Clinical trial NCT03400176
Conditions: Chronic Lymphocytic Leukemia (CLL)
Keywords: Ibrutinib VAY736 Chronic lymphocytic leukemia CLL Bruton's Tyrosine Kinase BTK mutation
Sponsor: Novartis Pharmaceuticals
Start date: 2018-04-09; Completion date: 2023-09-29
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Patients enrolled to the study had chronic lymphocytic leukemia (CLL) and received ibrutinib. Patients had either received ibrutinib for one year without having had a complete response or patients developed a resistance mutation to ibrutinib. This study had two parts, a dose escalation part and a dose expansion part.

Detailed description:

Arms: arm 1: Increasing doses of VAY736 in combination with a fixed dose of ibrutinib. arm 2: Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation.
Interventions: intervention 1: VAY736 intervention 2: ibrutinib
Intervention descriptions: intervention 1: Experimental intervention 2: Approved medication

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
VAY736
Clinical Trial Protocol CVAY736Y2102 / NCT03400176
Phase Ib open-label study of VAY736 and ibrutinib in 
patients with chronic lymphocytic leukemia (CLL) on 
ibrutinib therapy
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
v06 (Clean)
Clinical Trial Phase
Ib
Document status
Final
Release Date
20-Oct-2021
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 06-Apr-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 06 (20-Oct-2021) ..........................................................................................13
Amendment 05 (11-May-2020).........................................................................................16
Amendment 04 (November 2019).....................................................................................18
Amendment 03 (21-Aug-2019).........................................................................................20
Amendment 02 (03-Dec-2018)..........................................................................................23
Amendment 01 (02-Nov-2017).........................................................................................25
Protocol summary:.............................................................................................................26
1
Background........................................................................................................................28
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............28
1.2
Introduction to investigational treatment and other study treatment.....................29
1.2.1
Overview of VAY736...........................................................................29
..........................................................29
1.2.3
VAY736 clinical experience.................................................................32
1.2.4
Overview of ibrutinib............................................................................33
1.3
Overview of the combination of VAY736 and ibrutinib.......................................36
........................................................................36
1.3.2
Clinical experience................................................................................40
1.3.3
Potential drug-drug interactions between VAY736 and ibrutinib ........40
1.3.4
Expected overlapping toxicities............................................................41
2
Rationale............................................................................................................................41
2.1
Study rationale and purpose...................................................................................41
2.2
Rationale for the study design ...............................................................................42
2.3
Rationale for dose and regimen selection..............................................................42
2.3.1
Rationale for ibrutinib dose and schedule.............................................42
2.3.2
Rationale for VAY736 dose and schedule............................................43
2.4
Rationale for choice of combination drugs............................................................43
2.5
Rationale for choice of comparators drugs............................................................43
2.6
Risks and benefits..................................................................................................43
2.7
Rationale for Public Health Emergency mitigation procedures ............................43
3
Objectives and endpoints...................................................................................................44


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4
Study design ......................................................................................................................47
4.1
Description of study design ...................................................................................47
4.2
Timing of interim analyses and design..................................................................48
4.3
Definition of end of study......................................................................................49
4.4
Early study termination..........................................................................................49
5
Population..........................................................................................................................49
5.1
Patient population..................................................................................................49
5.2
Inclusion criteria ....................................................................................................49
5.3
Exclusion criteria...................................................................................................51
6
Treatment...........................................................................................................................53
6.1
Study treatment......................................................................................................53
6.1.1
Dosing regimen.....................................................................................53
6.1.2
Ancillary treatments..............................................................................54
6.1.3
Rescue medication ................................................................................55
6.1.4
Guidelines for continuation of treatment ..............................................55
6.1.5
Treatment duration................................................................................55
6.2
Dose escalation guidelines.....................................................................................56
6.2.1
Starting dose rationale...........................................................................56
6.2.2
Provisional dose levels..........................................................................56
6.2.3
Guidelines for dose escalation and determination of MTD/RD............57
6.2.4
Definitions of dose limiting toxicities (DLTs)......................................59
6.3
Dose modifications ................................................................................................60
6.3.1
Dose modification and dose delay ........................................................60
6.3.2
Follow-up for toxicities.........................................................................67
...................................................67
6.4
Concomitant medications ......................................................................................68
6.4.1
Permitted concomitant therapy .............................................................68
6.4.2
Permitted concomitant therapy requiring caution.................................68
6.4.3
Prohibited concomitant therapy ............................................................68
6.4.4
Use of Bisphosphonates (or other concomitant agents)........................68
6.5
Patient numbering, treatment assignment or randomization .................................69
6.5.1
Patient numbering .................................................................................69
6.5.2
Treatment assignment or randomization...............................................69
6.5.3
Treatment blinding................................................................................69
6.6
Study drug preparation and dispensation...............................................................69
6.6.1
Study treatment packaging and labeling ...............................................69


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6.6.2
Drug supply and storage........................................................................69
6.6.3
Study drug compliance and accountability ...........................................70
6.6.4
Disposal and destruction .......................................................................70
7
Visit schedule and assessments .........................................................................................70
7.1
Study flow and visit schedule................................................................................70
7.1.1
Screening...............................................................................................83
7.1.2
Treatment period...................................................................................83
7.1.3
Discontinuation of study treatment .......................................................84
7.1.4
Withdrawal of consent ..........................................................................85
7.1.5
Follow up for safety evaluations...........................................................85
7.1.6
Lost to follow-up...................................................................................86
7.2
Assessment types...................................................................................................86
7.2.1
Efficacy assessments.............................................................................86
7.2.2
Safety and tolerability assessments.......................................................87
7.2.3
Pharmacokinetics and immunogenicity: ...............................................90
............................................................................................94
8
Safety monitoring and reporting........................................................................................96
8.1
Adverse events.......................................................................................................96
8.1.1
Definitions and reporting ......................................................................96
8.1.2
Laboratory test abnormalities................................................................97
8.2
Serious adverse events...........................................................................................98
8.2.1
Definitions.............................................................................................98
8.2.2
Reporting...............................................................................................99
............................................................................................................99
8.4
Warnings and precautions....................................................................................100
8.5
Data Monitoring Committee................................................................................100
8.6
Steering Committee .............................................................................................100
9
Data collection and management.....................................................................................101
9.1
Data confidentiality .............................................................................................101
9.2
Site monitoring ....................................................................................................101
9.3
Data collection.....................................................................................................102
9.4
Database management and quality control..........................................................102
10 Statistical methods and data analysis ..............................................................................103
10.1
Analysis sets ........................................................................................................103
10.1.1
Full Analysis Set .................................................................................103
10.1.2
Safety set .............................................................................................104


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10.1.3
Per-Protocol set ...................................................................................104
10.1.4
Dose-determining analysis set.............................................................104
10.1.5
Pharmacokinetic analysis set...............................................................104
10.1.6
Other analysis sets...............................................................................104
10.2
Patient demographics/other baseline characteristics ...........................................104
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................105
10.4
Primary objective.................................................................................................105
10.4.1
Variable...............................................................................................105
10.4.2
Statistical hypothesis, model, and method of analysis........................105
.....................107
....................................................107
10.5
Secondary objectives ...........................................................................................108
10.5.1
Key secondary objective(s).................................................................108
10.5.2
Other secondary efficacy objectives ...................................................108
10.5.3
Safety objectives .................................................................................109
10.5.4
Pharmacokinetics ................................................................................110
..........................................................................................111
10.5.6
Resource utilization.............................................................................112
10.5.7
Patient-reported...................................................................................112
.........................................................................................112
......................................................................112
.......................................................113
...............................................................113
 
................................113
..............................................................113
10.7
Interim analysis....................................................................................................113
........................................................................................113
............................................................................113
............................................................................114
....................................................114
11 Ethical considerations and administrative procedures ....................................................115
11.1
Regulatory and ethical compliance......................................................................115
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................115
11.3
Informed consent procedures...............................................................................115
11.4
Discontinuation of the study................................................................................115


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11.5
Publication of study protocol and results.............................................................116
11.6
Study documentation, record keeping and retention of documents.....................116
11.7
Confidentiality of study documents and patient records .....................................117
11.8
Audits and inspections.........................................................................................117
11.9
Financial disclosures............................................................................................117
11.10 Participant Engagement.......................................................................................117
12 Protocol adherence ..........................................................................................................117
12.1
Amendments to the protocol................................................................................118
13 References (available upon request)................................................................................119
14 Appendices ......................................................................................................................124
14.1
Appendix 1 – Guidelines for NCI CLL Working Group 2018 (IWCLL) ...........124
14.2
Appendix 2 – BLRM, prior, hypothetical dose escalation scenarios and 
operating characteristics ......................................................................................126
14.2.1
Statistical model..................................................................................126
14.2.2
Prior specifications..............................................................................127
14.2.3
Hypothetical on-study data scenarios..................................................132
14.2.4
Operating characteristics.....................................................................132
14.3
Appendix 3 – Drugs which are prohibited or to be used with caution ................136
List of tables
Table 3-1
Objectives and related endpoints ..........................................................45
Table 6-1
Dose and treatment schedule.................................................................54
Table 6-2
VAY736 provisional dose levels ..........................................................57
Table 6-3
Criteria for defining dose-limiting toxicities.........................................60
Table 6-4
Criteria for dose reduction / interruption and re-initiation of 
VAY736 treatment for adverse drug reactions. ....................................62
Table 6-5
Follow-up evaluations for selected toxicities........................................67
Table 7-1
Visit evaluation schedule for Q2W VAY736 dosing regimen..............72
Table 7-2
Visit evaluation schedule for Q4W VAY736 dosing regimen..............77
Table 7-3
Disease assessment collection plan.......................................................87
Table 7-4
ECOG Performance Status....................................................................88
Table 7-5
Local clinical laboratory parameters collection plan ............................88
Table 7-6
Pharmacokinetic blood collection log for VAY736 Q2W dosing 
(VAY736, IG, 
) ..............................................91
Table 7-7
Pharmacokinetic blood collection log for VAY736 Q4W dosing 
(VAY736, IG, 
) ..............................................92
...........................93


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.........................................................95
Table 10-1
Noncompartmental pharmacokinetic parameters................................110
.....114
 
..................................................114
Table 14-1
Response definition after treatment for patients with CLL.................124
Table 14-2
Grading scale for hematologic toxicity in CLL studies ......................125
Table 14-3
Prior distributions for the parameters of the MAP model used to 
derive the prior for single-agent VAY736 model parameters.............128
Table 14-4
Historical DLT data from Studies VAY736X2101, 
VAY736X2201, VAY736X2202, VAY736X2203 and 
VAY736Y2101 ...................................................................................129
Table 14-5
Historical data for ibrutinib.................................................................130
Table 14-6
Prior distribution for the model parameters ........................................131
Table 14-7
Summary of prior distribution of DLT rates.......................................131
Table 14-8
Hypothetical dose escalation scenarios...............................................132
Table 14-9
True probability of DLT for simulation scenarios ..............................133
Table 14-10
Summary of simulation results............................................................134
Table 14-11
Drugs prohibited while on study.........................................................136
List of figures
Figure 1-1
Ibrutinib resistance mutations can be detected prior to clinical 
relapse ...................................................................................................36
.......................37
 
.................................................................................................37
 
............................................................................................38
............................................................................................39
 
.............................................................40
Figure 4-1
Study design..........................................................................................48


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List of abbreviations
ADA
ADCC
Anti-Drug Antibody
Antibody Dependent Cellular Cytotoxicity
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT/SGPT
Alanine aminotransferase/Glutamic pyruvic transaminase
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST/SGOT
Aspartate aminotransferase/glutamic oxaloacetic transaminase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
BP
Blood Pressure
BTK
Bruton’s Tyrosine Kinase
BTKi
Bruton’s Tyrosine Kinase inhibitor
BUN
Blood Urea Nitrogen
BVN
Bivariate Normal
CI
Confidence Interval
CK
Creatinine Kinase
CL
Clearance
CLL
Chronic Lymphocytic Leukemia
CMO&PS
Chief Medical Office and Patient Safety
CNS
Central Nervous System
CPK
Creatinine Phosphokinase
CR
Complete Response
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Cardiovascular
DBL
Database Lock
DDI
Drug-Drug Interaction
DDS
Dose-determining analysis set
DLT
Dose Limiting Toxicity
DMSO
Dimethyl Sulfoxide
DOR
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ELISA
Enzyme-Linked ImmunoSorbant Assay
EOT
End Of Treatment


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EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
First In Human
G-CSF
Granulocyte Colony Stimulating Factor
GFP
Green Fluorescent Protein
GLP
Good Laboratory Practice
GVHD
Graft vs. Host Disease
Hgb
Hemoglobin
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IFN
Interferon
IFNR
Interferon Receptor
Ig
Immunogenicity
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgG1
Immunoglobulin G1
IgM
Immunoglobulin M
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine System
i.v.
Intravenous(ly)
IWCLL
International Working Group - CLL
JAGS
Just Another Gibbs Sampler
LC-MS/
Liquid Chromatography Mass Spectrometry Assays
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLOQ
Lower Limit Of Quantification
mAb
Monoclonal antibody
MAP
Meta-Analytic-Predictive
MCH
Mean Corpuscular Hemoglobin
MCL
Mantle Cell Lymphoma
MCMC
Markov Chain Monte Carlo
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MZL
Marginal Zone Lymphoma
NCI
National Cancer Institute


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NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse events
NYHA
New York Heart Association
OCP DDI
Oncology Clinical Pharmacology Drug-Drug Interaction
ORR
Overall Response Rate
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics
PFS
Progression-Free Survival
PHI
Protected Health Information
PK
Pharmacokinetics
PLT
Platelets
PR
Partial Response
PR-L
PR with lymphocytosis
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
PXR
Pregnane X Receptor
Q2W
Once Every Two Weeks
Q4W
Once Every Four Weeks
RA
Rheumatoid Arthritis
RD
Recommended dose
REB
Research Ethics Board
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Stable Disease
SDS
Sodium Dodecyl Sulfate
SLL
Small Lymphocytic Lymphoma
SUSARs
Suspected Unexpected Serious Adverse Reactions
TK
Toxicokinetic
TLS
Tumor Lysis Syndrome
TSH
Thyroid Stimulating Hormone
TTP
Time to Progression
ULN
Upper Limit of Normal
WHO
World Health Organization
WM
Waldenstrom’s Macroglobulinemia


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Patient Number
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study treatment
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
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Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
Withdrawal of study consent
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


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Amendment 06 (20-Oct-2021)
Amendment rationale
The purpose of this amendment is primarily three fold: 
 
 
 3) allow for 
the closure of Arm B (patients with BTK inhibitor resistance mutations) due to slower than 
anticipated enrollment.
 
 
 
 
 
 
 
 
 
 
 
 
 
3) The decision to close Arm B is not based on any safety concerns. Patients currently 
enrolled may continue on study as long as they are tolerating study treatment and will
continue to be followed per protocol.
Other changes that have been incorporated into the amendment are as follows:

Update Exclusion Criteria # 3 to modify the washout period (from 30 days to 2 weeks 
or 5 half- lives, whichever is shorter) for drugs used in combination with ibrutinib as 
first line treatment or as a sequential combination partner. For subjects that received 
antibodies, the washout period is 4 weeks prior to study treatment. This will allow 
patients who are in need of urgent therapy for leukemia control to commence the study 
treatment as soon as possible. 

Update Exclusion Criteria # 6 to modify the timeframe for administration of live 
vaccines prior to VAY736 treatment based on practice guidelines in order to prevent 
potential risks associated with a live vaccine. A ≥4 week period is recommended for 
patients who will be receiving B-cell depleting agents including an anti-CD20 
monoclonal antibody (Furer et al 2020). Further information is available in the current 
version of the VAY736 Investigator Brochure.


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Study status
At the time of this amendment, dose escalation has been completed with 15 patients enrolled 
(none ongoing) and dose expansion is ongoing with 11 patients receiving study treatment.
Changes to the protocol
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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Amendment 05 (11-May-2020)
Amendment rationale
The purpose of this amendment is to:
In addition, the amendment will:
1.
 
 
2. Increase the time between CT scans from every 3 months to every 6 months during the time-
to-progression (TTP) efficacy assessment as there is no clear benefit demonstrated to
perform frequent radiographic assessments, in addition to avoiding the unnecessary 
exposure to radiation for the patient.
3. Update the guidelines for determination of MTD to the most current standard. The change 
in the guidance language was necessary to clarify that listed conditions only apply to 
MTD declaration, as RDE has already been assessed.
4.
 
5. Correct minor inconsistencies and typographical errors throughout the document.
Study status
At the time of this amendment, dose escalation is ongoing and a total of 15 patients have been 
enrolled.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track change version of the 
 
 
 
 
 


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


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Amendment 04 (November 2019) 
Amendment rationale
The purpose of this amendment is to address the following health authority requests:

Clarify that treatment decisions will be solely made based on radiological and clinical 
response following IWCLL response criteria.

Revise the study protocol to state that treatment decisions will not be made based on the 
minimal residual disease (MRD) assessment. The statistical analysis plan will reflect this 
change.
 

Clarify that a MRD assay implemented in the current study is multicolor flow cytometry 
and provide a method description of the MRD assay.

