations
3.3.1
Disease assessment
Disease assessment will be carried out in patients by radiological assessments (e.g. CT 
/MRI/bone scan).
All the components of the disease assessment will be listed. These components will be further 
assessed based on the responses provided by the Investigator on centrally and locally assessed 
data. The response assessment by Investigator should be based on all available data as per 
RECIST V1.1 guidelines. 
Patients should have at least one documented measurable lesion (per RECIST v1.1) or in the 
absence of measurable disease, have at least one lytic or mixed (blastic/lytic) bone lesion at 
study entry.
Table 3-1
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 CSP Section 14.2.6.


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Table 3-2 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).
Table 3-3
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 CSP Section 14.2.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).


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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.
Further details can be found in Protocol Appendix 2.
3.3.1.1
Measurable disease
Measurable disease will be defined as 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 more details on nodal and non-nodal lesion, 
refer protocol Section 14.2.4.
3.3.1.2
Responder
A patient will be called a responder if at any post baseline visit, patient is assessed to have 
response (PR and higher) and if the response is confirmed atleast 4 weeks apart.
3.3.1.3
Non Responder
A patient will be called a non-responder if at any baseline visit, patient is assessed to have no 
response (unconfirmed response of CR/PR or response of SD, PD). A patient who discontinues 
for any reason before the data cut-off date of the CSR without a confirmed assessment of 
response will be considered a non-responder. Patients with unknown or missing response, or 
who are treated in the study but provide no information on response at the end of treatment will 
also be treated as non-responders. 
The non-responders will be included in the denominator while calculating percentages.
3.3.1.4
Adequate tumor response assessment
An adequate tumor response assessment is considered as disease assessment that is indicating 
any disease status apart from “unknown” or “not done”. 
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.
The tumor assessment will be time slotted using the time windows displayed in Table 3-4:
Table 3-4
Time windows for tumor assessment
Time window
Planned Visit Timing
Time Window Definition
Week 8
57 (week 8)
(1,86] days ; (1, 12] weeks
Week 16
113 (week 16)
(86, 142] days ; (12, 20] weeks
Week 24
169 (week 24)
(142, 198] days; (20, 28] weeks
Week 32
225 (week 32)
(198, 282] days; (28, 36] weeks


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Week 40
280 (week 40)
(282, 352] days; (36, 44] weeks
Week 48
337 (week 48)
(282, 380] days; (44, 52] weeks
Until week 48 (12 
months)
X (week Y)
(X-27, X+29] days; (Y-4, Y+4] weeks
Week 60
421 (week 60)
(380, 464] days; (54, 66] weeks
Week 72
505 (week 72)
(464, 548] days; (66, 78] weeks
Week k (beyond 12 
months)
X (week Y)
(X-43, X+41] days; (Y-6, Y+6] weeks
3.3.1.5
Confirmation of response
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.
3.3.1.6
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. BOR will be assessed based 
on the responses provided by the Investigator on centrally and locally assessed data. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. 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.
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

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 

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).


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3.4
PK evaluations
The LLOQ for ribociclib (and LEQ803) in plasma is approximately 1.00 ng/mL. The
LLOQ for everolimus in whole blood is approximately 0.3 ng/mL. The LLOQ for exemestane
in plasma is approximately 0.0200 ng/mL. All concentrations below the LLOQ or missing data 
will be labeled as such in the concentration data listings.
Only PK concentration data will be summarized for CSR. The PK parameters will be 
summarized outside of CSR.
3.5
Analysis of the primary objective
The primary objectives of the trial are as follows:

Phase I
The primary objective of this dose escalation part of the study is to estimate the MTD(s) and/or 
RP2D of ribociclib in combination with everolimus and exemestane in postmenopausal women 
with HR+, HER2 negative advanced breast cancer.

Phase II
The primary objective is to evaluate efficacy measured by Clinical benefit rate (CBR) at 24 
weeks for the triple combination of ribociclib + everolimus + exemestane among patients with 
HR+, HER2 negative advanced breast cancer following the progression of CDK 4/6 inhibitors.
CBR will be assessed based on the responses provided by the Investigator on centrally and 
locally assessed data.
3.5.1
Primary end point
3.5.1.1
Phase I
The primary end point for the Phase I, dose escalation part of this study, is the incidence rate 
of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 day cycle).
3.5.1.2
Phase II
The primary end point of this Phase II part of this trial, is CBR at week 24. 
3.5.2
Statistical hypothesis, model, and method of analysis
3.5.2.1
Phase I
MTD definition: The MTD is defined as the highest combination drug dosage not causing 
medically unacceptable, DLT in more than 33% of the treated patients in the first cycle of
treatment. AEs and laboratory abnormalities considered to be DLTs are defined in
Protocol Table 6 -3 . Only one RP2D will be tested in the Phase II.
In the dose escalation a total of 6 patients will be treated at dose-level 1 (cohort A). Patients
must complete a minimum of one cycle of treatment with the minimum safety evaluation and


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drug exposure or have had a DLT within the first cycle of treatment to be considered evaluable
for dose escalation decisions. 

