Conditions: Tumors With CDK4/6 Pathway Activation
Keywords: Solid malignancy Hematologic malignancy Mutations Amplifications Signature CDK4 CDK6 CDK4/6 Cyclin D1 CCND, Cyclin D3 p16 mutation CDKN2A LEE011 Breast cancer Ovarian cancer Lymphoma Mesothelioma Pancreatic neuroendocrine Leukemia Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 106
Healthy volunteers: no

Brief summary:
The purpose of this signal seeking study was to determine whether treatment with LEE011 demonstrates sufficient efficacy in CDK4/6 pathway activated solid tumors and/or hematologic malignancies to warrant further study.

Detailed description:

Arms:
arm 1: LEE011 600 mg (hard gelatin capsules) was administered orally once daily for 3 weeks on/1 week off. A complete treatment cycle was defined as 28 days.

Interventions: intervention 1: LEE011
Intervention descriptions: intervention 1: Study drug was provided in 200 mg and 50 mg hard gelatin capsules to be taken orally

Protocol document:
Prot_001.pdf: 
Clinical Development
Ribociclib (LEE011)
Protocol CLEE011XUS03 / NCT02187783
Modular phase II study to link targeted therapy to patients 
with pathway activated tumors:
Module 8 – Ribociclib for patients with CDK4/6 pathway 
activated tumors
Authors
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
03 (Clean)
Development phase
II
Document status
Final
Release date
10-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 3 (10-Apr-2017)............................................................................................12
Amendment 2 ....................................................................................................................12
Amendment 1 ....................................................................................................................14
Protocol summary..............................................................................................................16
1
Background........................................................................................................................19
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............19
1.1.1
Overview of G1 to S phase transition in mammalian cells...................19
1.1.2
Alterations in the D-cyclin-CDK4/6-INK4a-pRb pathway in 
human malignancies:.............................................................................19
1.2
Introduction to investigational treatment(s) and other study treatment(s).............20
1.2.1
Overview of Ribociclib.........................................................................20
2
Rationale............................................................................................................................25
2.1
Study rationale and purpose...................................................................................25
2.2
Rationale for the study design ...............................................................................26
2.3
Rationale for dose and regimen selection..............................................................26
3
Objectives and endpoints...................................................................................................26
4
Study design ......................................................................................................................28
4.1
Description of study design ...................................................................................28
4.1.1
Treatment phase ....................................................................................29
4.1.2
Follow-up phase....................................................................................29
4.2
Definition of end of the study................................................................................29
4.3
Early study termination..........................................................................................30
5
Population..........................................................................................................................30
5.1
Patient population..................................................................................................30
5.2
Inclusion criteria ....................................................................................................30
5.3
Exclusion criteria...................................................................................................32
6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Dosing regimen.....................................................................................36
6.1.2
Guidelines for continuation of treatment ..............................................38


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6.1.3
Treatment duration................................................................................38
6.2
Dose escalation guidelines.....................................................................................38
6.3
Dose modifications................................................................................................38
6.3.1
Dose modification and dose delay ........................................................38
6.3.2
Permitted study treatment adjustments for Ribociclib..........................38
6.3.3
Criteria for interruption and re-initiation of ribociclib treatment..........39
6.3.4
Follow-up for toxicities.........................................................................43
6.3.5
Anticipated risks and safety concerns of the study...............................44
6.4
Concomitant medications ......................................................................................44
6.4.1
Permitted concomitant therapy .............................................................44
6.4.2
Concomitant therapy requiring caution.................................................45
6.4.3
Prohibited concomitant therapy ............................................................45
6.5
Patient numbering, treatment assignment and enrollment.....................................45
6.5.1
Patient numbering .................................................................................45
6.5.2
Treatment assignment and randomization ............................................45
6.5.3
Treatment blinding................................................................................46
6.6
Study drug preparation and dispensation...............................................................46
6.6.1
Study drug packaging and labeling.......................................................46
6.6.2
Drug supply and storage........................................................................46
6.6.3
Study drug compliance and accountability ...........................................46
6.6.4
Disposal and destruction .......................................................................47
7
Visit schedule and assessments .........................................................................................47
7.1
Study flow and visit schedule................................................................................47
7.1.1
Screening...............................................................................................56
7.1.2
Treatment period...................................................................................58
7.1.3
End of treatment visit, including premature withdrawal and study 
discontinuation visit ..............................................................................58
7.1.4
Follow up period ...................................................................................60
7.1.5
End of post-treatment follow-up (Study phase completion).................60
7.2
Assessment types...................................................................................................60
7.2.1
Efficacy assessments.............................................................................61
7.2.2
Safety and tolerability assessments.......................................................67
7.2.3
Pharmacokinetics ..................................................................................71
71
7.2.5
Other assessments .................................................................................73
8
Safety monitoring and reporting........................................................................................73


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8.1
Adverse events.......................................................................................................73
8.1.1
Definitions and reporting ......................................................................73
8.1.2
Laboratory test abnormalities................................................................75
8.2
Serious adverse events...........................................................................................75
8.2.1
Definitions.............................................................................................75
8.2.2
Reporting...............................................................................................76
8.3
Emergency unblinding of treatment assignment ...................................................76
8.4
Pregnancies............................................................................................................76
8.5
Warnings and precautions......................................................................................77
8.6
Data Monitoring Committee..................................................................................77
8.7
Steering Committee ...............................................................................................77
9
Data collection and management.......................................................................................77
9.1
Data confidentiality ...............................................................................................77
9.2
Site monitoring ......................................................................................................78
9.3
Data collection.......................................................................................................78
9.4
Database management and quality control............................................................78
10 Statistical methods and data analysis ................................................................................79
10.1
Analysis sets ..........................................................................................................79
10.1.1
Full Analysis Set ...................................................................................79
10.1.2
Safety Set ..............................................................................................79
10.2
Patient demographics/other baseline characteristics .............................................80
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................80
10.3.1
Study medication...................................................................................80
10.3.2
Concomitant therapies...........................................................................80
10.4
Primary objective...................................................................................................80
10.4.1
Variable.................................................................................................80
10.4.2
Statistical hypothesis, model, and method of analysis..........................81
10.4.3
Evaluation of trial success and futility..................................................82
10.4.4
Handling of missing values/censoring/discontinuations.......................83
10.4.5
Supportive analyses...............................................................................83
10.5
Secondary objectives .............................................................................................83
10.5.1
Key secondary objective(s)...................................................................83
10.5.2
Other secondary efficacy objectives .....................................................83
10.5.3
Safety objectives ...................................................................................84
85
10.7
Interim analysis......................................................................................................86


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10.8
Sample size calculation..........................................................................................86
11 Ethical considerations and administrative procedures ......................................................87
11.1
Regulatory and ethical compliance........................................................................87
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................87
11.3
Informed consent procedures.................................................................................87
11.4
Discontinuation of the study..................................................................................88
11.5
Publication of study protocol and results...............................................................88
11.6
Study documentation, record keeping and retention of documents.......................88
11.7
Confidentiality of study documents and patient records .......................................89
11.8
Audits and inspections...........................................................................................89
11.9
Financial disclosures..............................................................................................89
12 Protocol adherence ............................................................................................................89
12.1
Amendments to the protocol..................................................................................89
13 References (available upon request)..................................................................................90
14 Appendices ........................................................................................................................93
Appendix A: Concomitant Medications............................................................................93
Appendix B: Criteria for therapeutic response/outcome assessment of solid tumors 
and/or lymph nodes (based on RECIST 1.1).........................................................95
Appendix C: Criteria for therapeutic response/outcome assessment in lymphoma 
studies (based on Cheson response criteria) ........................................................101
Appendix D: Ann Arbor staging classification ...............................................................111
Appendix E: Rai Staging Systema...................................................................................112
Appendix F: Criteria for Response assessment in Acute Myeloid Leukemia (based 
on IWG and Cheson) ...........................................................................................113
114
Appendix H: Criteria for Response assessment in Acute Lymphoblastic Leukemia 
(based on NCCN Guidelines Version 1.2013) ....................................................115
Appendix I: Criteria for Response assessment in Chronic Myelogenous Leukemia 
(based on NCCN Guidelines Version 4. 2013) ...................................................116
Appendix J: Criteria for Response assessment in Chronic Lymphocytic Leukemia 
(based on modified IWG guidelines)...................................................................117
Appendix K: Eastern Cooperative Oncology Group (ECOG) Performance status.........118
Appendix L: International Myeloma Working Group (IMWG) uniform response 
criteria for multiple myeloma1.............................................................................119
Appendix M: Criteria for Response assessment in Myelofibrosis (based on modified 
IWG-MRT guidelines and European LeukemiaNet (ELN) consensus report)1 ..121


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Appendix N: Criteria for Response assessment in polycythemia vera (based on 
modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1................................................................................................124
Appendix O: Criteria for Response assessment in Essential thrombocythemia (based 
on modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1................................................................................................125
Appendix P: Criteria for Response assessment in Myelodysplasia (based on modified 
IWG guidelines)1 .................................................................................................126
Appendix Q: Myeloproliferative Neoplasm (MPN) Symptom Assessment Form 
Total Symptom Score (MPN-SAF TSS) .............................................................127
Appendix R: Bayesian Adaptive Design Framework for the Modular Phase II Study 
to Link Targeted Therapy to Patients with Pathway Activated Tumors. ............128
List of figures
Figure 1-1
Pharmacodynamic response in tumor tissue from a patient with 
mantle cell lymphoma treated with LEE011.........................................25
Figure 4-1
Study Start-up Design ...........................................................................28
List of tables
Table 1-1
Serious adverse events with a suspected causal relationship with 
LEE011 single agent .............................................................................23
Table 3-1
Objectives and related endpoints ..........................................................27
Table 6-1
Dose and treatment schedule.................................................................37
Table 6-2
Ribociclib dose modifications...............................................................39
Table 6-3
Ribociclib related toxicity management guidelines ..............................39
Table 6-4
Recommendations for dose modification in case of hepatic 
toxicities................................................................................................40
Table 6-5
Dose modification guidance in case of QT Prolongation .....................42
Table 6-6
Ribociclib dose adjustment and management recommendation for 
all other adverse reactions.....................................................................43
Table 6-6
Packaging and labeling .........................................................................46
Table 7-1
Visit evaluation schedule ......................................................................48
Table 7-2
ECG Collection Plan.............................................................................70
72
73


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List of abbreviations
ADME
Absorption Distribution Metabolism and Excretion
AE
Adverse Event
AKT
Protein Kinase B
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AML
Acute myelogenous leukemia
ANC
Absolute Neutrophil Count 
AP
Alkaline Phosphatase
APL
Acute promyelcytic leukemia
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Chemical Classification System
AUC0-24h
Area Under the Curve 0-24 h
BCC
Basal cell carcinoma
BCRP
Breast cancer resistance protein
BID
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BP
Blood pressure
BSC
Best supportive care
BUN
Blood Urea Nitrogen 
Ca
Calcium
CA-125
Cancer Antigen-125
CABG
Coronary artery bypass graft
CBC 
Complete blood count
CBR
Clinical Benefit Rate
CFR
Code of Federal Regulations
CHF
Congestive heart failure
CI
Confidence Interval
CL
Clearance
CLIA
Clinical Laboratory Improvement Amendments
CLL
Chronic lymphocytic leukemia
Cmax
Maximum Concentration
CML
Chronic Myeloid Leukemia
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central Nervous System 
CPK
Creatine phosphokinase
CR
Complete Response
CRC
Colorectal Cancer
CrCl
Creatinine clearance
CRO
Contract Research Organization
CRPC
Castrate Resistant Prostate Cancer
CSF
Clinical service form
CSR
Clinical study report


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CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebrovascular accident
CYP
Cytochrome P
DLs
dose levels
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
DVT
Deep vein thrombosis
e.g.
for example
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor 
EOT
End of Treatment
ERK/MAPK
Extracellular signal-regulated kinase/Mitogen-Activated Protein Kinase
FDA
Food and Drug Administration
FAS
Full Analysis Set
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
FFPE
Formalin fixed paraffin embedded
FSH
Follicle-stimulating hormone 
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor 
GGT
Gamma-glutamyltranspeptidase
GI
Gastrointestinal
GLP
Good laboratory practice
GM-CSF
Granulocyte macrophage colony-stimulating factor 
GVHD
Graft-versus-host disease
HBV
Hepatitis B Virus
hCG
human chorionic gonadotrophin
HCV
Hepatitis C Virus
HDL
High density lipoprotein
hERG
human Ether-à-go-go Related Gene
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
hr
hour
IB
Investigators Brochure
IC50
Half maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMWG
International Myeloma Working Group
IN
Investigator notification
INR
International Normalized Ratio


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IRB
Institutional Review Board
IUD
intrauterine device 
IUS
intrauterine system
IWG
International working group
KA
Keratoacanthoma
LDL
Low density lipoprotein
LVEF
Left Ventricular Ejection Fraction 
MedDRA
Medical Dictionary for Regulatory Activities
MEK
Mitogen-activated ERK Kinase
mg
milligram
MI
Myocardial infarction
MM
Multiple Myeloma
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated acquisition scan
N
Sample size
NA
Not applicable
Na
Sodium
NCCN
National Comprehensive Cancer Network
NCI CTC
National Cancer Institute Common Terminology Criteria
nM
Nano molar
NSCLC
Non-small cell lung carcinoma
OC
Oral contraception 
OR
Overall response
ORR
Overall Response Rate
OS
Overall survival 
PD
Progressive disease
PD
Pharmacodynamics
PE
Pulmonary embolism
PET
Positron emission tomography
PFS
Progression-free survival 
Ph
Philadelphia chromosome
PHI
Protected health information
PK
Pharmacokinetics
PLT
Platelets
PR
Partial Response
PSA
Prostate-specific antigen
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
QD
quaque die/once a day
QTc
QT corrected
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia)
RAP
Report Analysis Plan
RBC
Red Blood Cells
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase two dose


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RU
Resource utilization
SAE
Serious Adverse Event
SBP
Systolic blood pressure
SC
Steering Committee
SCC
Squamous cell carcinoma
SCT
Stem cell transplant
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase/AST
SGPT
Serum glutamic pyruvic transaminase/ALT
SPEP
Serum protein electrophoresis
SUSAR
Suspected unexpected serious adverse reaction
TdP
Torsade de Pointes
TIA
Transient ischemic attack
Tmax
The time at which the maximum observed concentration (Cmax) occurs
TSH
Thyroid stimulating hormone
ULN
Upper Limit of Normal
UPEP
Urine protein electrophoresis
WBC
White Blood Cell 
WHO
World Health Organization
WNL
Within normal limits


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days. For this protocol, a complete treatment cycle 
is defined as 28 days. Ribociclib will be dosed once daily, 3 weeks on and 1 
week off. The first dose of ribociclib defines Day 1 of the treatment cycle.
Baseline
Pre-dose Cycle 1 day 1
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. Ribociclib is the investigational drug in this 
study.
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. Ribociclib is the investigational 
treatment.
Patient Number (Patient No.)
A unique identifying number assigned to each patient who enrolls in the 
study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival
Screening
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)
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, completion of treatment, etc.
Stage in cancer
The extent of 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
Ribociclib (LEE011)
Study treatment discontinuation
Point/time when patient permanently stops taking ribociclib, for any reason.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints


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Amendment 3 (10-Apr-2017)
Study CLEE011XUS03 was initiated in August 2014 and closed to enrollment on May 8,
2015 with 106 patients enrolled.  As of April 6, 2017, one patient remains on study.
Amendment rationale
The main purpose of this amendment is to introduce language to allow for the one ongoing 
patient to rollover onto a Novartis sponsored Rollover Study for patients receiving LEE011.  
Protocol changes
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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.
Section 4.2 Definition of End of Study: Further defines the end of study to include termination 
by the study or another clinical study becoming available for the patients to transfer.
Section 7.1.3.2 Criteria for premature patient withdrawal (EOT phase completion): Clarified 
that patients who rollover to another study will have EOT procedures performed but will not 
have further follow up on the current study.
Throughout the document:  Changed the name of Novartis Drug Safety and Epidemiology 
Department (DS&E) to  Novartis Chief Medical Office & Patient Safety (CMO&PS).
Amendment 2
Study CLEE011XUS03 was initiated in August 2014 and as of April 2nd, 2015, a total of 78 
patients have been dosed.
Amendment rationale
The main purpose of the amendment is to align safety and general program information across 
ribociclib studies.
The amendment contains changes to:
1. Reduce the frequency of disease assessments from every 8 weeks to every 16 weeks for 
patients who have completed 16 weeks on treatment. This change will bring the disease 
assessment close to standard of care after the primary endpoint.
2. Clarify that survival follow-up may be discontinued if the primary endpoint is not met.
3. Definition of end of study, to clarify when data will be reported. 
4. Align the inclusion and exclusion criteria to the requirements across ribociclib studies.
5. Include specific dose modification guidance for cases of hepatic toxicity in order to better 
manage patient safety: dose adjustments as well as additional follow up for bilirubin 
and/or transaminases increase have been detailed and separated from the dose 
modification guidance for other adverse events.


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6. Guidance for management of QTc prolongation has been extended to all AEs regardless of 
the grades to better manage patient safety.
7. Update the protocol requirements for consistency with the most recent preclinical 
information: 
a. In the initial rat ADME study cited in previous IB version, thyroid had the highest 
exposure in albino animals only. As a precaution, thyroid function was monitored in 
all clinical study protocols. A most recent study (DMPK 1300792) using p.o. dosing 
in partially pigmented animals with a longer observation period showed the highest 
distribution to the melanin-containing structures and not to the thyroid gland. In 
addition, no clinically significant thyroid adverse events have been reported in clinical 
trials so far. Based on this information, the risk to thyroid gland is removed from the 
reference safety information for the compound and thyroid laboratory monitoring in 
clinical protocols are no longer mandated. 
b. In the 15-week rat toxicity study, kidney has been identified as an additional organ of 
toxicity for LEE011. In order to better characterize this potential side effect, as well 
as improve the management of the safety of the patients, monthly urinalysis has been 
added as well as blood urea nitrogen assessment with each chemistry panel.
8. Concomitant medications: bisphosphonate and denosumab, palliative radiotherapy, 
concomitant medications requiring caution and prohibited concomitant therapy sections 
have been updated to better manage concomitant medication use.
9.
 
 
 
 
 
10. Bayesian adaptive design for the Modular Phase II Study to link Targeted Therapy to 
Patients with Pathway Activated Tumors. In a single arm trial without control arm, the 
quality of the inferences depend strongly on historical data used to create a credible 
estimate of the baseline control rate. For this study this required an estimate of the patient 
population that would be enrolled. A control estimate was initially formed for each group 
based on the population estimate which differed from the patient population was enrolled 
in terms of previous line of therapy (heavily pretreated). In order to produce the best 
inferences for future development decisions, it is important to change the assumed 
baseline control rates to match the population enrolled in the study rather than rely on the 
pre-trial assumptions. The appendix has been changed to be standard across the Modules
rather than being study specific.
11. This amendment also includes minor editorial changes as described in the list of changes 
below.
Protocol changes
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.


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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.

Section 1.2.1.1.2 Nonclinical pharmacokinetics and metabolism of ribociclib: Provides the 
most recent nonclinical pharmacokinetics information on ribociclib.

Section 1.2.1.2 Clinical experience with ribociclib: Provides status update on clinical 
experience with ribociclib.

Section 1.2.1.2.1 Clinical safety of ribociclib: Provides the most recent available safety 
information on ribociclib.

Protocol summary, Section 4.1.1, Table 7-1: reduced the frequency of disease assessments 
after 16 weeks on treatment from every 8 weeks to every 16 weeks.

Protocol summary, Section 4.1.2, Table 7-1, section 7.1.4.3: provides updated information 
on how survival follow-up will be handled.

 

Section 4.2: provides updated definition of end of study, and clarifies when the study data 
will be reported.

Section 5.2, number 13f: provides most recent inclusion bilirubin values available for 
ribociclib.

Section 5.3: provides updated exclusion values based on clinical experience with 
ribociclib.

Section 6.3.3: provides the most recent criteria for interruption and re-initiation of 
ribociclib based on available clinical experience.

Section 6.4, Appendix A: provides updated information on concomitant medication based 
on available clinical experience.

 

Table 7-1, Section 7.2.2.6.1, Table 7-2: provides updated information ECG plan.

Section 10.5.1: added information to clarify how ORR will be presented if the sample size 
is small.

Section 10.8: provides updated information on sample size calculation.

Appendix R: provides revised Bayesian Adaptive Design for the Modular Phase II Study 
to Link Targeted Therapy to Patients with Pathway Activated Tumors.

Changed LEE011 to ribociclib through-out the protocol. 
Amendment 1
Amendment Rationale
The amendment contains changes to clarify that tumor aberration resulting from CDK4/6 
pathway activation is required for study. Other changes in the protocol include updates to the 
inclusion and exclusion criteria, addition of confirmatory requirement for solid tumor 


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assessment responses of PR or greater and updates to in text appendix references. The 
changes were implemented to make protocol clear, standardize leukemia requirements and 
update hyperlinks.
Changes to the Protocol
Changes to specific sections of the protocol are shown in track change version using strike 
through red font for deletions and red underlined for insertions.

Protocol title has been revised to state: “Modular phase II study to link targeted therapy to 
patients with pathway activated tumors: Module 8 -  LEE011 for patients with CDK4/6 
pathway activated tumors”.

Protocol Summary: the title, brief title, purpose and rationale, 
, 
study design and efficacy assessment sections were revised to clarify CDK 4/6 pathway 
activation and streamline the summary.

Section 2.1: the study purpose was streamlined to reflect the protocol title.

 

Sections 4.1.2, 7.2.4.2.2 and Table 7-3: revised to remove ambiguity from collection 
timepoint for optional tumor sample at disease progression.

Sections 5.2 and 5.3: updated for leukemia patients.

Sections 7.2.1.1 and 10.4: added disease assessment confirmatory requirement for solid 
tumor patients who achieved a response of PR or greater.

Section 11.3: updated contraception requirement for males to make it consistent with 
section 5.3, #30.

Updated appendix references and hyperlinks, and removed typographical errors 
throughout the protocol.


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Protocol summary
Protocol number
CLEE011
Title
Modular phase II study to link targeted therapy to patients with pathway activated tumors:
Module 8 - Ribociclib for patients with CDK4/6 pathway activated tumors
Brief title
Ribociclib for patients with CDK4/6 pathway activated tumors
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this signal seeking study is to determine whether treatment with ribociclib 
demonstrates sufficient efficacy in CDK4/6 pathway activated solid tumors and/or 
hematologic malignancies to warrant further study.
Primary 
Objective(s) and 
Key Secondary 
Objective
Primary objectives:
To assess clinical benefit associated with ribociclib treatment based on local investigator 
assessment.
For patients with solid tumors the assessment criteria will be RECIST  1.1 and will include 
responses of CR or PR or SD ≥ 16 weeks. For hematologic tumors, other appropriate 
hematological response criteria will apply and are included in the appendices.
Key Secondary objective:
To assess Overall Response (OR) of Partial Response (PR) or greater based on local 
investigator assessment.
For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will include 
responses of CR and/or PR. For hematologic tumors, other appropriate hematological 
response criteria will apply and are included in the appendices.
Table 
T1-1 o assess:
Progression-Free Survival (PFS) based on local investigator assessment per RECIST 1.1 
or other appropriate hematological response criteria
Overall Survival (OS)
Duration of Response (DOR) based on local investigator assessment per RECIST 1.1 or 
other appropriate hematological response criteria
Safety and tolerability
Study design
This is a phase II, open label study to determine the efficacy and safety of treatment with 
LEE011 in patients with a diagnosis of select solid tumors or hematological malignancies 
that have been pre-identified (prior to study consent) to have CDK 4/6 pathway activation , 
and whose disease have progressed on or after standard treatment.
Genomic profiling is becoming more accessible to patients and their physicians. As such, 
more patients have been identified with potentially-actionable mutations or pathway-
activations but do not have access to targeted drug treatment. This is a signal-seeking 
study to match patients with tumors containing the relevant gene aberrations to treatment 
with CDK4/6 inhibitor, LEE011. Pre-identification of the pathway aberration status will be 
performed locally at a CLIA certified laboratory prior to participation on the trial. 
Once the patient has been identified, treating physicians who are qualified investigators 
may contact Novartis to consider enrollment in this study. For the purpose of this study, 
genomic profiling is not considered part of screening. Informed consent must be signed 


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before any screening activities take place. Once eligibility (inclusion/exclusion criteria) has 
been confirmed by Novartis, the patient will initiate therapy with ribociclib single-agent. The 
patient may not receive any additional anti-cancer therapy during treatment with ribociclib.
Patients will continue to receive study treatment until disease progression (assessed by
investigator per RECIST 1.1 or appropriate hematologic response criteria), unacceptable 
toxicity, death or discontinuation from study treatment for any other reason (e.g., 
withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the 
investigator), otherwise known as End of Treatment. All patients who discontinue from 
study treatment due to disease progression must have their progression clearly 
documented.
Disease assessment (per RECIST 1.1 or appropriate hematological response criteria) will 
be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd 
cycle), until disease progression or end of treatment, whichever occurs first. The frequency 
of disease assessment will be reduced to every 16 weeks after patients have completed 16 
weeks on treatment. Scans will be assessed locally by the investigator.
After discontinuation of treatment, patients, regardless of reason for treatment 
discontinuation, will be followed for safety for 30 days after the last dose.
All patients will be followed for survival status every 3 months for 2 years after the last 
patient has enrolled in the study, regardless of treatment discontinuation reason (except if 
consent is withdrawn or patient is lost to follow-up). If the study primary efficacy endpoint is 
not met, Novartis may discontinue survival follow-up for this study.
Population
The study population consists of approximately 70-90 adult patients with a diagnosis of a 
solid tumor or hematological malignancy that have been pre-identified as having relevant 
CDK4/6, cyclin D1/3, or p16 aberrations. Patients must have received at least one prior 
treatment for their recurrent, metastatic and/or locally advanced disease and have no 
remaining standard therapy options anticipated to result in a durable response. Patients 
must have progressive and measurable disease (per RECIST 1.1 or appropriate 
hematological response criteria) and be in need of treatment. 
This is a signal seeking study, attempting to identify additional patient populations who may 
benefit from treatment with single agent ribociclib. Tumors currently being studied under 
some key Novartis-sponsored trials will be excluded. These include breast cancer (except 
triple negative), mantle cell lymphoma, teratoma, castrate resistant prostate cancer 
(CRPC), melonoma and liposarcoma. Additional tumor types may be excluded during the 
course of the study at the discretion of Novartis.
Patients must have archival tissue available for submission to allow for molecular testing 
related to pathway activation. If tissue is not available or is insufficient the patient must be 
willing to undergo a fresh tumor biopsy to allow for these analyses.
Enrollment is meant to encompass select solid tumors and hematologic malignancies that 
have the relevant CDK4/6, cyclin D1/3 or p16 aberrations and who otherwise meet all the 
inclusion and none of the exclusion criteria. Though common for phase I studies, tissue-
agnostic enrollment is unusual for phase II studies, which typically limit enrollment to one or 
a few well-defined tumor types. We expect that the study will enroll patients whose tumors 
have already been pre-identified. such as ovarian, mesothelioma, breast (triple negative), 
colorectal, biliary, pancreatic neuroendocrine cancer, and lymphomas (excluding mantle 
cell lymphoma) (enrollment will not be strictly limited to those particular cancers).  The total 
number of patients to be enrolled per tumor type will be based on an adaptive design. The 
adaptive design will be patient-sparing and allow the early closure of non-responding arms 
or arms where early success can be declared.
Inclusion criteria
Patient has a confirmed diagnosis of a solid tumor (except  breast cancer (triple negative
will be enrolled), teratoma, CRPC, melanoma, and liposarcoma) or hematologic 
malignancies (except mantle cell lymphoma,) and is in need of treatment because of 


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progression or relapse.
Patient’s tumor has been evaluated and pre-identified as having a tumor with relevant 
CDK4/6, cyclin D1/3, or p16 aberration. The qualifying alteration must be assessed and 
reported by a CLIA-certified laboratory
Patient must have received at least one prior treatment for recurrent, metastatic and /or 
locally advanced disease and for whom no standard therapy options are anticipated to 
result in a durable remission.
Patient must have progressive and measurable disease per RECIST 1.1. or other 
appropriate hematological response criteria.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
See Section 5.2 for complete Inclusion criteria
Exclusion criteria
Patient has received prior treatment with ribociclib
Patients with primary Central Nerve System (CNS) tumors or CNS tumor involvement
Patient has received chemotherapy or other anticancer therapy ≤ 4 weeks (6 weeks for 
nitrosourea, antibodies or mitomycin-C) prior to starting study drug.
Patients with acute or chronic pancreatitis.
Patients with impaired cardiac function or clinically significant cardiac diseases
Patients with another primary malignancy within 3 years prior to starting study treatment, 
with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or 
other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix
See Section 5.3 for complete Exclusion criteria
Investigational 
and reference 
therapy
Ribociclib will be dosed on a flat scale of 600 mg once daily, 3 weeks on and 1 week off. A 
complete treatment cycle is defined as 28 days.
Efficacy 
assessments
Clinical benefit rate (CBR), overall response (OR), progression free survival (PFS), overall 
survival (OS) and duration of response (DOR) based on local investigator assessment per 
RECIST 1.1 for solid tumors or appropriate hematological response criteria.
During treatment phase, disease assessments must be performed every 8 weeks (±4 days) 
after first dose of study drug (Day 1 of every odd cycle), until disease progression or end of 
treatment, whichever occurs first. The frequency of disease assessment will be reduced to 
every 16 weeks after patients have completed 16 weeks on treatment.
Safety 
assessments
Adverse events.
Physical examination including vital signs and weight.
Performance status evaluation
Cardiac monitoring (cardiac enzymes, ECGs, and assessment of LVEF)
Laboratory evaluations (hematology, biochemistries, pregnancy tests and urinalysis)
Data analysis
The Full Analysis Set (FAS) will include all patients who have received at least one dose of 
study drug. FAS will be the primary population for the analysis of efficacy endpoints.
Key words
Solid tumor malignancy, hematologic malignancy, mutations, amplifications, signature,
CDK4, CDK6, CDK4/6, cyclin D1, CCND1, cyclin D3, CCND3, p16 mutation, CDKN2A, 
LEE011, breast cancer, ovarian cancer, colon cancer, mesothelioma, pancreatic 
neuroendocrine  