Investigators may consider discontinuation of ibrutinib for patients who achieve a CR at 
the primary endpoint (C9D1) and be followed every 3 months for two years for TTP 
unless the patient experiences disease progression or the administration of a new therapy.

Allow investigators to treat patients with 2 additional cycles of VAY736 therapy in 
combination with ibrutinib through Cycle 8 if the patient shows evidence of disease in 
radiological assessment or abnormal blood counts, defined by IWCLL response criteria, at 
the Cycle 6 Day 15 time point. Based on the preliminary efficacy data that 3 out of 5 
patients had evidence of disease at the primary endpoint (C9D1), the addition of 2 more 
cycles of VAY736 therapy in combination with ibrutinib through Cycle 8 will help determine if 
further VAY736 therapy has an enhanced effect on clinical response at C9D1. 

Minor inconsistencies and typographical errors have been corrected throughout the 
document.
Study status
At the time of this amendment, this study has enrolled 14 patients.
Changes to the protocol
 
 
 
 


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
This document (090095af8f475292 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 10/20/2021 7:48:19 PM, signing status at this time:  Completed (1 of 1 signatures) 
Approved for report publication by Acosta Alexandra in East Hanover at Wed, 20 Oct 2021 03:47:07 PM EDT


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Amendment 03 (21-Aug-2019)
The primary purpose of this amendment is to:

Expand study eligibility for dose expansion to include CLL patients who have received 
ibrutinib either alone or in combination as first-line CLL therapy and have either not 
achieved a complete response after 1 year of therapy or have developed a resistance 
mutation to ibrutinib at any time.
Even though ibrutinib is approved for all lines of CLL therapy, recent results from 2 phase 
III US Oncology cooperative group studies have demonstrated the superiority of ibrutinib
or ibrutinib and rituximab combination as initial therapy in chemoimmunotherapy naive 
patients with improved progression-free survival and decreased toxicity compared to 
bendamustine and rituximab (BR) in older (≥65) patients and fludarabine, 
cyclophosphamide, and rituximab (FCR) in younger patients (<70) (Woyach et al 2018, 
Shanafelt et al 2018). There was an overall survival advantage with ibrutinib and rituximab 
in younger patients (Shanafelt et al 2018). These studies have definitively set ibrutinib or 
ibrutinib and rituximab as the standard first-line therapy in all patients with CLL without 
contraindications. Despite its remarkable clinical activity, the limitations of ibrutinib 
therapy include intolerance in a subset of patients who experience adverse events, 
emergence of resistance mutations, and absence of deep complete remissions which 
necessitates indefinite continuous therapy (Byrd et al 2014, O’Brien at al 2018). 
Indefinite therapy with extended dosing for years is a major limitation of ibrutinib, as it puts 
patients at risk for chronic toxicities, such as hypertension, atrial fibrillation, and 
cardiovascular events (Wiczer et al 2017).  In addition, the cost of ibrutinib is substantial 
and indefinite ibrutinib treatment will be costly for both patients and the healthcare system 
as a whole (Shanafelt et al 2015).  As ibrutinib is now the standard frontline therapy for 
CLL, these issues will affect a growing number of people.
In the current study, the addition of 6 cycles of 
,
antibody VAY736 (12 doses) to ibrutinib for patients who are receiving ibrutinib after 
progression on a prior line of therapy and have either not achieved a complete response
(CR) or have developed a resistance mutation has now been shown to be safe.
Eleven patients have been treated at 3 dose levels and demonstrated improved clinical 
activity with 1 patient achieving a minimal residual disease (MRD) negative CR and one 
patient achieving a MRD positive CR at 9 months (time of the final response) at the initial 
dose level. The other 3 patients to reach the 9-month assessment had stable disease. The 
study treatment has been shown to be safe, without dose limiting toxicities (DLTs). Five of 
eleven patients experienced adverse events related to study treatment.  The most common 
adverse events related to study drug have been constipation (G1), hypertriglyceridemia (G1), 
abdominal distension (G2), blood alkaline phosphatase increased (G1), diarrhea (G2) and 
an infusion-related reaction (G2).

Recommend that investigators consider discontinuation of ibrutinib for patients who 
achieve 
. This will allow investigators 
to follow patients for durability of response and minimize intolerance and toxicities 
associated with continuous ibrutinib therapy while maximizing patient quality of life. 
Patients will discontinue all therapy and be observed off therapy for progression.


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
Allow investigators to treat patients with 2 additional cycles of VAY736 therapy in 
combination with ibrutinib through Cycle 8 if the patient does not achieve a 
 
status in the blood at the Cycle 6 Day 15 time point. Based on the preliminary efficacy data 
and MRD positivity seen in 4 out of 5 patients that have reached the primary endpoint 
(C9D1), the addition of 2 more cycles of VAY736 therapy in combination with ibrutinib 
through Cycle 8 will help determine if prolonged VAY736 therapy has an effect on 
 
 

 
 
 

 
 
 
 

Minor inconsistencies and typographical errors have been corrected throughout the 
document.
Study Status

At the time of this amendment, dose escalation is ongoing and a total of 11 patients have 
been enrolled. 
Changes to the Protocol
 
 
 
 
 
 


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


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Amendment 02 (03-Dec-2018)
Amendment rationale 
The purpose of this amendment is to address the following changes:

Clarify that subjects enrolled in the study may receive either ibrutinib tablets or capsules 
as these formulations are bioequivalent.

 

 

 
 

Update Table 14-11 in Appendix 3 based on the Novartis PK Sciences DDI List (v01 
released in 2018 January).

Provide other minor changes/corrections for consistency and/or clarification. 
Study status
At the time of this amendment, dose escalation is ongoing and 7 patients have been enrolled. 
Changes to the protocol
 
 
 
 
 
 
 
 


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 01 (02-Nov-2017) 
Amendment rationale 
The purpose of this amendment is to address the following health authority requests:

Clarify that patients will not be enrolled based on lack of MRD (-) CR after > 1 year of 
treatment with ibrutinib

Revise the study protocol to only enroll patients with CLL in both the dose escalation and 
expansion parts who are receiving ibrutinib in the relapsed setting

Revise the dose limiting toxicity (DLT) definitions to remove previously listed exceptions

Add direct and indirect Coomb’s testing at baseline and as clinically indicated
Study status
At the time of this amendment, this study has not been opened for recruitment.
Changes to the protocol
 
 
 
 
 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Protocol summary:
Title
Phase Ib open-label study of VAY736 and ibrutinib in patients with chronic 
lymphocytic leukemia (CLL) on ibrutinib therapy
Brief title
Phase Ib study of VAY736 and ibrutinib in patients with CLL
Sponsor and Clinical 
Phase
Novartis
Phase Ib
Investigation type
Drug, Biological
Study type
Interventional
Purpose and rationale
The purpose of this study is to characterize the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the 
combination of VAY736 with ibrutinib.
Primary Objective(s) and 
Key Secondary Objective
To determine the maximum tolerated dose (MTD) and/or RD (recommended 
dose) of the combination of VAY736 and ibrutinib.
To characterize the safety and tolerability of the combination of VAY736 and 
ibrutinib
Secondary Objectives
To assess any preliminary antitumor activity of the combination of VAY736 and 
ibrutinib
To characterize the PK of VAY736 and ibrutinib when used in combination 
therapy
To assess the immunogenicity (IG) following one or more intravenous infusions 
of VAY736
Study design
This is a Phase Ib, open-label study to characterize the safety, tolerability, PK, 
PD, and preliminary anti-tumor activity of the combination of VAY736 with 
ibrutinib in patients with CLL who have been receiving ibrutinib for more than one 
year and who have not achieved a complete response to ibrutinib or who have 
developed a resistance mutation to ibrutinib.  The study has two parts, dose 
escalation and dose expansion.  The dose escalation part will determine the 
maximum tolerated dose (MTD) or the recommended dose (RD) for expansion of 
the combination of VAY736 with ibrutinib. In the expansion part, patients will be 
enrolled to one of two arms to further explore the safety, tolerability, and 
preliminary efficacy of the combination. As of Amendment 6, patients will no 
longer be enrolled into Arm B (expansion).
Population
Adults with CLL who have been receiving ibrutinib following relapse on another 
approved therapy and either have not had a complete response after 1 year of 
treatment or have developed a resistance mutation to ibrutinib without clinical 
relapse at any time during treatment. The dose expansion part of the study will 
also include patients who have received ibrutinib either alone or in combination
(or have received ibrutinib continuously with multiple sequential combination 
partners) as first-line therapy and have either failed to achieve a complete 
response after 1 year of therapy or have developed a resistance mutation to 
ibrutinib.
Inclusion criteria
Written informed consent
Ibrutinib dose  
Escalation: Patients must be receiving 420 mg ibrutinib
Expansion: Patients may be on a dose of ibrutinib lower than 420 mg.  Any dose 
must have been stable for 2 months prior to the start of study treatment.
Diagnosis of CLL as per World Health Organization (WHO) classification
Lack of a complete response after receiving ibrutinib for > 1 year OR presence of 
known ibrutinib resistance mutation
Platelets ≥ 25 x 109/L without transfusion support within 7 days of the first dose 
of VAY736
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2


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Exclusion criteria
Receipt of live vaccine within 4 weeks of starting VAY736
Known history of HIV
Active hepatitis B or C infection
Investigational and 
reference therapy
VAY736
Ibrutinib
Efficacy assessments
Rate of patients with CR (complete response) as assessed by investigators per 
IWCLL at cycle 9 day 1
Overall response rate (ORR) assessed by investigators per IWCLL criteria and 
Time To Progression (TTP)
Clearance of ibrutinib resistance mutations (BTKC481 and/or PLCγ2 hotspot), 
defined as less than 1% mutation bearing alleles (Arm B only).
Safety assessments
Safety
Escalation only:
Incidence of DLTs in cycle 1 (28 days)
Escalation and expansion:
Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters and vital signs
Tolerability
Dose interruptions, reductions, and dose intensity
Other assessments
Plasma concentrations of VAY736 and ibrutinib and derived parameters
Presence of anti-VAY736 antibodies
 
 
Data analysis
The study data will be analyzed and reported based on patient’s data from the 
dose escalation and dose expansion parts of the study up to the time when all 
patients have completed the treatment period and follow-up for disease 
progression or discontinued the study for any reason.
Data will be summarized using descriptive statistics (continuous data) and/or 
contingency tables (categorical data) for demographic and baseline 
characteristics, efficacy measurements, safety measurements, and all relevant 
PK and PD measures.
The Bayesian logistic regression model with overdose control will be used to 
assess safety for new patients treated at the dose levels that will be used for 
dose cohorts that occur after the initial dose cohort.
Key words
Chronic lymphocytic leukemia, CLL, VAY736, ibrutinib, 
 
, ibrutinib 
resistance mutation, BTK (Bruton’s tyrosine kinase), Phase Ib


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
CLL is the most prevalent adult leukemia in the Western hemisphere.  Patients with early stage 
disease have a greater than 10 year life expectancy.  However, patients with more advanced 
disease have a median survival of only 18 months to 3 years (Rai et al 1975).  The development 
of chemoimmunotherapy regimens combining cytotoxic agents such as alkylating agents and 
purine nucleoside analogs with monoclonal antibodies such as rituximab have attained overall 
response (OR) rates of over 90% and CR rates of over 70% in patients with previously untreated 
CLL, with similar improvement in progression free survival (PFS).  Notwithstanding the 
therapeutic advance represented by chemoimmunotherapy combinations, these treatments are 
not curative in the majority of cases (Nabhan and Rosen 2014).  Additionally, several features 
of CLL are predictive of poor response to chemoimmunotherapy treatments as measured by 
response duration and shortened survival.  These include 
 resulting in 
 
 (Dohner et al 2000, Damle et al 1999, Chen et al 2002).  Patients with 
 
treated with fludarabine, fludarabine and rituximab, fludarabine plus cyclophosphamide, or 
fludarabine, cyclophosphamide, and rituximab have a shorter duration of progression-free 
survival and overall survival compared to patients without this finding (Badoux et al 2009, Tam 
et al 2014). 
Ibrutinib, an inhibitor of BTK in the B-cell receptor signaling cascade, is a disease-altering 
therapy in chronic lymphocytic leukemia and has the advantage of effecting responses in 
patients with these characteristics associated with poor responses to chemoimmunotherapy.  
Ibrutinib additionally provides a progression free and overall survival advantage over other 
standard therapies (Byrd et al 2013, Woyach et al 2015, Byrd et al 2015).  At the 5-year follow 
up time from the initial ibrutinib studies, 92% of untreated and 43% of previously heavily 
treated patients maintain a durable remission (O’Brien et al 2016)  Ibrutinib is approved by the 
US FDA for all patients with CLL and is widely prescribed as a new standard of care for CLL 
patients.
However, patients in both untreated and previously treated settings typically have small 
detectable clonal disease leading to their being classified as minimal residual disease positive 
(MRD+) CR or PR (partial response).  To date, combination studies of BTKi (Bruton’s tyrosine 
kinase inhibitor) with rituximab, ofatumumab, bendamustine + rituximab, and venetoclax + 
obinutuzumab have not demonstrated elimination of these residual cells in the majority of 
patients (Burger et al 2014, Jaglowski et al 2015, Chanan-Khan et al 2016).  This long-term 
persisting MRD+ disease has significant implications for individual patients and the health care 
system because continuation of ibrutinib is required in this setting.
Additionally, many patients with CLL will stop responding to ibrutinib either by developing 
transformation to a large-cell lymphoma (Richter’s syndrome) or as progressive CLL, the risk 
of which increases over time (Maddocks et al 2015, Woyach et al 2017).  As ibrutinib is dosed 
indefinitely, the number of patients with progressive CLL during ibrutinib therapy is expected 
to increase.  Furthermore, survival for patients discontinuing ibrutinib due to CLL progression 
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phenotype (Woyach et al 2017).  It is imperative to develop novel treatments for CLL that 
address lack of MRD (-) CRs and resistance as major limitations of ibrutinib therapy. 
1.2
Introduction to investigational treatment and other study 
treatment
1.2.1
VAY736 is a fully human monoclonal IgG1 antibody 
 
VAY736 is currently being 
developed for the treatment of human autoimmune diseases and B cell malignancies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.3
VAY736 clinical experience
1.2.3.1
Clinical safety
As of 24-Mar-2021, a total of 495 patients have been enrolled in 11 clinical studies, 9 of which 
were single blinded or double blinded, randomized, controlled trials .It is estimated that 455 
patients have been treated with VAY736 across these 11 studies. Data from patients in 7 studies 
have been analyzed as of 24-Mar-2021 and summaries of safety data can be found in the 
VAY736 Investigator Brochure.
CLL
Three patients with refractory, relapsing CLL were enrolled to the dose escalation part of the 
CVAY736Y2101 clinical trial.  Each patient received 0.002 mg/kg of VAY736 per iv infusion, 
with four infusions planned per 28 day cycle. The first patient enrolled received 3 doses of 
VAY736 prior to being hospitalized due to grade 3 autoimmune hemolytic anemia and 
eventually discontinued treatment.  This patient had a positive Coombs test before enrolling in 
the trial and the event of hemolytic anemia was considered related to disease. The second patient 
enrolled received 5 doses of VAY736, and the third patient received 8 doses of study medication.  
Both of these patients were discontinued due to progressive disease.  Grade 3 events that were 
reported regardless of relation to study treatment were anemia, anemia hemolytic autoimmune, 
and neutropenia. The study was terminated early for non-safety related concerns and there was 
no formal efficacy analysis.
As of15-May-2021, in the ongoing CVAY736Y2102 clinical trial, a total of 15 patients have 
received VAY736 at various doses, including 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 9 mg/kg IV
every 2 weeks in the escalation part of the study. No DLTs were observed. Of the 9 patients 
who reached the primary endpoint (C9D1), three treated in the 0.3 mg/kg cohort, two treated in 
the 1.0 mg/kg cohort and 4 treated in the 3.0 mg/kg cohort, four patients have achieved a 
complete response. As of 15-May-2021 a total of 15 patients received study treatment in the 
expansion part of the study. 11 patients are ongoing.
Other indications
There is considerable safety data available for use of VAY736 in humans from ongoing and 
completed trials in autoimmune indications such as RA, primary Sjögren’s syndrome, multiple 
sclerosis and pemphigus vulgaris.  The most common adverse events attributable to VAY736
in these studies were lymphopenia, upper respiratory tract infections and infusion related 
reactions. There were no treatment related serious adverse effects. Mild-moderate infusion 
reactions occurred that were fully reversible with or without treatment within the first 24 hours 
after VAY736 administration. Detailed summaries of safety data from the individual studies 
with VAY736 can be found in the [VAY736 Investigator Brochure].
1.2.3.2
Clinical Pharmacokinetics of VAY736
 
 
There was moderate between-subject variability with individual profiles 
overlapping across two consecutive doses. VAY736 showed a relatively short T1/2 of ~10 days 


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after single i.v. administration for the four highest doses (0.3 to 10 mg/kg), whereas it was 
around 7 days for the subcutaneous (s.c.) route following single dose and around 9 days 
following repeated doses. Based on trough concentrations following repeated administration of 
60 mg s.c., the steady state of the concentrations occurs around the third-fourth doses. 
Additional information is available in the [VAY736 Investigator Brochure].
 