If ≤33% of patients experience a DLT in cohort A (dose level 1), the dose will be 
escalated to the next level cohort B (dose level +1) where 3 patients will be enrolled.

If ≤33% patients experience DLTs in cohort B, additional 3 patients will be treated at the 
same dose level. 

If ≤33% patients experience a DLT in both cohorts, then the optimal treatment dose based 
on tolerability and safety profile will move into Phase II.

If >33% patients experience DLTs in both cohorts, the dose will be de-escalated to the 
next level down.
Dose escalation and R2PD decisions will be made jointly by Steering Committee members and
Novartis study personnel.
Listing and summary tables of DLT starting during the first 28 days of treatment by primary
system organ class, preferred term, by dose cohort and overall for Phase I will be presented
based on DLT-determining set (DDS).
3.5.2.2
Phase II

Clinical Benefit Rate (CBR):
Clinical Benefit Rate (CBR) is defined as the proportion of patients with a complete response 
(CR), partial response (PR), stable disease (SD) or Non-CR Non-PD (NCRNPD) at 24 weeks 
as per RECIST V1.1. Thus, any instance of CR, PR, SD or NCRNPD in the first 24 weeks of 
the treatment, without having an instance of progressive disease (PD) will be accounted for, 
while calculating CBR. The instances of unconfirmed CR and/or PR will also be accounted for, 
while calculating CBR.
Demonstration of significant Clinical Benefit Rate (CBR) will be based on this study with at 
least an 80% power to test the null hypothesis that the clinical benefit rate in 24 weeks is at least 
10% or less with an alternative hypothesis that this rate is above 10%. 
All the other patients will be counted as not having clinical benefit.
The study is designed to test the following statistical hypothesis: 
H0 : CBR ≤ 10% vs. H1 : CBR > 10%
The null hypothesis will be rejected and successful clinical benefit will be demonstrated if the
lower limit of the 95% confidence interval is greater than at least 0.10. Thus, if 8 or more 
patients show clinical benefit at 24 weeks then the null hypothesis will be rejected and 
significant clinical benefit will be demonstrated.
To show significant clinical benefit,currently atleast ≥ 8 patients  will have to achieve CBR at 
24weeks.But if number of patients enrolled in study is higher than the planned number of  33 
patients (approximately 44 to 46), then the requirement for number of patients to have achieved 
CBR will also increase (upto >= 10 patients). 


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CBR will be summarized by frequency and percentage together with the 95% confidence 
intervals. An exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement for one-way tables) will be calculated [Clopper & Pearson, 1934].
CBR will be calculated based on FAS; however, patients with only non-measurable disease at 
baseline will be included in the numerator if they achieved a complete response. 
For primary efficacy variable, the analysis time point is when all patients who are enrolled 
complete 24 weeks or discontinue from the study earlier. Phase 1 patients who had received the 
RP2D and are post CDK 4/6 completing 24 weeks or discontinue early will also be included in 
the final phase II analysis.
When examining clinical benefit, patients with a best overall response assessment of unknown 
(UNK) will not be regarded as “responders” but may be included in the denominator for CBR 
calculation.
For the primary analysis, CBR will be assessed based on the centrally assessed tumor responses 
provided by the Investigator according to RECIST Version 1.1. Additionally, above analysis 
will be repeated for CBR based on the locally assessed tumor response using full analysis set.
Analysis will also be performed using per protocol analysis set, as appropriate.
3.5.3
Handling of missing values/censoring/discontinuations
Not Applicable.
3.5.4
Supportive analyses
Not Applicable.
3.6
Analysis of the key secondary objective
Not Applicable
3.7
Analysis of secondary efficacy objective(s)

Phase I
The secondary objectives for the Phase I, dose escalation part of this study are:
o
To determine the safety and tolerability based on NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03 when treated with ribociclib + everolimus 
+ exemestane continuously in subjects with HR+, HER2 negative advanced breast 
cancer.
o
To determine the pharmacokinetic (PK) profile of everolimus and ribociclib when dosed 
continuously in the triplet combination.
o
To assess the preliminary anti-tumor activity of the triplet combination of ribociclib + 
everolimus + exemestane when combination is given continuously.

Phase II
The secondary objectives for the Phase II part of this trial are:


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o
To determine centrally assessed Progression Free Survival (PFS)
o
To determine Overall Response Rate (ORR)
o
To determine Overall Survival (OS)
o
To determine Duration of Overall Response (DOR)
o
To evaluate time to deterioration or ECOG performance status
o
To determine safety and tolerability
o
To determine the PK profile of ribociclib and everolimus in the triplet combination 
3.7.1
Secondary end points

Phase I
The secondary end points for the study are:

Incidence and severity of adverse events (AE) and serious adverse events (SAE), 
clinical laboratory values, vital signs and electrocardiogram (ECGs), dose 
interruptions, reductions and dose intensity.