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Overview of G1 to S phase transition in mammalian cells
Normal mammalian cells proliferate in response to extracellular signals by transitioning 
through a series of tightly controlled phases that culminate in cell division. The commitment 
to transition from G1 to S phase and the initiation of cell cycle progression is regulated by the 
retinoblastoma protein (pRb). In the absence of appropriate growth stimuli, pRb, in its 
unphosphorylated state, binds and inhibits the activity of the E2F family of transcription 
factors,  preventing these proteins from activating the genes required for  S phase transition    
(Oretega, Malumbres and Barbacid 2002, Shapiro 2006).  Upon mitogen stimulation, 
signaling through pathways such as the MAPK and PI3K pathways increases the abundance 
of  D-cyclins, which bind and activate cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6).  
Cyclin D-bound CDK4/6 then phosphorylates the pRb protein to deactivate it and release 
bound E2F. Once freed, E2F activates S phase-specific genes in order to start cell cycle 
progression.   Full deactivation of pRb requires its sequential phosphorylation at different 
sites by both cyclin D-CDK4/6 and cyclin E-CDK2.  The phosphorylation events mediated by 
CDK4/6 are prerequisites for those catalyzed by CDK2 (Lundberg and Weinberg 1998). The 
kinase activity of CDK4/6 is in turn inhibited by p16, encoded by the INK4a gene (Kamb et al 
1994, Ortega, Malumbres and Barbacid 2002).  The CIP/KIP proteins, inhibitors of cyclin E-
CDK2, also bind to the cyclin D-CDK4/6 complex, and this results in further activation of 
CDK2 by sequestering CIP/KIP proteins from their target (Sherr and Roberts 1999).  Cyclin 
D-CDK4/6 is therefore a key enzyme complex that regulates the G1 to S phase transition.
1.1.2
Alterations in the D-cyclin-CDK4/6-INK4a-pRb pathway in human 
malignancies:
The D-cyclin-CDK4/6-INK4a-pRb pathway is universally disrupted in cancer to favor cell 
proliferation. Eighty percent of human neoplasms maintain functional pRb but harbor 
aberrations that increase the activity of CDK4/6 to effectively inactivate pRb function. These 
aberrations include genetic or epigenetic changes that directly increase the kinase activity of 
CDK4/6 or defects that activate the upstream regulators (Ortega, Malumbres and Barbacid 
2002, Shapiro 2006).  One of the most common events is the inactivation of p16 via mutations, 
deletion and epigenetic silencing. p16 inactivation is frequently observed in a significant 
portion of non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer and 
mesothelioma (Cheng et al 1994, Cowgill and Muscarella 2003, Fountain et al 1995, Gazzeri 
et al 1998).  Moreover, a specific mutation of the CDK4 gene (CDKR24C), that confers 
resistance to p16 binding, has been shown to play a causal role in rare cases of familial 
melanoma, suggesting that unchecked CDK4 activity  is a key event in these cancers (Molven 
et al 2005).
Translocations of the genes encoding D-cyclins to the immunoglobulin heavy chain locus are 
found in a majority of mantle cell lymphomas (MCLs) and in many cases of multiple 


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myeloma (Bergsagel and Kuehl 2003). These translocations lead to constitutive expression of 
D-cyclins, which result in enhanced CDK4/6 kinase activity and unchecked cell proliferation 
(Amin et al 2003). Amplification of  cyclin D1 and overexpression of the protein have also 
been reported in approximately 50% of squamous cell esophageal cancers (Huang et al 2007) 
and  in 20-30% of breast cancers (Arnold and Papanikolau 2005, Sutherland and Musgrove 
2004), suggesting that activation of this pathway may play a role in the growth of these 
tumors.  Furthermore, many of the receptor-mediated growth pathways that are activated in 
human cancers increase D-cyclin transcription and expression to drive cell proliferation.  In 
mouse breast cancers driven by activated Ras or Her2/Neu oncogenes, cyclin D1 and CDK4 
have been shown to be necessary for the tumorigenic phenotype in both initiation and 
maintenance phases, demonstrating that Cyclin-D1/CDK4 is the key effector enzyme complex 
for Ras- or Her2/Neu-driven cancers (Landis et al 2006, Yu Geng and Sicinski 2001).  Other 
activating aberrations of mitogen pathways such as V600E B-Raf in the MAPK pathway and 
PTEN deletions in the PI3K pathway also increase D-cyclins to achieve unchecked 
proliferation, suggesting that CDK4/6 may also be crucial for the cancers bearing these 
alterations (Garcia-Echeverria 2009, Gray-Schopfer Dias and Marais 2005).  Finally, the 
genes encoding CDK4 and 6 are amplified in a subset of human neoplasms.  The CDK4 gene 
is amplified in 100% of liposarcomas along with the MDM2 gene, while CDK6 is frequently 
amplified in T-lymphoblastic lymphoma and/or acute lymphoblastic leukemia (Nagel et al 
2008, Sirvent et al 2007).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Ribociclib
Ribociclib is an investigational agent that is an orally bioavailable, small molecule inhibitor of 
CDK4/6. LEE011 exhibits highly specific inhibitory activity against CDK4/cyclinD1 and 
CDK6/cylinD3 complexes, with concentration resulting in 50% inhibition (IC50) values of 10 
nM and 39 nM, respectively, in isolated enzyme assays. It is inactive against the majority of 
other kinases.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacology of Ribociclib
Ribociclib inhibits the growth of many tumor cell types in vitro and in vivo including ER+ BC. 
In a panel of human breast cancer cell lines, dose-dependent inhibition of proliferation was 
observed in ER+ BC cell lines, with IC50 < 1µM being observed for most ER+ BC lines. 
Regardless of the various genetic aberrations that may be present in the cancer cells, the anti-
tumor activity of ribociclib requires the presence of functional retinoblastoma protein (Rb).
1.2.1.1.2 Non-clinical pharmacokinetics and metabolism of Ribociclib
Four different species were used to investigate the pharmacokinetics (PK) of ribociclib: 
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).


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Bioavailability was low to moderate in rat (37%) and cynomolgus monkey (17%), and 
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 LEE011 in males as 
compared to females and with higher exposure to the metabolite, LEQ803. 
Plasma protein binding was moderate in all species (unbound fraction (fu) in human: 30%).
In a rat (absorption, distribution, metabolism and excretion (ADME)) study, extensive 
distribution of [3H]LEE011 and its metabolites was seen. In pigmented rats, radioactivity was 
specifically found in melanin-containing structures, and 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. Tlast (last observation timepoint) 
was ≤ 48h for most tissues, but long (168 to 840h) for lymph nodes, preputial gland, testis, 
eye and meninges. At one week ≤ 0.04% of the dose was retained in the carcass.
LEQ803 (N-demethylation) was a prominent metabolite found in mouse, rat, dog, monkey 
and human hepatocytes. This metabolite retains some pharmacologic activity and interacts 
with human Ether-a-go-go Related Gene (hERG) channels in vitro. In male rats, unchanged 
LEE011 (24.7% of [3H]AUC0-24h) and its metabolite M11 (26.3% of [3H]AUC0-24h) were 
the major components in plasma. In rats, LEE011 was eliminated mainly by metabolism. The 
major metabolism pathway was direct sulfation of LEE011 to M8 and its excretion into the 
bile. Direct LEE011 secretion accounted for 18.2% of the total plasma clearance.
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, LEE011 was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 
CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. No pregnane X-receptor 
(PXR)-mediated CYP3A4 induction was observed. In vitro inhibition of drug transporters was 
observed with LEE011 for organic anion transporting polypeptide 1B1 (OATP1B1), breast 
cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), OCT2, multidrug 
andtoxin extrusion protein 1 (MATE1), MATE2K and bile salt export pump (BSEP). At 
therapeutic doses, LEE011 may affect substrates of CYP3A4, BSEP, MATE1, OCT2 and/or 
BCRP depending on the dose and concentrations achieved in vivo.
Elimination of LEE011 is dominated by oxidative metabolism mainly via CYP3A4 with a 
minor contribution by flavin-containing monooxygenase 3 (FMO3). The elimination of 
LEE011 may be affected by co-administered drugs that inhibit or induce CYP3A4. Although 
LEE011 is a substrate of the P-glycoprotein (P-gp) efflux transporter and subject to active 
uptake into hepatocytes, these processes are likely not clinically relevant due to the high 
passive permeability of LEE011. 
1.2.1.1.3 Safety pharmacology and toxicology of Ribociclib
In vitro, LEE011 did not show mutagenic or phototoxic potential. Safety pharmacology 
studies conducted did not reveal any effects on CNS or respiratory functions. In the dog 
telemetry study, prolongation of the average QT and QTc was observed with the potential to 


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induce PVCs at higher exposure levels. LEE011 and LEQ803 likely contributed to the QT 
prolonging effects seen in vivo.
In rats and dogs, ribociclib induced bone marrow hypocellularity, lymphoid depletion, atrophy 
of the skin and intestinal mucosa, decreased bone formation and testicular atrophy. These 
effects are considered to be related to the pharmacological inhibition of cell replication in 
these tissues due to CDK4/6 inhibition. The liver, bile system and gall bladder (proliferative 
changes, cholestasis, sand-like gallbladder calculi, and inspissated bile) were identified as 
additional target organs of toxicity which are not likely related to the primary pharmacology 
of ribociclib. Correlating hematological and/or biochemistry changes were seen for the effects 
described in the bone marrow, lymphoid system and liver. All of the described changes were 
fully reversible in rats and dogs.
Based on the mechanism of action and preclinical toxicology studies conducted, 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.
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety 
As of 24-Apr-2014, 132 patients have been treated with single agent LEE011 in the FIH phase 
I study; 85 patients have been treated in the dose escalation part and 47 patients in the dose 
expansion part of the study.
Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
LEE011 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. In addition, continuous 
dosing of LEE011 at 600 mg was evaluated (qd for 28 days of a 28-day cycle). Treatment has 
been discontinued in 111 (84%) patients; the primary reasons for treatment discontinuation 
were: disease progression (96 [72%] patients); AEs (8 [6%] patients); withdrawal of consent 
(3 [2%] patient); and loss to follow up (1 [1%] patient).
The most frequently reported AEs (≥10%), regardless of grade, causality and LEE011 dose 
were: fatigue (53.8%); nausea (50.8%); neutropenia (47.7%); leukopenia (46.2%); anemia 
(37.1%); vomiting (34.8%); thrombocytopenia (34.1%); diarrhea (32.6%); lymphopenia 
(30.3%); decreased appetite, hyperglycemia (21.2% each); constipation (19.7%); 
hypoalbuminemia (18.9%); dyspnea (18.2%); cough (16.7%); fever, increased creatinine 
(15.9% each); abdominal pain, AST increase, edema, headache (15.2% each); back pain 
(14.4%); dizziness (13.6%); ECG QT prolonged (11.4%); blood alkaline phosphatase 
increased and hypocalcemia (10.6% each).
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. 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.


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Asymptomatic Grade 2 QTcF prolongation was observed with increasing frequency when 
increasing the dose starting at 600 mg: twelve patients (18%) in the 600 mg cohort, three 
patients (21%) in the 750 mg cohort, four patients (31%) in the 900 mg cohort, and two 
patients (67%) in the 1200 mg cohort. Two patients (3%) at 600 mg and two patients (15%) at 
900 mg had asymptomatic QTcF prolongation that resulted in a QTcF interval of 500 ms or 
more. As compared to baseline value, QTcF prolongation was at least 30 msec in 2 patients 
(50%) at 250mg, 2 (40%) at 350 mg and 400 mg, 46 (73%) at 600 mg, 10 (71%) at 750 mg, 
11 (85%) at 900 mg and 2 (67%) at 1200 mg; and at least 60 msec as compared to baseline in 
respectively 16%, 0%, 39% and 67% of patients at 600 mg, 750 mg, 900 mg and 1200 mg. 
One grade 1 atrioventricular block of first degree was reported as related to LEE011 given at 
the dose of 140 mg. No other cardiac abnormalities were observed as related adverse events in 
any patient.
There have been no deaths related to study drug reported on study [CLEE011X2101].The 
following serious adverse events shown in Table 1-1 have been reported with a suspected 
causal relationship in study [CLEE011X2101] as of 19-Aug-2014. For a complete list of AEs, 
all grades and Grade 3/4 that are suspected to be related to LEE011 refer to the Investigator 
Brochure.
Table 1-1
Serious adverse events with a suspected causal relationship with 
LEE011 single agent 
Serious suspected adverse events which have occurred with LEE011 ( single agent)
System Organ Class Preferred Term
Preferred Term
Blood and lymphatic system disorders
Anaemia, Febrile neutropenia, 
Neutropenia,Thrombocytopenia
Gastrointestinal disorders
Diarrhoea, Nausea
General disorders and administration site 
conditions
Generalized oedema
Infections and infestations
Herpes simplex
Investigations
Blood creatinine increased
Events in bold indicate those events which are newly included since the previous edition of 
the reference safety information.
1.2.1.2.2 Clinical efficacy
Preliminary anti-tumor activity of ribociclib from trial [CLEE011X2101] was assessed across 
all dose levels. Out of 114 evaluable, 3 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) [LEE011 Investigator Brochure]. Stable disease (SD) was the best overall 
response in 41 (37%) patients. Stable disease ≥4 cycles and ≥6 cycles was observed in 26 
(24%) and 17 (15%) patients, respectively. Six patients with SD ≥4 cycles received treatment 
for >1 year, of these 2 patients were on study for >2 years (Jeffrey R Infante ASCO 2014 
abstract 2528).


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1.2.1.2.3 Clinical pharmacokinetics
As of 28-Mar-2014, PK data were available from approximately 128 patients from the first-
inhuman (FIH) study CLEE011X2101. Following oral dosing, LEE011 was rapidly absorbed 
with median Tmax ranging from 1 to 5 hours. LEE011 plasma exposure exhibited slightly 
over-proportional increases in exposure across the dose range tested (50 to 1200 mg), with no 
clear evidence of time-dependent auto-inhibition of its clearance mediated by CYP3A4. 
Steady-state was generally reached by Day 8 and the mean effective T1/2 based on 
accumulation ratio (i.e., T1/2,acc) ranged from 15.9 to 32.6 hours across the dose range tested.
The accumulation ratio based on AUC obtained in a dosing interval (Racc) across the studied 
doses ranged from 1.55 to 2.52. Details on the human pharmacokinetics of LEE011 can be 
found in the LEE011 Investigator Brochure.
A food effect study was conducted in 24 healthy subjects ([CLEE011A2111]). Compared to 
the fasted state, oral administration of a single 600 mg dose of LEE011 DiC with a high-fat, 
high-calorie meal decreased the rate of absorption of LEE011 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 LEE011 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 LEE011, with a decrease in Cmax (102 to 69.7 ng/mL), a 
delay in median Tmax (2.50 to 6.00h), and no substantial effect on overall exposure (2970 to 
2750 ng*h/mL). Based on these data, LEE011 DiC can be taken without regard to meals.
A drug-drug interaction (DDI) study with ritonavir (a strong CYP3A4 inhibitor) and 
rifampicin (a strong CYP3A4 inducer) conducted in healthy subjects [CLEE011A2101] 
indicated that concurrent use of strong CYP3A4 inhibitors or strong CYP3A4 inducers may 
markedly affect LEE011 exposure and should be avoided. Details can be found in Section 
5.1.5 of the Investigator Brochure.
A DDI cocktail study with midazolam (a sensitive CYP3A4 substrate) and caffeine (a 
sensitive CYP1A2 substrate) was conducted in healthy subjects [CLEE011A2106]. PK data 
indicate that LEE011 (400 mg) is a moderate inhibitor of CYP3A4 (≥ 2-fold but < 5-fold 
increase in AUC), but did not have a substantial effect on CYP1A2 substrates in humans. 
Concurrent use of sensitive CYP3A4 substrates with a narrow therapeutic index should be 
avoided. Concurrent use of CYP1A2 substrates is not expected to lead to clinically important 
DDIs. Details can be found in the LEE011 Investigator Brochure Section 5.1.5.
1.2.1.2.4 Clinical pharmacodynamics
Paired skin biopsies from 55 patients treated with LEE011 at doses ranging from 50 to 900 
mg and paired tumor biopsies from 20 patients (16 patients at 600 mg, 2 patients at 900 mg, 
and 1 patient each at 70 and 750 mg) were assessed for changes in Ki67 and pRb levels. 
Preliminary results indicate the following: in skin biopsies, reductions in Ki67 from baseline 
were observed across all dose levels with a more consistent trend from 400 mg onwards; in 
tumor biopsies, reductions in Ki67 from baseline were observed in 18/20 patients; however, 
limited samples and varied tumor types prevent conclusions about any dose-response 


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relationship from being drawn. Changes in pRb were not significant or consistent in either 
skin or tumor samples, possibly due to varied tumor types.
LEE011 was shown to decrease Ki67 and pRb in tumor tissue from a patient with mantle cell 
lymphoma treated with LEE011 daily [CLEE011X2101] (see Figure 1-3). Neutropenia and 
thrombocytopenia are also considered to be on target inhibition of rapidly dividing cells.
Figure 1-1
Pharmacodynamic response in tumor tissue from a patient with 
mantle cell lymphoma treated with LEE011
Change from baseline in Ki67 and p-pRb positive cells in tumor biopsies at C2D15 in a 
patient with mantle cell lymphoma treated with 900mg LEE011 in the phase I clinical trial 
[CLEE011X2101]. Left panels present positive immunostaining (brown color) for 2 PD 
markers: Ki67 and pRb. Right panels show a decrease of these markers following treatment of 
LEE011 (day 15 of cycle 2).
2
Rationale
2.1
Study rationale and purpose
Genomic profiling is becoming more accessible to patients and their physicians. As such, 
more patients have been identified with potentially actionable mutations or pathway-
activations but do not have access to targeted drug treatment. This is a signal seeking study to 
match patients with CDK4/6 amplification or mutations, cyclin D1/3 amplifications, or p16 


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mutation to treatment with the CDK4/6 inhibitor, ribociclib. Pre-identification of the relevant 
gene mutation or amplification status will be performed locally at a CLIA certified laboratory 
prior to participation on the trial.
The purpose of this signal seeking study is to determine whether treatment with ribociclib
demonstrates sufficient efficacy in CDK4/6 
pathway-activated solid tumors and/or 
hematologic malignancies to warrant further study.  Breast cancer (triple negative will be 
enrolled), liposarcoma, teratoma, castrate resistant prostate cancer (CRPC), melanoma and 
mantle cell lymphoma will be excluded from this exploratory study because these indications 
may be studied under key Novartis-sponsored ribociclib trials. Triple negative breast cancer 
will be allowed to enroll in this study. Additional tumor types may be excluded during the 
course of the study in the case of early futility or success based upon an interim analysis.
Additionally, increased understanding of the genomic changes in tumors allows the selection 
of patients more likely to benefit from treatment. In most cases patients who respond well 
initially to treatment soon develop resistance; also, many patients have disease that does not 
respond. The biological complexity of cancers and lack of knowledge of the mechanisms 
responsible for resistance in patients pose challenges, therefore a successful development of 
treatments that provide sustained disease control or cure requires improving the understanding 
of the mechanisms responsible for drug resistance. Therefore, in patients with a best response 
of SD or better, an optional tumor sample at the time of disease progression could be obtained 
for genomic analysis.
 
Details of the study design are provided in Section 4.
2.2
Rationale for the study design
This is a phase II, open label study to determine the efficacy and safety of treatment with 
ribociclib in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have relevant aberrations and whose disease has 
progressed on or after standard treatment.
2.3
Rationale for dose and regimen selection
In the first in human study of single agent ribociclib in adult patients with solid tumors 
[CLEE011X2101], the MTD of ribociclib was determined at 900 mg QD with a 3 weeks on/1 
week off schedule. The recommended dose for future development is 600 mg QD with a 3 
weeks on/1 week off schedule which has an acceptable safety profile, lower risk for QTcF 
prolongation, adequate exposures, and preliminary evidence of clinical activity, [LEE011 
Investigator’s Brochure]. The starting dose is shown in Table 6-2. It will be dosed on a flat 
scale and not adjusted by weight or body surface area.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary:
To assess clinical benefit associated with ribociclib  treatment based 
on local investigator assessment.
For patients with solid tumors the assessment criteria will be RECIST 
1.1 and will include responses of CR or PR or SD. For hematologic 
tumors other appropriate hematological response criteria will apply 
and are included in the appendices.
Clinical benefit rate (e.g. defined as CR or PR or SD ≥16 weeks for 
solid tumors)
Refer to Section 10.4
Key secondary:
To assess Overall Response (OR) of Partial Response (PR) or 
greater based on local investigator assessment.
For patients with solid tumors the assessment criteria will be RECIST 
1.1 and will include responses of CR and/or PR. For hematologic 
tumors other appropriate hematological response criteria will apply 
and are included in the appendices.
Overall response rate (PR or greater)
Refer to Section 10.5.1
Other secondary:
To assess Progression-Free Survival (PFS) based on local 
investigator assessment per RECIST 1.1 or other appropriate 
hematological response criteria
Time from the date of first dose to the date of first documented 
disease progression or relapse or death due to any cause
Refer to Section 10.5.2
To assess Overall Survival (OS)
Time from the date of first dose to the date of death due to any cause
Refer to Section 10.5.2
To assess Duration of Response (DOR) based on local investigator 
assessment per RECIST 1.1 or other appropriate hematological 
response criteria
Time from the first documented response to the date first documented 
disease progression or relapse or death due to any cause
Refer to Section 10.5.2
To assess safety and tolerability
Incidence of adverse events (AEs), serious adverse events (SAEs), 
changes from baseline in vital signs, laboratory test 
results(hematology, biochemistry), ECG, and cardiac imaging will be 
assessed by the Common Terminology Criteria for Adverse Events 
(CTCAE), v4.03
Refer to Section 10.5.3


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4
Study design
4.1
Description of study design
This is a phase II, open label study to determine the efficacy and safety of treatment with 
ribociclib in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have CDK4/6 amplifications or mutations, 
cyclin D1/3 amplifications, or p16 mutation and whose disease has progressed on or after 
standard treatment.
This study is intended for patients who have already had genomic profiling of their tumors in 
a CLIA certified laboratory and have already been pre-identified to have a tumor with a 
relevant gene aberration. Eligibility is based on the gene aberration status as assessed in a 
local, CLIA certified laboratory. The results of this testing must be known prior to signing the 
ICF and before formal screening begins. Once the patient has been identified, treating 
physicians who are qualified investigators may contact Novartis to consider enrollment in this 
study. For the purpose of this study, genomic profiling is not considered part of screening. 
Informed consent must be signed before any screening activities take place. After the 
eligibility criteria is met, the patient will initiate therapy with ribociclib single-agent. The 
patient may not receive any additional anti-cancer therapy during treatment with ribociclib.
A schematic representation of the study start-up design is shown in Figure 4-1.
Figure 4-1
Study Start-up Design
Physician
Patient being 
treated for solid 
tumor or hem 
malignancy
Tissue
Sample
CLIA 
Certified Lab
Actionable 
mutation 
identified by 
profiling
Central IRB Approved 
Protocol Package and 
standardized budget and 
contract sent to site
Research physician 
contacts Novartis to 
include patients in the 
study
Open Study
Expedited SIV
Genomic 
Profiling 
Report 
generated
Site begins study 
start-up process


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4.1.1
Treatment phase
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 or appropriate hematologic response criteria), unacceptable 
toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal 
of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), 
otherwise known as End of Treatment. All patients who discontinue from study treatment due 
to disease progression must have their progression clearly documented.
Disease assessments (per RECIST 1.1 or appropriate hematological response criteria) will be 
performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), 
until disease progression or end of treatment, whichever occurs first. The frequency of disease 
assessment will be reduced to every 16 weeks after patients have completed 16 weeks on 
treatment. Scans will be assessed locally by the investigator.
4.1.2
Follow-up phase
After discontinuation of treatment, patients, regardless of reason for treatment discontinuation,
will be followed for safety for 30 days after the last dose.
All patients will be followed for survival status every 3 months for 2 years after the last 
patient has enrolled in the study, regardless of treatment discontinuation reason (except if 
consent is withdrawn or patient is lost to follow-up). If the primary efficacy endpoint is not 
met, Novartis may discontinue survival follow-up for this study.
For patients with a best response of SD or better who discontinue study treatment due to 
disease progression, an optional tumor sample should be obtained for genomic analysis. This 
tumor sample must be obtained within 28 days of stopping the study treatment and no more 
than 14 days after starting another treatment for their cancer (at a time most convenient for the 
patient); exceptions may be made after discussion with the sponsor. 
 
For details on required assessments, please refer to Table 7-1.
4.2
Definition of end of the study
End of study is defined as the time when the last patient completes the survival follow-up as 
described in Section 7.1.4.3 , when the last patient on study has died, been lost to follow up, 
or withdraws consent, whichever occurs first, or if the study is terminated early or another 
clinical study becomes available that can continue to provide LEE011 in this patient 
population and all patients ongoing are eligible to be transferred to that clinical study.
The analysis of study data will be based on all patients’ data up to the time when all patients 
have had the opportunity to complete at least 4 cycles (or 16 weeks) of treatment or 
discontinued the study. This will be the cut-off point for the clinical study report (CSR). 
Additional data for patients continuing to receive study treatment past the data cutoff date for 
the CSR will be reported once all patients have discontinued treatment or been lost to follow-
up. 
At the time of CSR data cut-off, if patients are ongoing after 16 weeks on treatment and 
benefitting, they will continue to receive treatment.


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4.3
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for an end of treatment (EOT) visit and the 
assessments for EOT should be performed as described in Section 7 for a prematurely 
withdrawn patient. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator will be responsible for informing the Institutional Review Board 
(IRB) and/or Ethics Committee (EC) of the early termination of the trial.
5
Population
5.1
Patient population
The study population will consist of 70-90 adult patients with a diagnosis of a solid tumor or 
hematological malignancy with a CDK 4/6 mutation or amplification, cyclin D 1/3 
amplification, or p16 mutation. Patients must have received at least one prior treatment for 
their recurrent, metastatic and/or locally advanced disease and have no remaining standard 
therapy options anticipated to result in a durable response. Patients must have progressive and 
measurable disease (per RECIST 1.1 or other appropriate hematological response assessment 
criteria) and be in need of treatment. This is a signal seeking study, attempting to identify 
additional patient populations who may benefit from treatment with single agent ribociclib.  
Tumors currently being studied under some key Novartis-sponsored trials will be excluded. 
These include breast cancer (except triple negative), liposarcoma, teratoma, CRPC, melanoma
and mantle cell lymphoma. Additional tumor types may be excluded during the course of the 
study at the discretion of Novartis.
Patients must have archival tissue available for submission to allow for molecular testing 
related to pathway activation. If tissue is not available or is insufficient the patient must be 
willing to undergo a fresh tumor biopsy to allow for this analysis.
 
We expect that the study will enroll patients whose tumors have already been pre-identified 
such as ovarian, mesothelioma, breast (triple negative), colorectal, biliary, pancreatic 
neuroendocrine cancer, and lymphomas (excluding mantle cell lymphoma) (enrollment will 
not be strictly limited to those particular cancers). The total number of patients to be enrolled 
per tumor type will be based on an adaptive design. The adaptive design will be patient-
sparing and allow the early closure of non-responding arms or arms where early success can 
be declared.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient has provided a signed study Informed Consent Form prior to any screening 
procedure.
2. Patient is ≥ 18 years of age on the day of consenting to the study.


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3. Patient has a confirmed diagnosis of a solid tumor (except breast cancer (however, triple 
negative will be included), liposarcoma, CRPC, melanoma and teratoma) or hematological 
malignancy (except mantle cell lymphoma). Additional tumor types may be excluded 
during the course of the study at the discretion of Novartis.
4. Patient is in need of treatment because of progression or relapse defined as:
a. radiological progression for solid tumor and lymphoma 
b. for hematologic malignancies, measureable progression or relapse by appropriate 
criteria (see appendices)
5. Patient must have been pre-identified as having a tumor with any of the following. The 
qualifying alteration must be assessed and reported by a CLIA-certified laboratory.
a. CDK4 amplification or mutation
b. CDK6 amplification or mutation
c. Cyclin D1 (CCND1) amplification
d. Cyclin D3 (CCND3) amplification
e. p16 (CDKN2A) mutation
6. Patient must have archival tissue available for submission to allow for molecular testing 
related to pathway activation. If the tissue is not available or is in sufficient, the patient 
must be willing to undergo a fresh tumor biopsy to allow for this analysis. The sample 
must be submitted prior to first study dose unless agreed upon between Novartis and the 
investigator. See Section 7.2.4.2.1.
Note: An archival or fresh sample may not be required if the patient had their genomic 
profiling performed at the same laboratory that will be used for confirmatory analysis, and the 
patient consents to allow Novartis use that data as their baseline molecular analysis results.
7. Patient must have received at least one prior treatment for recurrent, metastatic and /or 
locally advanced disease and for whom no standard therapy options are anticipated to 
result in a durable remission.
8. Diffuse large B cell lymphoma only: Patient has received or is ineligible for autologous 
stem cell transplant.   
9. Patients must have measurable disease as per appropriate guidelines:
a. Solid Tumors: by RECIST 1.1 (Appendix B)
b. Lymphoma: Patient has at least one measurable nodal lesion (≥2 cm) according to 
International Working Group (IWG) criteria (Cheson 2007). In case where the patient 
has no measurable nodal lesions ≥ 2 cm in the long axis at screening, then the patient 
must have at least one measurable extra-nodal lesion (Appendix C)
c. Symptomatic Multiple Myeloma: by International Myeloma Working Group 
(IMWG)
i. Serum M-component of ≥1 gm/dL
ii. Urine M-component of ≥200 mg/24 h
iii. Patients with plasmacytoma must have a definite increase in the size; a definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by 
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d. Leukemia only: Relapsed/refractory leukemia for which no standard therapy options 
are anticipated to result in a durable remission:
i. Acute myelogenous leukemia (AML) by World Health Organization (WHO) 
classification or acute lymphoblastic leukemia (ALL) relapsed or refractory to 
standard chemotherapy; unsuitable for standard chemotherapy or unwilling to 
undergo standard chemotherapy. Philadelphia chromosome (Ph) positive ALL 
eligible if failed prior tyrosine-kinase inhibitor therapy.
ii. Age > 60 years with AML not candidates for or have refused standard 
chemotherapy, excluding patients with acute promyelocytic leukemia (APL) or 
with favorable cytogenetic abnormalities [inv16, t(8;21)].
iii. For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast 
phase CML will be allowed.
10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status≤1
(Appendix K).
11. Patient has a life expectancy of at least 16 weeks.
12. Patients must have adequate bone marrow as described below:
a. Absolute Neutrophil Count (ANC) ≥1.5 x 109/L (no growth factor within past 14 
days) (not applicable for leukemia patients)
b. Platelets (PLT) ≥100 x 109/L (no platelet transfusion within past 14 days) (not 
applicable for leukemia patients)
c. Hemoglobin (Hgb) ≥9 g/dL (no blood transfusion within past 14 days) (not 
applicable for leukemia patients
d. International Normalized Ratio (INR) ≤ 1.5
13. All patients must have adequate organ function defined as described below:
a. Potassium, total calcium (corrected for serum albumin), magnesium, sodium and 
phosphorus within normal limits (WNL). Supplementation is allowed to meet 
eligibility requirements
b. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥50 mL/min
c. Alanine aminotransferase (AST) and/or aspartate aminotransferase (ALT) < 2.5 x 
upper limit of normal range (ULN), or ≤5 x ULN if liver metastases are present.
d. Alkaline phosphatase (AP) ≤2.5 x ULN
e. Albumin ≥2.0 g/dl
f.  Total bilirubin  ≤  ULN; or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤1.5 x ULN 
in patients with well-documented Gilbert’s syndrome.
14. For leukemia patients, peripheral blast counts < 50,000 blasts/mm3
15. Must be able to swallow ribociclib capsules.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients who have received prior treatment with ribociclib.
2. Patients with a known hypersensitivity to ribociclib or to its excipients.