 
 
 
 
 
 
 
 
 
 
 
1.2.3.2.2 Immunogenicity of VAY736 in human studies
Immunogenicity was analyzed as part of the CVAY736X2101 clinical trial. A total of five 
patients (all receiving 10 mg/kg VAY736) out of 23 VAY736-treated patients had at least one 
sample (post dose) with confirmed anti-drug antibody (ADA) against VAY736. No SAE and 
no hypersensitivity reaction occurred to any of these five patients. No hypersensitivity reaction, 
AEs or reduced efficacy was observed in these five patients. 
1.2.4
Overview of ibrutinib
Ibrutinib (PCI-32765, Imbruvica™) is a first-in-class, orally-administered, covalently-binding 
small molecule inhibitor of BTK.  The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-
phenoxyphenyl)-1Hpyrazolo[3,4d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor 
pathways.  BTK’s role in signaling through the B-cell surface receptors results in activation of 
pathways necessary for B-cell trafficking, chemotaxis, and adhesion.  
Ibrutinib is currently under development for the treatment of B-cell malignancies 
(Janssen Research & Development, 2016). Ibrutinib is approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with CLL/small lymphocytic lymphoma 
(SLL), mantle cell lymphoma (MCL), Waldenstrom’s Macroglobulinemia (WM), and marginal 
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1.2.4.1
Ibrutinib clinical experience
For detailed information on use of ibrutinib in CLL, refer to locally approved ibrutinib 
prescribing information.
1.2.4.1.1 Clinical pharmacokinetics of ibrutinib 
Ibrutinib exposure increases with doses up to 840 mg. Ibrutinib is absorbed after oral 
administration with a median Tmax of 1 to 2 hours. Absolute bioavailability in fasted condition 
was 2.9%. Administration with food increased ibrutinib Cmax and AUC. Reversible binding of 
ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence. The 
volume of distribution (Vd) was 683 L. Metabolism is the main route of elimination for ibrutinib. 
It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor 
extent by CYP2D6. Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, 
respectively. The half-life of ibrutinib is 4 to 6 hours. For further details refer to the ibrutinib 
product insert and prescribing information.
1.2.4.1.2 Clinical trial data with ibrutinib in CLL
The safety and efficacy of ibrutinib in patients with CLL/SLL were demonstrated in one 
uncontrolled trial and three randomized, controlled trials. The most commonly occurring 
adverse reactions (≥ 20%) in patients with CLL/SLL receiving ibrutinib were neutropenia, 
thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, 
pyrexia and hemorrhage. Four to 10 percent of patients receiving ibrutinib in patients with 
CLL/SLL discontinued treatment due to adverse reactions. These included pneumonia, 
hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to 
dose reduction occurred in approximately 6% of patients. In an open-label, multi-center trial 
conducted in 48 previously treated CLL patients, the ORR was 58.3% (95% CI: 43.2%, 72.4%), all 
partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 
to 24.2+ months. The median duration of response (DOR) was not reached (de Claro et al 2015).
PCYC-1102/1103
The phase 1b/2 PCYC-1102 study included 85 patients with relapsed or refractory CLL or SLL 
and 31 symptomatic treatment naïve patients with CLL or SLL aged ≥65 years.  Patients who 
completed a minimum of 6 treatment cycles with no evidence of disease progression could 
enroll in a long-term extension study (PCYC-1103) to continue ibrutinib therapy.  Treatment 
consisted of 420 or 840 mg/day ibrutinib administered orally until progressive disease or poor 
tolerance (Byrd et al 2013, Byrd et al 2015). 
After a median follow-up of 22.1 months, 22 (71%) of the 31 symptomatic treatment naïve 
patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a 
complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had 
a partial response (O'brien et al 2014).  When these data were updated at median 30 months of 
follow-up, ORR had improved to 84%, with 23% attaining CR, 55% PR, and 6% PR with 
lymphocytosis (PR-L).  The estimated PFS rates was 96% (95% CI, 76.5-99.5%) at 30 months 
(Bryd et al, 2015).  Five-year follow-up data were recently presented (O’Brien et al 2016).  65% 
of patients remained on active treatment, and 92% were progression free.  Notably, with 
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PCYC-1115
PCYC-1115 (RESONATE-2) was a randomized phase 3 study comparing ibrutinib versus 
chlorambucil for treatment-naive non-del (17p) CLL in patients aged 65 years or older 
(Byrd et al 2013).  Enrolled patients were randomized to receive either oral ibrutinib (at a dose 
of 420 mg once daily) until disease progression or development of unacceptable toxicity or up 
to 12 cycles of chlorambucil.  At median follow-up 18.4 months, 86% of patients in the ibrutinib 
arm (versus 35% in the chlorambucil arm) had achieved an objective response (CR + PR + PR-
L).  At the time of this initial report, complete responses (including those in patients with 
incomplete blood-count recovery) had occurred in 4% of patients.  Further, the majority of 
ibrutinib-treated patients with baseline anemia or thrombocytopenia experienced sustained 
improvement in the hemoglobin level and platelet count (84% and 77%, respectively).  
Among patients treated in the ibrutinib arm, the median PFS had not been reached, and ibrutinib 
was associated with a nearly 83% reduced risk of disease progression or death (Hazard Ratio 
(HR) 0.161, 95%CI 0.091, 0.283).  Overall survival was also similarly improved after ibrutinib 
treatment versus chlorambucil (HR 0.162, 95% CI 0.048, 0.558). 
Updated efficacy and safety data from this study were recently presented (Barr 2016).
At median follow-up of 29 months, 92% of ibrutinib-treated patients had achieved an objective 
response.  Ibrutinib CR rates likewise continue to improve over time: increasing from 7% at 12 
months to 15% at 24 months to 18% with median follow-up of 29 months.  Most Grade ≥ AEs, 
as well as dose reductions and discontinuations due to AEs decreased over time.  79% of 
patients continue on ibrutinib treatment on study and 83% of patients had received at least 2 
years of treatment.  24-month PFS and OS were 89% v. 24% and 95% v. 84% in the ibrutinib 
and chlorambucil arms, respectively.
1.2.4.2
Ibrutinib Resistance in CLL
A major limitation of ibrutinib as a CLL therapy is that many patients with CLL will stop 
responding to ibrutinib either by developing transformation to large-cell lymphoma (Richter’s 
syndrome) or by progressive disease due to resistance to ibrutinib therapy.  Relapses as 
Richter’s syndrome tend to occur early and are rare after >2 years of ibrutinib treatment but the
risk of progressive CLL increases over time (Maddocks et al 2015, Woyach et al 2017).  
An analysis of 308 patients who received ibrutinib as participants in clinical trials and followed 
for a median of 33 months (range 4-61), revealed a cumulative incidence of ibrutinib 
discontinuation for progressive CLL of 0.7% (95% CI: 0-1.6%) at 1 year and 19.1% (95% CI: 
13.9-24.3%) at 4 years (Woyach et al 2017)..  As ibrutinib is dosed indefinitely, the number of 
patients with progressive CLL during ibrutinib therapy is expected to increase over time.  
Furthermore, survival for patients discontinuing ibrutinib due to CLL progression was short 
22.7 months (95% CI 13.5-NR) and associated with a clinically aggressive disease phenotype 
(Woyach et al 2017).
CLL progression due to ibrutinib resistance can be mediated by at least two separate 
mechanisms: mutations in BTK (BTKC481S) which decreases the affinity of ibrutinib for BTK 
and changes its binding from irreversible to reversible, and mutations in the immediate 
downstream target of BTK, PLCγ2 (Woyach et al 2014b).  These mutations appear during the 
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are detected on two separate occasions they do not disappear and patients invariably relapse 
(Maddocks et al 2015, Albitar et al 2015, Albitar et al 2017, Liu et al 2015,
Woyach et al 2014b).  In ibrutinib-treated patients with a detectable mutation in BTK or PLCγ2 
at time of relapse, a clone with the mutation could be detected in 18/20 patients prior to clinical 
relapse at a median of 9.3 (95% CI: 7.6-11.7) months before clinical progression (Figure 1-1).
Figure 1-1
Ibrutinib resistance mutations can be detected prior to clinical relapse
These patients can be identified by screening and in a cohort of 112 patients that were followed 
with testing for BTK and PLCγ2 mutations every three months during ibrutinib treatment, 8 
developed the BTKC481S mutation and all went on to clinically relapse (Woyach et al 2014b).  
Once these mutations are detected they do not decrease in allelic frequency or become 
undetectable and patients invariably develop clinical relapse.
1.3
Overview of the combination of VAY736 and ibrutinib
 
 
 
 
 


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1.3.2
Clinical experience
There are no clinical data or ongoing trials for the combination of VAY736 and ibrutinib.
1.3.3
Potential drug-drug interactions between VAY736 and ibrutinib
Specific studies to investigate drug-drug interactions (DDI) have not been conducted. 
The likelihood of DDI between VAY736 and ibrutinib is low since VAY736 is a monoclonal 
antibody and will likely be degraded to small peptides and amino acids by proteases. Therefore, 
VAY736, will not share a common clearance pathway with ibrutinib that is metabolized by the 
cytochrome P450 enzymes, CYP3A4 and CYP2D6. Additionally, there is no evidence that 
 and/or 
 ligand are involved in the regulation of the expression of drug 
metabolizing enzymes for ibrutinib. However, ibrutinib and VAY736 PK will be monitored in 
this study.


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1.3.4
Expected overlapping toxicities
Combination toxicology studies have not been conducted.  Preclinical and preliminary clinical 
data available from ongoing studies with VAY736 and ibrutinib monotherapy do not indicate a 
risk for overlapping toxicities. The most common adverse reactions (≥20%) in patients with 
B-cell malignancies (MCL, CLL/SLL, WM and MZL) treated with ibrutinib were neutropenia, 
thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, 
hemorrhage, and pyrexia (see ibrutinib package insert).  The most common adverse events 
attributable to VAY736 were lymphopenia, upper respiratory tract infections and infusion 
related reactions.
An increased number of infusion reactions occurred in the VAY736-treated patients compared 
to placebo treated patients despite pre-treatment with paracetamol. All infusion-related 
reactions were mild to moderate in severity. Symptoms all resolved within 24 hours, either 
spontaneously or with additional paracetamol treatment (for more information please refer to 
[VAY736 Investigators Brochure]). 
No evidence of VAY736-driven reduction in neutrophil counts or hemoglobin levels have been 
seen to date in ongoing studies. Significant, but transient and reversible, reductions in 
lymphocyte and NK cell counts were observed in patients treated with VAY736. 
These reductions are consistent with the intended PD of the compound and activation and 
redistribution of these cell types in the process of killing of B cells by ADCC. The transient 
lowering in these cell counts were resolved in all affected patients by the next scheduled 
evaluation at study day 7.
2
Rationale
2.1
Study rationale and purpose
 
 
 
 
 
 
 
 
 
Ibrutinib has become the standard treatment for many advanced CLL patients. Although most 
patients benefit from ibrutinib treatment, only a small percentage (7% at one year) achieve 
complete response and acquired resistance leads to disease progression over time. Combination 
of VAY736 and ibrutinib has potential to deepen the response to ibrutinib, eliminate the CLL 
cells with acquired resistance to ibrutinib, and potentially allow for discontinuation of long-term 
therapy.


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The purpose of this study is to determine the safe and tolerable dose of VAY736 for use in 
combination with ibrutinib and explore preliminary efficacy of the combination.   After the safe 
and tolerable dose of VAY736 is determined in dose escalation, two expansion arms will enroll 
CLL patients currently taking ibrutinib who have either failed to achieve a CR after >1 year of 
treatment or who have developed a mutation known to confer molecular resistance to ibrutinib 
and predict relapse.  The purpose of the expansion arms is to gather preliminary efficacy data 
in these specific groups and will test whether addition of VAY736 to ibrutinib can deepen 
responses and increase the complete response rate. 
2.2
Rationale for the study design
This open label, phase 1b study has two parts.  The purpose of the dose escalation part is to 
characterize the safety and tolerability of VAY736 in combination with ibrutinib in patients 
with relapsed, refractory CLL.  The dose escalation part of the study will be guided by a 
Bayesian Logistic Regression Model (BLRM).
The BLRM is a well-established method to estimate the MTD/RD in cancer patients.  
The adaptive BLRM will be guided by the escalation with overdose control (EWOC) principle 
to control the risk of DLT in future patients on study.  The use of Bayesian response adaptive 
models for small datasets has been accepted by EMEA (Guidelines on clinical trials in small 
populations”, February 2007) and endorsed by numerous publications (Babb et al 1998, 
Neuenschwander et al 2008, Neuenschwander et al 2010, Neuenschwander et al 2014) and its 
development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
The decision on new dose combinations are made by the Investigators and Sponsor and will be 
based upon the assessment of risk to new patients as estimated by the BLRM, patient tolerability 
and safety (including lower grade and later cycle AEs).  
 
 
The dose expansion part of the study will further evaluate safety, tolerability, as well as PK, PD 
(if available), and preliminary anti-tumor efficacy of the drug combination in specific 
populations.
2.3
Rationale for dose and regimen selection
This is the first trial that will evaluate the combination of VAY736 with ibrutinib. Drug-drug 
interactions are not expected; overlapping toxicities are not anticipated but are possible. See 
Section 1.3.3 and Section 1.3.4.
2.3.1
Rationale for ibrutinib dose and schedule
Ibrutinib will be administered at the standard approved dose in CLL, 420 mg orally 
administered daily. See ibrutinib package insert for additional information. 


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2.3.2
Rationale for VAY736 dose and schedule
Based on PK/PD modeling developed for RA patients and simulation adjusted for B cell 
baseline and dynamics in CLL patients, the proposed starting dose of VAY736 is 0.3 mg/kg i.v. 
Q2W. 
 
. Additionally, 
90% B cell depletion is associated with the mitigation of neutropenia risk and the recovery of 
absolute neutrophil counts, as described in Section 1.2.2.3. A dose-escalation approach will be 
undertaken in order to determine the appropriate dose in combination with ibrutinib. The dose 
of VAY736 will be escalated in sequential cohorts guided by a BLRM and following clinical 
review of available data as described in Section 2.2. 
2.4
Rationale for choice of combination drugs
See Section 2.1.
2.5
Rationale for choice of comparators drugs
Not applicable
2.6
Risks and benefits
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules, are included in this protocol. The risk to subjects in this trial 
may be minimized by compliance with the eligibility criteria and study procedures, as well as 
close clinical monitoring. There may be unforeseen risks with the combination of VAY736 with 
ibrutinib which could be serious. Refer to the latest version of the [VAY736 Investigators 
Brochure] and the ibrutinib package insert for more information.
 
 
 
 
 
 
 
 
2.7
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To determine the MTD and/or RD of the combination 
of VAY736 with ibrutinib
To characterize the safety and tolerability of the 
combination of VAY736 and ibrutinib
Safety
Escalation only:

Incidence of DLTs in cycle 1 (28 days)
Escalation and expansion:

Incidence and severity of AEs and SAEs, including 
changes in laboratory parameters and vital signs
Tolerability
Dose interruptions, reduction, and dose intensity
Secondary 
Refer to Section 10.5
To assess any preliminary antitumor activity of the 
combination
Rate of patients with CR as assessed by 
investigators per IWCLL at cycle 9 day 1
Overall response rate (ORR) assessed by 
investigators per IWCLL criteria and Time To 
Progression (TTP)
Clearance of ibrutinib resistance mutations (BTKC481 
and/or PLCγ2 hotspot), defined as less than 1% 
mutation bearing alleles (Arm B only).
To characterize the PK of VAY736 and ibrutinib when 
used in combination therapy
Plasma concentration of VAY736 and ibrutinib, and 
derived parameters
To assess immunogenicity (IG) following one or more 
intravenous infusions of VAY736
Presence of anti-VAY736 antibodies


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Objective
Endpoint
Analysis
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Approved for report publication by Acosta Alexandra in East Hanover at Wed, 20 Oct 2021 03:47:07 PM EDT


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4
Study design
4.1
Description of study design
The MTD and/or RDE of the combination of VAY736 with ibrutinib will be determined in this 
open-label phase Ib dose escalation trial.  Upon identification of the MTD or RDE, an expansion 
part will be opened to patient enrollment to further characterize the safety, PK, and 
pharmacodynamics (PD) of the combination.
Both the dose escalation and dose expansion parts will enroll patients with CLL who are 
currently receiving ibrutinib therapy following relapse on another approved therapy AND have 
either failed to achieve a CR after > 1 year of ibrutinib treatment OR who have developed a 
resistance mutation to ibrutinib without clinical relapse at any time during treatment. The dose 
expansion part of the study will also include patients who have received ibrutinib either alone 
or in combination (or have received ibrutinib continuously with multiple sequential 
combination partners) as first-line therapy and have either failed to achieve a complete response 
after 1 year of therapy or have developed a resistance mutation to ibrutinib. Approximately 
15-20 patients will be enrolled to the dose escalation part of the study. In the expansion part, 
approximately 40 patients will be enrolled to two arms (approximately 20 patients in each arm).  
One arm will enroll patients who have been on ibrutinib treatment for more than one year with 
evidence of residual disease and which places them at risk for clinical relapse; the other arm 
will enroll patients with acquired resistance mutations to ibrutinib who have not yet 
demonstrated clinical relapse, see Figure 4-1. All patients with acquired resistance mutations 
who are enrolled to the dose expansion part of the study will be enrolled in Arm B, irrespective 
of ibrutinib treatment duration.
Patients will receive the combination of VAY736 and ibrutinib for 6 cycles. Starting with C7D1, 
VAY736 will be discontinued if the patient has achieved a CR per IWCLL response criteria
with no evidence of disease per radiological assessment and normal blood counts at C6D15.
Ibrutinib will be administered per protocol for an additional two cycles (through C8D28). If a 
patient has not achieved a CR per IWCLL response criteria at C6D15, VAY736 and ibrutinib 
will be continued for 2 additional cycles (Cycle 7 and Cycle 8). At C9D1 (±7 days), patients 
will have their final disease assessment 
 of the study. All patients 
who have remained on study, including those who have discontinued treatment due to reasons 
other than disease progression, will be assessed at this time point. For patients who achieve a 
complete response at this assessment, investigators may consider discontinuing ibrutinib in 
order to follow patients for durability of response and minimize intolerance and toxicity 
associated with continuous ibrutinib therapy while maximizing patient quality of life.