PK parameters including, but not limited to, AUC(0-4), Ctrough, Cmax, accumulation ratio 
(Racc).

Progression Free Survival (PFS), Overall response rate (ORR), Disease Control Rate 
(DCR), Clinical benefit rate (CBR) based on the responses provided by the 
Investigator on locally assessed data per RECIST v1.1. 
ORR, DCR and CBR will be assessed based on the responses provided by the Investigator on 
centrally and locally assessed data.

Phase II
The secondary end points for the Phase II part of this trial, are:

PFS

ORR 

OS 

DOR 

Time to definitive deterioration of ECOG performance status from baseline.

Adverse Events (AEs), serious AE (SAEs), changes in hematology and chemistry 
values, vital signs, dose interruptions, reductions and dose intensity.

PK parameters including, but not limited to, AUC(0-4), Ctrough, Cmax, accumulation ratio 
(Racc). 
ORR, DOR, and PFS will be assessed based on the responses provided by the Investigator on 
centrally and locally assessed data.
3.7.2
Statistical hypothesis, model, and method of analysis

Phase I


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3.7.2.1
ORR, DCR and CBR

ORR:
Overall response rate (ORR) defined as the proportion of patients who’s best overall response 
is either complete response (CR) or partial response (PR) according to RECIST 1.1. ORR will 
be calculated based on FAS; however, patients with only non-measurable disease at baseline 
will be included in the numerator if they achieved a complete response. ORR will be 
summarized by frequency and percentage. The exact 95% two-sided confidence interval will 
also be provided.
When examining overall response, 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 
calculation. 
Best overall response for each patient will be listed and summarized on FAS. 

DCR:
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. DCR will be calculated based on FAS; however, patients with only non-measurable 
disease at baseline will be included in the numerator if they achieved a complete response. DCR 
will be summarized by frequency and percentage. The exact 95% two-sided confidence interval 
will also be provided.
When examining 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 DCR 
calculation.

CBR:
CBR is defined as the proportion of patients with a CR, PR, SD or NCRNPD as per RECIST 
V1.1 by week 24. Thus, any instance of CR, PR, SD or NCRNPD in the first 24 weeks of the 
treatment, without having an instance of PD will be accounted for, while calculating CBR. The 
instances of unconfirmed CR and/or PR will also be accounted for, while calculating CBR. 
CBR will be calculated based on FAS; however, patients with only non-measurable disease at 
baseline will be included in the numerator if they achieved a complete response. CBR will be 
summarized by frequency and percentage together with the 95% confidence intervals. An exact 
binomial confidence interval (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated [Clopper & Pearson, 1934].
When examining clinical benefit, patients with a best overall response assessment of unknown 
(UNK) will not be regarded as “responders” but may be included in the denominator for CBR 
calculation.

Phase II
3.7.2.2
PFS, ORR, OS and DOR

PFS:


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Progression-free survival (PFS) is defined as the time from date of treatment to the date of first 
documented progression or death due to any cause. For PFS, a patient who didn’t have the event 
at the date the analysis data cut-off will be censored at the time of the last adequate assessment, 
prior to data cut-off. PFS will be assessed based on the responses provided by the Investigator 
on centrally assessed data. The PFS will be analyzed using FAS.
PFS will be analyzed using the Kaplan-Meier Product-Limit method. Estimates of the 25th, 
median and 75th percentile of the PFS and their 95% confidence intervals will be provided, if 
applicable. Additionally, above analysis will be repeated on the locally assessed tumor response.
Analysis will also be performed using per protocol analysis set, as appropriate.

ORR:
Overall response rate (ORR) defined as the proportion of patients who’s best overall response 
is either complete response (CR) or partial response (PR) according to RECIST 1.1. ORR will 
be calculated based on FAS; however, patients with only non-measurable disease at baseline 
will be included in the numerator if they achieved a complete response. ORR will be 
summarized by frequency and percentage. The exact 95% two-sided confidence interval will 
also be provided.
When examining overall response, 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 
calculation. 
Best overall response for each patient will be listed and summarized on FAS. 

OS:
Overall survival (OS) is defined as the time from date of first treatment to the date of death due 
to any cause. If a patient is not known to have died, survival will be censored at the last date of 
contact. 
OS will also be summarized by Kaplan-Meier Product-Limit method based on FAS. Estimates 
of the 25th, median and 75th percentile of the PFS and their 95% confidence intervals will be 
provided, if applicable.