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3. Patients with primary CNS tumor or CNS tumor involvement. However, patients with 
metastatic CNS tumors may participate in this study if the patient meets criteria a-e:
a. 4 weeks from prior therapy completion (including radiation and/or surgery)
b. Clinically stable with respect to the CNS tumor at the time of study entry
c. Not receiving steroid therapy
d. Not receiving enzyme inducing anti-convulsive medications (that were started for 
brain metastases)
e. Patient with no leptomeningeal involvement
4. Patients with clinical evidence of active CNS leukemia
5. Patients who have received allogeneic SCT and/ or have active GVHD
6. Patients who have received autologous SCT within the last 3 months
7. Patients with diarrhea ≥ CTCAE grade 2.
8. Patients with neuropathy ≥ CTCAE grade 2.
9. Patients with acute or chronic pancreatitis.
10. Patients with external biliary drains.
11. Patients with clinically significant uncontrolled heart disease and/or recent events , 
including any of the following:
a. History of acute syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic 
pericarditis with 12 months prior to screening
b. History of documented congestive heart failure (New York Association functional 
classification III-IV) 
c. Documented cardiomyopathy
d. Left ventricular ejection fraction (LVEF) ≤ 50% as determined by MUGA scan or
ECHO
e. History of any cardiac arrthythmias, e.g., ventricular, supraventricular, nodal 
arrhythmias or conduction abnormality within 12 months of screening.
f.
Congenital long QT syndrome or family history of long QT syndrome.
g. Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening.
h. Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening. 
i.
12. On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not 
interpretable) or QTcF >450ms (using Fridericia’s correction).
13. Patients with uncontrolled diabetes mellitus.
14. Impairment of GI function or GI disease that may significantly alter the absorption of 
ribociclib (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection).
15. Any other condition that would, in the Investigator’s judgment, cause unacceptable safety 
risks, contraindicate patient’s participation in the clinical study due to safety concerns or 
compliance with clinical study procedures (e.g. infection/inflammation, intestinal 
obstruction, unable to swallow oral medication, social/psychological complications, active 
or uncontrolled fungal, bacterial or viral infections, etc).


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16. Patients who have been treated with any hematopoietic colony-stimulating growth factors 
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or 
darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued. 
Restriction is not applicable for patients with Leukemia.
17. Patient has received chemotherapy or anticancer therapy ≤ 4 weeks (6 weeks for 
nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who 
have not recovered to a grade 1 from side effects of such therapy (except for alopecia and 
neuropathy). Patients with leukemia may receive therapy with hydroxyurea and/or steroids 
for the purpose of cytoreduction but must discontinue use prior to first dose of study drug.
18. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical applications 
(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular).
19. Patients who have received the last administration of an anticancer targeted small 
molecule therapy (e.g. sunitinib, pazopanib, everolimus) ≤ 2 weeks prior to starting study 
drug, or who have not recovered from the side effects of such therapy.
20. Patients not able to discontinue their current anti-cancer therapy prior to first dose of study 
drug.
21. Patients currently receiving warfarin or other coumarin-derived anticoagulant for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH) or fondaparinux is allowed.
22. Participation in a prior investigational study with 30 days prior to enrollment or within 5 
half-lives of the investigational product, whichever is longer.
23. Patients who have received radiotherapy ≤ 4 weeks prior to starting the study drug or 
limited field radiation for palliation ≤ 2 weeks prior to starting study drug, and who have 
not recovered to grade 1 or better from related side effect  of such therapy (exceptions 
include alopecia) and /or in whom ≥ 25% of the bone marrow was irradiated.
24. Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal, intra-
pelvic) ≤ 2 weeks prior to starting study treatment or who have not recovered from side 
effects of such surgery.
25. Patients with another primary malignancy within 3 years prior to starting study treatment, 
with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or 
other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix (curatively 
resected cervical cancer).
26. Cirrhosis of the liver or known hepatitis B or C infection that is either acute or is 
considered chronic because the virus did not become undetectable:
a. Hepatitis C Virus (HCV) infection: acute or chronic infection as depicted by a 
positive HCV RNA testing (note: in a patient with known anti-HCV but with a 
negative test for HCV RNA, re-testing for HCV RNA 4-6 months later is requested to 
confirm the resolution of HCV infection).


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b. Hepatitis B Virus (HBV) infection: acute infection (HBsAg+ with or without 
HBeAg+ or detectable serum HBV DNA), HBV carriers as evidence by ongoing 
presence of HBsAg and detectable serum HBV DNA levels.
27. Patients who have received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks
when half-life is unknown) prior to starting study drug.
28. Patient is currently receiving any of the following substances and cannot be discontinued 
7 days prior to starting study drug (Refer to Appendix A):
a. Known strong and moderate inducers or inhibitors of CYP3A4/5, including grapefruit, 
grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
b. Medications with known risk to prolong the QT interval or induce Torsades de Pointes.
c. Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5.
d. Herbal preparations and dietary supplements.
29. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory).
30. Patient has a history of non-compliance to medical regimen.
31. 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.
32. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
(defined below). Highly effective contraception must be used by both sexes (female 
patients and their male partners) during study treatment and for 8 weeks after the last dose 
of study medication.
Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment
c. Male partner sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the female study patient’s sole partner
d. Combination of the following (a+b or a+c, or b+c):
i. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception.
ii. Placement of a non-hormonal intrauterine device (IUD) or non-hormonal 
intrauterine system (IUS)
iii. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository


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Note : In case of oral contraception, women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment
Women of child-bearing potential (sexually mature) who have not undergone a 
hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive 
months (i.e., who has had menses any time in the preceding 12 consecutive months), must 
have a negative serum pregnancy test ≤ 14 days prior to starting study drug.
Post-menopausal women are allowed to participate in this study and do not require 
pregnancy or hCG laboratory test. Women are considered post-menopausal and not of 
child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) 
or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have 
had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks 
prior to entry in the study. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment, then she 
will be considered not of child bearing potential.
33. Fertile males must be willing to use contraception. Fertile males must use condom with 
spermicide (double barrier method). Highly effective contraception, as defined above, 
must be used by both sexes (male patients and their female partners) during study 
treatment and for 21 days after the last dose of study 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
The investigational or study drug to be used for this trial is ribociclib.
Novartis Drug Supply Management or its designee will provide ribociclib as 200-mg hard 
gelatin capsules as individual patient supply, packaged in bottles or blisters. Ribociclib will be 
dosed on a flat scale and not be adjusted to body weight or body surface area.
6.1.1
Dosing regimen
Ribociclib will be dosed on a flat scale of 600 mg (e.g., 3 x 200 mg capsules) once daily for 3 
weeks on/1 week off. A complete treatment cycle is defined as 28 days (refer to Table 6-1).
The patient must continue to meet all eligibility criteria on C1D1, as they did during the 
screening period. Refer to Section 7.1 for more details


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Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and route 
of administration
Dose
Frequency and/or Regimen
Ribiciclib
Capsule for oral use
600 mg/day
Daily (3 weeks on/1 week off)
6.1.1.1
Ribociclib administration
The following general guidelines should be followed for administration.

Patients should be instructed to take their daily dose with a large glass of water (~250 ml) 
and swallow the required number of capsules at approximately the same time on each day.
The capsules should be consumed over as short a time as possible (e.g. 1 capsule every 2 
minutes) and can be taken without regard to meals. However, dietary habits around the 
time of dosing should be as consistent as possible throughout the study.

At each visit, responsible site personnel will ensure that the appropriate dose of each study 
drug is administered and will provide the patient with the correct amount of study drug(s) 
for subsequent dosing. Patients will be instructed to return unused study drugs to the site 
at the end of each cycle.

Patients should be instructed to swallow the capsules whole and not to chew or crush them.

Any doses that are missed should be skipped and should not be replaced or made up 
during the next scheduled dosing or on a subsequent day, whichever applies.

Patients must avoid consumption of grapefruit, pomelos, pomegranates, star fruits, Seville 
oranges or products containing the juice of each during the entire study and preferably 7 
days before the first dose of study medications, due to potential CYP3A4/5 interaction 
with the study medications. Orange juice is allowed.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increased stool frequency) must be noted in the AEs section of the eCRF.

If patient forgets to take his/her daily dose of ribociclib within 6 hours of the usual dosing 
time, then that day’s dose should be omitted and the patient should continue treatment 
with the next scheduled dose

The investigator (or his/her designee) must instruct the patient to take ribociclib exactly as 
prescribed. The patient should be instructed to contact the investigator (or his/her designee) 
if he/she is unable for any reason to take ribociclib as prescribed. All dosages prescribed 
and dispensed to the patient, and all dose changes during the study, must be recorded on 
the Dosage Administration Record eCRF. Patients must be advised to bring their unused 
ribociclib capsules/tablets to the investigative site at each visit.


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6.1.2
Guidelines for continuation of treatment
Patients will be treated until disease progression (as assessed by investigator per RECIST 1.1 
or appropriate hematologic response criteria) or unacceptable toxicity death or discontinuation 
from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-
neoplastic therapy or at the discretion of the investigator). Guidance for continuation of study 
treatment in case of toxicity (e.g. dose delay and/or modification) is provided in Section 6.3.
6.1.3
Treatment duration
Patients may continue treatment with the study drug until the patient experiences unacceptable 
toxicity that precludes further treatment, disease progression as assessed by the investigator 
(per RECIST 1.1 or appropriate hematological response assessment criteria), death and/or 
treatment is discontinued due to any other reason. The reason for end of treatment (EOT) will 
be recorded in the corresponding eCRF.
6.2
Dose escalation guidelines
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Any changes in 
LEE011 administration must be recorded on the Dosage Administration Record eCRF.
Ribociclib dose modification guidelines are described in Section 6.3.2. Any planned variance 
from these guidelines in the view of the patient safety must be previously discussed with the 
sponsor unless there is an urgent need for action.
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria for adverse events (NCI-
CTCAE version 4.03). Once a dose has been reduced during a treatment cycle, re-escalation 
will not be permitted during any subsequent cycle.
If the administration of ribociclib is interrupted for reasons other than toxicity, then treatment 
with the study drug may be resumed at the same dose. The same applies if the patient 
experienced an unacceptable toxicity not specifically described in Table 6-3 or Section 6.3.3, 
provided this toxicity resolved to ≤ CTCAE grade 1, unless otherwise specified.
6.3.2
Permitted study treatment adjustments for Ribociclib
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
or interruptions are permitted to manage drug-related toxicities.

When dose reduction is necessary, the dose of ribociclib may be reduced to 400 mg.

If an additional dose reduction is required, ribociclib may be reduced to 200 mg.

Once the ribociclib dose is reduced it cannot be re-escalated.


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
All dose reductions should be based on the worst preceding toxicity.

Patients are allowed only 2 dose reductions (to 400 mg and 200 mg) as specified in (Table 
6-2).
Table 6-2
Ribociclib dose modifications
LEE011 Dose Level
LEE011 Dose 
Frequency
Starting dose level (0)
600 mg po 
Daily (3 weeks on/1 week off)
Dose level – 1
400 mg po 
Daily (3 weeks on/1 week off)
Dose level – 2
200 mg po 
Daily (3 weeks on/1 week off)
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
including abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first. The maximum time allowed for treatment interruption due to toxicity is 21 days 
(3 weeks) from the intended dosing day. If interruption is > 21 days, the patient must be 
discontinued from the study treatment. However, the patient will continue to be followed for 
toxicity. Dose interruptions should be reported on the appropriate Dosage Administration 
eCRF.
6.3.3
Criteria for interruption and re-initiation of ribociclib treatment
If the administration of ribociclib must be interrupted because of an unacceptable toxicity, 
ribociclib dosing will be interrupted or modified according to rules described in Table 6-3.
A patient who requires a dose interruption (regardless of the reason for the interruption) 
lasting >21 days (counting from the first day when a dose was missed) must discontinue the 
study treatment.
Table 6-3
Ribociclib related toxicity management guidelines
Toxicity
Grade
Dose Adjustment and Management Recommendations
Thrombocytopenia
Grade 1
≥75 x 109/L
No dose adjustment required.
Grade 2
≥50 x 109/L – <75 x 109/L
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the same dose.
Grade 3
≥25 x 109/L - <50 x 109/L
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to grade ≤1 and reduce ribociclib to the next lower 
dose level.
Grade 4
<25 x 109/L
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the next lower dose level.
If toxicity recurs at grade 4: discontinue ribociclib.
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.


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Toxicity
Grade
Dose Adjustment and Management Recommendations
Grade 3
≥0.5 - <1.0 x 109/L
Dose interruption until recovery to ≥1.0 x 109/L.
Re-initiate ribicoclib at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until 
recovery to ≥1.0 x 109/L. If resolved within ≤ 7 days, then 
maintain dose level. If resolved >7days, then reduce ribociclib
dose to the next lower dose level.
Grade 4
<0.5 x 109/L
Dose interruption until recovery to ≥1.0 x 109/L.
Re-initiate LEE011 at the next lower dose level.
If toxicity recurs at grade 4: temporary dose interruption until 
recovery to ≥1.0 x 109/L and reduce LEE011 at the next lower 
dose level.
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 until improvement of ANC ≥1.0 x 109/L and 
no fever. Restart at the next lower dose level.
If febrile neutropenia recurs, discontinue ribociclib.
Grade 4
Life-threatening 
consequences;
urgent intervention 
indicated
Discontinue ribociclib.
Anemia
(Hemoglobin)
Grade 1
≥10.0 – LLN g/dL
No dose adjustment required.
Grade 2
≥8.0 – <10.0 g/dL
No dose adjustment required.
Grade 3
<8.0 g/dL
Dose interruption until recovery to grade ≤2.
Re-initiate ribociclib at the same dose.
Grade 4
Life-threatening 
consequences;
urgent intervention 
indicated
Discontinue ribociclib.
Table 6-4
Recommendations for dose modification in case of hepatic toxicities
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (>ULN – 1.5 x ULN) (confirmed 48-72hrs
later)
Maintain dose level with LFTs monitored bi-weekly
Grade 2 (> 1.5 – 3.0 x ULN) 
Dose interruption of ribociclib
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose 
level
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
then reduce 1 dose level
If toxicity recurs after two dose reductions, discontinue 
ribociclib
Grade 3 (> 3.0 – 10.0 x ULN) 
Dose interruption of ribociclib
If resolved to ≤ grade 1 in ≤ 21 days, lower 1 dose level 
of ribociclib
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
discontinue ribociclib


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HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST)
TOTAL BILIRUBIN without ALT/AST increase above baseline value
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 Syndrome, pharmacologic treatment, viral hepatitis,
alcoholic or autoimmune hepatitis, other hepatotoxic drugs.
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct  bilirubin only.
Bilirubin will be fractionated if elevated.
AST or ALT
AST or ALT without bilirubin elevation > 2 x ULN
Same grade as baseline or increase from baseline 
grade 0 to grade 1
(confirmed 48 – 72 hrs later)
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or bi-weekly in case 
of increase from baseline grade 0 to 1
Increase from baseline grade 0 or 1 to grade 2 (> 3.0 
– 5.0 x ULN)
or
from baseline grade 2 to grade 3 (> 5.0 – 20.0xULN)
Dose interruption of ribociclib
If resolved to ≤ baseline value in ≤ 21 days, then 
maintain dose level
If resolved to ≤ baseline value in > 21 days or toxicity 
recurs, then reduce 1 dose level
If toxicity recurs after two dose reductions or recovery to
≤ baseline value is > 28 days, discontinue ribociclib
Increase from baseline grade 0 or 1 to grade 3 (> 5.0 
– 20.0 x ULN)
Dose interruption of ribociclib until resolved to ≤ baseline 
value, then lower 1 dose level of ribociclib
If recovery to ≤ baseline value is > 28 days, discontinue 
ribociclib
If toxicity recurs, discontinue ribociclib
Grade 4 (> 20.0 x ULN)
Discontinue ribociclib
AST or ALT and concurrent Bilirubin
AST or ALT ≥ grade 2 (> 3 x ULN) in patients with 
normal values at baseline and total bilirubin  > 2 x 
ULN
or
AST or ALT ≥ grade 3 (> 5 x ULN) in patients with 
grade 1 or 2 at baseline, and total bilirubin  > 2 x ULN
Discontinue ribociclib
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. 
6.3.3.1
Additional follow-up for hepatic toxicities
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT. For patients with Gilbert Syndrome: total and 
direct bilirubin must be monitored, intensified monitoring applies to changes in direct 
bilirubin only.
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves:

Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values.


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
Obtaining a more detailed history of current symptoms.

Obtaining a more detailed history of prior and/or concurrent diseases.

Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets.

Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).

Considering gastroenterology or hepatology consultations.

Assessing cardiovascular dysfunction or impaired liver oxygenation, including
hypotension or right heart failure as possible etiologies for liver dysfunction.
Table 6-5
Dose modification guidance in case of QT Prolongation
Grade
Dose Modification
For all grades
Check the quality of the ECG.
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If below the 
lower limit of normal, interrupt ribociclib administration, correct with 
supplements or appropriate therapy as soon as possible, and repeat 
electrolytes until documented as normal.
Review concomitant medication usage for the potential to inhibit CYP3A4 
and/or to prolong the QT interval.
Check compliance with correct dose and administration of ribociclib.
Grade 1
QTc 450-480 ms
No dose adjustment required.
Grade 2
QTc 481-500 ms
Interrupt ribociclib
Perform a repeat ECG 1 hour after the QTcF of ≥ 481 ms
If QTcF <481 ms, restart ribociclib at the same dose. No dose adjustment 
required for first occurence.
If QTcF remains ≥481 ms, repeat ECG as clinically indicated until QTcF 
returns to < 481 ms. Restart ribociclib at the same dose level. No dose 
adjustments required for first occurrence.
If QTcF ≥ 481 ms recurs, ribociclib should be reduced by 1 dose level.
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patient who has therapy interrupted due to QTcF ≥ 481 ms.
Grade 3
QTc ≥ 501 ms on at least two 
separate ECGs
Interrupt LEE011
Consider consulting a local cardiologist
Perform a repeat ECG one hour after the first QTcF of ≥501 ms.
If QTcF remains > 501 ms, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to < 481 ms.
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level. Refer 
to Table 6-2 for dosing schedule.
Repeat ECGs 7 days and 14 days after dose resumption for any patient who 
had therapy interrupted due to QTcF ≥501 ms
If QTcF of ≥501 ms recurs, discontinue ribociclib


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Grade
Dose Modification
Grade 4
[QT/QTc ≥ 501 or > 60 ms 
change from baseline]
and
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia]
Discontinue ribociclib
Obtain local cardiologist consultation
Perform a repeat ECG 1 hour after the first QTcF of ≥ 501 ms
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to < 501 ms.
6.3.3.2
Management of all other adverse reactions
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium 
for all adverse reactions that are potentially associated with electrolyte imbalance (e.g. 
diarrhea, nausea/vomiting). If electolyte values are below the lower limit of normal, interrupt 
ribociclib administration, correct electrolyte with supplements as soon as possible, and repeat 
electrolyte testing until documented normalization of the electolytes.
Table 6-6
Ribociclib dose adjustment and management recommendation for all 
other adverse reactions
Grade
Dose Adjustment and Management Recommendations
1
No dose adjustment recommended. Initiate appropriate medical therapy and monitor.
2
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor.
Re-initiate LEE011 at the same dose.
If the same toxicity recurs at grade 2, interrupt LEE011 until recovery to grade ≤1. Re-initiate LEE011 at 
the next lower dose level.
3
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor.
Re-initiate LEE011 at the next lower dose level.
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade ≤1 and reduce LEE011 
dose the next lower dose level.
If toxicity recurs at grade 3, discontinue LEE011.
4
Discontinue LEE011 and treat with appropriate medical therapy.
6.3.3.3
Adjustment of starting dose in special populations
Renal impairment
Insufficient data are available to provide a dosage to provide a dosage recommendation for 
ribociclib for patients with renal impairment. Patients with baseline renal impairment are 
excluded from the study  (serum creatinine > ULN or creatinine clearance < 50mL/min). 
Patients who experience renal impairment of grade 2 or higher during the treatment period 
should discontinue treatment and should be followed safety assessments.
Elderly
Physicians should exercise caution in monitoring the effects of ribociclib in the elderly. 
Insufficient data are available to provide a dosage recommendation.
6.3.4
Follow-up for toxicities
Patients who complete treatment or whose treatment is interrupted or permanently 
discontinued due to an AE must be followed at least once a week for 4 weeks, and then at 4 


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weeks intervals until resolution or stabilization of the event. All patients will be followed for 
onset of any new serious adverse events for 30 days following the last dose of study treatment.
6.3.5
Anticipated risks and safety concerns of the study
Appropriate eligibility criteria, as well as specific dose modifications and stopping rules are 
included in this protocol. Refer to Section 6.3.1 and Section 6.3.2 for details.
6.4
Concomitant medications
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted, except as specifically prohibited. Refer to LEE011 Investigator’s 
Brochure and Appendix A for information on possible drug-drug interactions.
Patients must be instructed to not take additional medications (including over-the-counter 
products and herbal/alternative medications) during the study without prior consultation with 
the investigator.
Patients taking chronic medications should be maintained on the same dose and schedule 
throughout the study period, if medically feasible.
6.4.1
Permitted concomitant therapy
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents, such as packed red blood cells (PRBC), pain medications, anti-emetics 
and anti-diarrheals 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. 
Hematopoietic growth colony stimulating factors may be used therapeutically or as secondary 
prophylaxis.
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of study treatment. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, oxygen, and blood transfusions) administered 
to the patient within 30 days prior to the first dose of study drug, during the study, and until 
30 days after the last dose of study drug, must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies eCRFs.
6.4.1.1
Bisphosphonates and denosumab
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and 
prevention of skeletal related events for patients with bone metastases. Chronic concomitant 
bisphosphonate/denosumab therapy for the prevention of bone metastasis is not permitted.
6.4.1.2
Palliative radiotherapy
Palliative radiation is permitted if done solely for bone relief. It should not be delivered to a 
target lesion and it should not encompass more than 25% of irradiated bone marrow.
Refer to the ribociclib (LEE011) Investigator’s Brochure, Table 1 and Table 2, for 
information on possible interaction with other drugs.


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6.4.2
Concomitant therapy requiring caution
The following therapies are permitted in this study; however, they should be used with 
caution. This list is not comprehensive and is only meant to be used as a guide. These 
medications should be excluded from patient use if possible. If they must be given, 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 with wide therapeutic index

Sensitive substrates of the renal transporters, MATE1 and OCT2

Sensitive substrates of BCRP

Known inhibitors of BSEP

Medications that carry a possible risk for QT prolongation
6.4.3
Prohibited concomitant therapy
The following medications are prohibited during treatment in this study (Appendix A). This 
list is not comprehensive and is only meant to be used as a guide:

Strong inhibitors or inducers of CYP3A4/5

Substrates of CYP3A4/5 with narrow therapeutic window

Medications with a known risk for QT prolongation

Other investigational and antineoplastic therapies

Primary prophylactic hematopoietic growth factors

Herbal medications. These herbal medications include, but are not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop using all herbal 
medications at least 7 days prior to first dose of study treatment.

Patients should be instructed not to take grapefruit products/juice, or Seville (sour) 
oranges/juice while taking study drug and preferably 7 days before the first dose due to 
potential CYP3A4/5 interaction. Oranges juice is allowed.
6.5
Patient numbering, treatment assignment and enrollment
6.5.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first screened and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center 
No.) (as assigned by Novartis to the investigative site) with a sequential patient number 
suffixed to it, so that each Patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient No. 
available at the site.
6.5.2
Treatment assignment and randomization
Not applicable.


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6.5.3
Treatment blinding
This is an open-label study.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Patients will be provided with an adequate supply of study drug for self-administration at 
home, including instructions for administration, until at least their next scheduled study visit. 
Patients will receive ribociclib on an outpatient basis. The investigator shall provide the 
patient with instructions for ribociclib administration according to the protocol.
6.6.1
Study drug packaging and labeling
Ribociclib will be supplied as 200 mg or 50 mg hard gelatin capsules (refer to Table 6-6).
Medication labels will comply with US legal requirements and are printed in the local 
language. The label contains LEE011 identifying information (e.g., formulation, batch 
number, and expiration date), the patient number (to be entered by the investigator or designee) 
and storage conditions.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Ribociclib (LEE011)
Capsules or tablets (200 mg or 
50 mg) in bottles or blisters
Labeled as LEE011
Dosing frequency: once-a-day, 3 weeks on/1 week off
6.6.2
Drug supply and storage
Each site will be supplied by Novartis with oral ribociclib. Study drug must be received by a 
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, ribociclib should be stored according to the instructions specified on the drug 
labels and in the [Investigator’s Brochure]. These instructions should also be made clear to the 
patient for storage and self-administration of ribociclib at home.
Site staff will be responsible for managing adequate re-supplies for ribociclib.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver must be captured in the source 
document at each patient visit.


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6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to Novartis or designee.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column). Every effort must
be made to follow the schedule of assessments within the ±4 days.