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Figure 4-1
Study design
4.2
Timing of interim analyses and design
The dose-escalation design foresees that decisions on future dose levels based on available data 
are taken at the end of each cohort. These are described in Section 6.2.3 and Section 10.7.
The RD will be selected based on a review by Novartis study personnel and Investigators of 
available safety and tolerability information (including the DLT risk assessment from the 
BLRM using EWOC) along with PK, PD and efficacy data. The expansion part will then begin 
as specified in Section 4.1.
Details about the timing and interim analysis decisions can be found in Section 10.7.
DOSE ESCALATION
Ibrutinib daily + VAY736 IV ~20 
pts*
MTD/
RDE
DOSE EXPANSION 
Arm A (~20 pts)
CLL pts on ibrutinib ≥1 year with 
residual disease but without clinical 
relapse
Arm B (~20 pts)
CLL pts on ibrutinib with acquired 
resistance mutations but without clinical 
relapse   *Note: As of Amendment 6,  
patients will no longer be enrolled into 
Arm B
*Combination administered for either 6 cycles or 8 cycles, ibrutinib continued through 
C8D28. For patients who achieve a CR at the primary endpoint (C9D1), investigators may 
consider discontinuing ibrutinib.
**Patients will be evaluated for the final disease assessment on C9D1 (± 7 days) in 
accordance with IWCLL guidelines. 
Ibrutinib + VAY736 for 6 
cycles
C1D1
C7D1
Ibrutinib through 
C9D1*
*
Follow-up Q 3M 
for 2 years
VAY736 through C8D28 
if patients have 
evidence of disease at 
C6D15
+


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4.3
Definition of end of study
The study will end when all patients have completed the treatment period, safety period and 
two-year efficacy follow-up or have been lost to follow-up, discontinued the study for any 
reason, or the study is terminated early.
See Section 10 for details of timing of the primary analysis and final reporting of data.
4.4
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed by the sponsor of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study will enroll patients with CLL who are currently taking ibrutinib therapy following 
relapse from another approved therapy AND have either failed to achieve a CR after >1 year of 
ibrutinib treatment OR who have developed a resistance mutation to ibrutinib without clinical 
relapse at any time during treatment. The dose expansion part of the study will also include 
patients who have received ibrutinib either alone or in combination (or have received ibrutinib 
continuously with multiple sequential combination partners) as first-line therapy and have  
failed to achieve a complete response after 1 year of therapy or have developed a resistance 
mutation to ibrutinib. Patients must be taking and tolerating ibrutinib at time of enrollment with 
no limits to their continued ibrutinib use.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Patient must meet the following laboratory values at the screening visit unless cytopenias are 
related to CLL:
1. Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the World 
Health Organization (WHO) classification of hematologic disorders or International 
Workshop on Chronic Lymphocytic Leukemia (IWCLL) (Hallek et al 2018).  Variant 
immunophenotype and prolymphocytic morphology change after diagnosis of CLL is 
allowed.
2. Age ≥ 18 years
3.
 
4. Male patients agree to avoid fathering a child as per the ibrutinib package insert


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5. Dose escalation:
a. On ibrutinib > 1 year following relapse from another approved therapy without 
achieving a complete response
OR
b. On ibrutinib following relapse with another approved therapy and the presence of a 
known ibrutinib resistance mutation (BTK or PLCγ2) at ≥1 variant allele frequency 
OR <1% with two separate measurements at least 4 weeks apart with increasing 
variant allele frequency.  
6. Dose expansion:
a. Arm A: On ibrutinib > 1 year following relapse from another approved therapy 
without achieving a complete response and patients who have received ibrutinib either 
alone or in combination (or have received ibrutinib continuously with multiple 
sequential combination partners) as first-line therapy and have failed to achieve a 
complete response after 1 year.
b. Arm B: On ibrutinib following relapse with another approved therapy and patients who 
have received ibrutinib either alone or in combination (or have received ibrutinib 
continuously with multiple sequential combination partners) as first-line therapy and the 
presence of a known ibrutinib resistance mutation at ≥1% variant allele frequency OR 
<1% with two separate measurements at least 4 weeks apart with increasing variant allele 
frequency. *Note: As of Amendment 6, patients will no longer be enrolled into Arm B.
7. Ibrutinib dose:

Escalation: Patients must be receiving 420 mg ibrutinib

Expansion: Patients may be on a dose of ibrutinib lower than 420 mg.  Any dose must 
have been stable for 2 months prior to the start of study treatment.
8. Absolute Neutrophil Count ≥ 750 cells/µL (0.75 x 109/L) independent of growth factor 
support within 7 days of the first dose of VAY736
9. Platelets ≥25 x 109/L without transfusion support within 7 days of the first dose of study 
drug.  Patients with transfusion dependent thrombocytopenia are excluded.
10. Hemoglobin (Hgb) ≥8 g/dL without transfusion support within 7 days prior to the first 
dose of VAY736.
11. Creatinine Clearance ≥ 30 mL/min using Cockcroft-Gault formula (or similar institutional 
standard) or creatinine < 2x ULN
12. Total bilirubin ≤1.5 x ULN (For patients with Gilbert’s Syndrome: total bilirubin < 3.0 x 
ULN with direct bilirubin < 1.5 x ULN)
13. Aspartate transaminase (AST) ≤ 3.0 x ULN
14. Alanine transaminase (ALT) ≤ 3.0 x ULN
15. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
16. Written informed consent must be obtained prior to any screening procedures.
17. Patients with relapsed disease after prior allogeneic stem cell transplant (myeloablative or 
nonmyeloablative) will be eligible if they meet all other inclusion criteria and:
a. Do not have active (chronic or acute) GVHD and no immunosuppression
b. Are more than 6 months from transplant


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5.3
Exclusion criteria
1. History of transformation to aggressive disease histology (Large cell lymphoma) within 2 
years prior to enrollment.
2. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study entry; completely resected basal cell and squamous cell skin 
cancers, superficial bladder cancer, and completely resected carcinoma in situ of any type.
3a. Received cytotoxic or small molecule targeted anti-neoplastics, any experimental therapy 
in combination with ibrutinib as first line therapy or as a sequential combination partner, 
within 14-days or 5 half-lives whichever is shorter before the first dose of study treatment. For 
subjects that received antibodies or immunotherapies, the washout period is 4 weeks prior to 
study treatment. Patient must have recovered from any adverse effects of prior treatment prior 
to enrollment.
Protocol amendment 06 exclusion criterion #3a (denotes the first change to criterion #3)
4. Non-palliative radiotherapy within 2 weeks prior to the first dose of study drug.  
Palliative radiotherapy to a limited field, such as for the treatment of bone pain or 
focally painful tumor mass is allowed.  To allow for assessment of response to 
treatment, patients must have remained measurable disease that has not been 
irradiated
5. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes (e.g., mAb of IgG1 class)
6.
Receipt of live vaccine within a two month period before VAY736 treatment. As of 
Amendment 6, patients who received live vaccine within 4 weeks before VAY736 will 
be excluded.   
7. All acute toxic effects of any prior antitumor therapy (including ibrutinib) resolved to 
≤Grade 1 before study enrollment (with the exception of alopecia, grade 2 
neurotoxicity, or grade 2 or 3 bone marrow parameters)
8. Presence of active CNS disease
9. Known history of HIV infection
10.
 
  
 
 
 
 
11. Active, uncontrolled autoimmune cytopenias (including autoimmune hemolytic 
anemia or immune thrombocytopenia)
12. Current treatment with medications or consuming foods that are strong/moderate 
inhibitors or strong inducers of CYP3A that cannot be discontinued at least one week 


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prior to the start of treatment. Refer to Section 6.4.3 for guidance on prohibited 
medication.
13. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia
14. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following:

Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (NYHA Grade ≥ 2), uncontrolled hypertension or 
clinically significant arrhythmia

Acute myocardial infarction or unstable angina pectoris < 3 months prior to study 
entry
15. Patients with impaired hepatic function as defined by Childs-Pugh class B or C.
16. History of stroke or intracranial hemorrhage within 6 months prior to start of study 
drug
17. Evidence of active ongoing systemic bacterial, mycobacterial, fungal, or viral 
infection at the time of study enrollment. Note: Subjects with localized fungal 
infections of skin or nails are eligible. Subjects may be receiving prophylactic antiviral 
or antibacterial therapies at the discretion of the investigator.  
18. Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of study drugs, with the exception of prior 
gastrectomy (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome)
19. Unable or unwilling to swallow the oral drug as per dosing schedule
20. Two weeks since major surgery treatment (mediastinoscopy, insertion of a central 
venous access device and insertion of a feeding tube are not considered major surgery)
21. Current use of therapeutic doses of warfarin sodium or any other Coumadin-derivative 
anticoagulants.
22. Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment 
of CLL. Note: Subjects may use topical or inhaled corticosteroids as therapy for 
comorbid conditions and low-dose systemic corticosteroids (≤25 mg/day of 
prednisone or equivalent) for endocrine or rheumatologic conditions. During study 
participation, subjects may receive systemic or other corticosteroids as pretreatment 
for VAY736 infusions or as needed for treatment-emergent comorbid conditions.
23. Life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, or put the study 
outcomes at undue risk
24a. 
 
 


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6
Treatment
6.1
Study treatment
The investigational drug VAY736 will be used in combination with the marketed drug ibrutinib.
6.1.1
Dosing regimen
The dosing cycle is 28 days.  Patients will receive ibrutinib once daily continuously and 
VAY736 by i.v. once every 2 weeks (Days 1 and 15).  During the dose escalation part of the 
study, the dose of ibrutinib will be 420 mg.  During the dose expansion part of the study, 
ibrutinib will be continued at the same dose schedule as tolerated before study enrollment, see 
exclusion criteria in Section 5.2 for additional information on dose level.
A Q4W dosing schedule may also be evaluated if supported by emerging clinical data (e.g., 
safety or PK/PD or activity).  The escalation of the Q4W dosing schedule will be guided by a 
separate BLRM.  The DLT data available from VAY736 Q2W will be used to derive a MAP 
prior distribution for the Q4W dosing schedule as described in Section 10.4.2. This decision 
will be formally documented in dose-escalation meeting minutes and distributed to all study 
sites. 


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Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or 
Regimen
VAY736
Powder for solution for 
infusion
As assigned
Once every 2 weeks or 
every 4 weeks, as 
assigned
Ibrutinib
Solid dose (tablet or 
capsule) for oral use
Dose escalation: 420 mg
Dose expansion: 420 mg 
or highest tolerated dose
Daily (28 day cycles)
6.1.1.1
Instructions for ibrutinib administration

Patients should be instructed to take their dose at approximately the same time on the 
appropriate days.

On days when blood for PK samples needs to be collected, the patient should take the dose 
in the clinic.

Each dose should be taken with a glass of water and consumed over as short a time as 
possible unless otherwise instructed.

Patients should be instructed to swallow capsules/tablets whole and to not chew or open 
them unless otherwise instructed.  Patients may take either tablets or capsules as they are 
bioequivalent (Please see latest version of the ibrutinib Package Insert)

Grapefruit, grapefruit juice and Seville oranges should be avoided during the treatment 
period of the study  

On days of PK/PD sampling, every effort must be made to capture the time of any vomiting 
within 8 hours of drug administration.

If vomiting occurs during the course of the treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose.

If the patient forgets to take his/her daily dose of ibrutinib, then he/she should take the dose 
within 8 hours after the missed dose. If more than 8 hours have passed, then that day’s dose 
should be omitted and the patient should continue treatment with the next scheduled dose.

Refer to the ibrutinib package insert for additional information.
Patients should inform the investigational site staff of any missed or delayed doses.
6.1.1.2
Instructions for VAY736 administration
Refer to VAY736 pharmacy manual for information.
6.1.2
Ancillary treatments
Mild to moderate infusion related reactions have been reported in VAY736 clinical trials of 
autoimmune diseases. For the first two infusions, premedication for the risk of infusion 
reactions is required. Premedications should be administered 30 minutes to 2 hours prior to each 
of the first two infusions of VAY736 and should include oral acetaminophen 1,000 mg (or 
equivalent), oral or intravenous antihistamine, and intravenous corticosteroid (prednisolone 100 mg 
or equivalent) or similar prophylaxis based on institutional guidelines. For subsequent infusions 


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(infusions three and beyond), premedication may be administered if deemed appropriate by the 
treating physician. 
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade ≥3 anaphylactic/anaphylactoid 
reaction, the patient will be discontinued from the study. The CTCAE category of “Infusion 
related reaction” should be used to describe study treatment related infusion reactions, unless 
the investigator considers another category, such as “Allergic reaction,” “Anaphylaxis,” or 
“Cytokine release syndrome” more appropriate in a specific situation.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
Refer to Section 6.3 and Section 6.3.2 and Table 6-4
6.1.5
Treatment duration
Patients will receive VAY736 and ibrutinib in combination for up to a total of six cycles.
Patients will continue on VAY736 and ibrutinib therapy for Cycle 7 and Cycle 8 if the patient 
has evidence of disease at the radiological assessment or abnormal blood counts defined by 
IWCLL response criteria at C6D15. Starting with C7D1, VAY736 will be discontinued if the 
patient has no evidence of disease in radiological assessment and normal blood at C6D15 and 
ibrutinib will be administered for the next two cycles. 
 
 Further treatment with ibrutinib is dependent upon the outcome 
of the assessment that is conducted at C9D1 (see Section 7.1.2).
Patients may be discontinued from treatment with the study drug(s) earlier due to unacceptable 
toxicity, disease progression and/or at the discretion of the investigator or the patient. Patients, 
who discontinue VAY736 for reasons other than disease progression prior to 6 cycles of 
treatment, may continue with ibrutinib through the C9D1 assessment.  Patients who discontinue 
ibrutinib for reasons other than disease progression prior to 6 cycles of treatment may continue 
with VAY736 through cycle 6 and have a disease assessment at C9D1.  Patients who have 
disease progression and who have evidence of clinical benefit, such as disease shrinkage at 
other sites or symptomatic improvement, may continue treatment with the agent(s) being 
administered at the time disease progression is recorded. In addition, treatment may be 
temporarily interrupted to permit local therapy for symptomatic metastases after disease 
progression has been documented. Patients who continue on treatment after disease progression 
should discontinue study treatment once they are no longer deriving benefit as assessed by the 
investigator.
A patient who has experienced an interruption of more than 28 days of either one or both drugs 
may remain on study if the patient has experienced clinical benefit and the investigator believes 
it is in the best interest of the patient to remain on study and such action is agreed to by Novartis. 
Both the decision and documentation of the discussion with Novartis, must be available in the 
source documentation and described as an investigator comment in the eCRF.


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6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
6.2.1.1
Starting dose rationale for ibrutinib
Patients will be treated with the standard, approved dose of ibrutinib (420 mg). Ibrutinib will 
be taken orally continuously on 28- day cycles. This ibrutinib dose will not be escalated. See
Section 1.2, Section 2.3 and Section 6.1 as well as the ibrutinib package insert for additional 
information.
6.2.1.2
Starting dose rationale for VAY736
The starting dose of VAY736 is 0.3 mg/kg i.v. Q2W on a 28-day cycle. The selection of the 
starting dose for this study in CLL patients was determined based on the available PK/PD 
modeling developed for a single agent study in RA. Differences between RA and CLL patients
were considered for the simulations, including higher B cell baseline due to the presence of 
leukemia, lower 
 density (Rogier van Gent et al 2008, Defoiche et al 2008, Mihalcik et al 
2010), and potentially compromised ADCC effect due to long-term pre-treatment of ibrutinib 
(Kohrt et al 2014, Ysebaert et al 2014). Simulations suggest that VAY736 at 0.3 mg/kg i.v. 
 