DOR:
Duration of Overall Response (DOR) applies only to patients whose best overall response is 
CR or PR according to RECIST 1.1. The start date is the date of first documented response (CR 
or PR) and the end date is the date defined as first documented progression or death due to 
underlying cancer. In other words, the start date should be determined using the time that the 
response was first determined and not using the time the response was confirmed. If a patient 
had not had an event, duration will be censored at the date of the last adequate tumor assessment. 
DOR will be listed and summarized based on FAS. 
DOR will also be summarized by Kaplan-Meier Product-Limit method based on FAS. 
Estimates of the 25th, median and 75th percentile of the DOR and their 95% confidence intervals 
will be provided, if applicable.


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In addition of above endpoints waterfall plot and swimmer plot will also be presented. The 
waterfall plot displays the best percentage change from baseline in the sum of the longest 
diameter of all target lesions for each patient by dose cohort of phase I and by group of phase 
Viand swimmer plot displays patient’s tumor response status with length of treatment duration.  
Additionally, the concordance in best response according RECIST1.1 per central review and 
local evaluation will be summarized. Kappa coefficients were calculated to characterize the 
agreement in response assessments between local evaluation and central review (kappa = 1 
implies perfect agreement).
3.7.2.3
Safety and Tolerability
Please refer to the Section 3.8 for Safety analysis details.
3.7.2.4
PK profile of ribociclib and everolimus
Please refer to the Section 3.9 for details on PK analysis for ribociclib and everolimus. 
3.7.2.5
Definitive deterioration of the ECOG PS:
ECOG performance scale will be used to assess physical health of patients. 
An analysis of the time to definitive deterioration of the ECOG PS by one category of the score 
from the date of first treatment will be performed. Baseline is the last available assessment on 
or before date of first treatment. Definitive deterioration is defined as an increase in ECOG PS 
by at least one category from the baseline score or death due to any cause. Deterioration is 
considered definitive if no improvements in the ECOG PS status is observed at a subsequent 
time of measurement during the treatment period following the time point where the 
deterioration is observed. (Example 1: if the score is 1 at baseline and then 1 , 2 , 1 , 2 , 3 at 
study days 28 , 57 , 83 , 115 , 150, respectively, then the time to definitive deterioration is 115 
days, Example 2: if the score is 1 at baseline and then 1 , 1 , 2 at study days 28 , 57 , 83, 
respectively, with no assessment of the ECOG PS status after day 83 then the time to definitive 
deterioration is 83 days).
If a definitive deterioration is observed after ≥ 2 missing assessments, this event will be 
censored at the date of the last ECOG PS assessment prior to the deterioration. Patients that 
have not worsened will be censored at the date of last available assessment
Time to Definitive Deterioration (TDD) will be summarized by Kaplan-Meier Product-Limit 
method based on FAS. Estimates of the 25th, median and 75th percentile and their 95% 
confidence intervals will be provided, if applicable.
Additionally, ECOG PS data will be summarized at each scheduled assessment time point.
The following time based intervals will be used to group the ECOG PS data over time.
        Table 2-6           Time window for ECOG assessment
Time Interval
Baseline
Day 1 (if Day 1 data is missing then use the screening)


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Cycle 2 Day 1
Day 2 to day 42 (2nd assessment)
Cycle 3 Day 1
Day 43 to day 70 (3rd assessment)
Cycle  4, 5,… 
until end of 
treatment
+/- 2 weeks centered around the planned assessment date:
i.e. days 71 to 98 for Day 1 of cycle 4 (4th assessment)
      days 99 to 126 for Day 1 of cycle 5 (5th assessment)
      days [(k-1)*28-14; (k-1)*28+13] for Day 1 of cycle k (k+1th assessment)
End of 
Treatment
Assessment taken at the end of treatment visit
3.7.2.6
Safety and Tolerability
Please refer to the Section 3.8 for Safety analysis details.
3.7.2.7
PK profile of ribociclib and everolimus
Please refer to the Section 3.9 for details on PK analysis for ribociclib and everolimus. 
3.7.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed in any manner. 
3.8
Safety analyses
For all safety analyses, the safety analysis set will be used. All safety data will be listed and 
tables will be summarized by dose cohorts of Phase I and overall for Phase II.
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 30+1 after last dose of study medication.
3.8.1
Adverse events (AEs)
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though the Study Evaluation Completion page. Adverse events will be coded 
using the most recent version of the medical dictionary for regulatory activities (MedDRA)
available at the time of each analysis.
The AEs experienced by the patients in all the observation periods will be listed. The AEs 
reported in pre-treatment and post-treatment period will be flagged in the listing. In an AE 
listing, details will be provided for severity grade of AE, seriousness of AE, its relationship to 