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Table 7-1
Visit evaluation schedule
Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
ALL PATIENTS
INFORMED CONSENT
Tumor sample (archival or fresh) 
for pathway activation
D
7.1.1 & 7.2.4.1
X
X13
Informed consent
D
7.1.1
X
PATIENT HISTORY
Demography
D
7.1.1.3
X
Inclusion/exclusion criteria
D
5.2 & 5.3
X
Eligibility checklist
S
7.1.1.1
X
End of phase disposition
D
7.1.3.1 & 7.1.1.2
X
X
Relevant medical history/ 
current medical conditions
D
7.1.1.3
X
Diagnosis and Extent of cancer
D
7.1.1.3
X


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
Prior anti-neoplastic therapy
D
7.1.1.3
X
PHYSICAL EXAMINATION
Physical examination
S
7.2.2.1
X
X4
X
X
X
Vital signs
D
7.2.2.2
X
X4
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X4
X
X
X
ECOG performance status
D
7.2.2.4
X
X4
X
X
X
IMAGING AND OTHER ASSESSMENTS
Cardiac imaging (MUGA/ECHO)
D
7.2.2.6.2
X
If clinically indicated
ECG 
D
7.2.2.6.1
X12
X
X
X
X
X
MRI (optional)
S
LABORATORY ASSESSMENTS
Hematology
D
7.2.2.5.1
X
X4
X
X
X
X
X
Biochemistry
(including liver function tests)
D
7.2.2.5.2
X
X4
X
X
X
X
X
Thyroid function test
D
7.2.2.5.3
X
X4
Every 3 cycles starting at C3D1, and if 
clinically indicated
X
Coagulation
D
7.2.2.5.4
X
X4
If clinically indicated


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
Urinalysis
D
7.2.2.5.5
X
X4
X
X
X
Pregnancy test6
D
7.2.2.5.6
X
X4
X
X
X
SAFETY
Prior and concomitant 
medications
D
6.4
X
Continuous
X
Surgical and medical 
procedures
D
6.4
X
Continuous
X
Adverse events
D
8.1
X
Continuous
X
DRUG ADMINISTRATION AND OTHERS
Ribociclib administration
D
6.1.1
Daily (3 weeks on/1 week off)
Survival
D
7.1.4.3
X15
ADDITIONAL EFFICACY ASSESSMENTS
SOLID TUMOR
Physical examination for 
measurement of superficial 
disease (only if present) 9
D
7.2.1.1.1
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8)
D
7.2.1.1.4
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
Cancer Antigen-125
(for ovarian cancer only)
D
7.2.1.1.2
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
Prostate-specific antigen (PSA)
(for prostate cancer only)
D
7.2.1.1.3
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
LYMPHOMA
Examination for enlarged spleen 
or liver
D
7.2.1.2.1
X
To confirm response of CR
X
Physical examination for 
measurement of superficial 
disease and B symptoms 9
D
7.2.1.2.2
X
Day 1 of every cycle (±4 days) after first dose of 
study drug
X
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8)
D
7.2.1.2.3
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
Bone Marrow Biopsy or aspirate
D
7.2.1.2.4
X
To confirm response of CR10


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
Serum protein electrophoresis 
(SPEP)
D
7.2.1.2.5
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter, only if abnormal M-protein
detected at baseline
X
PET Scan
D
7.2.1.2.6
To confirm response of CR (can be part of 
CT/PET)
SYMPTOMATIC MULTIPLE MYELOMA
Skeletal Survey
D
7.2.1.3.1
X
If clinically indicated
Urine protein electrophoresis 
(UPEP)7
D
7.2.1.3.2
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
Free light chain7
D
7.2.1.3.3
X
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X
Serum protein electrophoresis 
(SPEP)7
D
7.2.1.3.4
X
Every 8 weeks (±4 days) after first dose of study
drug (Day 1 of every odd cycle) ) for the 1st 16 
weeks of treatment and every 16 weeks (±4 
days) thereafter
X


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
MRI/CT Scans (For 
plasmacytoma Only)
D
7.2.1.3.5
X
Every 8 weeks (±4 days) after first dose of study drug
(Day 1 of every odd cycle) ) for the 1st 16 weeks of 
treatment and every 16 weeks (±4 days) thereafter
Bone Marrow Biopsy or aspirate
D
7.2.1.3.6
X
To confirm response of CR
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Examination for enlarged spleen 
or liver
D
7.2.1.2.1
X
To confirm response of CR
Physical examination for 
measurement of superficial 
disease and B symptoms 9
D
7.2.1.2.2
X
Day 1 of every cycle (±4 days) after first dose of study 
drug
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans 3, 5, 7, 8)
D
7.2.1.2.3
X
Every 8 weeks (±4 days) after first dose of study drug 
(Day 1 of every odd cycle) ) for the 1st 16 weeks of 
treatment and every 16 weeks (±4 days) thereafter
Bone Marrow Biopsy or aspirate
D
7.2.1.2.4
To confirm response of CR 
Peripheral Blood for CBC 
differential and blast count
D
7.2.1.4.1
X
X
X
X
X
X
X
Physical examination for 
assessment of Extramedullary 
disease or Organomegaly (if 
present)
D
7.2.1.4.3
X
X
X
X
X
X
X
LEUKEMIA, MDS, MF, PV and ET


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
Peripheral Blood for CBC 
differential and blast count
D
7.2.1.4.1
X
X
X
X
X
X
X
Physical examination for 
assessment of Extramedullary 
disease or Organomegaly (if 
present)
D
7.2.1.4.3
X
X
X
X
X
X
X
Bone Marrow Biopsy or aspirate
D
7.2.1.4.2
X
To confirm response of CR or if clinically 
indicated
History/assessment of 
chromosomal 
abnormalities/Karyotype
S
7.2.1.4.4
X11
Evaluation of transfusion 
dependency
D
7.2.1.4.5
X
X
X
X
X
X
X
Myeloproliferative Neoplasm 
(MPN) Symptom Assessment
D
Appendix Q
X
X
X
X
X
X
X


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Category
Reference to 
assessment
Screening 
phase
Treatment Phase
Post treatment 
follow-up 
phase
Survival 
phase
Screening
C1
C2
Subsequent 
cycles
EOT
Safety follow 
up
Survival FU
Visit Number
1
2
3
4
5
6
777
501
701
Cycle days1
-28 to -1
1
15
1
15
1
EOT + 30 (±4) 
days
EOT + every 
3 months2
1.
A complete cycle is defined as 28 days.
2.
Additional survival assessments may be performed outside the 3 months follow-up schedules if a survival update is required for an interim assessment to meet safety 
or regulatory needs.
3.
Tumor assessments at EOT are required for patients who discontinue study treatment before the first scheduled post-screening tumor assessment and for patients 
whose previous tumor assessment did not demonstrate PD and was done at least 8 weeks (± 4 days) prior to end of treatment visit.
4.
These assessments should be performed only if the screening assessment occurred > 4 days from Cycle 1 Day 1.  The patient must continue to meet all eligibility 
criteria on C1D1, as they did during the screening period.
5.
Tumor assessments include CT/MRI of the chest abdomen and pelvis at all timepoints. Tumor assessments are described in Section 7.2.1
6.
Women of childbearing potential must undergo a serum pregnancy test at screening and EOT. Women of child-bearing potential will undergo a monthly urine 
pregnancy tests during the study.
7.
For patients who have a response of PR or greater, a confirmation assessment must be performed at least 4 weeks after the initial observation.
8.
The frequency of disease assessment will be reduced to every 16 weeks after patient have completed 16 weeks on treatment.
9.
Skin lesions should be documented using a digital camera (color photography) in clear focus showing the ruler or calipers and the corresponding measurement in 
such a way that the size of the lesion(s) can be determined from the photograph
10. To confirm complete responses in patients with bone marrow tumor involvement prior to study treatment
11. History must be present in the patient’s source documents. Additional testing to confirm is not required and should be done based on the investigator’s judgment
12. Screening ECGs should performed ≤ 7 days from C1D1
13. For patients with a best response of SD or better who discontinue study treatment due to disease progression, an optional tumor sample should be obtained for 
genomic analysis. For details, refer to Section 7.2.4
15. Survival follow-up may be discontinued if the primary efficacy endpoint is not met.


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7.1.1
Screening
For the purpose of this study, genomic profiling is not considered part of screening. This 
study is intended for patients who have already had genomic profiling of their tumors in a 
CLIA certified laboratory and have already been pre-identified to have tumors with relevant 
pathway activation. The results of this testing must be known prior to signing the ICF and 
before formal screening begins. Written informed consent must be obtained before any study 
specific assessments are performed, including screening. All screening evaluations must be 
performed as closely as possible to the beginning of treatment and never more than 28 days 
prior to starting study drug dose of ribociclib.
Upon signing the Informed Consent Form (ICF), a patient will be assigned a 7-digit patient 
number.
Patient must have archival tissue available for submission to allow for molecular testing 
related to pathway activation and other analyses. If the tissue is not available or is insufficient,
the patient must be willing to undergo a fresh tumor biopsy to allow for this analysis. The 
tissue submitted will not be used to determine study eligibility. Eligibility is based on the local 
assessment. 
 
An archival or fresh tumor sample may not be required if the patient has had their genomic 
profiling performed at the same laboratory that will be used for confirmatory analysis, and the 
patient consents to allow Novartis to use that to use that data as their baseline molecular 
analysis results.
For the purposes of enrollment, the patient’s pathway activation status is based on the 
presence of known aberrations identified in Section 5.2.
Patients who fail to start on treatment within 28 days of screening may be re-screened.
Disease assessments (per RECIST 1.1 or appropriate hematologic response criteria) must be 
performed within 28 days prior to enrollment and will be assessed locally by the investigator.
Information from procedures (for example imaging assessments) that may have been 
previously performed as part of the patient’s routine disease care (prior to enrolling in the trial) 
is allowed to be used to satisfy inclusion criteria, if it was performed <28 days before the start 
of study treatment.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is 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. If the 
repeated laboratory result does not meet the criteria, the patient will be considered ineligible 
and a screening failure.
For details of assessments, refer to Table 7-1 and Section 7.2.
7.1.1.1
Eligibility screening
Once all screening procedures are completed, eligibility should be confirmed prior to the 
subject receiving the first dose of study drug.


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7.1.1.2
Information to be collected on screening failures
Patient who sign the ICF, but are not started on treatment for any reason will be considered a 
screen failure. For screen failure patients, the reason for not proceeding with treatment will be 
entered on the Screening Log eCRF. No waivers will be granted.
The following eCRFs must be completed for screening failure patients:

Screening Log eCRF page (including reason for not starting treatment)

Informed Consent

Demography

Serious Adverse Event after signing the ICF - see Section 8 for SAE reporting details.
7.1.1.3
Patient demographics and other baseline characteristics
Patient information to be collected at screening include:

Pathway aberration status as identified in section 5.2

Demographic data (age, gender, race)

Diagnosis and Extent of Cancer

Relevant 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 before the first dose of study drug is administered).

Cancer-related conditions and symptoms which are recorded on the Medical History 
eCRF should include the grade

Prior Anti-neoplastic Medications

Prior Anti-neoplastic Radiotherapy

Prior Anti-neoplastic Surgery

All other medications and non-drug therapies (including physical therapy, oxygen and 
blood transfusions) administered to the patient within 28 days prior to the first dose of 
study drug) must be reported on the appropriate eCRFs

Furthermore the following assessments will be performed to assess the eligibility of the 
patient:

Physical Examination (See Section 7.2.2.1)

Vital signs (See Section 7.2.2.2)

Height, weight (See Section 7.2.2.3)

ECOG performance status (See Section 7.2.2.4)

Laboratory evaluations (e.g., hematology, coagulation, biochemistry, urinalysis, liver 
function monitoring) (See Section 7.2.2.5)


Serum pregnancy (See Section 7.2.2.5.6)

Cardiac assessment (See Section 7.2.2.6)

Disease evaluations (See Section 7.2.1.)


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
Radiological assessments (e.g., CT scan) if clinically indicated (See Section 7.2.1)
7.1.2
Treatment period
Patients will be treated with ribociclib (600 mg, orally) until disease progression, 
unacceptable toxicity, death or discontinuation from the study treatment due to any other 
reason.
For details of safety and efficacy assessments, refer to Table 7-1 and Section 7.2.

Visits and associated assessments that occur ± 4 days from the scheduled date (except for 
cycle 1 Day1 where no visit window is allowed) will not constitute protocol deviations.

The cycle length is 28 days. Day 1 of subsequent cycles will be calculated from cycle 1, 
day 1.

Disease Assessments (per RECIST or appropriate hematological response criteria) must 
be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd 
cycle), until disease progression or end of treatment, whichever occurs first. The 
frequency of disease assessment may be reduced to every 12 weeks for patients who have 
at least 4 post-baseline disease assessments and are clinically stable (except MM patients).

Laboratory assessments performed as part of the screening evaluations, more than 4 days
prior to the first dose of study treatment, must be repeated on the first dosing day.

 
7.1.3
End of treatment visit, including premature withdrawal and study 
discontinuation visit
7.1.3.1
End of treatment (EOT) visit
Patients who completely discontinue study treatment should be scheduled for an End of 
Treatment (EOT) visit within 7 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 Treatment Phase Disposition eCRF page should be completed, giving the date and 
reason for stopping the study treatment. If a study 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 End of Treatment Phase 
Disposition eCRF page.
End of treatment/Premature withdrawal visit is not considered as the end of the study.
For patients with a best response of SD or better who discontinue study treatment due to 
disease progression, an optional tumor sample should be obtained for genomic analysis. 
For solid tumor patients with at least ≥ 20% reduction in overall tumor assessment (PR or 
better for hematological tumors) who discontinue study treatment due to disease progression, 


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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.
7.1.3.2
Criteria for premature patient withdrawal (EOT phase completion)
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator or by the sponsor at any time.
Premature patient withdrawal refers to the point/time when the patient exits from the study 
treatment prior to the planned completion of all study treatment administration and/or 
assessments; at this time, all study drug treatment is discontinued and no further assessments 
are planned, unless the patient will be followed for progression and/or survival.
Patients may be withdrawn from the study treatment if any of the following occur:

Adverse Event

Lost to follow-up

Non-compliance with study treatment

Physician decision

Pregnancy

Progressive Disease

Protocol deviation

Study terminated by sponsor

Subject/guardian decision

Death

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 
6.3

Use of prohibited medication. Please refer to Section 6.4.3

Interruption of study treatment for > 21 days, regardless of reason, from the intended 
day of the next scheduled dose
Patients that transition into the rollover clinical trial will perform end of treatment procedures.  
However, follow-up for safety, survival and disease progression will not be performed.


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7.1.4
Follow up period
7.1.4.1
Safety follow up
All patients who discontinue study treatment, including those who refuse to return for a final 
visit, will be contacted for safety evaluations (i.e., assessment of AEs and/or SAEs, 
concomitant medications) for 30 days after the last dose of study treatment. Patients whose 
treatment is interrupted or permanently discontinued due to an adverse event, including 
abnormal laboratory value, must be followed at least once a week for 4 weeks and 
subsequently at 4-weeks intervals until resolution or stabilization of the event, whichever 
comes first.
If patients refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
patient should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.).
7.1.4.2
Efficacy follow-up
Not applicable.
7.1.4.3
Survival follow-up
All patients will be followed for survival status every 3 months regardless of treatment 
discontinuation reason (except if consent is withdrawn). Survival information will be 
collected every 3 months until 2 years after the last patient has enrolled in the study. 
Additional survival assessments may be performed outside the 3 months follow-up schedules 
if a survival update is required for an interim assessment to meet safety or regulatory needs.
Survival information can be obtained via phone, and information will be documented in the
source documents and relevant eCRFs.
If the primary efficacy end-point is not met, Novartis may discontinue survival follow-up for 
this study.
7.1.4.4
Lost to follow-up
Patients lost to follow up should be recorded as such in the eCRFs. For patients who are lost 
to follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
7.1.5
End of post-treatment follow-up (Study phase completion)
Not applicable.
7.2
Assessment types


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7.2.1
Efficacy assessments
The primary efficacy endpoint is clinical benefit rate as defined in Section 10.4. The key 
secondary efficacy endpoint is overall response rate of PR or greater as defined in Section 
10.5. Other secondary endpoints are time from the date of first dose to the date of first 
documented disease progression or relapse or death due to any cause, time from the date of 
first dose to the date of death due to any cause, time from the first documented response to the 
date first documented disease progression or relapse or death due to any cause, AE rate, and 
other safety measurements as defined in Section 10. The local investigator’s assessment will 
be used for the analysis and for treatment decision making.
Clinical suspicion of disease progression at any time will require assessment and confirmation 
to be performed promptly, rather than waiting for the next scheduled tumor assessment. In 
case of an unscheduled or delayed tumor assessment for any reason, subsequent disease 
assessments must be performed according to the originally planned schedule from baseline.
7.2.1.1
Solid Tumors
Response will be evaluated, using modified Response Evaluation Criteria in Solid Tumors,
based on RECIST 1.1. For complete details, refer to Appendix B.
Clinical evaluation and tumor assessments will be performed as is indicated in Table 7-1, 
based on physical examination and radiological evaluation. For solid tumors, an assessment of 
PR or greater based on RECIST 1.1 must be confirmed at least 4 weeks after initial 
observation. If the two assessments differ, the best overall response will be determined by 
Table 3-3 of Appendix B.
Any lesion that has been previously treated with radiotherapy should be considered as a non-
target lesion. However, if a lesion previously treated with radiotherapy has clearly progressed 
since the radiotherapy, it can be considered as a target lesion.
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Definitions for measurable and non-measurable lesions, and criteria for response, should be 
based on RECIST 1.1 (Appendix B).
7.2.1.1.1 Physical examination for superficial disease
Clinical assessment of any existing superficial lesions (skin nodules and palpable lymph 
nodes) at screening and at each subsequent tumor assessment must be performed on the same 
schedule as radiological tumor assessments (see Section 7.2.1.1.4).
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening.


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7.2.1.1.2 Cancer Antigen-125 (CA-125)
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian cancer at screening.
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Section 7.2.1.1.4).
7.2.1.1.3 Prostate Specific Antigen (PSA)
Prostate Specific Antigen (PSA) will be used in the assessment of prostate cancer at screening. 
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Section 7.2.1.1.4).
7.2.1.1.4 Radiological tumor assessment
At screening and at each subsequent tumor assessment, all patients must have a CT scan with 
contrast of the Chest/Abdomen and Pelvis. If a patient is known to have a contraindication to 
CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed.
The same type of CT scan used at screening must be used for all subsequent assessments. 
MRI with contrast will be allowed only in those cases when CT scan cannot be performed and 
will be used at baseline and all subsequent assessments in these patients. No modality change 
would be allowed during the study when assessing overall tumor status. For subsequent scans 
in the same patient, the radiologist must account for all lesions that were present at screening 
and must use the same technique as used at screening. If possible, a single radiologist should 
perform all tumor response evaluations for an individual patient. Only in exceptional cases 
when during the study a patient develops intolerance to the CT scan contrast medium, a CT 
scan without contrast will be acceptable to avoid modality change. At screening, tumor 
assessments should preferably be performed ≤ 4 days prior to the first dose of ribociclib, 
however tumor assessments ≤ 28 days prior to first dose of study drug will be acceptable.
Tumor assessments will be performed at screening and every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle). The frequency of disease assessment will be 
reduced to every 16 weeks after the 1st 16 weeks on treatment.
7.2.1.2
Lymphoma
Response will be evaluated, using modified criteria for malignant lymphoma Cheson
(Appendix C) and Ann Arbor Staging Classification (Appendix D).
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in
Table 7-1, based on evaluation of spleen and liver, physical examination for superficial 
disease and B symptoms, radiological evaluation, Serum Protein electrophoresis (SPEP), core 
bone marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 
involvement prior to study treatment), and positron emission tomography (PET) (only to 
confirm complete responses in patients where PET was used for study entrance).


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7.2.1.2.1 Enlarged spleen and liver
The presence of enlarged spleen or liver before start of treatment on the basis of CT scan (or 
MRI scan) should be recorded on the corresponding eCRF at baseline, and reassessed if the 
patient has a radiological CR.
A maximum of four of the largest dominant measurable nodules representing all involved 
anatomic locations should be selected as splenic and hepatic index lesions to be measured.
All other splenic or hepatic nodules (both measurable and non-measurable) are considered as 
non-index lesions.
7.2.1.2.2 Physical examination for superficial disease and B symptoms
Tumor assessment by physical examination and evaluation of disease related B symptoms 
(unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained 
loss of >10% body weight within the previous 6 months) will be performed at screening and 
day 1 of every cycle (±4 days) after first dose of study drug. Refer to Appendix C for 
specifications and measurement.
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening.
7.2.1.2.3 Radiological tumor assessment
Tumor assessments will be performed at screening, every 8 weeks (±4 days) after first dose of 
study drug (Day 1 of every odd cycle), until disease progression or end of treatment, 
whichever occurs first. The frequency of disease assessment may be reduced to every 16
weeks after the 1st 16 weeks on treatment.
Refer to Section 7.2.1.1.4 for requirements
All patients should have at least one site of measurable nodal disease ≥2.0 cm in the longest 
transverse diameter and clearly measurable in at least two perpendicular dimensions, as 
determined by CT scan (MRI is allowed only if CT scan cannot be performed). Complete 
guidance for selecting index lesions is provided in Appendix C. Index lesions will be 
measured and recorded at baseline and during the course of the study. They should be selected 
on the basis of their size and suitability for accurate repeat measurements. Skin lesions, if the 
area is ≥ 2 cm in at least one diameter, must be histologically conformed for lymphoma 
involvement (the site must document the histological confirmation (yes or no) on the 
corresponding eCRF) and photographed (color photography using camera).
A sum of the product of diameters (SPD) for lesions measured prior to study treatment will be 
calculated and reported at cycle 1 day 1.
Conventional CT and MRI should be performed with contiguous cuts of 7.5 mm or less in 
slice thickness. Spiral CT should be performed using a 5 mm or less contiguous 


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reconstruction algorithm (this specification applies to tumors of the chest, abdomen and 
pelvis).
If a very small lesion cannot be reliably measured because of its size, it is recommended to 
enter the minimum lesion size (i.e., 5 mm for spiral CT). In other cases where the lesion 
cannot be reliably measured for reasons other than its size (i.e., borders of the lesion are 
confounded by neighboring anatomical structures), no measurement should be entered and the 
lesion cannot be evaluated.
Any measurable extranodal lesions (organs other than lymph nodes) that resolves from 
baseline (disappear completely) must be assigned a size of 0 mm when documenting on the 
corresponding eCRFs. An extranodal lesion must be ≥ 1 cm x 1 cm to be considered 
measurable. Refer to Appendix C for complete reporting guidelines.
7.2.1.2.4 Bone marrow assessment
Information on the patient’s bone marrow involvement based on documented history prior to 
study entry must be present in his/her source documents. Prior tumor bone marrow 
involvement should be entered on the corresponding eCRF.
Core bone marrow biopsy will not be performed at screening but is required to confirm 
complete responses (at the first occurrence of radiological and clinical evidence of CR) in 
patients with bone marrow tumor involvement prior to study treatment who achieve Complete 
Response based on clinical and radiological evidence. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). Bone 
marrow biopsy should be obtained no later than at the next visit immediately following 
clinical and radiological evidence of CR (i.e. < 28 days ± 7 days from the date of the 
radiological assessment, on which the CR is based on).
7.2.1.2.5 Serum Protein electrophoresis (SPEP)
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as radiological tumor assessments (see Section 7.2.1.2.3) only if 
abnormal M-protein is detected at screening.
7.2.1.2.6 Positron emission tomography (PET)
The use of Positron emission tomography (PET) is not standard in Novartis Oncology 
Lymphoma studies. PET evaluations that have been done as standard of care prior to 
enrollment will be recorded in the eCRF. Repeat PET will be required only for patients who 
have responses of CR for the purpose of this study and should be done within +/- 7 days of the 
CT or MRI to confirm CR. Refer to Appendix C for lesion measurements.
7.2.1.3
Symptomatic multiple myeloma
Response will be evaluated using the International Myeloma Working Group (IMWG) 
Uniform Response Criteria for Multiple Myeloma. For complete details, refer to Appendix L.
Clinical evaluation and disease assessments will be performed periodically, as is indicated in 
Table 7-1, based on a skeletal survey Urine protein electrophoresis (UPEP), Free light chain, 


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Serum Protein electrophoresis (SPEP), bone marrow biopsy, and MRI/CT Scans (For 
plasmacytoma only).
7.2.1.3.1 Skeletal survey
Skeletal survey will be performed at screening and if clinically indicated as outlined in Table 
7-1.
7.2.1.3.2 Urine protein electrophoresis (UPEP)
Urine protein electrophoresis (UPEP) will be performed by the local laboratory at screening, 
every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle) refer to 
Table 7-1 and EOT.
7.2.1.3.3 Free Light Chain
Free Light Chain will be performed by the local laboratory at screening and on the same 
schedule as UPEP assessments (see Section 7.2.1.3.2).
7.2.1.3.4 Serum protein electrophoresis (SPEP)
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as UPEP assessments (see Section 7.2.1.3.2).
7.2.1.3.5 MRI/CT scans (for plasmacytoma only)
For patients with plasmacytoma, a MRI/CT scan will be performed by the local laboratory at 
screening and on the same schedule as UPEP assessments (see Section 7.2.1.3.2).
7.2.1.3.6 Bone marrow assessment
Information on the patient bone marrow involvement prior to study entry must be present in 
his/her source documents. Prior tumor bone marrow involvement should be entered on the 
corresponding eCRF.
Core bone marrow biopsy is required to confirm Complete Responses (at the first occurrence 
of radiological and clinical evidence of CR) in patients with bone marrow tumor involvement 
prior to study treatment who achieve Complete Response based on clinical and radiological 
evidence. The biopsy sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). Bone marrow biopsy should be obtained no later than at the 
next visit immediately following clinical and radiological evidence of CR (i.e. < 28 days ± 7 
days from the date of the radiological assessment, on which the CR is based on).
7.2.1.4
Leukemia
Response for AML will be evaluated using the revised recommendations of the International 
Working Group (IWG) as noted in Cheson 2003 (Appendix F). Response for ALL will be 
evaluated using guidelines adapted from NCCN Guidelines Version 2.2012 (Appendix H). 
CML will be evaluated using guidelines adapted from NCCN Guidelines Version 13 2013
(Appendix I). The response for CLL will be evaluated using the revised recommendation of 
the IWG as noted in Hallek 2008 (Appendix J). The response for myelodysplasia (MDS) will 


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be evaluated using the revised recommendation of the IWG as noted in Cheson 2006
(Appendix P). The response for polycythemia vera (PV) and essential thrombocythemia (ET) 
will be evaluated using the recommendation of IWG-MRT as noted in Barosi 2013 (Appendix 
N and Appendix O
respectively). The response for myelofibrosis (MF) will be evaluated 
using IWG-MRT as noted in Tefferi 2013 (Appendix M).
Clinical evaluation and disease assessments for AML, ALL, CML, MDS, PV, ET, and MF 
will be performed periodically, as is indicated in Table 7-1, based on peripheral blood and
bone marrow assessment as well as the presence or absence of extramedullary disease, and
organomegaly, and evaluation of transfusion dependency.
Clinical evaluations and disease assessments for CLL will be performed periodically as is 
indicated in Table 7-1, based on the lymphoma schedule for evaluation of physical 
examination for superficial disease and B symptoms, radiological evaluation, core bone 
marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 
involvement prior to study treatment) and Rai staging criteria (Appendix E).
Peripheral 
blood, and the presence or absence of extramedullary disease and organomegaly will also be 
performed on the same schedule as other leukemia evaluations as indicated below.
To assess response, the time interval between bone marrow and blood assessments may not 
exceed 5 days. If the time interval is more than 5 days, response status cannot be assessed at 
that time point. Regular bone marrow assessments are not required after achieving a CR 
unless indicated by blood counts or clinical assessments or specified in the protocol
The response assessment date is defined as the last of all dates of measurements which are 
required to qualify for a response category within the period listed above. This rule applies 
also in case of multiple measurements of the same variable. In case of relapse, the first of all 
measurement dates associated with a disease assessment will be used as assessment date. The 
assessment date will be used for the derivation of the time-to-event endpoints
7.2.1.4.1 Peripheral blood evaluation for CBC
Peripheral blood will be performed by the local laboratory at screening, Day 1 and Day 15 of 
Cycles 1 and 2, at Day 1 of each subsequent cycle, and at EOT.
Peripheral blood evaluation for CBC will be taken from the same sample as hematology and
include evaluation of blast, neutrophil, and platelet cell count.
7.2.1.4.2 Bone Marrow assessment
Bone marrow will be assessed for blast cell count at screening, to confirm response of CR or 
if clinically indicated.
Percent blast cell count will be determined by cytological examination. This assessment can 
be performed in terms of bone marrow aspirate and/or biopsy. Results from these tests are 
considered to be interchangeable to assess blasts counts. In case both aspirate and biopsy were 
done, both tests will be considered for response assessment:
In case of only one assessment with non-missing values: Data of the non-missing test result 
will be used.


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In case of both assessments with differing, non-missing data: For blast counts, the highest 
value will be considered. For Auer rods, the positive finding will be considered, if applicable
7.2.1.4.3 Physical examination for Extramedullary disease and/or organomegaly
Extramedullary involvement (CNS and/or soft tissue) is to be assessed at each visit for 
response assessment. Presence with specification of location or absence of extramedullary 
disease is to be captured in the eCRF. Extramedullary disease is to be assessed via clinical 
examination or relevant imaging techniques as clinically appropriate.
In case of extramedullary disease at baseline or (re-)appearance during the study, the lesions 
need be confirmed cytologically if technically and/or clinically feasible. A clinical assessment 
will be made in case a cytological confirmation is not possible
The presence of organomegaly (hepatomegaly and/or splenomegaly) is to be assessed at 
baseline at visits as part of the response assessment. The modality used: scan or palpation is to 
be noted.
7.2.1.4.4 Assessments of chromosomal abnormalities
Information on the patient’s chromosomal abnormalities/karyotyping based on documented 
history prior to study entry must be present in his/her source documents. Additional testing to 
confirm these response categories will not be required and should be done at the discretion of 
the attending physician.
7.2.1.4.5 Evaluation of transfusion dependency
Transfusion dependency will be assessed at screening as well as during the course of the trial 
for all patients. Transfusion of blood products will be recorded in a separate module of the 
eCRF. The type and reason for transfusion, start and end date as well as the number of units 
will be captured at each visit with hematologic assessment.
A period of one week without any transfusion has been taken as a convention to define the 
status of transfusion independence to assess response. Any sample of peripheral blood which 
was taken within seven days after a transfusion will be considered as transfusion dependent.
For the definition of transfusion dependency, it does not matter which type of blood product 
was transfused. Moreover, the rules and time windows apply not only to blood transfusions 
but also to erythropoietin, thrombopoietic agents and/or myeloid growth factors.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, weight, performance 
status evaluation, ECG, cardiac imaging, laboratory evaluations as well as collecting all 
serious and non-serious Adverse Events (AE). For details on AE collection and reporting, 
please refer to Section 8.1.
Clinically 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 and meet the 
definition of an AE must be recorded on the Adverse Event page of the patient’s eCRF.