 
The DLT data available from VAY736 Q2W will be used to derive a MAP prior distribution 
for the Q4W dosing schedule and separate BLRM will be set up for Q4W schedule.  The starting 
dose for Q4W will not exceed the highest tolerated dose evaluated using the Q2W schedule and 
satisfies the EWOC criteria for Q4W. 
6.2.1.3
VAY736 in combination with ibrutinib
No DDI is expected, and minimal overlapping toxicity is predicted (see Section 1.3.3 and
Section 1.3.4). Based on these prior safety data and the assumptions for DDI, the starting dose 
combination satisfies the EWOC criteria within BLRM (see Section 14.2)
6.2.2
Provisional dose levels
Table 6-2 describes the starting dose and the dose levels of VAY736 that may be evaluated 
during this trial. Ibrutinib will be administered at 420 mg daily during dose escalation.  During 
the dose expansion part of the study, ibrutinib will be continued at the same dose schedule as 
tolerated before study enrollment.


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Table 6-2
VAY736 provisional dose levels
Dose level
Proposed dose of VAY736*
-1**
0.1 mg/kg
1
0.3 mg/kg
2
1 mg/kg
3***
3 mg/kg
*Proposed dose regardless of whether Q2W or Q4W regimen is used. It is possible for additional and/or 
intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level 
below the MTD in order to better understand safety, PK, or PD.
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.
***If clinically indicated, dose levels higher than 3.0 mg/kg may be investigated.
6.2.3
Guidelines for dose escalation and determination of MTD/RD 
The MTD is defined as the highest combination drug doses not expected to cause DLT in 33% 
or more of the treated patients in the first cycle of treatment. Adverse events and laboratory 
abnormalities considered to be DLTs are defined in Table 6-3. This MTDs or a lower dose 
combination will then be selected as the RD(s).
The BLRM provides an estimate of the combination of VAY736 and ibrutinib not exceeding 
the MTD. Typically the MTD is the highest tested combination with less than 25% risk of 
excessive toxicity (see Section 10.4.2).
The Recommended Dose (RD) will be a dose that is less than or equal to MTD and has, in the 
view of the investigators and Novartis study personnel, the most appropriate benefit-risk 
assessment based on the review of safety and tolerability, PK, PD, and activity information. 
Note, that it is possible that the MTD may not be reached in some situations. 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level. The first cohort will be treated with the 
starting dose of 0.3 mg/kg i.v. Q2W of VAY736 in combination with 420 mg of ibrutinib daily.
Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation 
and drug exposure or have had a DLT within the first cycle of treatment to be considered 
evaluable for dose escalation decisions. Dose escalation decisions will occur when the cohort 
of patients has met these criteria and a minimum of three patients are determined to be evaluable. 
If only 2 patients in a cohort are evaluable and neither subject has experienced a treatment-
related clinically significant non hematological toxicity > CTCAE grade 1, dose escalation 
decisions may be considered.
Dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1, PK, and PD data from evaluable patients. The recommended dose 
for the next cohort of subjects will be guided by the Bayesian logistic regression model (BLRM) 
with EWOC principle.


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The adaptive Bayesian methodology provides an estimate of all dose levels of VAY736 in 
combination with 420 mg daily ibrutinib that does not exceed the MTD and incorporates all 
DLT information at all dose levels for this estimation. In general, the next dose will have the 
highest chance that the DLT rate will fall in the target interval [16-33%) and will always satisfy 
the EWOC principle. In all cases, following the half log principle for dose escalation of biologic 
agents, the dose for the next cohort will not exceed a 3.16 fold increase from the previous dose 
of VAY736. Smaller increases in dose may be recommended by the Investigators and Sponsor 
upon consideration of all of the available clinical data.
Any dose escalation decisions made by investigators and Novartis personnel will not exceed 
the dose level recommended by the BLRM using the EWOC principle. If needed to better define 
the dose-toxicity relationship additional patients may be enrolled to the current dose level, to a 
preceding dose level, or to an intermediate dose level before proceeding with further dose 
escalation.
If 2 patients in a previously untested dose level experience a DLT, enrollment to that cohort 
will stop, the BLRM will be updated and the next cohort will be opened at the next lower dose 
level or an intermediate dose level that satisfies the EWOC criteria. However, if 2 patients in a 
new cohort at a previously tested dose level experience a DLT (e.g., a total of 8 patients are 
treated on this dose level with 2 DLT observed), further enrollment to that cohort will stop, the 
BLRM will be updated with this new information and re-evaluation of the available safety, PK, 
and PD data will occur. By incorporating information gained at the preceding dose cohorts, 
additional patients may be enrolled into the current dose cohort only if the combination still 
meets the EWOC criteria and as agreed by Investigators and Novartis personnel. Alternatively, 
if recruitment to the same cohort may not resume, a new cohort of patients may be recruited to 
a lower dose combination as agreed by Investigators and Novartis personnel and if the BLRM 
predicts that the risk for this lower dose combination to exceed the MTD remains below 25% 
(EWOC). Re-escalation may then occur if data in subsequent cohorts supports this (EWOC 
criteria are satisfied) and Investigators and Novartis personnel agree.
Dose escalation will continue until identification of the MTD or a suitable lower dose for 
expansion. The MTD declaration will occur when the following conditions are met:
1. at least 6 patients have been treated at this dose
2. this dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50%  and is the 
highest among potential doses, or
b. minimum of 15 patients have already been treated on the trial.
3. it is the dose recommended for patients, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, 
see Section 6.2.3.1.
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional patients are enrolled 
at that higher dose level. Subjects ongoing will continue treatment at their assigned dose levels.


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6.2.3.1
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK and PD information will all be evaluated by the Investigators and Novartis 
study personnel (including the study physician and statistician) during a dose decision meeting 
by teleconference. Drug administration at the next higher dose level may not proceed until the 
investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level.
6.2.3.2
Intra-Patient dose escalation
Intra-patient dose escalation is not permitted at any time within the first two cycles of treatment. 
After the second cycle is completed, individual patients may be considered for treatment at a 
dose of VAY736 that is higher than the dose to which they were initially assigned. In order for 
a patient to be treated at a higher dose of VAY736, he or she must have tolerated the lower dose 
of VAY736 for at least two cycles of therapy (e.g., he or she must not have experienced at the 
lower dose pair originally assigned a toxicity of non-hematological CTCAE grade ≥ 2 for which 
relationship to study drug cannot be ruled out). Moreover, the new, higher dose level of 
VAY736 with which the patient is to be treated must be a dose that has completed evaluation 
in a dose-escalation meeting and that has not exceeded the MTD estimated by the Bayesian 
model given all available data.
Documented consultation with Novartis must occur prior to any intra-patient dose escalation 
occurring. These changes must be recorded on the Dosage Administration Record CRF.
6.2.4
Definitions of dose limiting toxicities (DLTs)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first 28 days of treatment with the combination of VAY736 
and ibrutinib and meets any of the criteria included in Table 6-3. National Cancer Institute 
Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for 
all grading. For the purpose of dose-escalation decisions, DLTs will be considered and included 
in the BLRM.  
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level.


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Table 6-3
Criteria for defining dose-limiting toxicities
For the purpose of dose escalation, DLT is defined as:
Any Grade 4 AEs are DLTs with the exception of:
Neutropenia lasting ≤ 7 days (G-CSF may be used to treat patients who have developed dose-
limiting neutropenia, as per institutional guidelines)
Lymphopenia or Leukopenia unless clinically significant
Electrolyte abnormalities that are not associated with clinical sequelae or deemed to be not 
clinically significant and are corrected with appropriate management or supplementation within 72 
hours of the onset.
Platelet count CTCAE grade 4 lasting ≤ 7 days
Thrombocytopenia not associated with clinically significant bleeding
Infection without neutropenia lasting for ≤ 7 days
Tumor lysis syndrome (TLS) persisting for ≤ 7 days despite optimal treatment
Any Grade 3 AEs are DLTs with the exception of:
Lymphopenia or leukopenia unless clinically significant
Infusion reaction that resolves to ≤ Grade 1 within 6 hours.
Infection without neutropenia lasting for ≤ 7 days
Febrile neutropenia CTCAE grade 3
Serum lipase and/or serum amylase (asymptomatic) ≤ 7 consecutive days
Nausea and vomiting that resolves within 2 days after starting optimal anti-emetic therapy.
Thrombocytopenia without significant bleeding.
Anemia that resolves within 7 days in the absence of transfusion
Isolated AST or ALT for ≤ 7 days
Diarrhea that resolves within 2 days after starting optimal anti-diarrhea treatment.
Rash or photosensitivity lasting ≤ 7 days despite skin toxicity treatment
Fatigue that resolves within 7 days
Hypertension lasting ≤ 7 days despite treatment
TLS  persisting for ≤ 7 days despite optimal treatment
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected with 
appropriate management or supplementation within 72 hours of the onset
Clinically insignificant abnormal laboratory values lasting ≤ 7 days
Hyperglycemia ≤ 7 days
The following Grade 2 AEs are considered DLTs:
Newly emerging total bilirubin ≥ 2 x ULN with ≥ CTCAE Grade 2 AST/ALT.
Total bilirubin lasting longer than 7 days
Other AEs
Any AE that leads to a dose reduction during the DLT observation period will be considered as a 
DLT.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
Dose delays or adjustments are permitted in order to allow the patient to continue study 
treatment.  If during the first cycle of treatment, a patient experiences an AE meeting the criteria 
for DLT as outlined in Table 6-3, treatment should be held.  Following interruption, treatment 
may resume at a reduced level if the toxicities resolve to grade 1 or to the patient’s baseline 


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value within the timeframes outlined in Table 6-4.  If the AE recurs any time after treatment is 
restarted, treatment must be discontinued. Adverse events that occur outside the first cycle of 
treatment should be managed as outlined below and in Table 6-4.
6.3.1.1
VAY736
Dose interruptions and/or reductions for VAY736 are recommended in order to allow patients 
to continue the study treatment. Upon the first dose adjustment, the dose of VAY736 should be 
reduced to the next lowest safe dose (or the -1 dose if toxicity occurs in the first cohort) as 
described in Table 6-2. Dose reduction below -1 dose level is not permitted. These dose 
modifications are summarized in Table 6-4. Each patient is allowed only 2 dose reductions of 
VAY736. Further dose reduction may be permitted for patients who have benefitted from 
treatment upon documented agreement by Novartis.  A patient must discontinue treatment if, 
after treatment is resumed at a lower dose, the toxicity recurs with the same or worse severity. 
6.3.1.2
Ibrutinib
For patients who do not tolerate treatment with ibrutinib, dose interruptions and/or reductions 
should be undertaken as directed in the package insert and per institutional standard. Ibrutinib 
dose should be held if VAY736 is interrupted for toxicity that is not related to infusion reactions
and resumed as per package insert following resolution of toxicity.
6.3.1.3
VAY736 and ibrutinib
Any dose changes must be recorded on the Dosage Administration Record eCRF.
If a patient requires a dose interruption of > 28 days of either VAY736 or ibrutinib from the 
intended day of the next scheduled dose, then the patient must be discontinued from the study 
unless otherwise specified in Section 6.1.5. Patients who discontinue the study for a study 
related adverse event or an abnormal laboratory value must be followed as described in
Section 6.3.2.


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Table 6-4
Criteria for dose reduction / interruption and re-initiation of VAY736 treatment for adverse drug reactions. 
Dose modifications for VAY736
Worst toxicity
CTCAE Gradea (value) during a cycle of therapy
Investigations (Hematologic)
Neutropenia (ANC)
Grades 1 -3
Maintain dose level
Grade 4 (ANC < 500/mm3)
Hold VAY736 until ANC ≥ 0.5 x 109/L, then resume VAY736 at same dose levels (with G-CSF support) or 
lower dose levels at investigator discretion.
Thrombocytopenia
Grade 4 (PLT < 25,000/mm3)
Hold VAY736 until ≤ Grade 3  then resume VAY736 at same dose levels  or lower dose levels at 
investigator discretion 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 38.5°C)
Hold VAY736 until ANC ≥ 0.75 x 109/L, then resume VAY736 at same dose levels (with G-CSF support) or 
lower dose levels at investigator discretion. 
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
May maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Delay study treatment until resolved to Grade 1 or baseline
If resolved by ≤ 7 days maintain dose level
If resolved ≥ 7 days reduce one dose level
Grade 3 (> 3.0 - 6.0 x ULN)
Delay study treatment until resolved to Grade 1 or baseline
If resolved by ≤ 7 days maintain dose level
If resolved ≥ 7 days reduce dose of VAY736
Grade 4 (> 6.0 x ULN)
Omit dose and discontinue patient from study drug treatments
Investigations (Hepatic) 
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Maintain dose level
> 1.5 - 3.0 x ULN 
Omit dose. Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 1.5 x ULN.
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level


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> 3.0 - 10.0 x ULN* 
Omit dose. Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 1.5 x ULN:
If resolved in ≤ 7 days, then ↓ 1 dose level
If resolved in > 7 days, then discontinue patient from study drug treatments. The patient should be 
monitored weekly (including LFTsb), or more frequently if clinically indicated, until total bilirubin have 
resolved to baseline or stabilization over 4 weeks. 
> 10.0 x ULN*
Discontinue patient from study drug treatments
The patient should be monitored weekly (including LFTsb), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks.
Isolated AST or ALT elevation 
> ULN - 3.0 x ULN
Maintain dose levels
> 3.0 - 5.0 x ULN
For patients with baseline value ≤ 3.0 x ULN
For patients with baseline value > 3.0 -5.0 x ULN
Maintain dose levels. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsb
weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
Maintain dose levels
> 5.0 - 10.0 x ULN
For patients with baseline value ≤ 3.0 x ULN
For patients with baseline value > 3.0 -5.0 x ULN
Omit doses. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x 
ULN Then
If resolved in ≤ 7 days, maintain dose level
If resolved in > 7 days, ↓ 1 dose level
Maintain dose level. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsb, 
weekly, or more frequently if clinically indicated, until resolved to ≤ 5.0 x ULN
> 10.0 - 20.0 x ULN 
Omit dose. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 
baseline. Then↓ 1 dose level. 
> 20.0 x ULN
Discontinue patient from study drug treatment
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to baseline or stabilization 
over 4 weeks.


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Combined c elevations of AST or ALT and total bilirubin
AST or ALT >3.0xULN combined with total bilirubin >2.0 
x ULN without evidence of cholestasisd
Permanently discontinue patient from study drug treatment.
Repeat as soon as possible, preferably within 48 hours from awareness of the abnormal results, then with 
weekly monitoring of LFTsb, or more frequently if clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks. 
Investigation (metabolic)
Asymptomatic amylase and/or lipase elevation
Grades 1-2
Maintain dose level
Grade 3 (> 2.0 - 5.0 x ULN)
Omit dose until resolved to Grade ≤,1 or baseline then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (> 5.0 x ULN)
Omit dose and discontinue patient from study drug treatment.
Vascular disorders
Hypertension
CTCAE Grade 3
Omit dose until resolved to Grade ≤,1 or baseline then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
CTCAE Grade 4
Omit dose and discontinue patient from study drug treatment
Gastro intestinal
Pancreatitis
Grade 2
Maintain dose level
Grade ≥ 3
Omit dose and discontinue patient from study drug treatment
Diarrhea**
Grade 1
Maintain dose level but, initiate anti-diarrhea treatment
Grade 2
Omit dose until resolved to ≤ grade 1, then maintain dose level.
If diarrhea returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1, then ↓ 1 dose level
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level
Grade 3
Omit dose until resolved to Grade ≤ 1, then:


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If resolved in ≤ 7 days, then↓ 1 dose level
If resolved in > 7 days (despite appropriate therapy), then discontinue patient from study drug treatment
Grade 4
Omit dose
Discontinue patient from study drug treatment
Skin and subcutaneous tissue disorders
Rash/photosensitivity
Grade 1
Maintain dose level. Consider to initiate institute appropriate skin toxicity therapy (such as antihistamines, 
topical corticosteroids and low-dose systemic corticosteroids)
Grade 2
Maintain dose level, but initiate/intensify appropriate skin toxicity therapy (such as antihistamines, topical 
corticosteroids and low-dose systemic corticosteroids)
Grade 3, despite skin toxicity therapy
Omit dose until resolved to Grade ≤ 1, then:
If resolved in ≤ 7 days, then↓ 1 dose level
If resolved in > 7 days (despite appropriate skin toxicity therapy), then discontinue patient from study drug 
treatment
Grade 4, despite skin toxicity therapy
Omit dose
Discontinue patient from study drug treament
Infusion Reaction
Grade 1
Decrease infusion rate until recovery
Grade 2
Stop infusion
Before restarting – pre-medicate as outlined in Section 6.1.2.
Restart infusion at 50% of previous rate under continuous observation. Ensure that there is a minimum 
observation period of 1 hour prior to restarting the infusion(s)
If the AE recurs at the reinitiated slow rate of infusion, and despite pre-medication, then discontinue patient 
from study
Grade 3 or 4
Discontinue treatment
Other adverse events
Grade 1 or 2
Maintain dose level
Grade 3 or 4
Hold VAY736 until resolved to ≤ Grade 1 or baseline. If toxicity resolves within 7 days, resume at the same 
dose. If treatment delay is > 7 days and ≤ 28 days, restart at lower dose level of the VAY736.  If delay is 
greater than 28 days, discontinue treatment.
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03)