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study treatment, its duration, action taken, outcome, and whether medication or therapy was 
given to patient. 
Treatment Emergent AEs are those, which start in on-treatment period, or which start in pre-
treatment period but worsen in on-treatment period. Summary tables for all TEAEs will be 
provided by study treatment group. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
The tables will be summarized alphabetically by SOC and in decreasing frequency of PTs. The 
decreasing order of PTs will be based on the total count.
AE overview table will be provided with information on number and percentage of patients 
having any AE, any SAE, any Severe AE, any AE leading to discontinuation of study drug, 
dose adjustments and interruption, any fatal AE and deaths due to any cause. The incidences of 
all TEAEs will be summarized by the SOC and PT. In addition to this, the incidences of all 
grades of TEAE and of grades 3 and 4 TEAE will be summarized. Serious TEAEs including 
fatal and non-fatal AEs, Severe TEAEs, AEs with relationship to study treatment, AEs leading 
to discontinuation of any study treatment, AEs leading to dose adjustment or interruption, will 
also be summarized. All AEs will be summarized regardless of relationship to study treatment.
3.8.1.1
Adverse events of special interest / grouping of AEs
Not Applicable
3.8.2
Deaths
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment) will be 
produced by study dose group, system organ class and preferred term. All deaths will be listed 
and post treatment deaths will be flagged. 
3.8.3
Laboratory data
The grading of the laboratory data will be done using the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. For laboratory tests, the study’s bio statistical and
reporting team will grade laboratory data accordingly. For laboratory tests covered by CTCAE,
a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will
not be used. For laboratory tests where Grades are not defined by CTCAE, results will be
graded by the low/normal/high classifications based on laboratory normal ranges.
If there are multiple post-baseline evaluations within each visit, the second unscheduled 
measurement will be summarized. If there is only one unscheduled measurement, then the 
unscheduled measurement will be used for reporting.
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by a clinical meaningful limit.


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The results will be listed separately for hematology, biochemistry and urinalysis laboratory tests, 
along with details on the CTCAE grades and/or classifications relative to laboratory normal 
ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests, by dose cohorts of Phase I and by group of Phase II:

Change  from baseline to worst value by dose groups (descriptive statistics)

Shift table from baseline to maximum value on-treatment value, for those lab tests having 
CTCAE grades (frequency count and percentages)

Shift table from baseline to worst on-treatment value, for those lab tests not having CTCAE 
grades, based on the low/normal/high classification (frequency count and percentages)

Table for newly occurring on-treatment grades 3 or 4 (frequency count and percentages)

Number and percentage of patients with notable hepatic laboratory values by regimen and 
treatment group. Please note that notable hepatic laboratory values are defined as: 
o
ALT or AST > 3xULN, > 5xULN, > 8xULN, > 10xULN, > 20xULN
o
TBIL > 1.0x ULN and <= 2.0x ULN, TBIL > 2.0x ULN
o
ALP > 1.5 xULN
o
ALP>2.0xULN
o
ALT or AST > 3.0x ULN and TBIL > 2.0x ULN and ALP<2.0x ULN at any time 
during the trial enrollment and not necessarily concomitant
Listing of all laboratory data with values flagged to show the corresponding CTCAE Grades 
and the classifications relative to the laboratory normal ranges.
3.8.4
Other safety data
3.8.4.1
ECG and cardiac imaging data
3.8.4.1.1 ECG data
12-lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
subject during the study. All ECG data will be listed, notable values will be flagged and any 
other information collected will be listed as appropriate. Triplicate ECGs, performed in case 
when QTcF prolongation of >= 480 msec is observed, will also be listed.
The following summaries will be provided by dose cohorts of Phase I and overall for Phase II:
o
Change from baseline in QT intervals for each visit. 
o
The frequency and percentage of patients with notable ECGs and newly occurring 
qualitative ECG abnormalities. 
Listing of ECG intervals will be provided, where ECG notable parameters will be flagged. 
Listing of ECG findings, cardiac imaging and QT prolonging concomitant medication will also 
be produced.


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The overall assessment results will be summarized using frequency and percentages, for shifts 
from baseline to worst ECG value on treatment.
The number and percentage of subjects with notable ECG values will be presented by dose 
group. Notable abnormal values for ECG parameter will be listed and flagged. 
QT, or QTcF 

New value of > 450 and ≤ 480 ms 

New value of > 480 and ≤ 500 ms 

New value of > 500 ms 

Increase from Baseline of > 30 ms to ≤60ms 

Increase from Baseline of > 60 ms 
HR 

Increase from baseline >25% and to a value > 100 bpm 

Decrease from baseline >25% and to a value < 50 bpm 
PR 

Increase from baseline >25% and to a value > 200 ms 

New value of > 200 ms 
QRS 

Increase from baseline >25% and to a value > 110 ms 

New values of QRS > 110 ms 
3.8.4.1.2 Cardiac Imaging Data
Cardiac imaging results from MUGA Scan or ECHO, collected at screening will also be listed.
3.8.4.2
Vital signs
The vital sign parameters, sitting blood pressure, sitting pulse, respiratory rate, weight, height, 
BMI and body temperature, will be listed for each visit. Notable abnormal values will be flagged.
The vital sign value results will be summarized by dose cohort of Phase I and by group of Phase 
II as mentioned below:

Change  from baseline to worst value (descriptive statistics)

Shift table from baseline to maximum value on-treatment value, for all vital sign 
parameters (frequency count and percentages)

Clinically notable vital sign abnormalities (frequency count and percentages)
Notable abnormalities for vital sign values is as follows:


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Table 3-7
Clinically notable elevated values
Variable 
Criteria
Systolic BP
≥ 180 mmHg and an increase ≥ 20 mmHg from baseline
Diastolic BP
≥ 105 mmHg and an increase ≥ 15 mmHg from baseline
Body temperature
≥ 39.1°C (102.3°F)
Weight
increase from baseline of ≥ 10%
Heart rate
≥ 120 bpm with increase from baseline of ≥ 15 bpm
Table 3-8
Clinically notable below normal values
Variable 
Criteria
Systolic BP
≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline
Diastolic BP
≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline
Body temperature
≤ 35°C (95°F)
Weight
decrease from baseline of ≥ 10%
Heart rate
< 50 bpm with decrease from baseline of ≥15 bpm
3.8.4.3
Pregnancy Test
Pregnancy test results in serum and urine will be listed.
3.8.4.4
Physical Examination
The results of Physical examination at screening will be listed. 
3.8.4.5
Tolerability
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose change. Reasons for dose interruption and dose change will be listed 
by patient and summarized for Safety set, and will be presented by dose cohorts of Phase I by 
group of Phase II. 
Cumulative dose, dose intensity and relative dose intensity of ribociclib, everolimus and 
exemestane will be listed by patient and summarized. 
Categories for relative dose intensity for ribociclib, everolimus and exemestane will be 
specified as follows:
o
<0.7
o
≥0.7 - <0.9 


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o
≥0.9 
The number and proportion of patients within each category will be presented.
3.9
Pharmacokinetic end points
Ribociclib and everolimus concentrations will be listed and summarized descriptively based on 
planned timepoints. The concentration data will be provided for all patients in PK analysis set. 
Descriptive statistics will include mean, standard deviation, CV%, median, range. All PK 
parameters will be provided by dose group and study day. When a geometric mean is
presented, it will be stated as such. Only median values and ranges will be given for Tmax.
Descriptive graphical plots of individual plasma concentration by time will be generated for
ribociclib (and LEQ803) and everolimus. Also mean concentration-time profiles will be 
generated for ribociclib (and LEQ803) and everolimus.
3.10
PD and PK/PD analyses
Not Applicable
3.11
Patient-reported outcomes
Not Applicable


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3.15
Interim analysis
No formal interim analysis is planned One interim statistical analysis will be done after 
completing Phase I part of the study. The final analysis will be after completing Phase II of the 
study.
4
Sample size calculation
Phase I: In the phase I of the study, there will be 3-6 patients per dose level cohort (for a total
of 3 cohorts). A RP2D will be based on safety profile of the dose escalation (cohort A&B) and 
the dose de-escalation (cohort C). RP2D will be defined as the optimal dose level at which 33% 


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or less experience DLTs. Thus, including confirmation, at least 3-6 patients will be required for 
Phase I for each cohort.
Phase II: The sample size is based on an exact test for single proportion to test the null 
hypothesis H0: p ≤ 0.10 where p is the clinical benefit rate in 24 weeks. If the true rate is p ≥
30%, then with one-sided alpha level of 0.05% and a power of 80%, a minimum of 
approximately 60 (30 per group) evaluable patients are required for the study.
Including dropout rate of 10%, to get 60 evaluable patients, a total of approximately 66 patients
(33 patients per group) will be enrolled for the phase 2 of the study for each group (group 1 and 
group 2). Thus, if fewer than 8 patients show clinical benefit at 24 weeks out of 33 patients 
within each group then the study will not show significant clinical benefit. Thus, approximately
at least 66 patients (33 patients per group (group 1&2)) will be required to be enrolled for the 
Phase II of the study.
So far 46 patients for group 1 and 33 patients for group 2 are recruited for phase 2.
5
Change to protocol specified analyses
None
6
Appendix
6.1
Imputation rules
6.1.1
Study drug
In the calculation of treatment exposure duration, if a dosing record has either a missing end 
date (for the last record for that treatment component) or an end date after the cut-off date, the 
cut-off date will be used as the end date. Such imputed data will be flagged in the listings. 
Where a date is recorded as a partial date, the missing day will be imputed as follows:
Start date: The day will be imputed by the 15th of the month. If day and month are missing 
day and month will be imputed by July 1st of the year. If there is a record indicating that the 
dose record started earlier, the start date will be imputed by the end date of the previous record 
+ 1 day. In case the imputed start date is later than the complete end date, the record will not be 
considered for analysis.
End date: The day will be imputed by the 15th of the month, and if day and month are missing 
then by July 1st of the year. If there is a record indicating that this started later, the end date will 
be imputed by the start date of the next record - 1 day. In case the imputed end date is earlier 
than the complete start date, the record will not be considered for analysis.
Imputed DAR start and end dates will be flagged in the listings.
The protocol allows for continuous dosing record entry with start dates and end dates for all 
compounds of study treatment. A separate dosing record should be entered whenever there is a 