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7.2.2.1
Physical examination
A complete physical examination will be performed at screening, at Day 1 of each cycle and 
at the EOT visit. Visit windows of ± 4 days are allowed (except at cycle 1 Day 1). As 
specified in Table 7-1, a screening physical examination performed within 4 days prior first 
dosing does not need to be repeated at Cycle 1 Day 1.
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) will be monitored at screening, 
before administration of ribociclib at Day 1 of each cycle, and EOT. Screening vital sign 
assessments performed within 4 days of first dosing do not need to be repeated at Cycle 1 Day 
1. Vital signs will be measured according to normal medical practice.
7.2.2.3
Height and weight
Height and body weight will be measured. Weight will be measured at the screening visit, at 
Day 1 of each cycle, and at EOT. Screening weight assessment performed within 4 days of 
first dosing does not need to be repeated at Cycle 1 Day 1. Height will be collected at 
screening only.
7.2.2.4
Eastern Cooperative Oncology Group (ECOG) Performance status
The performance status will be assessed according to the ECOG performance status scale 
(Oken 1982). ECOG performance status will be assessed at screening, at Day 1 of each cycle
and at the EOT visit (Appendix K). ECOG performance assessment performed within 4 days 
of first dosing does not need to be repeated at Cycle 1 Day 1.
7.2.2.5
Laboratory evaluations
Clinical laboratory analyses (Hematology, biochemistry, coagulation, urinalysis, pregnancy 
test, thyroid function test) are to be performed by the local laboratory according to the Visit 
Schedule outlined in Table 7-1. Visit windows of ± 4 days are allowed (except at cycle 1 Day 
1). As specified in Table 7-1, screening laboratory assessments performed within 4 days of 
first dosing do not need to be repeated at Cycle 1 Day 1.
Novartis must be provided with a copy of the local laboratory’s certification (if applicable), 
and a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study 
must be reported via an updated tabulation indicating the date of revalidation. Additionally, 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 and units for this laboratory as well. The investigator is responsible for reviewing all 


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laboratory reports for patients in the study and evaluating any abnormalities for clinical 
significance.
More frequent laboratory examinations may be performed at the investigator’s discretion if 
clinically indicated.
At any time during the study, abnormal laboratory parameters which are clinically relevant 
and require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the 
Adverse Events eCRF page. Laboratory data will be summarized using the Common 
Terminology Criteria for Adverse events (CTCAE) version 4.0.3. Additional analyses are left 
to the discretion of the investigator.
7.2.2.5.1 Hematology
Hematology tests are to be performed by the local laboratory at screening, Day 1 and Day 15 
of Cycles 1 and 2, at Day 1 of each subsequent cycle and at EOT according to the Visit 
Schedule outlined in Table 7-1. The hematology panel includes hematocrit, hemoglobin,
platelet count, total red blood cells (RBC), total white blood cells (WBC) count, and a WBC 
differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils.
7.2.2.5.2 Biochemistry
Biochemistry tests are to be performed by the local laboratory at screening, Day 1 and Day 15 
of Cycles 1 and 2, at Day 1 of each subsequent cycle and at EOT according to the Visit 
Schedule outlined in Table 7-1. The full biochemistry panel includes albumin, amylase, 
bicarbonate, calcium, creatinine, glucose, lactate dehydrogenase (LDH),  lipase, magnesium, 
potassium, total protein, , phosphorus, sodium, urea or blood urea nitrogen (BUN), uric acid,
total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and 
triglycerides. Additionally liver function test including AST/SGOT, ALT/SGPT, GGT, 
alkaline phosphatase, total, direct and indirect bilirubin will be measured.
7.2.2.5.3 Thyroid Panel
Thyroid test will be performed at screening, C1D1, every 3 cycles starting at C3D1, and EOT, 
and during the treatment phase if clinically indicated. Thyroid panel test include TSH, free T3, 
and free T4.
7.2.2.5.4 Coagulation
International normalized ratio (INR)
and pro-thrombin time (PT), activated partial 
thromboplastin time and fibrinogen will be measured at screening, Day 1 of Cycle 1 and 
during the treatment phase if clinically indicated.
7.2.2.5.5 Urinalysis
Urinalysis includes dipstick analysis (WBC, blood, protein, specific gravity, pH, bilirubin, 
ketones and glucose) which will be performed at screening, Day 1 of each cycle and at EOT.


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7.2.2.5.6 Pregnancy and assessments of fertility
Women of childbearing potential must undergo a serum pregnancy test at screening to 
confirm eligibility in the trial (≤ 4 days before first dose of either study drug), and at EOT. 
Women of child-bearing potential must additionally undergo a monthly urine pregnancy test 
during the treatment phase.
In case of pregnancy, the patient must permanently stop study treatment immediately, 
withdraw from the trial, and the pregnancy must be reported on the Clinical Trial Pregnancy 
Form.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
Standard triplicate 12 lead ECG assessments will be performed after the patient has been 
resting for 5-30 min prior to each time point indicated in Table 7-2 below. The triplicate 
ECGs should be taken approximately 2 minutes apart. The combined QTcF values from 
triplicate ECGs will be averaged to provide a single value for each patient. If an abnormal 
ECG or QTcF value of ≥ 481 ms is obtained at any time during the study, study treatment 
must be interrupted, repeat the ECG measurements and follow management guidelines 
detailed in Table 6-5.
Table 7-2
ECG Collection Plan
Cycle/ Visit3
Day
Time
ECG Type
Screening
-7 to 1
Any time
12 Lead1
1
1
Pre-dose
12-Lead
1
1
2, 4 and 6 h post-dose
12-Lead
1
15
Pre-dose
12 Lead
1
15
2, 4 and 6 h post-dose
12 Lead
2
1
Pre-dose
12 Lead
2
1
2 h post-dose
12 Lead
3
1
Pre-dose
12 Lead
3
1
2 h post-dose
12 Lead
Cycles 4 and subsequent cycles2
1
Pre-dose
12 Lead
End of treatment
Any time
12 Lead
Unscheduled sample
Anytime
12 Lead
Triplicate 12 lead ECG is not required at screening.
For C4D1 and subsequent visits, the ECG will be measured only at pre-dose, except when clinically indicated.
For patients with QTcF ≥ 481ms at any time, interrupt study treatment and follow the procedures described in the 
“Ribociclib Dose Modification section”. If treatment is resumed, repeat ECGs 7 days and 14 days after dose 
resumption (and then as clinically indicated). During subsequent cycles, perform predose ECG for every cycle,
and 2 h post dose starting at every 3rd cycle after thereafter.
The interpretation of the tracing must be made by a qualified physician and documented in the 
ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient 
initials (if permitted by local regulations), Patient Number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities should be reported in the 
Adverse Events eCRF. Clinically significant abnormalities present when the patient signed 


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informed consent should be reported on the Medical History eCRF page. Clinically significant 
findings must be discussed with the Novartis Medical Monitor prior to enrolling the patient in 
the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the Adverse Events eCRF page.
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
MUGA (multiple gated acquisitions) scan or echocardiogram (ECHO) will be used to assess 
LVEF at screening and during the treatment phase as clinically indicated to assess signs or 
symptoms of cardiotoxicity. In case of clinically significant abnormalities, they should be 
reported on the Adverse Events eCRF.
In case a patient develops left ventricular systolic dysfunction while on study treatment dose 
adjustment guidelines described in Section 6.3 must be followed.
7.2.3
Pharmacokinetics
Not Applicable.


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7.2.5
Other assessments
No additional tests will be performed on patients entered into this study.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event (AE) is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
For patients who sign the ICF, all AEs will be captured in the AE eCRF from time of 
signature through 30 days after permanent study treatment discontinuation. For patients who 
fail the screening, only SAEs will be captured in the AE eCRF page.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 


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recorded in the Medical History eCRF. Adverse event monitoring should be continued for at 
least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(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)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy taken (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 serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
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 (as per RECIST 1.1 criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event or 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 
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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 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 eCRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. 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 CTCAEv4.03 does not 
automatically indicate an SAE unless it meets the definition of serious as defined below 
and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality may 
be required by the protocol and is still, by definition, an adverse event.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

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

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
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8.2.2
Reporting
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.
SAE collection starts at time of ICF signature whether the patients is a screen failure or not.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form on a paper SAE Form. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), and complete the SAE Report Form in English.
The SAEs recorded on the paper SAE form should be faxed to 
within 24 hours 
of awareness of the SAE to the local Novartis Chief Medical Office & Patient Safety
(CMO&PS). The original copy of the SAE Report Form and the fax confirmation sheet must 
be kept with the case report form documentation at the study site.
Note that any follow up information provided should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs.
Refer to Section 7.1.1.2 for additional details regarding the reporting of SAEs which occur 
during the screening period.
8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to 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 CMO&PS department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
the Novartis study treatment of any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form.


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Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided 
[Investigator’s Brochure]. Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be included in 
the patient informed consent and should be discussed with the patient during the study as 
needed.
8.6
Data Monitoring Committee
Not applicable
8.7
Steering Committee
Not applicable
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 at least vital status (i.e. that the subject is alive) 
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 
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9.2
Site monitoring
Before study initiation, Novartis personnel (or designated CRO) will review the protocol and 
eCRFs with the investigators and their staff. During the study, the Investigator or designee 
will enter all required patient data into the eCRF within 72 hours (3 days) of the patient visit. 
The field monitor will visit the site regularly to check the completeness of patient records, the 
accuracy of entries on the eCRFs, the adherence to the protocol to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs 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 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
This study will use Electronic Data Capture (EDC) and the designated investigator staff will 
enter the data required by the protocol into the eCRF. The eCRFs have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, 
Investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs and, allow 
modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Mutational analysis data will be generated by CLIA certified local labs. We anticipate that the 
data available in the report will vary from lab to lab. The PI will enter data directly onto the 
eCRF to verify that the patient meets the requirements of “pathway activation” as outlined in 
the inclusion criteria Section 5. Anonymized lab reports will be collected to gather 
information regarding pathway activations.
Laboratory assessments for hematology, biochemistry, coagulation, urinalysis, MUGA and 
ECGs will be collected locally and entered directly onto the eCRFs.
9.4
Database management and quality control
This study will be using eCRFs and the 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 


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values and sent to the investigational site via the EDC system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA current version) 
terminology.
Data from the screening molecular analysis will be collected locally and entered directly onto 
the eCRF. Tissue samples for pathway activation confirmation will be analyzed centrally.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the US Oncology Medical Affairs Franchise Head and the US 
Oncology Medical Affairs Franchise Vice President.
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
All data except the primary efficacy variable clinical benefit rate will be analyzed by a 
designated CRO in collaboration with Novartis. Any data analysis carried out independently 
by the investigator should be submitted to Novartis before publication or presentation. The 
data from all centers that participate in this study will be combined in the final safety and 
efficacy analysis.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) will include all patients who have received at least one dose of 
study drug.
FAS will be used for the analysis of efficacy endpoints.
10.1.2
Safety Set
The Safety Set will include all patients who received at least one dose of study treatment and 
had at least one post-baseline safety assessment.
Please note: the statement that a patient had no adverse event (on the Adverse Event eCRF) 
constitutes a safety assessment.


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized by patients groups formed by the type of cancer at study entry using the FAS.
Additional groups may be added based on enrollment (See Appendix R). Categorical data, 
such as gender, race, etc., will be presented by frequencies and percentages. Descriptive 
summary statistics (e.g., frequency, mean, median, range and standard deviation) will be used 
to present numeric data.
10.3
Treatments (study treatment, concomitant therapies, compliance)
10.3.1
Study medication
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
by the patient groups as above using the Safety Set. The number of patients with dose 
changes/interruptions will be presented along with reasons for the dose change/interruption. 
The safety set will be used for the tables and listings.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized for the FAS by Anatomical Therapeutic Chemical
Classification System (ATC) term, preferred term and treatment arm by means of frequency 
counts and percentages. These summaries will include medications starting on or after the 
start of study treatment (defined as cycle 1 day 1) 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 safety set will be used for all above 
mentioned concomitant medication tables and listings.
10.4
Primary objective
The primary objective is to assess clinical benefit associated with ribociclib treatment based 
on local investigator assessment.
For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR or PR or SD ≥ 16 weeks. For hematologic tumors other appropriate 
hematological response criteria will apply and are included in the appendices.
For solid tumors, an assessment of CR or PR using RECIST 1.1 must be confirmed at least 4 
weeks after initial observation. If the two assessments differ, the best overall response will be 
determined by Table 3-3 of Appendix B.
10.4.1
Variable
The primary efficacy variable is the clinical benefit rate (CBR) (e.g. defined as CR or PR or 
SD ≥ 16 weeks for solid tumors).


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10.4.2
Statistical hypothesis, model, and method of analysis
The study will enroll patients from at least 8 tumor cohorts, with each tumor cohort containing 
possible tumors of interest as shown in Appendix R. 
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
 = log 

1 −
 −log 

1 −

Thus, θg is the group specific logistic regression coefficient for group g. The primary analysis 
is a set of group specific tests that θg>0, meaning that the treatment is better than the assumed 
control rate for that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0
H1g : θg>0
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,
Pr(θg>0 | data) > 0.80
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups..
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ. In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR.
The hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 


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our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in the appendix.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the  have an across groups distribution
θg ~ N(μ, τ2)
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups.  Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 
different results with borrow far less information between them (they will have a low 
probability of being in the same cluster).
Details of the hierarchical model is provided in Appendix R.
10.4.3
Evaluation of trial success and futility
The clinical benefit rate will be evaluated for futility and early success by comparing posterior 
quantities for the rate to pre-specified early stopping criteria. The evaluation are planned to 
occur after the first 30 patients overall (across all groups) have been dosed for at least 16 
weeks or discontinued, and then every 13 weeks thereafter until the end of the study. An 
additional CBR evaluation will be performed at the end of the study.
Early Futility
If there is less than 10% probability that the response rate in a subgroup exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.10.
A group is only eligible for early stopping once a minimum of 10 patients have been 
evaluated for response in that group.
Early Success
If there is at least 95% probability that the response rate in a subgroup exceeds the historical 
rate, then the subgroup will stop enrollment early for success. Formally, enrollment will stop 
early for success if:


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Pr(πg > Rg) > 0.95.
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious.
Final Analysis
The final analysis will occur when both accrual and follow-up are complete for all groups. If, 
at the completion of the trial, there is at least 80% probability that the response rate in a group 
exceeds the historical rate, then the group will be considered a success. Formally:
Pr(πg > Rg) > 0.80.
10.4.4
Handling of missing values/censoring/discontinuations
A patient who has not progressed or died at the date of the analysis cut-off would have his/her 
PFS and OS censored at the time of the last adequate assessment before the cut-off date. Any 
disease assessment indicating response status other than “unknown” or “not done” is 
considered an adequate response assessment.
10.4.5
Supportive analyses
Not applicable.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
The key secondary objective of this study is to assess Overall Response (OR) of Partial 
Response (PR) or Complete Response (CR) based on local investigator assessment.
For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR and/or PR. For hematologic tumors other appropriate hematological response 
criteria will apply and are included in the appendices.
The overall response rate (ORR, PR plus CR) and its 95% exact confidence interval will be 
provided for each patient group. In the event where sample size in each patient group is small 
(<10), only ORR summary for entire study cohort will be presented.
10.5.2
Other secondary efficacy objectives
The secondary objectives of the study:

To assess progression free survival (PFS) based on local investigator assessment per 
RECIST 1.1 or other appropriate hematological response criteria

To assess overall survival

To assess duration of response (DOR) based on local investigator assessment per RECIST 
1.1 or other appropriate hematological response criteria

To assess safety and tolerability


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The secondary efficacy variable progression free survival (PFS) is defined as the time from 
the date of first dose to the date of first documented disease progression or relapse or death 
due to any cause.
PFS will be summarized and graphed using the Kaplan-Meier product-limit method for each 
patient group. Patients who drop-out without progression will be censored at the time of last 
adequate assessment. The estimates of the 25th, median, 75th percentiles of the PFS and their 
95% confidence intervals will be provided, if applicable.
Overall survival (OS) is defined as the time from the date of first dose to the date of death due 
to any cause. If a patient is not known to have died, survival time will be censored at the date 
of the last contact.
OS will be summarized and graphed using the product-limit method as above.
The duration of response applies only to patients whose best response was PR or CR. For 
patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR and/or PR. For hematologic tumors other appropriate hematological response 
criteria will apply and are included in the appendices. The duration of response is defined as 
the time from the first documented response to the date first documented disease progression 
or relapse or death due to any cause. The duration of response will be summarized 
descriptively for each patient group.
10.5.3
Safety objectives
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
patient groups.
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs) will be considered as appropriate. All safety data will be listed.
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. Those collected later than 30 days after study treatment 
discontinuation will be flagged in listings.
10.5.3.1 Analysis set and grouping for the analyses
10.5.3.1.1 Adverse events (AEs)
All adverse events recorded during the study will be summarized. The incidence of treatment-
emergent adverse events (new or worsening from baseline) will be summarized by system 
organ class and/or preferred term, maximum severity (based on CTCAE v4.03), type of 
adverse event, relationship to the 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 patient group.
Adverse events will be summarized by presenting the number and percentage of patients by 
system organ class and/or preferred term, the maximum severity (based on CTCAE v4.03) 
and treatment arm. Adverse events related to study treatment will also be summarized. In 


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addition, adverse events of related nature may be analyzed by categories regrouping the 
relevant preferred terms, as appropriate.
10.5.3.1.2 Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade will be calculated 
using appropriate common terminology criteria (CTCAE v4.03).
A severity grade of 0 will be assigned when the value is within normal limits. For lab 
parameters for which severity grades are determined both through normal limits and absolute 
cut-offs, in the unlikely case when a local laboratory normal range overlaps into the higher 
(i.e. non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits 
and assigned a CTCAE grade of zero.
A listing of laboratory values will be provided by laboratory parameter, patient, and treatment 
arm. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). Lab values collected later than 30 days after study 
treatment discontinuation will be flagged in the listings
The following by-group summaries will be generated separately for hematology, and 
biochemistry parameters:

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.
10.5.3.1.3 Other safety data
Summary statistics for data from other tests will be provided, notable values will be flagged,
and any other information collected will be listed as appropriate.
Descriptive summary statistics will be provided for :

Electrocardiograms: changes from baseline to last available ECG results

Cardiac imaging: number and percentage of patients with notable LVEF values

Vital signs: number and percentage of patients with at least one post-baseline vital sign 
abnormality

ECOG performance status: shift table comparing baseline to worst post baseline ECOG 
performance status.

All other safety related procedures as required

Listings with flagged notable values and any other information collected will be provided 
as appropriate.


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10.7
Interim analysis
Scheduled interim data reviews will occur for the primary endpoint of clinical benefit rate 
only as required by the Bayesian Hierarchical design. The first interim data review will be 
performed after the first 30 patients overall (across all groups) have been dosed for at least 16 
weeks or discontinued, and  then every 13 weeks thereafter, then every 13 weeks thereafter. 
Interim analyses may be performed more frequently dependent on enrollment rate to avoid 
over-enrollment in any of the disease cohorts. At each interim analysis, the groups will be 
evaluated for early futility and early success by comparing posterior quantities for the 
response rate to pre-specified early stopping criteria.
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable, and all important safety 
endpoints will be summarized. No formal report will be issued for these data reviews.
10.8
Sample size calculation
The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in Table 4.2.1 and Table 4.2.2 of Appendix R. This 
hypothesis corresponds to a generally effective treatment across groups and incorporates 
variation in treatment effects to reflect the realistic expectation that treatment effects may 
differ by group. In this setting, analytical power calculations are not possible, but the design 
was simulated to obtain the power of the study as shown in the appendix. The sample sizes 
shown (minimum of 10 for futility stopping, minimum of 15 for early success and maximum 
of 30 as a group cap) achieve adequate power for the alternative hypothesis. The simulations 


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included the expected variable accrual by simulating a Poisson process with expected accrual 
also shown in the appendix.
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 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent Informed consent 
must be obtained before conducting any study-specific procedures (i.e. all of the procedures 
described in the protocol). The process of obtaining informed consent should be documented 
in the patient source documents. The date when a subject’s Informed Consent was actually 
obtained will be captured in their eCRFs.
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH and 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 approval.
Women of child bearing potential and fertile males 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. Women of child bearing potential must agree to 
adhere to contraception requirement until at least 8 weeks after the final dose of study 
treatment. Fertile males must agree to adhere to contraception requirement until at least 21


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days after the final dose of study treatment. If there is any question that the patient will not 
reliably comply, they should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.2.
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 eCRF 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 eCRFs and all other required reports. Data reported on 
the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. An audit trail will be maintained by the system.
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 is 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 clinical study report (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/REB at the 
study site should be informed within 10 working days.


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References (available upon request)
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Barosi G, Mesa RA, Thiele J, et al; (2008)International Working Group for Myelofibrosis 
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Barosi G, et al; (2013) Revised response criteria for polycythemia vera and essential
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Barosi G, Mesa RA, Thiele J, et al; (2008)International Working Group for Myelofibrosis
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Cheson BD, et al (2003). Revised Recommendations of the International Working Group for
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Cheson, et al (2005) Clinical application and proposal for modification of the
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Cheson BD (2007a) The international harmonization project for response criteria in
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Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant
lymphoma. J Clin Oncol 25:579-586
Cowgill SM and Muscarella P (2003) The genetics of pancreatic cancer. American Journal of 
Surgery; 186 (3):279-286.
Emanuel RM, Dueck AC, Geyer HL, et al (2012) Myeloproliferative neoplasm (MPN)
symptom assessment form total symptom score: prospective international assessment of an
abbreviated symptom burden scoring system among patients with MPNs [published correction
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JW, Glendening JM, Flores JF, et al.(1995) Is P16 the Gatekeeper in Sporadic Melanoma. 
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Garcia-Echeverria C (2009) Protein and lipid kinase inhibitors as targeted anticancer agents of 
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Gray-Schopfer VC, Dias SD, Marais R (2005) The role of B-RAF in melanoma. Cancer and 
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Hallek M, et al. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic 
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Huang C, Yang L, Li ZF, et al.(2007) Detection of CCND1 amplification using laser capture 
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Landis MW, Pawlyk BS, Li T, et al.(2006) Cyclin D1-dependent kinase activity in murine 
development and mammary tumorigenesis. Cancer Cell; 9 (1):13-22.LEE011 Investigator’s 
Brochure ed.5
Lundberg AS and Weinberg RA (1998) Functional inactivation of the retinoblastoma protein 
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Nagel S, Leich E, Quentmeier H, et al.(2008) Amplification at 7q22 targets cyclin-dependent 
kinase 6 in T-cell lymphoma. Leukemia; 22 (2):387-392.National Cancer Institute (NCI) 
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Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5; 649-655
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Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008.
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Treatment. Blood; 2013 122: 1395-1398
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ablation. Nature; 411 (6841):1017-1021.


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14
Appendices
Appendix A: Concomitant Medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. 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 not comprehensive and are only meant to be used as a guide. The lists 
are based on the Oncology Clinical Pharmacology Drug-Drug Interaction Database (release 
date: 29 Oct 2012), which was compiled from the Indiana University School of Medicine’s
P450 Drug Interaction 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 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(https://crediblemeds.org/). Please contact the medical monitor with any questions. 
1 Prohibited Medications
Table 14-1 List of prohibited medications during LEE011 treatment
Category
Drug Name
Strong CYP3A4/5
inhibitors
Boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, 
ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, 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, astemizole, cisapride, cyclosporine, diergotamine (dihydroergotamine), 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine
Medications with a 
known risk for QT 
prolongation4
Amiodarone, arsenic trioxide, astemizole, azithromycin, bepridil, chloroquine, 
chlorpromazine, cisapride, citalopram, clarithromycin, disopyramide, dofetilide, 
domperidone, droperidol, erythromycin, flecainide, halofantrine, haloperidol, ibutilide, 
levomethadyl, mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, probucol, 
procainamide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine, vavdetanib
Herbal preparations/
medications
Herbal preparations/medications are prohibited throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kaya, 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 on study medication. If such 
agents are required for a patient then the patient must be discontinued from study drug.


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Category
Drug Name
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.crediblemeds.org
Table 14-2 List of medications to be used with caution1 during study drug 
treatment
Category
Drug Name
Moderate CYP3A4/5
inhibitors
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, 
darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit 
juice (citrus paradisi fruit juice), imatinib, Schisandra sphenanthera2, tofisopam, verapamil
Moderate CYP3A4/5
inducers
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, talviraline, 
thioridazine, tipranavir
P-gp inhibitors
captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar 
(GF120918), erythromycin, felodipine, fexofenadine, fluvoxamine, milk thistle (silybum 
marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, ranolazine, 
Schisandra chinensis, talinolol, telaprevir, telmisartan, ticagrelor, tolvaptan, valspodar 
(PSC 833), verapamil
P-gp inducers
Any known P-gp inducers
Sensitive CYP3A4/5
substrates2
Alpha-dihydroergocryptine, aplaviroc, aprepitant, atorvastatin, brecanavir, brotizolam, 
budesonide, buspirone, capravirine, casopitant, darifenacin, darunavir, dasatinib, 
dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, fluticasone, 
lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, sildenafil, simvastatin, ticagrelor, tolvaptan, 
triazolam, vardenafil, vicriviroc
Strong BSEP 
inhibitors
Bosentan, fusidate, glibenclamide, lovastatin, sulindac, troglitazone (TGZ-sulfate)
BCRP substrates 
Daunorubicin, doxorubicin, rosuvastatin, sulfasalazine, topotecan 
CYP1A2 substrates 
with NTI3
Theophylline, tizanidine
Medications that 
carry a possible risk 
for QT prolongation4
Alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, dolasetron, dronedarone, 
eribulin, escitalopram, famotidine, felbamate, fingolimod, foscarnet, fosphenytoin, 
gatifloxacin, gemifloxacin, granisertron, iloperidone, indapamide, isradipine, lapatinib, 
levofloxacin, lithium, moexipril, nicardipine, nilotinib, octreotide, ofloxacin, ondansetron, 
oxytocin, paliperidone, pasireotide, quetiapine, ranolazine, risperidone, roxithromycin, 
sertindole, sunitinib, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, 
venlafaxine, voriconazole, ziprasidone
MATE1 and OCT2 
substrates5
Acyclovir, amantadine, amiloride, cephalexin, cephradine, cimetidine, famotidine, 
fexofenadine, memantine, metformin (also a substrate for OCT1, MATE1 amd <ATE2K), 
pindolol, procainamide, ranitidine and varencicline
1 Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria as specified in Section 6.4.2 of the Study Protocol or listed in Table 14-1 and Table 14-2.
2 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor.
3 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).
4 Source: www.crediblemeds.org
5 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis and 
implications for Dosing and Labeling (February 2012) and Yonezawa and Inui (2011) Importance -of the multidrug 
and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and 
pharmacogenomics. Br J Pharmacology 164:1817-25


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Appendix B: Criteria for therapeutic response/outcome assessment of 
solid tumors and/or lymph nodes (based on RECIST 1.1)
Tumor assessments will be based on Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) guidelines (Eisenhauer 2009).
2 Measurability of tumor lesions at baseline
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
2.1 Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:

10mm by CT scan (CT scan slice thickness no greater than 5 mm).

10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).

20mm by chest X-ray..
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
2.2 Non-measurable
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with >10 to <15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: Leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
2.2.1 Bone lesions

B, PET and plain films are not adequate to measure bone lesions; they may be used to 
determine the presence or absence of a lesion.

Lytic or lytic-blastic lesions with identifiable soft tissue component that can be measured 
by CT or MRI and meets size requirement can be considered measurable. Blastic bone 
lesions are non-measurable
2.2.2 Cystic lesions

Cystic lesions that meet the criteria for simple cysts are not measurable

Cystic lesions that are thought to be cystic metastatic disease can be considered 
measurable disease, however if non-cystic lesions are present in the same patient these are 
preferable to include as target lesions.


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2.2.3 Lesions previously treated

Lesions within radiotherapy ports or who have been subject to other loco-regional 
treatment are usually not considered to be measurable and will be allowed on this study 
only with approval of the sponsor.
3 Specification by methods of measurement
3.1 Measurement of lesions
All measurements should be taken and recorded in metric notation. The same method of 
assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up.
3.1.1 Target lesions
All lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions. If the largest lesion 
does not lend itself to reproducible measurement, the next largest lesion which can be 
measured reproducibly should be selected.
Pathological lymph nodes which are measurable may be identified as target lesions if they 
have a short axis of >15mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained. The smaller of these measures is the short axis. All other pathological 
nodes (those with short axis >10mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis <10mm are considered non-pathological and should not be 
recorded or followed.
3.1.2 Non-target lesions
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout follow-up.
3.2 Response criteria
3.2.1 Evaluation of target lesions
This section provides the definitions of the criteria used to determine overall tumor response 
for target lesions as shown below in Table 2-1.


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Table 2-1 Evaluation of target lesions
Response Criteria
Evaluation of target lesions
Complete 
Response (CR):
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm.1
Partial Response
(PR):
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.
Progressive
Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute
increase of at least 5 mm (Note: the appearance of one or more new lesions is also 
considered progression)
Stable Disease
(SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study
Notes on the assessment of Lymph nodes: Lymph nodes identified as target lesions should 
always have the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to below 10mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of <10mm. In order to qualify for CR, each node must achieve a short axis 
<10mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions.
3.2.2 Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions as shown below in Table 2-2. While some non-target lesions 
may actually be measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.
Table 2-2 Evaluation of non-target lesions
Response Criteria
Evaluation of target lesions
Complete
Response (CR):
Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10mm short axis)
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive
Disease (PD):
Unequivocal progression of existing non-target lesions. (Note: the appearance of one or 
more new lesions is also considered progression).
3.2.3 New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded appropriately in the eCRF.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment.

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.
a. Negative FDG-PET at baseline, with a positive1 FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and 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 scans 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 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD
3.2.4 Tumor markers
Tumors markers alone will not be used to assess overall response. If elevated at baseline, they 
must normalize for a patient to be considered as having a CR. For the purpose of this protocol, 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian and Prostate Specific 
Antigen (PSA) will be used in the assessment of prostate.
4 Evaluation of best overall 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 indicated below in 
Table 3-1 and Table 3-2.
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence. The best overall response for CR and PR will be determined 
at 8 weeks as indicated below in Table 3-3.
Table 3-1 Time point response: patients with target (± non-target) disease
Target lesions
Non-target lesions
New lesions
Overall lesion response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD


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Target lesions
Non-target lesions
New lesions
Overall lesion response
Any
Any
Yes
PD
Table 3-2 Time point response: patients with non-target disease only
Non-target lesions
New lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/non-PRa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PR
Any
Yes
SD
a‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
Table 3-3 Best overall response when confirmation of CR and PR required
Overall lesion response at first
time point
Overall lesion response at 
subsequent time point
Best overall lesion response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SDb
CR
PD
SDb
CR
NE
SDc
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SDb
PR
NE
SDc
NE
NE
NE
a. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may 
be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, 
not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
b. Provided minimum criteria for SD duration met, otherwise, PD
c. Provided minimum criteria for SD duration met, otherwise, NE


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


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Appendix C: Criteria for therapeutic response/outcome assessment in
lymphoma studies (based on Cheson response criteria)
Disease assessments will be based on the International Working Group response criteria 
(Cheson 1999), and the International Harmonization Project revised response criteria (Cheson 
et al 2007b). Further clarification on these criteria has been published by (Cheson 2007a).
1 Definitions and criteria for normalization
1.1 Definitions
1.1.1 Nodal vs extranodal lesion
A lesion is categorized based on the location as:

Nodal lesion,

Extranodal lesion, if it is located in organs other than lymph node or nodal mass, but 
including spleen and liver.
2 Measurability of Tumor Lesions at Baseline
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
2.1 Measurable Nodal and extranodal lesions
A lesion will be called measurable if it can be measured accurately in 2 perpendicular 
dimensions and:

For nodal lesion, if the long axis is > 15 mm, regardless of the length of the short axis,

For extranodal lesion, if the long and short axes are ≥ 10 mm.
Patients should have at least one measurable nodal lesion greater than 20 mm in the long 
axis.
In cases where the patient has no measurable nodal lesions greater than 20 mm in the long 
axis at Screening, then the patient must have at least one measurable extranodal lesion
2.2 Classification of lymph nodes
Lymph nodes are classified according to their size and/or relationship to the disease:

A lymph node meeting the measurability requirement above will constitute a measurable 
nodal lesion.