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b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-
initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction
d “Cholestasis” defined as ALP elevation (>2.0 xULN and R value <2 ) in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes whether the relative pattern of ALT and/or ALP 
elevation is due to cholestatic (R ≤ 2), hepatocellular ( R ≥ 5), or mixed (R >2 and < 5) liver injury
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator.
** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea


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6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. 
Table 6-5 outlines the follow-up evaluation recommended for toxicities of specific types and 
CTCAE grades.
Table 6-5
Follow-up evaluations for selected toxicities
TOXICITY
FOLLOW-UP EVALUATION
Blood and lymphatic 
system disorders
If CTCAE Grade 4 neutropenia, thrombocytopenia or anemia, or febrile neutropenia 
occurs, test pertinent labs at least weekly until resolution to baseline or stabilization.
Hepatic 
If a hepatic adverse event occurs, ALT, AST and total bilirubin must be measured at 
least once a week until resolution to CTCAE Grade ≤ 1 or baseline.
In patients with total bilirubin Grade ≥ 2 (any duration) bilirubin should be fractionated 
into total/direct or indirect/direct components and any additional evaluation as clinically 
indicated by these results should be performed
Investigations 
(metabolic)
Amylase or lipase ≥ 
CTCAE grade 3
Test twice weekly until ≤ CTCAE grade 2, continue to test weekly until resolution to ≤ 
CTCAE grade 1 or stabilization.
A CT scan or equivalent imaging procedure to assess the pancreas, liver, and 
gallbladder is recommended within 7 days of the first occurrence of any ≥ CTCAE 
grade 3 result, to exclude disease progression or potential other liver disease.
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase also needs to be 
tested.
Cardiac disorders
QT and ECG
ECG changes 
indicative of ischemic 
event
Twice weekly ECGs until normalization or stabilization of ECG findings 
 
 
 
 
 
 
 
 
 
 


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6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF.
The use of growth-factor support (e.g. filgrastim, pegfilgrastim, erythropoietin, or darbepoetin) 
should follow standard practice according to product information and per institutional 
guidelines.  Growth factors should not be administered to allow for patient eligibility at 
screening.   Blood/platelet transfusions, the use of bisphosphonates and topical steroid products, 
and daily corticosteroid use of ≤ 10 mg/day prednisone (or equivalent) is permitted at the 
discretion of the treating physician. Therapeutic doses of anticoagulant will not be permitted. 
Low doses of warfarin for line patency are allowable.
Limited-field palliative radiotherapy to non-target lesion(s) may be allowed as concomitant 
therapy following a documented discussion with Novartis. Such local therapies administrated 
during the study treatment must be listed on the Concomitant radiotherapy/surgery case report 
form (CRF) page.
6.4.2
Permitted concomitant therapy requiring caution
Not Applicable
6.4.3
Prohibited concomitant therapy
Ibrutinib is primarily metabolized by CYP3A. The concomitant use of CYP3A inhibitors or 
inducers is likely to alter the exposure of ibrutinib, therefore moderate to strong CYP3A 
inhibitors and strong CYP3A inducers should not be used during this study. Please refer to the 
ibrutinib package insert for additional information.
6.4.4
Use of Bisphosphonates (or other concomitant agents)
Not applicable.


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6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject 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 subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the clinical database.
6.5.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort will be coordinated by Novartis or designee.
6.5.3
Treatment blinding
Not applicable
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take 
ibrutinib as per protocol. Ibrutinib will be dispensed to the patient by authorized site personnel 
only. VAY736 will be given as an IV infusion at the study center.  For specifics on the 
administration of VAY736, see the Pharmacy Manual.  All dosages prescribed to the patient 
and all dose changes during the study must be recorded on the Dosage Administration Record 
CRF.
Instructions for the preparation and storage conditions are described in the pharmacy manual.
6.6.1
Study treatment packaging and labeling
VAY736, will be provided as open label bulk medication and will be packed and labeled under 
the responsibility of Novartis, Drug Supply Management.
Ibrutinib, will be sourced as local commercial supply (in the locally approved formulation and 
packaging configuration) and labeled in the country when possible.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength) 
or randomization number if appropriate.
The storage conditions for study drug will be provided on the label.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure].


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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 will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment (VAY736 and ibrutinib) in a drug accountability log. Drug accountability 
will be noted by the field monitor during site visits and at the completion of the study. Patients 
will be asked to return all unused study treatment and packaging on a regular basis, at the end 
of the study or at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis
monitor or to the Novartis address provided in the investigator folder at each site.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 list all of the assessments and indicate with an “X”, the visits when 
they are performed. Unscheduled testing may be conducted as necessary to address safety 
concerns. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessment produce data to be entered into the 
database (D) or remain in source documentation only (S) (Category column). No CRF will be 
used as a source document.
C1D1 assessments can be conducted within 3 days prior to C1D1.  On treatment assessments 
can be conducted within 3 days prior to the planned assessment. If screening assessments are 
conducted within 3 days of C1D1, they do not need to be repeated for C1D1.


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After C1D1, tests and/or procedures should occur on schedule whenever possible. A visit 
window of +/- 3 days is allowed for assessments except imaging and PK. For PK samples, with 
the exception of collection(s) made on Day 1 (corresponding with dosing), if PK assessment 
must be delayed for scheduling purposes, it is mandatory that the correct date and time of the 
collection are captured in the eCRF.  On PK collection days, the time windows are provided in
Table 7-6, Table 7-7, and Table 7-8. In situations when dosing is delayed, PK collections should 
also be delayed until the subsequent dose is given. See Section 7.2.1 for windows on imaging.


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Table 7-1
Visit evaluation schedule for Q2W VAY736 dosing regimen
Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
15
1
15
Obtain Informed 
Consent
D
7.1.1.1
X
Demography
D
7.1.1.2
X
Inclusion/exclusion 
criteria
D
5
X
Relevant medical 
history/current 
medical conditions 
D
7.1.1.2
X
Diagnosis and 
extent of cancer
D
7.1.1.2
X
Prior 
antineoplastic 
therapy
D
7.1.1.2
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.2
X
X
Prior/concomitant 
medications
D
7.1.1.2
X
Continuous 


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Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X (Q3M after 
C9)
Performance 
status
D
7.2.2.4
X
X
X
X
X
X (Q3M after 
C9)
X
Height 
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
treatment)
Vital signs
D
7.2.2.2
X
X
X
X
X
X
Laboratory 
assessments
7.2.2.5
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X (Q3M after 
C9)
X (C5&C6)
(Additionally 
C7&C8 if 
continuing 
VAY736 
treatment)
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X (Q3M after 
C9)
X (C5&C6)
(Additionally 
C7&C8 if 
continuing 
VAY736 
treatment)
X
Direct and indirect 
Coomb’s test
D
7.2.2.5
X
Β2-microglobulin
D
7.2.2.5
X
Quantitative 
immunoglobulins
D
7.2.2.5
X
X
X (C6& C9)
This document (090095af8f475292 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 10/20/2021 7:48:19 PM, signing status at this time:  Completed (1 of 1 signatures) 
Approved for report publication by Acosta Alexandra in East Hanover at Wed, 20 Oct 2021 03:47:07 PM EDT


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Thyroid Panel
D
7.2.2.5
X
Coagulation
D
7.2.2.5
X
X
X
Urinalysis
D
7.2.2.5.3
X
Efficacy 
assessment
Radiologic1
evaluation
D
7.2.1
X
X
X ( C9)
X(C6)
X
 
 
 
D
Ibrutinib resistance 
mutation
D
7.2.2.7
X
X
X (C7 & C9)
X
ECG
D
7.2.2.6.1
X
X
Safety
Adverse events
D
8
X
Continuous 


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VAY736 
administration
D
6.1.1
X
X
X
X
X
X
X
X
X (through 
C6 if the 
patient has 
no evidence 
of disease at 
the 
radiological 
assessment 
and normal 
blood counts 
at C6D15 or
through C8 if 
there is 
evidence of 
disease at 
the 
radiological 
assessment 
or abnormal 
blood counts 
at C6D15)
X (through 
C6 if the 
patient has 
no evidence 
of disease 
at the 
radiological 
assessment 
and normal 
blood 
counts at 
C6D15 or
through C8 
if there is 
evidence of 
disease at 
the 
radiological 
assessment 
or abnormal 
blood 
counts at 
C6D15)
Ibrutinib 
administration
D
6.1.1 &
7.1.2
Continuous daily dosing through C9D1
PK sampling 
(VAY736) 
D
7.2.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (C5, C6 
only)
(Additionally 
C7, C8 if 
continuing 
VAY736 
treatment)
X (C5 & C6 
only)
(Additionally 
C7, C8 if 
continuing 
VAY736 
treatment)
X


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PK sampling 
(ibrutinib)
D
7.2.3.1
X
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
treatment)
X
VAY736 Ig
D
7.2.3.1
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
treatment)
X
End of study
D
7.1.5
X
X
Note: 1. During TTP efficacy follow up (every 3 months), radiological evaluations will be performed every 6 months
2
 


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Table 7-2
Visit evaluation schedule for Q4W VAY736 dosing regimen
Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
Obtain Informed 
Consent
D
7.1.1.1
X
Demography
D
7.1.1.2
X
Inclusion/exclusion 
criteria
D
5
X
Relevant medical 
history/current 
medical conditions 
D
7.1.1.2
X
Diagnosis and 
extent of cancer
D
7.1.1.2
X
Prior 
antineoplastic 
therapy
D
7.1.1.2
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D
7.1.2
X
X
Prior/concomitant 
medications
D
7.1.1.2
X
Continuous


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X (Q3M after 
C9)
Performance 
status
D
7.2.2.4
X
X
X
X
X
X (Q3M after 
C9)
X
Height 
D
7.2.2.3
X
X
Weight
D
7.2.2.3
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
therapy)
Vital signs
D
7.2.2.2
X
X
X
X
X
X
Laboratory 
assessments
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X (Q3M after 
C9)
X (C6)
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X (Q3M after 
C9)
X (C6)
X
Direct and Indirect 
Coomb’s test
D
7.2.2.5
X
Β2-microglobulin
D
7.2.2.5
X
Quantitative 
immunoglobulins
D
7.2.2.5
X
X
X (C6& C9)
Thyroid Panel
D
7.2.2.5
X
Coagulation
D
7.2.2.5
X
X
X


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
Urinalysis
D
7.2.2.5.3
X
Efficacy 
assessment
Radiologic1
evaluation
D
7.2.1
X
X
X ( C9)
X(C6)
X
 
 
 
D
Ibrutinib resistance 
mutation
D
7.2.2.7
X
X
X (C7 & C9)
X
ECG
D
7.2.2.6.1
X
X
Safety
Adverse events
D
8
X
Continuous 


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
VAY736 
administration
D
6.1.1
X
X
X
X
X (through 
C6 if the 
patient has 
no evidence 
of disease at 
the 
radiological 
assessment 
and normal 
blood counts 
at C6D15 or
through C8 if 
there is 
evidence of 
disease at 
the 
radiological 
assessment  
or abnormal 
blood counts 
at C6D15)
Ibrutinib 
administration
D
6.1.1 &
7.1.2
Continuous daily dosing through C9D1
PK sampling 
(VAY736) 
D
7.2.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X (C5, C6)
X


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
(Additionally 
C7, C8 if 
continuing 
VAY736 
treatment)
PK sampling 
(ibrutinib)
D
7.2.3.1
X
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
treatment)
X
VAY736 Ig
D
7.2.3.1
X
X
X
X
X
X (through 
C6 or through 
C8 if 
continuing 
VAY736 
treatment)
X
End of study
D
7.1.5
X
X


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Cycle 
4
Subsequent cycles
End of 
study 
treatment 
(EoT)
30-
day 
Follow 
up
TTP
Day of cycle 
1
2
4
8
15
1
15
1
2
4
8
15
1
1
15
Note: 1 During TTP efficacy follow up (every 3 months), radiological evaluations will be performed every 6 months
2
 


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7.1.1
Screening
Screening starts after a patient has provided written informed consent to participate in the study 
and ends on the day of the first dose of VAY736 and ibrutinib.  Screening assessments have to
be done within 21 days prior to the first dose with the exception of baseline tumor assessments 
and informed consent.  Screening tumor assessments collection can be conducted within 28 
days of first dose and informed consent can be obtained within 3 months of the first dose.  
Assessments conducted prior to obtaining informed consent as a part of routine disease care can 
be used to satisfy eligibly criteria as long as the procedures were performed within the allowed 
windows.
7.1.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on VAY736 for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details).
7.1.1.2
Patient demographics and other baseline characteristics
Participant demographics: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and relevant medical history/current medical 
conditions (until date of signature of informed consent) will be recorded in the eCRF. Where 
possible, the diagnosis and not symptoms should be recorded. Participant race/ethnicity data 
are collected and analyzed to identify any differences in the safety and/or efficacy profile of the 
treatment due to these characteristics. In addition, the diversity of the study population needs to 
be assessed as required by Health Authorities.
7.1.2
Treatment period
The study treatment period for each patient begins when the patient receives the first dose of 
VAY736 in combination with ibrutinib and ends at C9D1. Patients will receive the combination 
of VAY736 and ibrutinib for six cycles. Patients will continue VAY736 for 2 additional cycles 
in combination with ibrutinib if there is evidence of disease at the radiological assessment or 
abnormal blood counts defined by IWCLL response criteria at C6D15. For the purpose of 
scheduling and evaluations, a treatment cycle is 28 days. VAY736 will be discontinued at C7D1
if the patient shows a complete radiological response or normal blood counts at C6D15 and 
ibrutinib will continue for an additional 2 cycles. All patients will have final response 
assessment
 Further treatment or follow-up will depend 
on status of response at C9D1. One of the following actions will be taken for patients:

Patients who experience disease progression at C9D1 (or any time prior to C9D1) will 
discontinue treatment and will have required end of treatment assessments conducted.

Patients whose disease is assessed as stable disease, partial response, at C9D1 may 
continue ibrutinib and will be followed every 3 months for two years for TTP assessments, 


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with the exception of CT scans which will be performed every 6 months unless the patient 
experiences disease progression or the administration of a new therapy.  If the patient 
continues to receive ibrutinib past C9D1, the details of administration will be recorded on 
the Antineoplastic therapies since discontinuation eCRF.

For patients whose disease is assessed as CR at C9D1, investigators may consider
discontinuing ibrutinib, and be followed every 3 months for two years for TTP
assessments, with the exception of CT scans which will be performed every 6 months
unless the patient experiences disease progression or the administration of a new therapy.
Although investigators may consider discontinuing ibrutinib if patients have a  CR at 
C9D1, if the patient continues to receive ibrutinib past C9D1, the details of administration 
will be recorded on the Antineoplastic therapies since discontinuation eCRF.
Patients who discontinue one of the combination drugs (ibrutinib or VAY736) prior to six cycles 
of treatment for reasons other than disease progression may continue the other drug until the 
end of treatment period (VAY736 until C6D28 or ibrutinib until C8D28).  All patients 
regardless of study treatment duration, who have not progressed, will have a final disease 
assessment at C9D1 (end of treatment period).
7.1.3
Discontinuation of study treatment
Patients who discontinue study treatment (as defined in Section 7.1.2) on or before C9D1 for 
any reason will have an EOT visit and assessments conducted within 14 days of the last dose 
of study treatment or within 14 days of the decision to discontinue study treatment, see 
Table 7-1 or Table 7-2 for assessments to be conducted.  
During the study treatment period (defined in Section 7.1.2), patients will be monitored to assess 
safety and any anti-tumor activity of the treatment.  
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, 
or become lost to follow-up for any other reason.
Study treatment must be discontinued under the following circumstances:

Adverse events, that results in a significant risk to the patient’s safety.

The following deviation from the prescribed dose regimen for study treatment: dose 
interruption of > 28 days from the intended day of the next scheduled dose, unless 
otherwise specified in Section 6.1.5.

Pregnancy

Any other protocol deviation that results in a significant risk to the patient’s safety

Study terminated by Novartis

Patient/guardian decision
Patients who have achieved a CR may discontinue treatment at investigator discretion. 