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change in the dosing which can be due to dose change, delay or missed doses. If the start date 
and end date is on the same date then that DAR record will be called single dose DAR record.
For dates known to be within the trial period, the last known contact date will be used if this 
imputation makes the date later than the last known contact date but within the trial completion 
date. If the imputed date is earlier than the first medication date, the first medication date will 
be used.
For dates prior to the treatment start, the treatment start date will be used if this imputation 
makes the date later than the treatment start date.
6.1.2
AE date imputation
6.1.2.1
AE Start Date Imputation 
If the adverse event start date was entirely missing or patient has not yet started study treatment 
no imputation was done. 
1. If the AE start date year value is missing, the date uncertainty is too high to impute 
a rational date. Therefore, if the AE year value is missing, the imputed AE start date 
is set to NULL.
2. If the AE start date year is available and the year is less than year of the treatment 
start date, the AE started before treatment.  Therefore:
a.
If the AE year is less than the treatment year and the AE month is missing, 
the imputed AE start date is set to the mid year point (01JulYYYY).
b. Else if the AE year is less than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the mid month point 
(15MONYYYY).
3. If the AE start date year is available and value is greater than the treatment start date 
year value, the AE started after treatment.  Therefore:
a.
If the AE year is greater than the treatment year and the AE month is missing, 
the imputed AE start date is set to the year start point (01JanYYYY).
b. Else if the AE year is greater than the treatment year and the AE month is 
not missing, the imputed AE start date is set to the month start point 
(01MONYYYY).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start.
b. Else if the AE month is less than the treatment start month, the imputed AE 
start date is set to the mid month point (15MONYYYY).
c.
Else if the AE month is greater than the treatment start month, the imputed 
AE start date is set to the start month point (01MONYYYY).


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The table below presents the algorithm used to impute the partial AE start date:
MON 
MISSING
MON < TRT_MON
MON = TRT_MON
MON > TRT_MON
YYYY 
MISSIN
G
_null_
_null_
_null
_null_
YYYY < 
TRT_YR
01JULYYY
Y
15MONYYYY
15MONYYYY
15MONYYYY
YYYY = 
TRT_YR
TRTSTD+1
15MONYYYY
MAX(01MONYYY
Y, TRTSTD+1)
MAX(01MONYYY
Y, TRTSTD+1)
YYYY > 
TRT_YR
01JANYYY
Y
MAX(01MONYYY
Y, TRTSTD+1)
MAX(01MONYYY
Y, TRTSTD+1)
MAX(01MONYYY
Y, TRTSTD+1)
  Where:
    MON = Month of Partial Adverse Event Start Date
    AE_YR =Year of Partial Adverse Event Start Date
    TRT_MON= Month of Treatment Start Date
    TRT_YR= Year of Treatment Start Date
     TRTSTD = Treatment Start Date
6.1.2.2
AE End Date Imputation 
Rules for imputing the AE end date:

Rules for imputing the AE end date:

If AE day is missing but year and month are available, then the AE end date is set to 
minimum of (end date of follow-up period (treatment end date + 30 days), last day of 
the month, date of death, cutoff date).

If AE month and day are missing but year is available, then it is set to minimum of 
(end date of follow-up period, Dec-31 of the year, date of death, cutoff date).

If AE year is missing the end date will not be imputed. 

If complete (imputed) AE end date is available and the imputed AE start date is 
greater than the (imputed) AE end date, then imputed AE start date should be set to the 
(imputed) AE end date. If patient has not yet started study treatment, no imputation 
will be done for AE end date.
6.1.3
Concomitant medication date imputation
6.1.3.1
Concomitant medication start date imputation
Rules for imputing the CMD start date:


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1. If the CMD start date year value is missing, the imputed CMD start date is set to one 
day prior to the date of first dose. 
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before the treatment.  Therefore:
a) If the CMD month is missing, the imputed CMD start date is set to the mid-year 
point (01JulYYYY).
b) Else if the CMD month is not missing, the imputed CMD start date is set to the 
mid-month point (15MONYYYY).
3. If the CMD start date year value is greater than the treatment start date year value, the 
CMD started after the treatment. Therefore:
a) If the CMD month is missing, the imputed CMD start date is set to the year start 
point (01JanYYYY).
Else if the CMD month is not missing, the imputed CMD start date is set to the month start 
point (01MONYYYY).
1. If the CMD start date year value is equal to the treatment start date year value:
a) And the CMD month is missing or the CMD month is equal to treatment start 
month, then the imputed CMD start date is set to one day after the treatment start 
date. 
b) Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY).
c) Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY).
6.1.3.2
Concomitant medication end date imputation
Rules for imputing the CMD end date (including on-going records CM.CMONGO=’Y’):

If CMD end day is missing and CMD month/year are non-missing:
a) If day is missing but month/year are not missing impute day with the last day of 
the month.

If CMD end day/month are missing and CMD year is non-missing:
a) If CMD year is prior to or greater than the year of first dose of treatment, assume 
the 31 Dec.
b) Else if CMD year is equal to the year of first dose of treatment, the imputed end 
date is the min of (treatment end date, 31st of December).

If imputed CMD end date is less than the CMD start date, use the CMD end date as 
the imputed CMD start date.

If imputed CMD end date is greater than date of death, date of cutoff, or end date of 
follow-up period, then the imputed CMD end date will take the minimal date among 
date of death, date of cutoff, or end date of follow-up period.


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6.1.3.3
Prior therapies date imputation
Not Applicable 
6.1.3.4
Post therapies date imputation
Not Applicable
6.1.3.5
Other imputations
Not Applicable
6.2
AEs coding/grading
Adverse events will be coded using the Medical Dictionary For Regulatory Activities 
(MedDRA) version 19.1 or higher.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (specify CTCAE version used in the SAP).
6.3
Laboratory parameters derivations
6.3.1
Differential Counts:
CTCAE grading is based on absolute values. However, for some labs this data may not  present 
itself as absolute counts and be recorded as percentage or fraction in the database (e.g. 
neutrophils).
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100)
6.4
Statistical models
6.4.1
Analysis of Response Rate
Patients with clinical benefit, disease control and responders are summarized in terms of  
percentage rate with 95% confidence interval. An exact binomial confidence interval 
(implemented using the SAS procedure FREQ with the EXACT statement for one-way tables) 
is calculated (Clopper & Pearson, 1934).
The SAS procedure FREQ was used with the following code: 
PROC FREQ DATA=dataset; 
BY treatment; 
TABLES response / binomial;


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EXACT binomial;
RUN; 
6.4.2
Time to event analysis
For analyzing PFS, OS and DOR, TDD, PROC LIFETEST SAS® procedure will be used for 
Kaplan Meier plots for each dose group. Median PFS and Median OS, Median TDD  for each 
dose group will be obtained along with 95% confidence intervals calculated by SAS procedure 
LIFETEST using method of Brookmeyer and Crowley (1982).
The following variables will be used:
•
Progression, Survival, Definitive deterioration: 
Event
•
Censoring indicator variable:
1=Censored; 0=Event 
6.5
Rule of exclusion criteria of analysis sets 
Not Applicable
7
Reference
1. RECIST Guidelines version 1.1 - Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival  and Overall Survival (based on 
RECIST 1.1)
2. Health-Related Quality of Life of Patients With Advanced Breast Cancer Treated With 
Everolimus Plus Exemestane Versus Placebo Plus Exemestane in the Phase 3, 
Randomized, Controlled, BOLERO-2 Trial - Howard A. Burris, III, MD; Fabienne 
Lebrun, MD; Hope S. Rugo, MD; J. Thaddeus Beck, MD; Martine Piccart, MD, PhD; 
Patrick Neven, MD, PhD; Jose Baselga, MD, PhD; Katarina Petrakova, PhD; Gabriel 
N. Hortobagyi, MD; Anna Komorowski, MD; Edmond Chouinard, MD; Robyn Young, 
MD; Michael Gnant, MD; Kathleen I. Pritchard, MD; Lee Bennett, MS; Jean-Francois 
Ricci, PhD; Hounayda Bauly, PhD; Tetiana Taran, MD; Tarek Sahmoud, MD, PhD; and 
Shinzaburo Noguchi, MD
3. Safety and Efficacy of RAD001 (Everolimus) Monotherapy Plus Best Supportive Care 
in Patients With Advanced Gastric Cancer (AGC) (GRANITE-1) -
https://clinicaltrials.gov/ct2/show/results/NCT00879333?sect=Xa0156#outcome4
4. Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: 
BOLERO-2 Final Progression-Free Survival Analysis
http://link.springer.com/article/10.1007/s12325-013-0060-1
5.
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time, Biometrics 38, 29 - 41.
6. Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika; 26, 404-413.