A lymph node not meeting the measurability requirement but with long axis > 15 mm (e.g. 
short axis cannot be measured accurately) will constitute a non-measurable nodal lesion.

A lymph node not meeting the measurability criteria but with a size of 11 mm to 15 mm in 
the long axis and > 10 mm in the short axis will be checked for relationship to disease:

If it is thought to be disease related, it will constitute a non-measurable nodal lesion


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
If it is not thought to be disease related, it will constitute an abnormal lymph node
but not a lesion.

All other lymph nodes will be considered normal and will not constitute nodal lesions.
2.3 Criteria for normalization of lesions
The normalization of lesions is defined as follow:

A measurable nodal lesion must become ≤ 15 mm in long axis to be considered 
normalized.

A non-measurable nodal lesion must decrease to ≤ 10 mm in the short axis and be ≤ 15 
mm in long axis to be considered normalized.

An extranodal lesion must disappear completely (assigned a size of 0 mm x 0 mm) to be 
considered normalized.
3 Specification by methods of measurement
3.1 Measurement of lesions
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers.
3.1.1 PET
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.1 In brief, a positive scan is 
defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.1 Other 
causes of false-positive scans should be ruled out. Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG 
uptake lower than the surrounding liver/spleen
3.1.2 CT scan (or MRI)
For optimal evaluation of patients, the same methods of assessment and technique should be 
used to characterize each identified and reported lesion at Screening and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using a 
5mm 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 Screening a 
patient is known to be allergic to CT contrast or develops allergy 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, 


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or vice-versa), or a change in any other imaging modality. A change in methodology will 
result by default in an “Unknown” overall radiological response assessment. However, 
another overall radiological response than the Novartis calculated “Unknown” response may 
be accepted from the investigator if a definitive overall radiological response can be justified 
to be based on the available information.
In order to calculate the sum of the product of the diameters (SPD) of all index lesions (or 
extranodal lesions), their size must be entered throughout the study.
Actual lesion measurements should be entered on the corresponding eCRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion cannot be reliably 
measured because of its small size, it is recommended to enter the minimum limit of detection 
as the diameter size (e.g. 5 mm for spiral CT). In other cases when, during the course of the 
study, the diameter cannot be reliably measured for reasons other than its size (i.e. borders of 
the lesion are confounded by neighboring anatomical structures), no measurement should be 
entered and the lesion cannot be evaluated.
If lesions become confluent over time, it is recommended to measure them as one lesion, 
report the overall diameters to one of the lesions and assign 0 mm x 0 mm to each of the other 
previously measured lesions. If a lesion splits during the study, each sub-lesion should be 
measured separately for all subsequent assessments and all sub-lesions contribute to the SPD.
3.1.3 Bone marrow assessment
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at Screening for all patients.
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at Screening.
If bone marrow involvement is assessed by biopsy, the biopsy sample should have a goal of > 
20 mm unilateral core. If the biopsy
sample is indeterminate by morphology 
(immunohistochemistry), then flow cytometry may be performed on bone marrow aspirate to 
confirm the findings.
3.1.4 Physical examination and assessment of B-symptoms
Skin lesions, if the size is ≥ 20 mm in at least one diameter, must be histologically confirmed 
for lymphoma involvement (the investigational site must document the histological 
confirmation (yes or no) on the corresponding eCRF) and photographed including a ruler 
(color photography using digital camera). Tumor assessment will be performed and results 
will be recorded on the corresponding eCRF at Screening and at Day 1 of every cycle (±4 
days) after first dose of study drug..
B-symptoms are of importance in determining prognosis and should resolve completely in 
patients who have achieved complete response. B-symptoms in lymphoma patients are disease 
related clinical symptoms and are not caused by anticancer therapy (or drug toxicity).


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B-symptoms are defined as follows:

Significant unexplained fever (≥ 38°C),

Unexplained, recurrent drenching night sweats

Unexplained loss of > 10% body weight within the previous 6 months, as assessed and 
reported (present vs. absent) by the Investigator.
4 Evaluation of Radiological Response
For the sake of simplicity, complete remission and complete response will both be referred to 
as complete response.
Definitions of Response for Lymphoma patients are listed in Table 5-1. To evaluate disease 
response to treatment, all index and non-index lesions will be followed and assessed 
throughout the study. At each assessment, response is evaluated separately for the index 
lesions (Table 4-1) and non-index lesions (Table 4-2) identified at Screening, then a 
combined overall radiological response is determined (Table 4-3).
Table 4-1 Response Definition for Lymphoma
Response
Definition
Nodal Masses
Spleen. Liver
Bone Marrow
CR
Disappearance of 
all evidence of 
disease
a  FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET 
negative
b  Variably FDG-avid or PET 
negative; regression to 
normal size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
≥ 50% decrease in SPD of up 
to 6 largest dominant 
masses; no increase in size 
of other nodes
a  FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site
b  Variably FDG-avid or PET 
negative; regression on CT
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified
SD
Failure to attain 
CR/PR or PD
a  FDG-avid or PET positive 
prior to therapy; PET positive 
at prior sites of disease and 
no new sites on CT or PET
b  Variably FDG-avid or PET 
negative; no change in size 
of previous lesions on CT
Relapsed 
disease or 
PD
Any new lesion or 
increase by ≥ 
50% of previously 
involved sites 
from nadir
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis, ≥50% increase in SPD 
of more than one node, or ≥ 
50% increase in longest 
diameter of a previously 
> 50% increase 
from nadir in the 
SPD of any previous 
lesions
New or recurrent 
involvement


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Response
Definition
Nodal Masses
Spleen. Liver
Bone Marrow
identified node > 1 cm in 
short axis
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy
4.1 Evaluation of Index Lesions (nodal and extranodal)
4.1.1 When index nodal lesions are not in complete response
The response for index lesions is evaluated by calculating the Sum of the Products of 
Diameters (SPD) of all index lesions (see Table 4-2), except when there is a Complete 
Response for index nodal lesions (i.e. complete normalization of all index nodal lesions) (see 
Section 4.1.2).
Table 4-2 Radiological status based on SPD calculation for all index lesions
Response Criteria1
Evaluation of index lesions
Complete Response (CR)
See Table 4-4 below (not based on SPD calculation for all index lesions)
Partial Response (PR)
At least 50% decrease from Screening in the SPD of all index lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill the criteria for 
PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD of all index lesions
1 At each assessment (if the index nodal lesions are not in CR status), the response status based on SPD 
calculation will be first assessed for meeting PD status criteria, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters of all index lesions recorded so far, at or 
after Screening.
4.1.2 When index nodal lesions are in complete response
When there is a Complete Response for index nodal lesions (i.e. complete normalization of all 
index nodal lesions as defined in Section 4.1.5: all index lesion ≤ 15 mm in long axis), the 
SPD for these index nodal lesions may not be equal to zero and therefore a calculation of a 
SPD for all index lesions may be misleading. Therefore, by default, a specific response for 
extranodal index lesions needs to be evaluated, based on the SPD calculation restricted to all
index extranodal lesions only (see Table 4-3).
Table 4-3
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions
Response Criteria1
Evaluation of index extranodal lesions
Complete Response (CR)
Complete disappearance of all index extranodal lesions
Partial Response (PR)
At least 50% decrease from Screening in the SPD restricted to all index extranodal 
lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill the criteria for 
PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD restricted to all index extranodal 
lesions


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Response Criteria1
Evaluation of index extranodal lesions
1 At each assessment, response will be first assessed for meeting CR status. If CR status is not met, response will 
be assessed for PD status, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters restricted to all index extranodal lesions 
recorded so far, at or after Screening.
The algorithm for evaluating the response integrating index extranodal lesions and the SPD 
calculated on all index lesions (where appropriate) provides an overall response for index 
lesions.
4.1.3 Evaluation of response for all index lesions
The evaluation of response for all index lesions is based on the combination of the response 
for index nodal lesions (CR or non-CR), the response for index extranodal and the status 
based on the SPD calculated on all index lesions (nodal and extranodal), as described in Table 
4-4.
Table 4-4 Radiological response for index lesions
Response for index 
nodal lesions1
Response for index 
extranodal lesions1
Status based on SPD 
calculation for all index lesions
Response for index 
lesions
CR
CR
Not calculated
CR
CR
SD/ PR
Not calculated
PR
CR
PD
PD
PD
CR
PD
PR
PR
CR
PD
SD
SD
Non-CR
Not evaluated
PD
PD
Non-CR
Not evaluated
PR
PR
Non-CR
Not evaluated
SD
SD
1 If no index nodal lesions are present at Screening, then index lesions response is equal to the index extranodal 
lesions response. A similar rule applied if no index extranodal lesions are present at Screening, then index lesions 
response is equal to the index nodal lesions response.
In case of missing measurements of any of the index lesions, the radiological response for 
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”.
4.1.4 Evaluation of non-index lesions (including nodal, splenic and/or hepatic 
nodules and other extranodal lesions)
At each reassessment, a non-index lesion (or a group of non-index lesions) will be given one 
of the following designations:

Normalization (non-index nodal lesion has regressed to normal size; non-index extranodal 
lesion is no longer present). Normalization of non-index nodal lesions should be 
determined based on their size at Screening.


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
Improved, stable or worsened, but without unequivocal evidence of disease progression 
(non-index lesion is present but there is not sufficient worsening to declare PD based on 
the existing non-index lesions).

Unequivocal evidence of disease progression (worsening of existing non-index lesions is 
sufficient to declare PD)

Not assessed
Then, this status for each non-index lesion (or group of non-index lesions) will lead to a 
global response for non-index lesions (Table 4-5):
Table 4-5
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions)
Response Criteria
Evaluation of non-index lesions
Complete Response (CR)
Complete normalization of all non-index nodal and extranodal lesions: 
Radiological regression to normal size of all lymph nodes and complete 
disappearance of all extranodal (including splenic and/or hepatic nodules) 
lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR and failure to fulfill the criteria for PD
Progressive Disease (PD)
Unequivocal disease progression of any existing non-index lesions (nodal or 
extranodal)
In case of a missing status of any of the non-index lesions, the radiological response for non-
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for non-index lesions at that assessment will be 
“Unknown (UNK)”.
4.1.5 New lesions
The appearance of

any new nodal lesion >15 mm in any axis. New nodal lesion is defined by:

either a previously normal lymph node becoming > 15 mm in any axis,

or a previously identified abnormal lymph node showing an increase of at least 50% 
in the long axis,

as assessed by investigator
OR

any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after Screening
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in 
the appropriate module of the eCRF. Determination of new lymphoma involvement in organs 
other than lymph nodes or liver or spleen should be confirmed histologically and the site must 
document that in a comment to the corresponding eCRF.
4.1.6 Overall radiological response
Overall radiological response is calculated as shown in Table 4-6.


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Table 4-6 Overall radiological response at each assessment
Index lesions
Non-index lesions1
New lesions
Overall radiological response
CR
CR
No
CR
CR
SD
No
PR
PR
CR or SD
No
PR
SD
CR or SD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1If no non-index lesions are present at Screening, then this column is not used in evaluating overall radiological 
response.
If the evaluation of any of the index or non-index lesions identified at Screening could not be 
made during follow-up or if the index or non-index response is “Unknown (UNK)”, the 
overall response status at that assessment must be “Unknown (UNK)” unless progression or a 
new lesion was seen.
4.1.7 Evaluation of overall disease response
The evaluation of overall disease response at each assessment is a composite of the individual 
radiological responses (index and non-index lesions, new lesions), laboratory test (bone 
marrow) and clinical responses (lymphoma related clinical symptoms).
4.1.8 Bone marrow re-assessment at time of radiological CR
In order to confirm a Complete disease response (CR), bone marrow biopsy or aspirate may 
be required when a radiological CR has been achieved. Details are provided in the Study 
Protocol. The infiltrate of lymphoma in bone marrow must have cleared on repeat bone 
marrow biopsy or aspirate. Patients who achieve a CR by other criteria but who have 
persistent morphologic positive or inconclusive bone marrow involvement will be considered 
partial responders. New or recurrent bone marrow involvement anytime during the follow up 
will be considered PD. Bone marrow biopsy or aspirate will be performed after the first
assessment of CR or when clinically indicated.
The biopsy sample of bone marrow must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by immunohistochemistry.
4.1.9 Overall disease response
If a patient has an overall radiological response of CR then this response must be confirmed 
by bone marrow biopsy or aspirate, presence of normal liver and spleen size, and evaluation 
of lymphoma related B-symptoms. The patient’s overall response will be calculated as 
follows:
A patient will be deemed to have overall disease response of CR if bone marrow biopsy or 
aspirate becomes negative for tumor involvement (if the bone marrow was involved by 
lymphoma at Screening) and the liver and spleen are normal in size and there are no 
lymphoma related B-symptoms in addition to radiological CR.


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If assessments of any of the following: lymphomatous infiltration of bone marrow, or 
evaluation of B-symptoms is not done, unknown or indeterminate or B-symptoms are still 
present when the overall radiological response is assessed as CR or the liver or spleen are 
enlarged, then the overall disease response will be assessed as PR until evaluation of these 
factors have shown normalized results and recorded on the corresponding eCRF.
For patients whose radiological response is anything other than CR, assessment of bone 
marrow, liver, spleen and B-symptoms will not be required in evaluating overall response and 
overall disease response is the same as radiological response. However any new or recurrent 
bone marrow involvement at any time during follow-up will be considered PD.
Of note, appearance of B-symptoms or enlarged spleen or liver will not in themselves 
constitute documentation of progression. They are however expected to be associated with 
progressive disease. Every effort should be made to document that evidence radiologically 
and report the corresponding tumor assessments. Such tumor assessments are expected to be 
performed within 2 months of appearance of B-symptoms or enlarged spleen or liver.


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5 References (available upon request)
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854.
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743.
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an International Workshop to 
standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253.
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586.
FDA Guideline (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.


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Appendix D: Ann Arbor staging classification
Stage Area of involvement
I
Single lymph node group
II
Multiple lymph node groups on the same side of the diaphragm
III
Multiple lymph node groups on both sides of the diaphragm
IV
Multiple extranodal sites or lymph nodes and extranodal disease
X
Bulk disease > 10 cm
E
Extranodal extension or single isolated site of extranodal disease
Class A are patients who experience no B symptoms
Class B are patients experience unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained 
loss of >10% body weight within the previous 6 months
Cotswolds modification of Ann Arbor staging system adapted from 2007 NCCI guidelines for non-Hodgkin’s lymphoma


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Appendix E: Rai Staging Systema
Stage Area of involvement
Risk Status
0 Lymphocytosis, lymphocytes in blood >15 x 109/L and >40% lymphocytes in bone marrow
I Stage 0 with enlarged node(s)
IIStage 0-1 with splenomegaly, hepatomegaly, or both
IIIb Stage 0-II with hemoglobin < 11.0 g/dL or hematocrit <33%
IVb Stage 0-III with platelets <100 x 109/L
Low
Intermediate
Intermediate
High
High
a Research originally published in Blood. Rai KR,et al. Clinical staging of chronic lymphocytic leukemia. Blood 
1975;46(2):219-234. (c) The American Society of Hematology
b Immune-mediated cytopenias are not the basis for these stage definitions.


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Appendix F: Criteria for Response assessment in Acute Myeloid 
Leukemia (based on IWG and Cheson)
Disease assessments will be based on standardized response criteria as defined by the 
International Working Group (IWG) for AML (Cheson, et al 2003).
Response classification in AML at a given evaluation time (Cheson 2003)
Response category
Definition#
Complete remission 
(CR)
Bone marrow
< 5% blasts
no blasts with Auer rods
Peripheral blood
neutrophils ≥ 1.0 x 109/L
platelets ≥ 100 x 109/L
≤ 1% blasts
No evidence of extramedullary disease (such as CNS or soft tissue involvement).
Transfusion independent (see Section 7.2.1.4.5).
In case all criteria for CR apply and the patient receives platelet and/or neutrophil 
transfusions, the patient will be assessed as CRi.
Complete remission 
with incomplete blood 
count recovery (CRi)
Bone marrow
< 5% blasts
no blasts with Auer rods
Peripheral blood
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L
≤ 1% blasts
No evidence of extramedullary disease (such as CNS or soft tissue involvement).
Transfusion-independent (see Section 7.2.1.4.5). Exception: Platelet and neutrophil 
transfusions are allowed.
Partial Remission 
(PR)
Bone marrow
50% or greater decrease (absolute range 5-25% blasts)
< 5% of blasts contain Auer rods
Peripheral blood
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L
No evidence of extramedullary disease (such as CNS or soft tissue involvement).
Treatment failure
Treatment failure includes those patients for whom treatment has failed to achieve PR, 
CRi or CR throughout the treatment. 
Relapse from CR or 
CRi*
Only in patients with a CR or CRi:
Reappearance of blasts in peripheral blood (> 1%) OR
≥ 5% blasts in bone marrow OR
(Re-)appearance of extramedullary disease
No response
In case a patient does not achieve CR, CRi, PR or relapse for an individual response 
assessment.
Unknown
In case the response assessment was not done, the baseline assessment was not done, 
the assessment was incomplete or was not done within the respective time frame.
# If not defined otherwise, all of the criteria apply.
*Cheson et al (2003) does not specify relapse after PR.


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Appendix H: Criteria for Response assessment in Acute Lymphoblastic 
Leukemia (based on NCCN Guidelines Version 1.2013)
Response classification in ALL for Blood and Bone Marrow at a given evaluation time
Response category
Definition#
Complete remission (CR)
No circulating blasts or extramedullary disease (such as lymphadenopathy, 
splenomegaly, skin/gum infiltration, testicular mass, CNS or soft tissue 
involvement)
Trilineage hematopoiesis (TLH) and < 5% blasts
neutrophils ≥ 1.0 x 109/L
platelets ≥ 100 x 109/L
No recurrence for 4 weeks
Complete remission with 
incomplete blood count recovery 
(CRi)
Peripheral blood
Recovery of platelets but < 100 x 109/L or neutrophils is < 1.0 x 109/L.
Progressive Disease (PD)
Increase of at least 25% in the absolute number of circulating or bone marrow 
blasts or development of extramedullary disease.
Treatment failure
Treatment failure includes those patients for whom treatment has failed to 
achieve a CR at the end of treatment
Relapse from CR or CRi
Only in patients with a CR or CRi:
Reappearance of blasts in peripheral blood (> 1%) OR
≥ 5% blasts in bone marrow OR
(Re-)appearance of extramedullary disease
No response
In case a patient does not achieve CR, CRi, PR or relapse for an individual 
response assessment.
Unknown
In case the response assessment was not done, the baseline assessment was 
not done, the assessment was incomplete or was not done within the 
respective time frame.
#If not defined otherwise, all of the criteria apply.


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Appendix I: Criteria for Response assessment in Chronic Myelogenous 
Leukemia (based on NCCN Guidelines Version 4. 2013)
Response classification in CML for hematologic, cytogenetic, and molecular evaluation at a given 
evaluation time
Response category
Definition#
Complete hematologic response 
(CR)1
Complete normalization of peripheral blood counts with leukocyte count < 10 x 
109/L
platelets < 450 x 109/L
No immature cells such as myelocytes, promyelocytes, or blasts in peripheral 
blood
No signs and symptoms of disease with disappearance of splenomegaly
Cytogenetic response2,3
Complete
No Ph-positive metaphases
Partial
1% - 35% Ph-positive metaphases
Major
0% - 35% Ph-positive metaphases (complete + partial)
Minor
> 35% Ph-positive metaphases
Molecular response4,5
Complete
No detectable BCR-ABL mRNA by QPCR using an assay with a sensitivity of 
at least 4.5 logs below standardized baseline.
Major
≥ 3 log reduction in international scale of BCR-ABL mRNA
Treatment failure
Treatment failure includes those patients for whom treatment has failed to 
achieve a complete hematologic response (CR) throughout treatment.
No response
In case a patient does not achieve CR, PR or relapse for an individual 
response assessment.
Unknown
In case the response assessment was not done, the baseline assessment was 
not done, the assessment was incomplete or was not done within the 
respective time frame
# If not defined otherwise, all of the criteria apply.
1.
Federl S et al: Chronic myelogenous leukemia: Biology and therapy. Ann Intem Med 1999; 131:207-219.
2.
A minimum of 20 metaphases should be examined.
3.
O’Brien SG, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-
phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
4.
Hughes TP, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in 
newly diagnoses chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432
5.
Hughes T, et al: Monitoring CML patients responding to treatment with tyrosine kinase inhibitors; review and 
recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase 
domain mutations and for expressing results. Blood 2006;108:28-37 


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Appendix J: Criteria for Response assessment in Chronic Lymphocytic 
Leukemia (based on modified IWG guidelines)
Disease assessments will be based on standardized response criteria as defined by the 
modified IWG guidelines for CLL. Response in CLL must meet the criteria in both Group A 
and Group B. Group A criteria defines tumor load. Group B criteria define the function of the 
hematopoietic system (or marrow).
Response Definition for Chronic Lymphocytic Leukemia1
Group A Response for Tumor Burden
Response 
Nodal Masses
Organomegaly
Bone Marrow
CR
None > 1.5 cm
No splenomegaly
No hepatomegally
Normocellular >30% Lymph. No B 
lymphoid nodules
CRi
None > 1.5 cm
No splenomegaly
No hepatomegally
Hypocellular marrow
PR
Decrease ≥50%
Spleen/Liver decrease ≥50
50% reduction in marrow infiltrate, or 
B-lymphoid nodules
Group B Response for hepatopoietic system2
Response 
Platelet count 
Hemoglobin
Neutrophils
CR
>100 x 109/L
>11 g/dL
>1.5 x 109/L
CRi
If meets criteria from Group A but does not meet criteria from Group B
PR
>100 x 109/or increase 
≥50% over baseline
>11 g/dL or increase ≥50% 
over baseline
>1.5 x 109/L or >50% improvement 
over baseline
SD
Failure to attain CR/CRi/PR or PD 
Relapsed 
disease or 
PD
Appearance of any new lesions; at least one of the above criteria. Isolated progressive 
lymphocytosis in the setting of reduced lymph node size or organomegaly or improvement in 
hemoglobin/platelets will not be considered progressive disease
1 Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia updating the National 
Cancer Institute-Working Group 1996 Guidelines. Blood 2008; 111:5446-5456
2 All values are without transfusion or hepatopoietic growth factors


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Appendix K: Eastern Cooperative Oncology Group (ECOG) Performance 
status
Score
Performance 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 housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead


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Appendix L: International Myeloma Working Group (IMWG) uniform 
response criteria for multiple myeloma1
Response
IMWG Criteria
sCR
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow2 by 
immunohistochemistry or immunofluorescence3
CR
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow2
VGPR
Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥ 
90% reduction in serum M-component plus urine M-component < 100 mg per 24 hr
PR
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to 
< 200 mg/24 h
If the serum and urine M-protein are unmeasurable,4 a > 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30%
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of 
soft tissue plasmacytomas is also required
SD
Not meeting criteria for CR, VGPR, PR, or progressive disease
PD5
Increase of > 25% from lowest response value in any one or more of the following:
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)5
Urine M-component and/or (the absolute increase must be > 200 mg/24 h)
Only in patients without measurable serum and urine M-protein levels; the difference between 
involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL
Bone marrow plasma cell percentage; the absolute percentage must be > 10%6
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that 
can be attributed solely to the plasma cell proliferative disorder
Relapse
Clinical relapse requires one or more of:
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features).5 It is not 
used in calculation of time to progression or progression-free survival but is listed here as 
something that can be reported optionally or for use in clinical practice
Development of new soft tissue plasmacytomas or bone lesions
Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is 
defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products 
of the cross-diameters of the measurable lesion
Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L]
Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L]
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more]


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Response
IMWG Criteria
1.
BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1-7.
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 
2008;23:3-9
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria 
listed above. VGPR in such patients is defined as a >90% decrease in the difference between involved and 
uninvolved free light chain (FLC) levels.
2.
Confirmation with repeat bone marrow biopsy not needed.
3.
Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2.
4.
All relapse categories require two consecutive assessments made at any time before classification as relapse 
or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also 
meet the criteria for progressive disease shown here to be classified as progressive disease for the purposes 
of calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse 
and relapse from CR are not to be used in calculation of time to progression or progression-free survival.
5.
For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting 
M-component is >5 g/dL.
6.
Relapse from CR has the 5% cut-off versus 10% for other categories of relapse.
For purposes of calculating time to progression and progression-free survival, CR patients should also be 
evaluated using criteria listed above for progressive disease.


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Appendix M: Criteria for Response assessment in Myelofibrosis (based 
on modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1
Response category
Definition
CR
Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 X 109/L and 
<UNL;
Platelet count ≥100 X 109/L and <UNL; <2% immature myeloid cells‡ and
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH
PR
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 X 109/L and 
<UNL; platelet count ≥100 X 109/L and <UNL; <2% immature myeloid cells‡ and
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH or
Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, and 
peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 X 
109/L and <UNL; platelet count ≥50, but <100 X 109/L and <UNL; <2% immature 
myeloid cells‡ and
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH
Clinical improvement (CI)
The achievement of anemia, spleen or symptoms response without progressive 
disease or increase in severity of anemia, thrombocytopenia, or neutropenia§
Anemia response
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level||
Transfusion-dependent patients: becoming transfusion-independent^
Spleen response#
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable** or
A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by 
≥50%**
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for 
spleen response
A spleen response requires confirmation by MRI or computed tomography showing 
≥35% spleen volume reduction
Symptoms response
A ≥50% reduction in the MPN-SAF TSS††
Progressive disease
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or
A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-
10 cm or
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 
cm or
Leukemic transformation confirmed by a bone marrow blast count of ≥20% or
A peripheral blood blast content of ≥20% associated with an absolute blast count of 
≥1 X 10(9)/L that lasts for at least 2 weeks
Stable disease
Belonging to none of the above listed response categories
Relapse
No longer meeting criteria for at least CI after achieving CR, PR, or CI, or
Loss of anemia response persisting for at least 1 month or
Loss of spleen response persisting for at least 1 month
Recommendations for assessing treatment-induced cytogenetic and molecular changes


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Response category
Definition
Cytogenetic remission
At least 10 metaphases must be analyzed for cytogenetic response evaluation and
requires confirmation by repeat testing within 6 months window
CR: eradication of a preexisting abnormality
PR: ≥50% reduction in abnormal metaphases
(partial response applies only to patients with at least ten abnormal metaphases at 
baseline)
Molecular remission
Molecular response evaluation must be analyzed in peripheral blood granulocytes 
and
requires confirmation by repeat testing within 6 months window
CR: Eradication of a pre-existing abnormality
PR: ≥50% decrease in allele burden
(partial response applies only to patients with at least 20% mutant allele burden at 
baseline)
Cytogenetic/molecular 
relapse
Re-emergence of a pre-existing cytogenetic or molecular abnormality that is 
confirmed by repeat testing
1Tefferi et al. (2013) Revised response criteria for myelofibrosis: International Working (IWG-MRT) and European 
LeukemiaNet (ELN) consensus report Group-Myeloproliferative Neoplasms Research and Treatment. Blood; 
2013 122: 1395-1398
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-
proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit.
†Grading of MF is according to the European classification
Thiele et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 
2005;90:1128.
It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients in which 
all other criteria are met, including resolution of leukoerythroblastosis. It should also be noted that it was a 
particularly difficult task for the working group to reach a consensus regarding what represents a complete 
histologic remission.
‡Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells. In splenectomized patients, <5% immature myeloid cells is allowed.
§See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level from 
pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is 
defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according 
to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to CI 
requires a minimum platelet count of ≥25 000 X 10(9)/L and absolute neutrophil count of ≥0.5 X 109/L.
||Applicable only to patients with baseline hemoglobin of<100 g/L. In patients not meeting the strict criteria for 
transfusion dependency at the time of study enrollment (see as follows), but have received transfusions within the 
previous month, the pre-transfusion hemoglobin level should be used as the baseline.
^Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red 
blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence of 
bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 
28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of any PRBC 
transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a 
hemoglobin level of ≥85 g/L.


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Response category
Definition
#In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.
**Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume, as 
assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen or liver, by MRI or CT, 
constitutes a response regardless of what is reported with physical examination.
††Symptoms are evaluated by the MPN-SAF TSS.1 The MPN-SAF TSS is assessed by the patients themselves 
and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal 
discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as 
bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). 
Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
‡‡Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline. Baseline values for both physical examination and 
imaging studies refer to pretreatment baseline and not to post-treatment measurements.
Symptoms are evaluated by the MPN-SAF TSS.1 The MPN-SAF TSS is assessed by the patients themselves and 
this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal 
discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as 
bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). 
Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline. Baseline values for both physical examination and 
imaging studies refer to pretreatment baseline and not to post-treatment measurements.