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7.1.3.1
Replacement policy 
Escalation part:
Patients will not be replaced on study. However, if a subject is considered as non-evaluable for 
the DDS, enrollment of a new subject to the current cohort will be considered if there is less 
than the required number of evaluable subjects. Enrollment of new subjects may be considered 
until at least the minimum number (3) or at most the maximum number (6) of evaluable subjects 
is achieved within the cohort. Minimum and maximum numbers of evaluable subjects per 
cohort are defined in Section 6.2.3.
Expansion part:
During the dose expansion part no replacements will be needed.
7.1.4
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study anymore, and

Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.  
7.1.5
Follow up for safety evaluations
All patients will be followed for a 30 day safety follow-up period subsequent to completion of 
VAY736 therapy.  Patients who continue on ibrutinib after the discontinuation of VAY736 
regardless of when this occurred will be followed for safety according to the ibrutinib package 
insert. No new AEs or SAEs will be collected beyond the 30 day safety follow-up or during the 
two-year efficacy follow up period. Any data that is collected should be added to the Adverse 
Events CRF and the Concomitant Medications CRF. The end of study eCRF should be 


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completed after the patient has discontinued from the study, either after the 30 day safety 
follow-up period or at progression that occurs during the two-year efficacy follow-up.
7.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy will be evaluated as per the IWCLL Guidelines (Appendix 1).
Tumor assessments will be performed at screening and according to the schedule of -
assessments (Table 7-1 or Table 7-2, as applicable based on the dosing regimen of VAY736).  
All screening tumor assessments should be performed as closely as possible to the start of 
treatment (preferably within 7 days) and never more than 28 days before the start of treatment.  
On-treatment radiological examinations and MRD assessments have a +/- 7 day window.
Clinical suspicion of disease progression at any time will require a disease evaluation promptly, 
rather than waiting for the next scheduled tumor assessment.  In case of an unscheduled or 
delayed disease evaluation for any reason, subsequent tumor assessments should be performed 
according to the originally planned schedule unless a scan has been performed within 28 days.
All patients discontinuing from the study for progressive disease must have their disease 
progression documented.  
Chest, abdomen and pelvis CT scans are required for all subjects at screening. If clinically 
indicated, neck CT scans should also be acquired at screening.  Post baseline scans should only 
be performed in these anatomical regions that demonstrated disease at baseline.  In case of 
clinical complete response, confirmation scans of chest, abdomen and pelvis are required and 
neck if appropriate.
CT scans should be acquired with intravenous (i.v.) contrast. If a patient is known to have a 
medical contraindication to CT i.v. contrast agent or develops a contraindication during the 
study, a CT scan without contrast should be acquired. If inguinal and/or femoral nodes are 
present, every effort should be made to ensure that pelvis CT scans cover both inguinal areas in 
their entirety. 
Magnetic resonance imaging (MRI) will be allowed only in those cases when CT scans cannot 
be performed.  Each lesion that is measured at baseline/screening must be measured by the same 
method throughout the study so that the comparison is consistent. For complete details, refer to
Appendix 1.


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For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed as outlined in Table 7-1 or Table 7-2, as appropriate for the dosing regimen of 
VAY736, until documented disease progression, death, lost to follow-up, or withdrawal of 
consent.
 
 
 as indicated in Table 7-1 and 
Table 7-2.
 
 
(Hallek et al 2018). As such, patients will be defined as having 
 if they have blood or marrow with <1 CLL cell per 10, 000 leukocytes.
Table 7-3
Disease assessment collection plan
Procedure
Screening/baseline
During treatment/follow-up
CT or MRI 
with contrast enhancement 
(Chest, Abdomen, Pelvis)
Mandated
Refer to Table 7-1 or Table 7-2, 
as appropriate for VAY736 dose 
regimen.
 
 
 
7.2.2
Safety and tolerability assessments
Safety and tolerability assessments will include adverse event reporting and changes from 
baseline in laboratory measures and vital signs.  For details on AE collection and reporting, 
refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination will be conducted at screening and during Cycle 1 
(Table 7-1 or Table 7-2, as appropriate for VAY736 dose regimen) and include the examination 
of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
A short physical exam will include the examination of general appearance and vital signs (blood 
pressure [BP] and pulse). A short physical exam will be at all visits starting from Cycle 2, Day 1.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature.


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7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1 or Table 7-2, as appropriate for the dosing 
regimen of VAY736.
7.2.2.4
Performance status
ECOG performance status scale will be used as specified in Table 7-1 or Table 7-2, as
appropriate for the dosing regimen of VAY736.
Table 7-4
ECOG Performance Status
Score
Performance Status
0
Fully active, able to carry on all pre-disease activity 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 out any self-care. Totally confined to bed or chair.
5
Death
7.2.2.5
Laboratory evaluations
Table 7-5
Local clinical laboratory parameters collection plan 
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCV, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, 
Other (absolute value preferred , %s are acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT , AST, Lactate dehydrogenase (LDH), 
Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Direct Bilirubin, Total Bilirubin, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Amylase, Lipase, Glucose
Immunology
Β2-Microglobulin, quantitative immunoglobulins (IgA, IgG, IgM), Direct and  Indirect 
Coomb’s test
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells) – only to be done if needed based on Macroscopic Panel findings
Coagulation
Prothrombin time (PT) , International normalized ratio [INR]), Partial thromboplastin time 
(PTT), Activated partial thromboplastin time (APTT)
Thyroid
T4 [free], TSH


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7.2.2.5.1 Hematology assessments
Hematology assessments in Table 7-5 will be conducted at the time points listed below on the 
days outlined in Table 7-1 or Table 7-2, as appropriate for the VAY736 dosing regimen, within 
the windows outlined in Section 7.1.3.

C1D1: Pre-dose and 6 hours post-dose

Remaining time points are collected as per the table. If the collection is on a treatment 
day, the sample is collected pre-dose.
7.2.2.5.2 Chemistry assessments
Chemistry assessments will be conducted at the time points listed below on the days listed in 
Table 7-5 on the days outlined in Table 7-1 or Table 7-2, as appropriate for the VAY736 dosing 
regimen, within the windows outlined in Section 7.1.3.

C1D1: Pre-dose and 6 hours post-dose

Remaining time points are collected as per the table. If the collection is on a treatment 
day, the sample is collected pre-dose.
7.2.2.5.3 Urinalysis
Assessments will be conducted as directed in Table 7-5 on the days outlined in Table 7-1 or
Table 7-2 as appropriate for the VAY736 dosing regimen, within the windows outlined in
Section 7.1.3.
 
 
 
  
 
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed in accordance with institutional practice for patients 
at screening, end of treatment, and as clinically indicated.
7.2.2.7
Ibrutinib resistance mutation
Blood or bone marrow samples collected on the days outlined in Table 7-1 or Table 7-2 will be 
analyzed in accordance with the CVAY736Y2102 laboratory manual.


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7.2.3
Pharmacokinetics and immunogenicity:
PK samples will be collected from all enrolled patients to assess PK properties of VAY736 and 
ibrutinib. Immunogenicity (IG) samples will also be collected to monitor appearance of 
anti-drug antibodies (ADAs) directed against VAY736. Refer to Table 7-6, Table 7-7 and 
Table 7-8 for details on PK and IG sample collections. 
 
7.2.3.1
Pharmacokinetics and immunogenicity blood sample collection and 
handling
If the dosing of Cycle 3 Day 1 for VAY736 or Cycle 1 Day 8 for ibrutinib is delayed, the PK 
sampling for the full PK profile should be delayed until the dose of VAY736 or ibrutinib is 
administered.  On the date of administration, the PK samples should be collected to match the 
scheduled time points for Cycle 3 as outlined in Table 7-6 or Table 7-7 for VAY736 or Cycle 1 
in Table 7-8 for ibrutinib.
Exact dates and actual PK blood draw times will be recorded on the appropriate eCRF. 
Any sampling problems (e.g. patient administrated with study drug before the PK blood draw 
took place) must be noted in the comments section of the eCRF and on appropriate source 
documentation.
If any of the scheduled sampling times are missed or a sample is not drawn according to this 
schedule, the actual collection date and time will be recorded and the remaining samples will 
be collected on schedule whenever possible.
If vomiting occurs within 8 hours following ibrutinib administration on the day of PK sampling, 
where post-dose time-points are collected, no additional study medication should be taken in 
an effort to replace the material that has been vomited. The time (using the 24-hour clock) of 
vomiting should be recorded in the Adverse Events eCRF.
Unscheduled PK samples should be collected if any of the following events occur:

If a patient treated with investigational drugs experiences an AE that results in an 
unscheduled visit or fits the criteria of a SAE or DLT, as determined by the investigator.

Whenever an ECG with a QTcF change from baseline > 60 ms or a new absolute QTcF 
≥501 ms result is known. The exact time of sample collection should be noted in the 
unscheduled eCRF.

In the event of other clinically significant AEs (such as infusion reaction/anaphylaxis) or if 
immunogenicity is suspected.

During safety follow-up period either at or prior to end of safety follow-up period
Residual PK and IG serum or plasma samples used for PK and IG analysis may also be used 
for 
 metabolites and/or PD analyses related to VAY736 or ibrutinib therapy and 
cancer.  If conducted, these results will be reported separately.
Refer to the [VAY736Y2102 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK and immunogenicity samples.


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Table 7-6
Pharmacokinetic blood collection log for VAY736 Q2W dosing 
(VAY736, IG,
)
Cycle 
Day
Scheduled Time Point (hr)a,b
Analytesc,d
1
1
Pre-dose b
Post-dose 2 hr or End of infusion (±5 
min)
Post-dose 6 hr (±15 min)
VAY736, IG, 
VAY736, 
         
VAY736
1
2
Post-dose 24 hr (±1 hr)
VAY736, 
1
4
Post-dose 72 hr (±2 hr)
VAY736
1
8
Post-dose 168 hr (±2 hr)
VAY736, 
1
15
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
VAY736         
2
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
VAY736        
2
15
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736
VAY736         
3
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
VAY736, 
 
3
2
Post-dose 24 hr (±1 hr)
VAY736, 
3
4
Post-dose 72 hr (±2 hr)
VAY736
3
8
Post-dose 168 hr (±2 hr)
VAY736, 
3
15
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, 
 
VAY736         
4
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
         
VAY736        
4
15
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736
VAY736         
5
1
Pre-dose
VAY736, IG, 
         
5
15
Pre-dose
VAY736       
6
1
Pre-dose
VAY736, IG, 
         
6
15
Pre-dose
VAY736       
7 (if applicable)
1
Pre-dose
VAY736, IG, 
7 (if applicable)
15
Pre-dose
VAY736
8 (if applicable)
1
Pre-dose
VAY736, IG,


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Cycle 
Day
Scheduled Time Point (hr)a,b
Analytesc,d
8 (if applicable)
15
Pre-dose
VAY736
EOT 
---
VAY736, IG, 
              
Unscheduled 
---
VAY736, IG, 
              
a Blood samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will 
need to be flushed with 10 mL of saline prior to blood sample collection.
b Sampling time is relative to the start of the latest VAY736 infusion; Pre-dose blood samples should be 
collected prior to the start of the latest VAY736 infusion
c VAY736 PK, IG, and 
 samples in serum, and 
 samples in whole blood
d IG blood samples to be collected for anti-drug antibody together with PK samples
Table 7-7
Pharmacokinetic blood collection log for VAY736 Q4W dosing 
(VAY736, IG,
)
Cycle 
Day
Scheduled Time Point (hr)a,b
Analytesc, d
1
1
Pre-dose b
Post-dose 2 hr or End of infusion (±5 
min)
Post-dose 6 hr (±15 min)
VAY736, IG, 
VAY736, 
     
    
VAY736
1
2
Post-dose 24 hr (±1 hr)
VAY736, 
1
4
Post-dose 72 hr (±2 hr)
VAY736
1
8
Post-dose 168 hr (±2 hr)
VAY736, 
1
15
Post-dose 336 hr (±2 hr)
VAY736, IG, 
2
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG,
VAY736        
3
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
VAY736, 
 
3
2
Post-dose 24 hr (±1 hr)
VAY736, 
3
4
Post-dose 72 hr (±2 hr)
VAY736
3
8
Post-dose 168 hr (±2 hr)
VAY736, 
3
15
Post-dose 336 hr (±2 hr)
VAY736, 
        
4
1
Pre-dose
Post-dose 2 hr or End of infusion (±5 
min)
VAY736, IG, 
         
VAY736        
5
1
Pre-dose
VAY736, IG, 
         
6
1
Pre-dose
VAY736, IG, 
         


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Cycle 
Day
Scheduled Time Point (hr)a,b
Analytesc, d
7 (if applicable)
1
Pre-dose
VAY736, IG, 
8 (if applicable)
1
Pre-dose
VAY736, IG, 
EOT 
---
VAY736, IG, 
              
Unscheduled 
---
VAY736, IG,
              
a Blood samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will 
need to be flushed with 10 mL of saline prior to blood sample collection.
b Sampling time is relative to the start of the latest VAY736 infusion; Pre-dose blood samples should be 
collected prior to the start of the latest VAY736 infusion
c VAY736 PK, IG, and 
samples in serum, and 
 samples in whole blood
d IG blood samples to be collected for anti-drug antibody together with PK samples
Table 7-8
Pharmacokinetic blood collection log for ibrutinib
Cycle 
Day
Scheduled Time Point (hr)
Analytesb
1
1
Pre-dose
Post-dose 0.5 hr (±5 min) a
Post-dose 2 hr (±5 min) a
Post-dose 6 hr (±15 min)a
Ibrutinib
Ibrutinib
Ibrutinib
Ibrutinib
1
2
Pre-dose
Ibrutinib
1
8
Pre-dose
Post-dose 0.5 hr (±5 min)a
Post-dose 2 hr (±5 min) a
Post-dose 6 hr (±15 min)a
Ibrutinib
Ibrutinib
Ibrutinib
Ibrutinib
2
1
Pre-dose
Ibrutinib
3
1
Pre-dose
Ibrutinib
4
1
Pre-dose
Ibrutinib
5
1
Pre-dose
Ibrutinib
6
1
Pre-dose
Ibrutinib 
7 (if applicable)
1
Pre-dose
Ibrutinib
8 (if applicable)
1
Pre-dose
Ibrutinib
EOT 
---
Ibrutinib
Unscheduled 
---
Ibrutinib
a The need for these time points in expansion phase will be assessed based on emerging PK data analyzed 
during the dose escalation part of the study
bIbrutinib samples are collected in plasma
7.2.3.2
Analytical method
The assay to quantify ibrutinib in plasma will be a validated liquid chromatography mass 
spectrometry (LC-MS) assay. The details of the assay will be documented in the 
[VAY736Y2102 laboratory manual].
The assay to quantify VAY736 in serum will be a validated sandwich ELISA assay. The details 
of the assay will be documented in the [VAY736Y2102 laboratory manual].


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The assay to quantify and assess the ADA against VAY736 in serum will be a validated ECL 
(Electrochemiluminescence) assay. The details of the assay will be documented in the 
[VAY736Y2102 laboratory manual].
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring will be 
conducted as outlined in Section 7.1.5. 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 and graded 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, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.


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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 1-5)
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 was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved, 
recovered/resolved with sequelae, fatal, unknown).
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
disease assessment method (IWCLL), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should 
be followed until they have returned to normal or an adequate explanation of the abnormality 
is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 


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already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study.
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
to document the objective progression of underlying malignancy.
If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE.


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8.2.2
Reporting
For patients who sign the main study ICF, SAE collection starts at the time of main study 
informed consent, whether the patient is screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and as outlined in Section 7.1.5 must be reported to 
Novartis within 24 hours of learning of its occurrence. If a patient starts a post-treatment 
antineoplastic therapy, then only SAEs suspected to be related to study treatment will be 
reported.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes 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.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
 
 
 
 


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8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.5
Data Monitoring Committee 
A formal data monitoring board will not be used for this study. Novartis will have access to the 
Safety Data on a regular basis. Novartis will host investigator teleconferences on a regular basis 
during the study. Further, during the phase I part of the study Novartis and the investigators will 
meet at the end of each treatment cohort to discuss and evaluate all of the gathered safety data. 
At the dose escalation teleconference the clinical course (safety information including both 
DLTs and all CTCAE Grade 2 or higher toxicity data during the first cycle of treatment, and 
PK data) for each patient in the current dose cohort will be described in detail. Updated safety 
data on other ongoing patients, including data in later cycles, will be discussed as well.
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the BLRM with EWOC and a medical review of relevant clinical, PK and 
laboratory data. Novartis and the investigator parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or recruit an 
additional cohort of patients at the current dose level (Section 10.4.2).
8.6
Steering Committee 
Not applicable


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. 
If the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Age will be solicited (in the place of 
exact date of birth) to establish that the subject satisfies protocol age requirements and to enable 
appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The investigator is responsible for assuring that the data entered into eCRF is complete, accurate, 
and that entry and updates are performed in a timely manner.
In addition to data entered into the eCRFs, requisition forms may also need to be completed for 
 PK sample collection.
9.4
Database management and quality control
Novartis personnel, or designee, will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.


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10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized using 
descriptive statistics (continuous data) and/or contingency tables (categorical data) for 
demographic and baseline characteristics, efficacy measurements, safety measurements and all 
relevant pharmacokinetic and pharmacodynamics measurements.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Patients treated with the same dose level and schedule of VAY736 will be pooled into a single 
treatment group (includes patients from dose escalation and dose expansion parts) for all safety 
analysis. 
For efficacy all analysis will be provided by dose level in dose escalation and by two arms in 
dose expansion. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.
Continuing events (e.g., AEs, concomitant medication, etc.) will be summarized using the data 
cut-off date as the date of completion, with a flag to indicate within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event.
The primary clinical study report (CSR) will be written based on all patient data from the dose 
escalation and dose expansion parts at the time when all patients have completed the study 
treatment period, or discontinued the study, or the study is terminated early. The additional data 
for any patients remaining in safety or disease follow-up beyond the cut-off point will be 
summarized in a final CSR that will be prepared at the end of study (Section 4.3).
Details of the statistical analysis and data reporting will be provided in the Novartis report and 
analysis preparation documents finalized prior to database lock.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) and Safety set are defined in the same way and comprise all 
patients who received at least one dose of study treatment. Patients will be analyzed according 
to the study treatment received where treatment received is defined as the treatment most 
frequently taken between Study Day 1 and the end of cycle 1 (the first 28 days of dosing), the 
onset of a DLT or treatment discontinuation whichever occurs first. 