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Appendix N: Criteria for Response assessment in polycythemia vera 
(based on modified IWG-MRT guidelines and European LeukemiaNet 
(ELN) consensus report)1
Response categories
Required criteria
Complete remission
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement† AND
Durable peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, AND
Without progressive disease, and absence of any hemorrhagic or thrombotic event, 
AND
Bone marrow histological remission defined as the presence of age-adjusted 
normocellularity and disappearance of tri-linear hyperplasia, and absence of >grade 1 
reticulin fibrosis
Partial remission
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement† AND
Durable peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, AND
Without progressive disease, and absence of any hemorrhagic or thrombotic event, 
AND
Without bone marrow histological remission defined as persistence of tri-linear 
hyperplasia.
No response
Any response that does not satisfy partial remission
Progressive disease
Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute 
leukemia‡
Molecular response is not required for assignment as complete response or partial response. Molecular response 
evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a 
preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at 
baseline. Partial response is defined as ≥ 50% decrease in allele burden.
WBC, white blood cell.
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.2
‡For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria3; for the diagnosis of myelodysplastic 
syndrome and acute leukemia, see WHO criteria.
1.
Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and 
IWG-MRT consensus project. Blood 2013 121: 4778-4781
2.
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total 
symptom score: prospective international assessment of an abbreviated symptom burden scoring system 
among patients with MPNs [published correction appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 
2012;30(33):4098-4103
3.
Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and postessential 
thrombocythemia myelofibrosis: a consensus statement from the International Working Group for 
Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437-438


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Appendix O: Criteria for Response assessment in Essential 
thrombocythemia (based on modified IWG-MRT guidelines and European 
LeukemiaNet (ELN) consensus report)1
Response category
Definition
Complete remission
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement,† AND
Durable peripheral blood count remission, defined as: platelet count ≤400 X 109/L, 
WBC count <10 X 109/L, absence of leukoerythroblastosis, AND
Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND
Bone marrow histological remission defined as disappearance of megakaryocyte 
hyperplasia and absence of >grade 1 reticulin fibrosis.
Partial remission
Durable resolution of disease-related signs including palpable hepatosplenomegaly, 
and large symptoms improvement, AND
Durable peripheral blood count remission, defined as: platelet count ≤400 X 109/L, 
WBC count <10 X 109/L, absence of leukoerythroblastosis, AND
Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND
Without bone marrow histological remission, defined as the persistence of 
megakaryocyte hyperplasia.
No response
Any response that does not satisfy partial remission
Progressive disease
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute 
leukemia‡
Molecular response is not required for assignment as complete response or partial response. Molecular response 
evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a 
preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at 
baseline. Partial response is defined as ≥50% decrease in allele burden.
WBC, white blood cell.
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.3
‡For the diagnosis of PV see World Health Organization criteria (WHO)4; for the diagnosis of post-ET 
myelofibrosis, see the IWG-MRT criteria2; for the diagnosis of myelodysplastic syndrome and acute leukemia, see 
WHO criteria.4
1.
Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and 
IWG-MRT consensus project. Blood 2013 121: 4778-4781
2.
Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and postessential 
thrombocythemia myelofibrosis: a consensus statement from the International Working Group for 
Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437-438.
3.
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total 
symptom score: prospective international assessment of an abbreviated symptom burden scoring system 
among patients with MPNs [published correction appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 
2012;30(33):4098-4103.
4.
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues. Lyon, France: IARC; 2008.


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Appendix P: Criteria for Response assessment in Myelodysplasia (based 
on modified IWG guidelines)1
Category
Response Criteria
Complete remission
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines*
Persistent dysplasia will be noted*
Peripheral blood
Hgb ≥ 11 g/dL
Platelets ≥ 100 x 109/L
Neutrophils ≥ 1.0 x 109/L
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by  ≥ 50% over pretreatment but still > 5%
Cellularity and morphology not relevant
Marrow CR
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment
Peripheral blood: if HI responses, they will be noted in addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression for > 8 wks
Failure
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a 
more advanced MDS FAB subtype than pretreatment
Relapse after CR or PR
At least 1 of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence
Cytogenetic response 
Complete - Disappearance of the chromosomal abnormality without appearance 
of new ones
Partial - At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts
5%-10% blasts: ≥ 50% increase to > 10% blasts
10%-20% blasts: ≥ 50% increase to > 20% blasts
20%-30% blasts: ≥ 50% increase to > 30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or 
platelets
Reduction in Hgb by > 2 g/dL
Transfusion dependence
*Dysplastic changes should consider the normal range of dysplastic changes (modification).
1Cheson, et al. (2005) Clinical application and proposal for modification of the InternationalWorking Group (IWG) 
response criteria in myelodysplasia. blood-2005-10-4149.


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Appendix Q: Myeloproliferative Neoplasm (MPN) Symptom Assessment 
Form Total Symptom Score (MPN-SAF TSS)
Adapted from Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) 
symptom assessment form total symptom score: prospective international assessment of an 
abbreviated symptom burden scoring system among patients with MPNs [published correction 
appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103


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Appendix R: Bayesian Adaptive Design Framework for the Modular 
Phase II Study to Link Targeted Therapy to Patients with Pathway 
Activated Tumors.
1 Introduction
This document outlines the adaptive design framework to be used for all trials within 
Novartis’s Modular Phase II study to link targeted therapy to patients  with pathway activated 
tumors.
Although the selected tumor types may vary by trial, this document outlines the design and 
analysis approach based on 8 example tumor cohorts:

Lung NSC

Bladder

Breast

Colorectal

GIST

HNSCC

Ovarian

Sarcoma
Other tumor types may be considered for trials if 1) 4 or more patients are enrolled in the 
cohort, and 2) a reasonable estimate of the clinical benefit rate is available.
The primary endpoint is clinical benefit rate (CBR) in each cohort, with  clinical benefit being 
assessed at 16 weeks. All patients will receive the experimental treatment for that particular 
trial.
1.1Primary Analysis
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
 = log 

1 −
 −log 

1 −
.
Thus, θg is the group specific logistic regression coefficient for the treatment within group g. 
The primary analysis is a set of group specific tests that θg>0, meaning that the treatment is 
better than the assumed control rate for that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0
H1g : θg>0


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We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,
Pr(θg>0 | data) > 0.80
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below.
1.2Trial Logistics
The trial will enroll all available subjects in all cohorts for 2 years unless a cohort cap is 
reached or a cohort is stopped early, or the trial is stopped early by Novartis. The trial will 
enroll no more than 30 evaluable subjects in each cohort. Interim monitoring will be 
conducted starting after the first 30 patients are enrolled overall (across all cohorts), and 
continuing each 13 weeks thereafter till study enrollment closure. After that, one CBR 
analysis will be done at the end of the study. At each interim data review, response 
information for the various groups will be evaluated to determine the current Pr(θg>0 | data) 
within each cohort, with sufficiently high/low values used to stop the cohort for 
success/futility. A minimum of 10 patients will be required in a cohort before it may 
discontinue enrollment for futility, and a minimum of 15 patients are required before 
discontinuing a cohort for efficacy. If a cohort stops enrolling early, the remaining cohorts 
will continue until the end of 2 years or until the other groups reach their own early stopping 
criteria. The final analysis will occur after the analysis of the analysis of the study data for the 
primary CSR.
The trial will enroll subjects in all listed cohorts. In addition, should other cohorts be 
identified throughout the trial, the following mechanism will be used. If another cohort is 
identified, it will not be placed into the statistical analysis unless 3 subjects enroll within the 
cohort (thus, the trial may enroll multiple possible cohorts within the “other” category, but a 
cohort will only be added to the list if at least 3 patients enroll from that cohort). Thus, it is 
possible (but not viewed as likely) that multiple additional cohorts may be added to the trial if 
the trial has sufficient enrollment in multiple additional cohorts. In addition to sufficient 
enrollment, the sponsor must have a reasonable estimate of the control clinical benefit rate.
Subjects within any cohort which does not reach the minimum 3 subject enrollment will be 
excluded from the interim and final analyses. As the study continues, early interim data 
reviews may be based on fewer cohorts than later interim data reviews, as the interim data 
reviews will include whatever cohorts have satisfied the criteria at the time of the data review.
2 Statistical Modeling
We let Yi be the response indicator for the ith subject, and let Rg be the probability of response 
within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability of 
response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
 = log 

1 −
 −log 

1 −
.


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The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ.  In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR.
The purpose of such an analysis (discussed in more detail in Section 5) is to produce higher 
power or lower type I error in situations where we see some commonality (identical effects 
are not required) among the groups. The model will borrow more in situations where the 
groups appear similar than situations where the groups appear different.
2.1Hierarchical Model with Clustering
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in the appendix.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the  have an across groups distribution
θg ~ N(μ, τ2)
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups.  Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 


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The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 
different results with borrow far less information between them (they will have a low 
probability of being in the same cluster).
Details of the two stages may be found in Section 5.
3 Evaluation of Trial Success and Futility
Interim monitoring will occur after the first 30 patients are on study for 16 weeks, then every 
13 weeks thereafter till study enrollment closure. At each interim data review, the groups will 
be evaluated for early futility and early success by comparing posterior quantities for the 
response rate to pre-specified early stopping criteria.
3.1Early Futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility.  Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.10.
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group.
3.2Early Success
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success.  Formally, enrollment will stop early for 
success if:
Pr(πg > Rg) > 0.95.
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious.
3.3Final Analysis
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups. If, at the completion of the trial, there is at least 80% probability that the 
response rate in a group exceeds the historical rate, then the group will be considered a 
success. Formally:
Pr(πg > Rg) > 0.80.


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4 Simulation
We evaluated type I error and power for each of the 8 possible groups under a variety of 
possible “truths” indicating various possible true underlying probabilities within each group. 
4.1Assumptions
Accrual – Two scenarios for the assumed two-year expected accrual are investigated: 1) 10 
subjects per group and 2) 5 subjects per group. Note that these are averages, the actual number 
of available patients is simulated as a Poisson distribution with the specified mean. Also note 
that the group cap of 30 applies, and thus if the number of available patients in a group 
exceeds 30, only the first 30 available patients in that group will be enrolled in the study. 
Dropouts – We assume no dropouts for the purpose of this simulation.
Control Rates – Table 4.1.1 shows the assumed control clinical benefit rates for each group.
Table 4.1.1 Assumed control rates
Tumor Type
Assumed Control Rate (Rg)
Lung NSC
0.45
Bladder
0.47
Breast
0.50
Colorectal
0.38
GIST
0.50
HNSCC
0.45
Ovarian
0.47
Sarcoma
0.40
Table 4.1.1 – Assumed control CBR values used in the simulations.
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups.
Treatment Rates - The treatment rates for each scenario are shown in the Table 4.1.2. Values 
identical to the control are shown in bold, while values greater than the assumed control rate 
are italicized.
Table 4.1.2 Treatment rates
Null
Alternative
Two
Half
Lung NSC
0.45
0.71
0.45
0.45
Bladder
0.47
0.73
0.47
0.47
Breast
0.50
0.75
0.50
0.50
Colorectal
0.38
0.65
0.38
0.38
GIST
0.50
0.75
0.50
0.75
HNSCC
0.45
0.71
0.45
0.71
Ovarian
0.47
0.73
0.73
0.73
Sarcoma
0.40
0.67
0.67
0.67


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Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin.
4.2Results
A total of 8 scenarios were simulated (two accrual scenarios and four possible ‘truths’ for the 
clinical benefit rate). The probability of group success for each group is provided for each 
scenarios in the tables below.
Table 4.2.1 Probability of group success for each cohort assuming expected 
accrual of 10 subjects/cohort
Two-year expected accrual: 10 subjects/cohort
Group(Exp N)
Null
Alternative
Two
Half
Lung NSC
0.158
0.915
0.208
0.305
Bladder
0.131
0.918
0.232
0.322
Breast 
0.147
0.909
0.233
0.312
Colorectal 
0.138
0.921
0.200
0.276
GIST
0.162
0.921
0.233
0.826
HNSCC
0.139
0.906
0.217
0.834
Ovarian
0.145
0.929
0.786
0.829
Sarcoma
0.135
0.939
0.758
0.852
Table 4.2.2 Probability of group success for each cohort assuming expected 
accrual of 5 subjects /cohort
Two-year expected accrual: 5 subjects/cohort
Group
Null
Alternative
Two
Half
Lung NSC
0.132
0.803
0.204
0.258
Bladder
0.140
0.830
0.196
0.265
Breast 
0.160
0.807
0.232
0.261
Colorectal 
0.135
0.794
0.194
0.278
GIST
0.155
0.826
0.212
0.688
HNSCC
0.140
0.820
0.190
0.657
Ovarian
0.151
0.819
0.587
0.652
Sarcoma
0.139
0.799
0.579
0.667
Entries in bold represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in bold are type I errors. Italicized entries appear where the 
treatment is effective, and thus indicate the power of the design.
Generally, type I error is controlled at 0.20 under the null scenario (the borrowing 
compensates for the multiple interim data reviews) and power is an increasing function of the 
expected sample size (power is higher in the higher  accrual situation across treatment rate 
scenarios).  In the alternative scenario there remains decently high probability of success even 
in the lower enrolling groups. When fewer groups are effective in truth, the scenarios “half” 
and “two” are harder to discern. Note in any particular trial there should be a mix of high and 
low enrolling cohorts, thus some cohorts may enroll closer to 10 subjects while other may 
only enroll five. This would produce a power value somewhere between the two tables.


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Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the cohorts. Generally power is a function of the sample 
size.
5 Modeling Details
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model.
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 
clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 
clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering.
The details of the prior are as follows. Let zg represent the cluster to which group g belongs.  
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and ∑



= 1. We construct p using a stick-breaking process:
 =  (1 −)


and
βk ~ Beta(1, α).
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster. 
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution 
θg ~ N(μ, τ2)


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As discussed above, this across groups distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions
μ ~ N(0, 1.82)
and
τ2 ~ IG(3,0.5),
where IG(α, β) is the inverse gamma distribution defined by:
(| , ) = "#$ %
⁄
"'Γ( ).
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the 
model.

SAP_000.pdf: 
Clinical Development
Ribociclib (LEE011)
Protocol CLEE011XUS03 / NCT02187783
Modular phase II study to link targeted therapy to patients with pathway 
activated tumors:
Module 8 – Ribociclib for patients with CDK4/6 pathway activated tumors
RAP Module 3 – Detailed Statistical Methodology
Author:
Document type:
RAP Documentation
Document status:
Final v2.0
Release date:
27-Sep-2015
Number of pages:
32
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes


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Table of Contents
1
Introduction .........................................................................................................................5
2
Statistical and analytical plans.............................................................................................5
2.1
Study design.............................................................................................................5
2.2
General overview of statistical methodology ..........................................................6
2.3
Change in planned analyses from the protocol........................................................7
7
2.5
Definitions ...............................................................................................................7
2.5.1
Study drug...............................................................................................7
2.5.2
Date of first administration of study drug...............................................7
2.5.3
Date of last administration of study drug................................................7
2.5.4
Study day.................................................................................................8
2.5.5
Baseline...................................................................................................8
2.5.6
On treatment assessment.........................................................................8
2.5.7
Last contact date......................................................................................8
2.5.8
Year, month and week.............................................................................9
3
Patients and treatments........................................................................................................9
3.1
Analysis sets ............................................................................................................9
3.2
Protocol deviations ..................................................................................................9
3.3
Patient disposition....................................................................................................9
3.4
Patient background, demographics and baseline characteristics ...........................10
3.5
Study Treatment and concomitant medications.....................................................11
3.5.1
Study treatment .....................................................................................11
3.5.2
Concomitant medications/non-drug therapies.......................................13
4
Efficacy evaluation............................................................................................................13
4.1
Clinical Benefit Rate (CBR)..................................................................................13
4.2
Overall Response Rate (ORR)...............................................................................14
4.3
Duration of response..............................................................................................14
4.4
Progression Free Survival (PFS) ...........................................................................15
4.5
Overall Survival (OS)............................................................................................15
4.6
Clinical Benefit Rate by Gene Mutations..............................................................16
5
Safety evaluation ...............................................................................................................16
5.1
Adverse events.......................................................................................................16
5.1.1
Coding of AEs.......................................................................................16
5.1.2
Grading of AEs .....................................................................................16
5.1.3
General rules for AE reporting..............................................................16


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5.1.4
AE summaries .......................................................................................17
5.1.5
AEs of special interest...........................................................................18
5.2
Deaths ....................................................................................................................18
5.3
Laboratory evaluations ..........................................................................................19
5.4
Vital signs..............................................................................................................20
5.5
ECG .......................................................................................................................20
5.6
Other safety evaluations ........................................................................................21
6
Interim analyses.................................................................................................................21
7
Determination of sample size............................................................................................21
8
Bayesian Adaptive Design ................................................................................................23
8.1
Introduction............................................................................................................23
8.1.1
Primary Analysis...................................................................................23
8.1.2
Trial Logistics .......................................................................................24
8.2
Statistical Modeling...............................................................................................24
8.2.1
Hierarchical Model with Clustering......................................................25
8.3
Evaluation of Trial Success and Futility................................................................26
8.3.1
Early Futility .........................................................................................26
8.3.2
Early Success ........................................................................................26
8.3.3
Final Analysis........................................................................................26
8.4
Simulation..............................................................................................................26
8.4.1
Assumptions..........................................................................................27
8.4.2
Results...................................................................................................28
8.5
Modeling Details ...................................................................................................30
9
References .........................................................................................................................32


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1
Introduction
The primary efficacy variable, clinical benefit rate, will be analyzed by a Novartis designated 
Contract Research Organization (CRO), 
. Analysis details are provided in 
Appendix R of the protocol, which is also included in Section 8 of this Report Analysis Plan
(RAP). 
 
All other data will be analyzed by a different Novartis-designated CRO, 
 
according to Section 10 of the study protocol which will be available in 
Appendix 16.1.1 of the Clinical Study Report (CSR). Important information is given in the 
following sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR.
All statistical analyses will be performed using SAS® Version 9.3 (or higher).  
2
Statistical and analytical plans
2.1
Study design
This is a phase II, open label study to determine the efficacy and safety of treatment with 
ribociclib (LEE011) in patients with solid tumors or hematological malignancies that have 
been pre-identified as having CDK4/6, cyclin D1/3, or p16 aberrations and whose disease has 
progressed on or after standard treatment. Pre-identification of the relevant gene mutation or 
amplification status will be performed locally at a Clinical Laboratory Improvement 
Amendments (CLIA) certified laboratory prior to participation on the trial.  
To be eligible for enrollment to this study, patients must have archival tissue available for 
submission to allow for molecular testing related to pathway activation. If tissue is not 
available or is insufficient the patient must be willing to undergo a fresh tumor biopsy to 
allow for these analyses. Mutation types from both local and central laboratories will be 
analyzed.
Patients must have received at least one prior treatment for their recurrent, metastatic and/or 
locally advanced disease and have no remaining standard therapy options anticipated to result 
in a durable response. Patients received ribociclib on a flat scale of 600 mg once daily, 3 
weeks on and 1 week off. A complete treatment cycle is defined as 28 days. Patients may 
continue on study treatment until disease progression, withdrawal of consent, unacceptable
toxicity, death, or any other reasons (e.g., physician’s decision). The patient may not receive 
any additional anti-cancer therapy during treatment with ribociclib. After discontinuation of 
study treatment, patients, regardless of reason for study treatment discontinuation, will be 
followed for safety for 30 days after the last dose. Survival information will be collected every 
3 months until 2 years after the last patient has enrolled in the study regardless of treatment 
discontinuation reason (except if consent is withdrawn). If the study’s primary efficacy 
endpoint is not met, Novartis may decide not to conduct survival follow up for the study.


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2.2
General overview of statistical methodology
Data from all centers that participate in this protocol will be used. Data used for the analyses 
specified in this document will come from the Electronic Data Capture (EDC) system. In 
addition, the mutation data from the central laboratory will be collected in an Excel 
spreadsheet format and subsequently be uploaded to a secure FTP site by Novartis.
The analyses stated in this document will be based on all patients’ data up to the time when all 
patients have had the opportunity to complete at least 4 cycles (or 16 weeks) of study 
treatment or discontinued study. The data cut-off date will be the date when the last patient on 
treatment completes 4 cycles of study treatment.  This will be the cut-off point for the clinical 
study report (CSR). Additional data for patients continuing to receive study treatment beyond
the data cut-off date for the primary CSR will be reported once all patients have discontinued 
treatment or been lost to follow-up.
All statistical analyses presented in this document are related to patient background 
information, efficacy, and safety. All analyses are descriptive and no hypothesis testing is 
planned (except for the primary efficacy variable, which is described in Section 8 below). For 
continuous data, the mean, standard deviation (SD), median, 25th and 75th percentiles, 
minimum, and maximum will be presented. For categorical data, frequencies and percentages
will be presented. In general, data from all centers will be combined for any analysis. There 
will be no stratification factor considered for the analysis with the exception of tumor type in 
the primary efficacy variable analyses. Missing data will not be imputed. All data collected in 
the study will be presented in the listings.
The primary efficacy objectives of the study, clinical benefit (e.g., for solid tumor – CR, PR, 
stable disease [SD] ≥16 weeks) associated with ribociclib treatment based on local 
investigator assessment, will be analyzed by using a Bayesian hierarchical model for
evaluation of trial success and futility, and the relationship between pathway activation and 
response (if applicable). Analysis details are documented in Section 8.
In addition, with all solid tumor types combined and separately for each hematological tumor 
type, the clinical benefit rate (CBR) will be provided with its 95% exact confidence interval 
(CI) (using clopper-pearson1 method); overall response rate (ORR, e.g., partial response [PR]
and complete response [CR] for solid tumor) and its 95% CI will be presented. Summary on 
numbers and percentages of patients for each response category (e.g., for solid tumor - CR, 
PR, stable disease [SD], progressive disease [PD], not evaluable [NE]) will also be provided. 
For tumor types that have ten (10) or more patients, separate summaries will be performed by 
the tumor type using the same methodology. In the event that there are fewer than 4 patients 
for a hematological tumor type, only listing will be provided.  
Duration of response (DOR) based on local investigator assessment will also be analyzed. 
Progression-free survival (PFS) and overall survival (OS) will be summarized using Kaplan-
Meier (KM) methodology.
Patient demographics, disease characteristics (including mutation analyses), ribociclib 
treatment, and safety variables will be analyzed descriptively.
Details of the above analyses are presented in the following sections.


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2.3
Change in planned analyses from the protocol
Cardiac imaging is only collected post baseline where clinically indicated and the value and 
potential abnormality will only be listed, and not summarized.
Summaries will be conducted for all patients combined with the following exceptions –

Primary efficacy analysis on the clinical benefit via Bayesian hierarchical model

Other clinical benefit and tumor response summaries for tumor types that have 10 or 
more patients enrolled.
In the event of a low response rate, DOR will be listed only.
2.5
Definitions
2.5.1
Study drug
Study drug = ribociclib 600 mg once daily, 3 weeks on and 1 week off in a cycle of 28 days.
2.5.2
Date of first administration of study drug
The date of first administration of study drug is defined as the first date when a nonzero dose 
of study drug is administered and recorded on the dose administration electronic case report 
form (eCRF). The date of first administration of study drug will also be referred as start of 
study drug.
2.5.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered. Last date of study drug will also be referred as end of study drug.


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2.5.4
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date (date of first administration of study drug).
The study day will be calculated as the difference between the date of the assessment and the 
start of study treatment plus 1. If the date of the assessment is before the start of study 
treatment the study day will be negative and will be calculated as the difference between the 
date of the assessment and the start of study treatment.
2.5.5
Baseline
In general, the last available assessment before or at date of start of study treatment will be 
used as the ‘baseline’ assessment. For electrocardiogram (ECG), the average of the triplicate 
assessments prior to the first administration of study drug will be used as the ‘baseline’ 
assessment. In the event of missing pre-dose ECG time-point on the day of study treatment 
start, the screening ECG assessment will be used as the baseline.
2.5.6
On treatment assessment
On-treatment assessment is defined as any assessment obtained in the time interval: Date of 
first administration of study treatment through the date of last administration of study treatment + 
30 days. If the patient is still on treatment at the time of the cut-off, on-treatment assessments
include any assessment recorded in the database up to the cut-off and which occur after the 
start date of study treatment.
Data listings will include all assessments, flagging those which are not on-treatment 
assessments.
2.5.7
Last contact date
The last contact date will be derived for patients not known to be dead at the analysis cut-off 
using the last complete date among the following:

All assessment dates (e.g. vital signs assessment, performance status assessment). 
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, and concomitant medications
administered.

Adverse event dates

Last contact date collected on the ‘Survival information’ eCRF (only if the patient 
status is not unknown).

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


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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.
2.5.8
Year, month and week
For reporting purpose below mentioned rule will be followed to convert a year, month and 
week in days.
1 year = 365.25 days
1 month = 30.3475 days
1 week = 7 days
3
Patients and treatments 
3.1
Analysis sets
The following analysis data sets will be used in the analyses:
Full analysis set (FAS): The FAS will include all patients who have received at least one 
dose of the study drug.  The FAS will be the primary set for efficacy analyses. 
Safety set (SS): The SS will include all patients who have received at least one dose of the
study drug and had at least one post-baseline safety assessment. Any patient who has received 
a dose of study drug and who has no post-treatment safety data of any kind (i.e., no AE
assessment, no vital signs, no ECG, no cardiac imaging, no ECOG performance status, and no 
laboratory assessment) will be excluded from the SS.  Note that the statement ‘no AE’ is 
considered as an assessment of AE.
The number and percentage of patients in each analysis sets will be presented.
3.2
Protocol deviations
The complete list of CSR reportable protocol deviations are listed in the data handling plan. 
CSR reportable protocol deviations will be listed. 
3.3
Patient disposition
The FAS analysis set will be used for patient disposition summaries. Following categories 
will be summarized:
1. Number (%) of patients who are treated
2. Number (%) of patients who are still on treatment
3. Number (%) of patients who discontinued study drug
4. Reasons for discontinuation of study drug
5. Number (%) of patients who consent to be followed for survival follow-up


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6. Number (%) of patients who lost to follow-up during survival follow-up period (Note: 
it is defined as the patients whose last known survival status based on the survival 
follow-up contact occurred more than 6 months before the cut-off date)
For patients who were screened but did not take the study treatment, a listing with reasons for 
screen failure will be provided.
3.4
Patient background, demographics and baseline characteristics
Demographic and baseline characteristics data, disease characteristics, medical history, and 
prior anti-neoplastic therapies are collected at the screening visit. Descriptive summaries
and/or listings will be provided. The FAS analysis set will be used for the presentation.
Demographic and baseline characteristics
Demographic characteristic variables include: 

Age (years), age group (<65 and ≥65; <75 and ≥75 years)

Sex (Male, Female)

Race (White, Black or African American, Asian, Other [including American Indian or 
Other Alaska Native, Native Hawaiian or Other Pacific Islander, and Other])
Baseline characteristic variables include:

Height and weight

ECOG performance status

Cardiac imaging (Left Ventricular Ejection Fraction [LVEF])
Disease characteristics
Disease characteristic variables include:

Primary tumor type (Sponsor adjudicated)
Note: The tumor type adjudication is made based on the combination of the primary 
site of tumor with the tumor histology/cytology as collected in the CRFs.

Time (in months) from initial diagnosis to the first dose of ribociclib

Time (in months) from date of most recent recurrence/relapse to the first dose of 
ribociclib

Presence of B symptoms (for lymphoma patients only)

Stage at initial diagnosis

Prior lines of antineoplastic medication therapy

Prior lines of chemotherapy 

Prior antineoplastic radiotherapy (yes/no)

Prior antineoplastic surgery (yes/no)
Other patient characteristics

Gene mutations as detected by local and central labs in pre-defined per-protocol 
mutation categories


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
Age of biopsy samples (in months) calculated from date of biopsy sample date to the 
first dose of ribociclib
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
will be summarized and listed. The summaries will be presented by primary system organ 
class and preferred term. Medical history/current medical conditions are coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology (v18.0). A separate 
summary will be presented for ongoing medical conditions by severity of the condition (i.e., 
grade 1 to grade 4).
Prior anti-neoplastic therapies
Prior anti-neoplastic therapies will be listed in three separate listings:

Medications

Radiotherapy

Surgery
3.5
Study Treatment and concomitant medications
The safety set will be used for all analyses associated with study treatment and other 
medications/non-drug therapy.
3.5.1
Study treatment
Patients receive ribociclib (600 mg) once daily, 3 weeks on and 1 week off. A complete 
treatment cycle is 28 days.  There is no break between dosing cycles. For patients who are 
unable to tolerate the protocol-specified dosing schedule, dose reductions or interruptions are 
permitted to manage drug-related toxicities.

When dose reduction is necessary, the dose of ribociclib may be reduced to 400 mg.

If an additional dose reduction is required, ribociclib may be reduced to 200 mg.

Once the ribociclib dose is reduced it cannot be re-escalated.
Protocol Section 6.3 provides the detailed information for dose modifications or dose delays.
3.5.1.1
Duration of exposure
Duration of exposure (days) for study drug is defined as the days between the last ribociclib 
dose and first ribociclib dose, that is to say, duration of exposure (D1) = (date of last 
administration of ribociclib) – (date of first administration of ribociclib) + 1. Summary 
statistics will be displayed for the duration of exposure.
Duration of exposure to study drug will also be categorized into time intervals (< 3 months, 3 
< 6 months, 6 < 9 months,…, etc.). The number and percentage of patients in each
category will be presented.


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3.5.1.2
Adjusted duration of exposure
Adjusted duration of exposure (days) for ribociclib (D) is the number of ribociclib dosing 
days a patient would be expected to have received per protocol, given their duration of 
exposure to study treatment. Since ribociclib follows a 3 weeks on, 1 week off schedule, the 
adjusted duration of exposure to ribociclib is the duration of exposure to study treatment 
minus the planned off days for ribociclib. The adjusted duration of exposure to ribociclib (in 
days) is therefore 21 x (# completed 28 day cycles) + minimum of (21, duration of last 
incomplete cycle). Summary statistics will be displayed.
3.5.1.3
Cumulative dose and average daily dose
Cumulative dose is defined as the total dose actually given during the study treatment 
exposure. Average daily dose is defined as [cumulative dose (mg) / cumulative dosing days
(days)].
The dosing record, as collected in the eCRF, includes planned one week drug breaks, thus 
cumulative dose calculation will be adjusted according to the 3 weeks on, 1 week off 
schedule. That is, for each dosing record, the calculated total dose of ribociclib will be the
daily ribociclib dose x 21 x (# completed 28 day cycles) + daily ribociclib dose x minimum of
(21, duration of last incomplete cycle). Since the eCRF does not collect cycle start dates, it 
will be assumed that a new cycle starts when ribociclib resumes after a temporary 
interruption.
Cumulative dosing days are calculated based on actual dosing days, excluding both one week 
drug break and temporary dose interruption.
Cumulative dose and average daily dose will be summarized using descriptive statistics.
3.5.1.4
Dose intensity and relative dose intensity
Dose intensity (DI) will be calculated as follows:
DI = Cumulative dose (mg) / Adjusted duration of exposure (days)
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol. The planned dose intensity for ribociclib during the period of time the 
patient received drug is 600 mg/day.
RDI = DI (mg/day) / 600 mg/day.
DI and RDI will be summarized using descriptive statistics.
3.5.1.5
Dose interruption and dose reduction
Dose interruption: An interruption is defined as a 0 mg dose given on one or more days 
during the treatment period where a patient is not on the “off” part of a treatment cycle. For 
patients who have dose interruption checked but never resume the non-zero dose, the dose 
interruption will not be counted.
Dose reduction: A reduction is defined as a decrease in dose from the protocol planned dose 
or a decrease from the previous non-zero dose, during the dosing period, even if this decrease 
has been directly preceded by an interruption. For example, in the sequence 600 mg – 0 mg –


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400 mg, the 400 mg dose will be counted as a reduction; in the sequence 400 mg – 0 mg –
400 mg, the 400 mg dose will not be counted as a reduction.
The number and percentage of patients who have dose reductions or interruptions, and the 
reasons for such reductions/interruptions, will be summarized separately.
3.5.2
Concomitant medications/non-drug therapies
In general, concomitant medications and therapies deemed necessary for the care of the
patient are permitted (see Protocol Section 6.4.1), except as specifically prohibited (see 
Protocol Section 6.4.2). All medications, procedures and significant non-drug therapies 
(including physical therapy and blood transfusions) administered within 30 days prior to the 
administration of ribociclib and through 30 days after the last dose of study drug will be 
recorded in the corresponding eCRF page. 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, preceding or coinciding with 
the study assessment period.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List to allow for categorization by preferred term. In 
addition to categorizing medication data by preferred term, drugs will be classified according 
to their ATC classification in order to present and compare how they are being utilized. Non-
drug therapies will be coded using the MedDRA terminology (v18.0).
Concomitant medications taken concurrently with the study drugs will be listed and 
summarized by ATC class, preferred term by means of frequency counts and percentages. 
These summaries will include medications starting on or after the start of study treatment but 
no later than 30 days after last dose of study treatment or medications starting prior to the start 
of study treatment and continuing after the start of study treatment. Similarly, significant non-
drug therapies will be summarized by primary system organ class (SOC) and preferred term.
Any prior medications or significant non-drug therapies starting and ending prior to the start 
of study treatment or starting more than 30 days after the last date of study treatment will be 
listed.
The safety set will be used for all concomitant medication/non-drug therapy tables and 
listings. 
4
Efficacy evaluation
All efficacy analyses will be performed in FAS.
4.1
Clinical Benefit Rate (CBR)
Clinical benefit is determined by investigator assessment for each tumor assessment and is 
defined as responses of CR or PR or SD for ≥ 16 weeks. In addition to tumor-specific 
measurements (e.g., radiological assessment of tumor response for solid tumors), progressive 
disease will also be considered when it was indicated either as a reason for the study treatment 


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discontinuation or as a cause of on-treatment death. CR and PR (for solid tumors) require a 
confirmation that is at least a minimum of 4 weeks after the initial observation of response.
Patients who had confirmed CR/PR or SD prior to 16 weeks, but discontinued prior to 16 
weeks for reasons other than progressive disease, will have their clinical benefit defined as 
non-evaluable; patients who had confirmed CR/PR or SD prior to 16 weeks, but progressed 
prior to 16 weeks, will be considered as not achieving clinical benefit; patients who had
CR/PR/SD occurred prior to 16 weeks, but progressed at or after 16 weeks without evidence 
of CR/PR/SD at or after 16 weeks, will also be considered as not achieving clinical benefit.
CBR will be analyzed by comparing achieved CBR with a historical control rate of each 
tumor type, and if there is at least 80% probability that the response rate in a tumor type
exceeds the historical rate, then the tumor type will be considered a success. Details for the 
Bayesian analyses of CBR are located in Section 8.
In addition to the Bayesian analyses, with all solid tumor types combined and separately for 
each hematological tumor type, the CBR estimate will be provided with its 95% exact CI. For 
tumor types (within the solid tumors) that have ten (10) or more patients, separate summaries 
will be performed by the tumor type. In the event that there are fewer than 4 patients for a 
hematological tumor type, only listing will be provided for that tumor type.   
4.2
Overall Response Rate (ORR)
Overall response is determined by investigator assessment for each tumor assessment in the 
study. For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will 
include responses of CR and/or PR. For hematological tumors, other appropriate criteria (see 
Protocol Appendix section for corresponding criteria) will be used to determine the responses. 
Ninety-five percent (95%) exact CI will also be provided for the response rates. The number 
and percentage of patients for different categories of overall response (e.g., for solid tumor -
CR, PR, SD, PD, and NE) will be presented. These analyses will be performed with all solid 
tumor types combined and separately for each hematological tumor type. For tumor types that 
have ten (10) or more patients (within the solid tumors), separate summaries will be 
performed by the tumor type. In the event that there are fewer than 4 patients for a 
hematological tumor type, only listing will be provided for that tumor type.   
Components of tumor assessments (target lesion response, non-target lesion response, new 
lesion [yes/no]) will be listed. In addition, Cancer Antigen-125 (CA-125) in the assessment of 
ovarian cancer response, or Prostate-specific antigen (PSA) in the assessment of prostate 
cancer response will also be listed.
4.3
Duration of response
DOR applies only to patients who responded, e.g., for solid tumor, responder is defined as the 
patient’s best overall response being CR or PR. The start date is the date of first documented 
response, and the end date is the date of event defined as the first documented 
progression/relapse or death due to any cause within 30 days of the last study drug dose date. 
In other words, the start date will be determined using the time the response was first 
determined and not using the time the response was confirmed. If a patient has not had an 
event, duration is censored at the date of last adequate tumor assessment. Distribution of DOR
will be estimated using the Kaplan-Meier method and the median response duration will be 


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presented along with 95% confidence interval only if there are sufficient numbers of events, 
otherwise, only listing of DOR will be provided. Analyses will be based all tumor types 
combined.
4.4
Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose of ribociclib to the date of the first 
documented disease progression/relapse or death due to any cause within 30 days of the last 
study drug dose date, and is calculated as PFS = (date of progression/relapse or death – date of 
first study treatment + 1). Disease progression noted as the reason for discontinuation of 
treatment will also be considered as a progression event for PFS analyses.
Patients who discontinue or complete study treatment without disease progression will be 
censored at last adequate tumor assessment on or before the discontinuation/completion of the 
study. For patients who are still on study treatment at the time of data cut-off date for the
primary analyses, PFS will be censored at the last adequate tumor assessment before the data 
cut-off date for the analysis of PFS for the primary CSR. Patients who do not have any post 
baseline tumor assessment will be considered as censored at Day 1.
PFS will be summarized and graphed using the Kaplan-Meier product-limit method2. The 
estimated median survival time, the corresponding 95% CIs3, and 25th and 75th percentiles will 
be provided. In addition, survival-rate estimates with 95% CIs will also be provided at time 
points, such as 1, 2, 3, 4, 5, 6, 9 and 12 months. Analyses will be based on all tumor types 
combined. For tumor types that have ten (10) or more patients, separate summaries will be 
performed by the tumor type.
4.5
Overall Survival (OS)
Overall survival, defined as the time from the date of the first dose of ribociclib to the date of 
death due to any cause will be analyzed using methods similar to those stated above for PFS. 
That is, the 25th percentile, median, and 75th percentile of survival time with corresponding 
95% CIs will be provided; survival curve and survival rates at time points, such as 3, 6, 9, 12, 
18, and 24 months will also be presented. Patients who are alive at the time of 
discontinuation/completion of the study will be censored at the last contact date (as defined in 
Section 2.5.7). Analyses will be based on all tumor types combined. For tumor types that have 
ten (10) or more patients, separate summaries will be performed by the tumor type.
Handling missing month/day in date of death
For rare cases when either day is missing or both month and day are missing for the date of 
death, the follow imputation rules will be implemented: 

If only day is missing, then impute maximum of [(1 mmm-yyyy), minimum of (any 
valid date from data base used for deriving last contact date + 1, cut-off date)]. 

If both day and month are missing, then impute maximum of [(1 Jan-yyyy, minimum 
of (any valid date from data base used for deriving last contact date + 1, cut-off date)].


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4.6
Clinical Benefit Rate by Gene Mutations
The concordance between gene mutations detected by local and central labs will be 
summarized on protocol pre-defined mutations. A frequency summary will be provided for 
summarizing clinical benefit rate per gene mutation using mutation data provided by the 
central lab (on protocol pre-defined mutations only) as well as local lab. The data will also be 
presented in a listing.
5
Safety evaluation
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory/ECG values that fall outside of pre-determined ranges. Other safety data 
(e.g. vital signs) will be considered as appropriate.
All safety outputs will use the safety set. The safety summary tables will only include “on-
treatment” assessments (see the definition of “on-treatment” in Section 2.5.6), i.e. those 
collected on or after the first date of study treatment and collected no later than 30 days after 
the date of last study treatment administration. The AEs started before the first dose but 
worsened during the treatment are also considered as ‘on-treatment’ events. All safety 
assessments will be listed and those collected later than 30 days after the last treatment/exposure 
date will be flagged.
5.1
Adverse events
5.1.1
Coding of AEs
Adverse events are coded using the MedDRA (v18.0).
5.1.2
Grading of AEs
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a Grade 2 is not necessarily twice as bad as a Grade 1).
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the 
severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) 
will not be used in this project; rather, this information will be collected on the “End of 
Treatment”, “30-days safety follow-up” or “Survival Information” eCRF pages.
5.1.3
General rules for AE reporting
AE summaries will include all AEs starting on or after study Day 1 (i.e. on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last 
treatment/exposure date. All AEs will be listed. AEs starting prior to study Day 1 and AEs 
starting later than 30 days after the last treatment/exposure date will be flagged in the listings. 


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AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, having at least one AE in each body system/primary system organ class, and for each 
preferred term using MedDRA coding. A subject with multiple occurrences of an AE will be 
counted only once in the AE category. 
Separate AE summaries will be presented by primary system organ class (SOC), preferred 
term (PT), and maximum CTC grade. A patient with multiple CTC grades for an AE will be 
summarized under the maximum CTC grade recorded for the event. In the summaries 
presented by grade, all AEs will be pooled regardless of whether they are CTC gradable or 
not.
Any information collected (e.g. CTC grades, relatedness to study drug, action taken etc.) will 
be listed as appropriate.
5.1.4
AE summaries
The following summary tables will be provided:

AEs, regardless of study treatment relationship by primary SOC, PT, maximum 
CTCAE grade

Most frequent (≥ 5%) AEs, regardless of study treatment relationship by PT, 
maximum CTCAE grade

AEs suspected to be related to the study treatment by primary SOC, PT, maximum 
CTCAE grade

Most frequent (≥ 5%) AEs, suspected to be related to the study treatment by PT, 
maximum CTCAE grade

Serious adverse events (SAE), regardless of study treatment relationship, by primary 
SOC, PT, maximum CTCAE grade

SAEs suspected to be related to the study treatment, by primary SOC, PT, maximum 
CTCAE grade

Deaths on treatment by primary SOC and PT

AEs leading to study drug discontinuation, regardless of study treatment relationship, 
by primary SOC, PT and maximum CTCAE grade

AEs requiring dose adjustment or study treatment interruption, regardless of study 
treatment relationship, by primary SOC, PT, maximum CTCAE grade

AEs requiring additional therapy, regardless of study treatment relationship, by
primary SOC, PT, maximum CTCAE grade
In addition, subgroup analyses will be performed for all AEs and AEs suspected to be related 
to the study treatment.

Age (< 65 years vs ≥ 65 years, and <75 years vs. ≥ 75 years)

Race (Asian, Black or African American, White and others)

Gender (female vs. male)

Liver metastasis (yes vs. no)

Prior lines of chemotherapy (1, 2-3 vs. >=4 lines) 


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AEs of interest will also be summarized. Please see Section 5.1.5 for the grouping details
5.1.5
AEs of special interest
AE of special interest (AESI) consists of adverse events for which there is a specific clinical 
interest in connection with ribociclib treatment (i.e. where ribociclib may influence a common 
mechanism of action responsible for triggering them) or adverse events which are similar in 
nature (although not identical). 
Each of these AESI uses MedDRA categories (Standard MedDRA Query [SMQ], Novartis 
MedDRA Query [NMQ], High Level Group Term [HLGT], etc.) to group preferred terms for 
which there is a specific clinical interest. One AESI can be defined by one or several 
MedDRA categories. These AESIs are defined in the current version of the ribociclib Safety 
profiling plan/ ribociclib Case Retrieval Strategy (CRS) document.
The number and percentage of patients will be reported by AESI and by preferred term.
Groupings are displayed as below –

Hepatobiliary toxicity

QTc prolongation

Nausea, emesis

Diarrhea

Pneumonitis, interstitial lung disease

Anemia

Thrombocytopenia

Haematopoietic cytopenias affecting more than one type of blood cell

Leukopenia and neutropenia

Renal Toxicity
Additional AESIs may be reported if there are any updates to the CRS at the time of the 
analyses.
The number and percentage of patients will be reported by AESI, by MedDRA term, by PT, 
maximum CTCAE.
These analyses will be repeated in subgroups specified in Section 5.1.4, for the following 
AESIs:

Leukopenia and neutropenia

QT prolongation

Hepatobiliary toxicity
5.2
Deaths
The number and percentage of patients who died within 30 days of the last dose will be 
summarized with cause of deaths.  
A patient listing of all deaths with recorded principal cause of death (if available) will also be 
provided. All patients in FAS who died will be included, with deaths that are within 30 days 
of the last dose noted.


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5.3
Laboratory evaluations
Laboratory assessment will be collected at screening and post baseline (at scheduled visits 
outlined in the protocol or as clinically indicated). The collected laboratory values will be 
converted into standard units and the severity grade will be calculated using CTCAE v4.03. A 
severity grade of 0 will be assigned when the value is within normal limits. For laboratory
parameters where severity grades are determined both through normal limits and absolute cut-
offs, in the unlikely case that a local laboratory normal range overlaps into the higher (i.e.,
non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits and 
assigned a CTCAE grade of zero.
Abnormal on-treatment laboratory values will be summarized using shift tables (from baseline 
to any abnormal laboratory value post baseline) by each laboratory parameter at its worst 
severity grade. The number and percentage of patients with abnormal laboratory values will 
be presented by CTCAE grade for each laboratory parameter that is CTCAE gradable. For 
laboratory parameters 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
will 
be 
provided. 
Listings
of 
all 
laboratory 
values
(blood 
chemistry, 
hematology/coagulation parameters separately) in chronologic order will be provided for each 
laboratory parameter. Laboratory values collected more than 30 days after study treatment 
discontinuation will be flagged in the listing. Separate listings will also be provided for 
notable laboratory abnormalities (i.e., grade 3 or 4 laboratory toxicities post start of study 
treatment for CTC gradable parameters, or abnormal laboratory values for non-CTC gradable 
parameters). In addition, other lab tests such as those for urinalysis and pregnancy will be 
listed separately.
Patients’ hepatic toxicity will be evaluated for on-treatment liver parameter values. The worst 
case assessments are used for the analyses. The number and percentage of patients who met 
the following categories of the criteria will be presented.

ALT > 3xULN, ALT>5xULN, ALT>8xULN, ALT>10xULN, ALT>20xULN, 
separately

AST >3xULN, AST>5xULN, AST>8xULN, AST>10xULN, AST>20xULN, 
separately

ALT>3xULN or AST>3xULN, ALT>5xULN or AST>5xULN, ALT>8xULN or 
AST>8xULN, ALT>10xULN or AST>10xULN, ALT>20xULN or AST>20xULN, 
separately

TBILI>ULN, TBILI>2xULN, separately

ALP>1.5xULN, ALP>2xULN, ALP>3xULN,ALP>5xULN, ALP>8xULN,
ALP>10xULN, separately

(ALT>3xULN or AST>3xULN) and TBILI>ULN, (ALT>5xULN or AST>5xULN) 
and TBILI>ULN, (ALT>8xULN or AST>8xULN) and TBILI>ULN, (ALT>10xULN 
or AST>10xULN) and TBILI>ULN, (ALT>20xULN or AST>20xULN) and 
TBILI>ULN, separately

(ALT>3xULN or AST>3xULN) and TBILI>2xULN, (ALT>5xULN or AST>5xULN) 
and TBILI>2x ULN, (ALT>8xULN or AST>8xULN) and TBILI>2x ULN, 


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(ALT>10xULN or AST>10xULN) and TBILI>2x ULN, (ALT>20xULN or 
AST>20xULN) and TBILI>2x ULN, separately

(ALT>3xULN or AST>3xULN) and TBILI>=2xULN and ALP<2xULN
Note: ALT = Alanine Aminotransferase; AST =  
5.4
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height (cm), weight (kg), body temperature (°C), 
heart rate (beats per minute), and systolic and diastolic blood pressure (mmHg).
The number and percentage of patients with clinically notable vital signs changes from
baseline will be presented.
Clinically notable vital sign criteria are provided below.
Vital Sign (unit) 
Clinically notable criteria
Body weight (Kg)
decrease from Baseline of ≥ 10% 
increase from Baseline of ≥ 10% 
Systolic blood pressure 
(mmHg) 
≤ 90 and decrease from Baseline of ≥ 20 
≥ 180 and increase from Baseline of ≥ 20 
Diastolic blood pressure 
(mmHg) 
≤ 50 and decrease from Baseline of ≥ 15 
≥ 105 and increase from Baseline of ≥ 15 
Heart Rate (bpm) 
≤ 50 and decrease from Baseline of ≥ 15 
≥ 120 and increase from Baseline of ≥ 15 
5.5
ECG
Standard triplicate 12 lead ECG assessments are performed after the patient has been resting 
for 5-30 min prior to each time point. The average of the triplicate ECGs will be used for each 
time point. ECG values at each visit per each time point will be summarized descriptively for 
the SS.  Summary parameters are: QTcF, QTcB, HR, PR, QT, and QRS. In addition, the 
number and percentage of notable abnormal ECGs for the following categories at any time 
during the study will also be summarized. Shift table base on QTcF, QTcB, and QT categories 
will be presented from baseline to worst post-baseline values. 
ECG parameter (unit) 
Clinically notable criteria 
QT, QTcF, QTcB (ms) 
New > 450 ms 
New > 480 ms 
New > 500 ms 
Increase from Baseline > 30 ms 


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Increase from Baseline > 60 ms 
PR duration (ms)
Increase > 25% from Baseline and to PR duration > 200
QRS duration (ms)
Increase > 25% from Baseline and to QRS duration > 110
Heart Rate (bpm) 
≤ 50 and decrease from Baseline of ≥ 25% 
≥ 100 and increase from Baseline of ≥ 25% 
5.6
Other safety evaluations
ECOG performance status will be summarized by visit for SS. The number and percentage of 
patients in each score (0-5) will be displayed via shift table. In addition, the shift from 
baseline to the worst score post-baseline will also be presented. 
Other collected safety parameters, such as cardiac imaging (i.e., LVEF value), will be listed.
6
Interim analyses
Scheduled interim data reviews will occur for the primary endpoint of clinical benefit rate 
only as required by the Bayesian Hierarchical design. The first interim data review will be 
performed after the first 30 patients overall (across all groups) have been dosed for at least 16 
weeks or discontinued, and  then every 13 weeks thereafter. Interim analyses may be 
performed more frequently dependent on enrollment rate to avoid over-enrollment in any of 
the disease cohorts. At each interim analysis, the groups will be evaluated for early futility 
and early success by comparing posterior quantities for the response rate to pre-specified early 
stopping criteria.
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable, and all important safety 
endpoints will be summarized. No formal report will be issued for these data reviews. In the 
event of rapid enrollment, interim analyses for publication or other purpose may not be 
implemented
7
Determination of sample size
The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in Protocol Appendix R Table 4.2.1 and Table 
4.2.2. This hypothesis corresponds to a generally effective treatment across groups and 
incorporates variation in treatment effects to reflect the realistic expectation that treatment 
effects may differ by group. In this setting, analytical power calculations are not possible, but 
the design was simulated to obtain the power of the study as shown in the appendix. The 
sample sizes shown (minimum of 10 for futility stopping, minimum of 15 for early success 
and maximum of 30 as a group cap) achieve adequate power for the alternative hypothesis. 
The simulations included the expected variable accrual by simulating a Poisson process with 
expected accrual also shown in the appendix.


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Given the exploratory nature of the study design, there is no power consideration for 
secondary objectives.


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8
Bayesian Adaptive Design
8.1
Introduction
This document outlines the adaptive design framework to be used for all trials within 
Novartis’s Modular Phase II study to link targeted therapy to patients  with pathway activated 
tumors.
Although the selected tumor types may vary by trial, this document outlines the design and 
analysis approach based on 8 example tumor cohorts:

Lung NSC

Bladder

Breast

Colorectal

GIST

HNSCC

Ovarian

Sarcoma
Other tumor types may be considered for trials if 1) 4 or more patients are enrolled in the 
cohort, and 2) a reasonable estimate of the clinical benefit rate is available.
The primary endpoint is clinical benefit rate (CBR) in each cohort, with  clinical benefit being 
assessed at 16 weeks. All patients will receive the experimental treatment for that particular 
trial.
8.1.1
Primary Analysis
We let Yi be the response indicator for the ith patient, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
Thus, θg is the group specific logistic regression coefficient for the treatment within group g. 
The primary analysis is a set of group specific tests that θg>0, meaning that the treatment is 
better than the assumed control rate for that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0
H1g : θg>0
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,


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Pr(θg>0 | data) > 0.80
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below.
8.1.2
Trial Logistics
The trial will enroll all available patients in all cohorts for 2 years unless a cohort cap is 
reached or a cohort is stopped early, or the trial is stopped early by Novartis. The trial will 
enroll no more than 30 evaluable patients in each cohort. Interim monitoring will be 
conducted starting after the first 30 patients are enrolled overall (across all cohorts), and 
continuing each 13 weeks thereafter till study enrollment closure. After that, one CBR 
analysis will be done at the end of the study. At each interim data review, response 
information for the various groups will be evaluated to determine the current Pr(θg>0 | data) 
within each cohort, with sufficiently high/low values used to stop the cohort for 
success/futility. A minimum of 10 patients will be required in a cohort before it may 
discontinue enrollment for futility, and a minimum of 15 patients are required before 
discontinuing a cohort for efficacy. If a cohort stops enrolling early, the remaining cohorts 
will continue until the end of 2 years or until the other groups reach their own early stopping 
criteria. The final analysis will occur after the analysis of the analysis of the study data for the 
primary CSR.
The trial will enroll patients in all listed cohorts. In addition, should other cohorts be 
identified throughout the trial, the following mechanism will be used. If another cohort is 
identified, it will not be placed into the statistical analysis unless 3 patients enroll within the 
cohort (thus, the trial may enroll multiple possible cohorts within the “other” category, but a 
cohort will only be added to the list if at least 3 patients enroll from that cohort). Thus, it is 
possible (but not viewed as likely) that multiple additional cohorts may be added to the trial if 
the trial has sufficient enrollment in multiple additional cohorts. In addition to sufficient 
enrollment, the sponsor must have a reasonable estimate of the control clinical benefit rate.
Patients within any cohort which does not reach the minimum 3 patient enrollment will be 
excluded from the interim and final analyses. As the study continues, early interim data 
reviews may be based on fewer cohorts than later interim data reviews, as the interim data 
reviews will include whatever cohorts have satisfied the criteria at the time of the data review.
8.2
Statistical Modeling
We let Yi be the response indicator for the ith patient, and let Rg be the probability of response 
within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability of 
response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 


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differ.  In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR.
The purpose of such an analysis (discussed in more detail in Section 8.5) is to produce higher 
power or lower type I error in situations where we see some commonality (identical effects 
are not required) among the groups. The model will borrow more in situations where the 
groups appear similar than situations where the groups appear different.
8.2.1
Hierarchical Model with Clustering
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture
(DPM) model, described in the appendix.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the 
have an across groups distribution
θg ~ N(μ, τ2)
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups.  Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 


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Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 
different results with borrow far less information between them (they will have a low 
probability of being in the same cluster).
Details of the two stages may be found in Section 8.5.
8.3
Evaluation of Trial Success and Futility
Interim monitoring will occur after the first 30 patients are on study for 16 weeks, then every 
13 weeks thereafter till study enrollment closure. At each interim data review, the groups will 
be evaluated for early futility and early success by comparing posterior quantities for the 
response rate to pre-specified early stopping criteria.
8.3.1
Early Futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility.  Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.10.
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group.
8.3.2
Early Success
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success.  Formally, enrollment will stop early for 
success if:
Pr(πg > Rg) > 0.95.
A minimum of 15 patients will need to be evaluated prior to declaring a group to be 
efficacious.
8.3.3
Final Analysis
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups. If, at the completion of the trial, there is at least 80% probability that the 
response rate in a group exceeds the historical rate, then the group will be considered a 
success. Formally:
Pr(πg > Rg) > 0.80.
8.4
Simulation
We evaluated type I error and power for each of the 8 possible groups under a variety of 
possible “truths” indicating various possible true underlying probabilities within each group. 


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8.4.1
Assumptions
Accrual – Two scenarios for the assumed two-year expected accrual are investigated: 1) 10 
patients per group and 2) 5 patients per group. Note that these are averages, the actual number 
of available patients is simulated as a Poisson distribution with the specified mean. Also note 
that the group cap of 30 applies, and thus if the number of available patients in a group 
exceeds 30, only the first 30 available patients in that group will be enrolled in the study. 
Dropouts – We assume no dropouts for the purpose of this simulation.
Control Rates – Table 1.1 shows the assumed control clinical benefit rates for each group.
Table 1.1 
Assumed control rates
Tumor Type
Assumed Control Rate (Rg)
Lung NSC
0.45
Bladder
0.47
Breast
0.50
Colorectal
0.38
GIST
0.50
HNSCC
0.45
Ovarian
0.47
Sarcoma
0.40
Table 1.1 – Assumed control CBR values used in the simulations.
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups.
Treatment Rates - The treatment rates for each scenario are shown in the Table 1.2. Values 
identical to the control are shown in bold, while values greater than the assumed control rate 
are italicized.


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Table 1.2
Treatment rates
Null
Alternative
Two
Half
Lung NSC
0.45
0.71
0.45
0.45
Bladder
0.47
0.73
0.47
0.47
Breast
0.50
0.75
0.50
0.50
Colorectal
0.38
0.65
0.38
0.38
GIST
0.50
0.75
0.50
0.75
HNSCC
0.45
0.71
0.45
0.71
Ovarian
0.47
0.73
0.73
0.73
Sarcoma
0.40
0.67
0.67
0.67
Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin.
8.4.2
Results
A total of 8 scenarios were simulated (two accrual scenarios and four possible ‘truths’ for the 
clinical benefit rate). The probability of group success for each group is provided for each 
scenarios in the tables below.


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Table 2.1
Probability of group success for each cohort assuming expected 
accrual of 10 patients/cohort 
Two-year expected accrual: 10 patients/cohort
Group(Exp N)
Null
Alternative
Two
Half
Lung NSC
0.158
0.915
0.208
0.305
Bladder
0.131
0.918
0.232
0.322
Breast 
0.147
0.909
0.233
0.312
Colorectal 
0.138
0.921
0.200
0.276
GIST
0.162
0.921
0.233
0.826
HNSCC
0.139
0.906
0.217
0.834
Ovarian
0.145
0.929
0.786
0.829
Sarcoma
0.135
0.939
0.758
0.852
Table 2.2 
Probability of group success for each cohort assuming expected 
accrual of 5 patients /cohort
Two-year expected accrual: 5 patients/cohort
Group
Null
Alternative
Two
Half
Lung NSC
0.132
0.803
0.204
0.258
Bladder
0.140
0.830
0.196
0.265
Breast 
0.160
0.807
0.232
0.261
Colorectal 
0.135
0.794
0.194
0.278
GIST
0.155
0.826
0.212
0.688
HNSCC
0.140
0.820
0.190
0.657
Ovarian
0.151
0.819
0.587
0.652
Sarcoma
0.139
0.799
0.579
0.667
Entries in bold represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in bold are type I errors. Italicized entries appear where the 
treatment is effective, and thus indicate the power of the design.
Generally, type I error is controlled at 0.20 under the null scenario (the borrowing 
compensates for the multiple interim data reviews) and power is an increasing function of the 
expected sample size (power is higher in the higher  accrual situation across treatment rate 
scenarios).  In the alternative scenario there remains decently high probability of success even 
in the lower enrolling groups. When fewer groups are effective in truth, the scenarios “half” 
and “two” are harder to discern. Note in any particular trial there should be a mix of high and 
low enrolling cohorts, thus some cohorts may enroll closer to 10 patients while other may 
only enroll five. This would produce a power value somewhere between the two tables.
Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the cohorts. Generally power is a function of the sample 
size.


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8.5
Modeling Details
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model.
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 
clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 
clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing 
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering.
The details of the prior are as follows. Let zg represent the cluster to which group g belongs.  
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and 
. We construct p using a stick-breaking process:
and
βk ~ Beta(1, α).
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster. 
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution 
θg ~ N(μ, τ2)


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As discussed above, this across groups distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions
μ ~ N(0, 1.82)
and
τ2 ~ IG(3,0.5),
where IG(α, β) is the inverse gamma distribution defined by:
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the 
model.


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9
References
                                                
1 Clopper, C., Pearson, E. S.  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika. 1934; 26: 404-413.
2 Kaplan EL, Meier P.  Nonparametric Estimation from Incomplete Observations.  J Am Stat 
Assoc. 1958; 53: 457-81.
3 Brookmeyer R., Crowley, J.  A Confidence Interval for the Median Survival Time.  
Biometrics, 1982; 38: 29-41