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10.1.2
Safety set
See definition of FAS
10.1.3
Per-Protocol set
Not applicable
10.1.4
Dose-determining analysis set
The Dose-Determining Set (DDS) includes all patients from the FAS (escalation and expansion 
parts) who met the minimum exposure criterion and had sufficient safety evaluations, or 
experienced a dose limiting toxicity (DLT) during cycle 1 (the first 28 days of dosing).
A patient has met the minimum exposure criterion if the patient takes during the first 28 days 
the planned doses of VAY736 and 75% of the planned doses of ibrutinib  (i.e. two doses of 
VAY736 Q2W or one dose of VAY736 Q4W, and ≥ 21 of 28 daily doses of ibrutinib).
Patients who do not experience a DLT during cycle 1 (the first 28 days of dosing) are considered 
to have sufficient safety evaluations if they have been observed for ≥ 28 days following the first 
dose, and are considered by both the Sponsor and Investigators to have enough safety data to 
conclude that a DLT did not occur. Patients will be analyzed according to the study treatment 
received as defined for FAS.
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the DDS and an additional patient may be recruited (Section 7.1.3.1).
10.1.5
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all subjects who provide an evaluable PK
profile. A profile is considered evaluable if all of the following conditions are satisfied:

Subject receives one of the planned treatments

Subject provides at least one primary PK parameter

Subject did not vomit within 8 hours after the dosing of ibrutinib
10.1.6
Other analysis sets 
Not applicable
10.1.6.1 Efficacy/evaluable set
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively for the FAS.
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term for the FAS.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below.
The duration of exposure in days to VAY736 and ibrutinib as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 
the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics using the safety set.
The duration of exposure will also be presented for the combined study treatment by dose cohort 
in the dose escalation or by two arms in the dose expansion.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by dose cohort in the dose escalation or 
by two arms in the dose expansion and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
10.4
Primary objective
The primary objective is to characterize the safety and tolerability of the combination of 
VAY736 with ibrutinib and to determine the MTD/RD for expansion.
10.4.1
Variable

Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)

Changes in laboratory parameters, vital signs, and electrocardiograms (ECGs)

Incidence of DLTs during the first treatment cycle (escalation only)

Dose interruptions, reductions and dose intensity
Estimation of the MTD in the dose-escalation part of the study will be based upon the estimation 
of the probability of DLT in Cycle 1 for patients in the dose-determining set. This probability 
is estimated by the statistical models in Section 10.4.2.
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as clinically relevant, occurring ≤ 28 days following the first administration of study 
treatment as defined in Section 6.2.4, Table 6-3.
10.4.2
Statistical hypothesis, model, and method of analysis
Safety and tolerability
For the analysis of safety and tolerability endpoints see Section 10.5.3 in addition to DLT as 
below.


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Identification of a recommended dose
Estimation of the MTD of the treatment will be based upon the estimation of the probability of 
DLT in cycle 1 for patients in the DDS.  A recommended dose below the MTD may be identified 
based on other safety, clinical, PK, and PD data (Section 6.2.3).
Bayesian adaptive approach
The dose escalation part of this study will be guided by a Bayesian analysis of Cycle 1 dose 
limiting toxicity (DLT) data for VAY736 and ibrutinib.   The Bayesian analysis will be based 
on a model with three parts, representing:

Single agent VAY736 toxicity

Single agent ibrutinib toxicity

Interaction 
Single agent toxicity is modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose.  The odds of a DLT are then calculated under no 
interaction for the two single agent toxicities, and interaction is accounted for by adjusting these 
odds with an additional model parameter (odds multiplier).  Details of the model are given in 
(Appendix 2).
Assessment of patient risk
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated.  The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals: 
Under-dosing:
[0 , 0.16)
Targeted toxicity:
[0.16 , 0.33)
Excessive toxicity:
[0.33 , 1]
The escalation with overdose control (EWOC) principle
Dosing decisions are guided by the escalation with overdose control principle (Rogatko 2007).  
A combination dose may only be used for newly enrolled patients if the risk of excessive 
toxicity at that combination dose is less than 25%.
Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent VAY736, and single-agent ibrutinib model parameters.  The MAP prior for the 
logistic model parameters for this study is the conditional distribution of the parameters given 
the historical data (see Spiegelhalter 2004, Neuenschwander 2010, Neuenschwander 2014).  
MAP priors are derived from hierarchical models, which take into account possible differences 
between the studies.
A full description of the application of the MAP approach to derive the prior distributions of 
the single agent VAY736, and single-agent ibrutinib model parameters is given in Appendix 2
(Section 14.2).  


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The prior distribution for the interaction parameter was based upon prior understanding of 
possible drug safety interactions.  This prior allows for the possibility of either synergistic or 
antagonistic interaction, and is fully described in Appendix 2 (Section 14.2).
Starting dose
The starting dose is 0.3 mg/kg Q2W of VAY736 and 420 mg daily ibrutinib (Section 6.2.1). 
For this dose combination the prior risk of excessive toxicity is 8.9% approximately, which
satisfies the EWOC criterion.  A full assessment of the prior risk to patients is given in 
Appendix 2 (Section 14.2).
Change in dose schedule
In the case that additional dosing schedules for VAY736 are explored during dose-escalation, 
a BLRM of the same functional form will be used to estimate the dose-DLT relationship for 
each new schedule. Data from previous or concurrently explored schedules will be used to 
inform the dose escalation for the new schedule. At each time the decision is taken to explore a 
new schedule, the model to be used to guide escalation in that schedule will be constructed. 
The model will be finalized prior to first patient treated under the new schedule, and will be 
documented in full in CSR Section 16.1.9. The details may refer to Appendix 2 (Section 14.2). 
In addition in case VAY736 Q2W dosing schedule continues and new dosing schedule is 
explored during dose-escalation, a BLRM of the same functional form described in 
Appendix 2 (Section 14.2) will be used to estimate the dose-DLT relationship for each schedule 
based on a newly derived prior incorporating the historical trial data and the on-study data from 
previous schedule. 
Listing of DLTs
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 4.03).  Listings and summaries will be based on the DDS.
 
 
 
 
 


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10.5
Secondary objectives
Refer to Table 3-1 for secondary objectives.  The following subsections describe the analysis 
of related secondary objectives.
10.5.1
Key secondary objective(s)
Not applicable
10.5.2
Other secondary efficacy objectives
All efficacy analyses are based on FAS.
Rate of CR at C9 for expansion arm A and arm B: The proportion of patients with CR, 
assessed by investigators per IWCLL criteria (see Appendix 1 for details) at C9 will be provided.  
The rate of CR at C9 is the primary endpoint for the evaluation of anti-tumor activity and will 
be analyzed for each expansion arm using a Bayesian modeling approach.
A minimally informative beta distribution is used as prior distribution with parameters a=0.25 
and b=1. This assumes a priori response rate of 20%.
Posterior summaries for CR rate (posterior mean, including 90% credible intervals and the 
posterior probability that the true CR rate falls in the activity intervals defined below) will be 
provided:
Posterior probability of response rate intervals:
-
[0, 20%) – clinically not meaningful
-
[20%, 40%) – moderate clinical benefit
-
[40%, 100%] – superior clinical benefit
In addition, exact confidence interval (90% CI) also will be provided.
Clearance of ibrutinib resistance mutation for expansion arm B is defined as less than 1% 
mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. The proportion of patients 
with negative mutation will be provided along with corresponding 90% exact confidence 
interval (CI). 
Overall response rate (ORR) is defined as best overall response (BOR) of complete response 
(CR) or partial response (PR), assessed by investigators per IWCLL criteria (see Appendix 1
for details). ORR for each expansion arm along with corresponding 90% exact confidence 
interval (CI) will be provided.
Time to progression (TTP) is the time from start of treatment to the date of event which is 
defined as the first documented progression or death due to underlying cancer. If a patient has 
not had an event, time to progression is censored at the date of last adequate disease assessment.
TTP will be described using Kaplan-Meier methods and appropriate summary statistics. .


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10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Serious adverse events and non-serious adverse events will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE
Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE,


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
Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
10.5.3.4 Other safety data
ECG

Listing of ECG evaluations for all patients with at least one abnormality
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.

Shift table baseline to worst on-treatment result

Table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points
10.5.3.5 Supportive analyses for secondary objectives 
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the SAP prior to database lock (DBL). 
10.5.3.6 Tolerability
Tolerability of study drug will be assessed by summarizing the number of dose delays and dose 
reductions. Reasons for dose delays and dose reductions will be listed by patient and 
summarized.
10.5.4
Pharmacokinetics
PK parameters will be determined using non-compartmental method(s) for VAY736 and 
ibrutinib. PK parameters such as those listed in Table 10-1 will be estimated and reported, when 
applicable. PAS will be used in all pharmacokinetic data analysis and summary statistics. 
Table 10-1
Noncompartmental pharmacokinetic parameters 
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) after first dose and at steady-state 
(amount x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) (volume)
Descriptive statistics of all pharmacokinetic parameters will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 


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not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter. 
Summary statistics will be presented for VAY736 and ibrutinib concentrations at each 
scheduled time point. Descriptive graphical plots of individual concentration versus time 
profiles and mean concentration versus time profiles will be generated.
Dose Proportionality
The analysis of dose proportionality may be conducted for AUC and Cmax of VAY736 using 
a power model on log-transformed scale, if data allows. The log-transformed PK parameters 
will each be regressed onto a fixed factor for log (dose). The 90% confidence interval (CI) of 
the slope for each PK parameter will be computed from the model and presented in the summary 
table.
Immunogenicity
The presence and/or concentration of anti-VAY736 antibodies (Anti-Drug Antibody) will be 
listed by patient and summarized (when sample size is sufficient) using descriptive statistics to 
assess IG following one or more intravenous infusion of VAY736.
 
 
 
 
10.5.4.1 Data handling principles
Concentration values below the lower limit of quantitation (LLOQ) or missing data will be 
labeled as such in the concentration data listings. Concentrations below the LLOQ will be 
treated as zero in summary.


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10.5.6
Resource utilization
Not applicable
10.5.7
Patient-reported 
Not applicable


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10.7
Interim analysis
No formal interim analyses are planned. However, the dose-escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose escalation part, the next dose of VAY736 in combination with ibrutinib 
has to be chosen depending on the observed data. Details of this procedure and the process for 
communication with Investigators are provided in Section 6.2.3.
 
 
 
 


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pharmacokinetic parameters as required. Minimum of fifteen patients are expected to be treated 
 
 
 
 
 
.
 
 
 
 
 
 
 


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11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (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 CRFs.
Novartis, or designee, will provide to investigators, in a separate document, a proposed 
informed consent form (ICF) that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to this ICF suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
 
 
 
there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Not applicable
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4


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11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional clinical trials in adult patients are posted on
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion those for interventional clinical trials involving pediatric patients within 6 
months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 


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and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
11.10
Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.

Thank You letter

Plain language trial summary - after CSR publication
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 


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investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (available upon request)
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Mutations in Patients with CLL Treated with BTK Inhibitor and Lack of Mutations in 
Ibrutinib-Naive Patients. Blood, 126, 716-716.
Albitar A, Ma W, DeDios I, et al. (2017) Using high-sensitivity sequencing for the detection 
of mutations in BTK and PLCgamma2 genes in cellular and cell-free DNA and correlation 
with progression in patients treated with BTK inhibitors. Oncotarget.
Badoux X, Tam C, Lerner S, et al. (2009) Outcome of First Salvage Therapy in Patients With 
Chronic Lymphocytic Leukemia Relapsing After First-line Fludarabine, Cyclophosphamide, 
and Rituximab. Clinical Lymphoma & Myeloma, 9, E39-E40.
Barr PTR, Owen CJ, Tedeschi A, et al. (2016) Updated Efficacy and Safety from the Phase 3 
Resonate-2 Study: Ibrutinib As First-Line Treatment Option in Patients 65 Years and Older 
with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. American Society of 
Hematology Annual Meeting. Blood.
 
Burger JA, Keating MJ, Wierda WG, et al. (2014) Safety and activity of ibrutinib plus 
rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 
study. Lancet Oncol, 15, 1090-1099.
Byrd JC, Brown JR, O'Brien S, et al. (2014) Ibrutinib versus ofatumumab in previously 
treated chronic lymphoid leukemia. N Engl J Med; 371(3):213-223.
Byrd JC, Furman RR, Coutre S E, et al. (2015) Three-year follow-up of treatment-naive and 
previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, 125, 
2497-2506.
Byrd JC, Furman RR, Coutre SE, et al. (2013) Targeting BTK with ibrutinib in relapsed 
chronic lymphocytic leukemia. N Engl J Med, 369, 32-42.
Chanan-Khan A, Cramer P, Demirkan F, et al. (2016) Ibrutinib combined with bendamustine 
and rituximab compared with placebo, bendamustine, and rituximab for previously treated 
chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, 
double-blind, phase 3 study. Lancet Oncol, 17, 200-211.
 
Chen SS, Raval A, Johnson A J et al. (2009a) Epigenetic changes during disease progression 
in a murine model of human chronic lymphocytic leukemia. Proc Natl Acad Sci U S A, 106, 
13433-13438.
Chen SS, Sherman MH, Hertlein E, et al. (2009b) Epigenetic alterations in a murine model for 
chronic lymphocytic leukemia. Cell Cycle, 8, 3663-3667.
 
Damle RN, Wasil T, Fais F, et al. (1999) Ig V gene mutation status and CD38 expression as 
novel prognostic indicators in chronic lymphocytic leukemia. Blood, 94, 1840-1847.


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DeClaro RA, McGinn KM, Verdun N, et al (2015) FDA Approval: Ibrutinib for Patients with 
Previuosly Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic 
Leukemia. Clin Cancer Res, 21, 3586-3590.
Defoiche J, Debacq C, Asquith B, et al. (2008) Reduction of B Cell Turnover in Chronic 
Lymphocytic Leukaemia. Brit J Haematology , 143, 240-247.
Dohner H, Stilgenbauer S, Benner A, et al. (2000) Genomic aberrations and survival in 
chronic lymphocytic leukemia. N Engl J Med, 343, 1910-1916.
 
 
 
Enzler T, Kater AP, Zhang W et al. (2009) Chronic lymphocytic leukemia of Emu-TCL1 
transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to 
accelerate disease progression. Blood, 114, 4469-4476.
Furer V, Rondaan C, Heijstek MW, et al. (2020) 2019 Update of EULAR recommendations 
for vaccination in adult patients with autoimmune inflammatory rheumatic diseases Annals of 
the Rheumatic Diseases, 79, 39-52.
 
Gorgun, G, Ramsay AG, Holderried, TA, et al. (2009) E(mu)-TCL1 mice represent a model 
for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. 
Proc Natl Acad Sci U S A, 106, 6250-6255.
Hallek, M, Cheson, BD, Catovsky, D, et al. (2018 iwCLL guidelines for diagnosis, indications 
for treatment, response assessment, and supportive management of CLL. Blood,131, 2745-
2760.
He B, Chadburn A, Jou E et al. (2004) Lymphoma B cells evade apoptosis through the TNF 
family members BAFF/BLyS and APRIL. J Immunol, 172, 3268-3279.
Jaglowski, SM, Jones, JA, Nagar, V, et al. (2015) Safety and activity of BTK inhibitor 
ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. 
Blood, 126, 842-850.
Janssen Research & Development, L. 2016. Investigator's Brochure IMBRUVICATM 
(ibrutinib) JNJ-54179060. 10.1 ed.
Johnson AJ, Lucas DM, Muthusamy N, et al. (2006) Characterization of the TCL-1 transgenic 
mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. 
Blood, 108, 1334-1338.
 


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Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. (2014) Ibrutinib antagonizes rituximab-dependent NK 
cell-mediated cytotoxicity. Blood, 123, 1957-1960.
Liu TM, Woyach, JA, Zhong Y, et al. (2015) Hypermorphic mutation of phospholipase C, 
gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor 
activation. Blood, 126, 61-68.
Maddocks KJ, Ruppert AS, Lozanski G, et al. (2015) Etiology of Ibrutinib Therapy 
Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA 
Oncol, 1, 80-87.
 
 
 
 
 
 
 
Moore P A, Belvedere O, Orr A, et al. (1999)  BLyS: member of the tumor necrosis factor 
family and B lymphocyte stimulator. Science, 285, 260-263.
Nabhan C and Rosen, ST (2014) Chronic lymphocytic leukemia: a clinical review. JAMA, 
312, 2265-2276.
 
 
Neuenschwander B, Capkun-Niggli G, Branson M, et al. (2010) Summarizing Historical 
Information on Controls in Clinical Trials. Clin Trials, 7, 5-18.
Neuenschwander B, Matano A, Tang Z, et al. (2014) A Bayesian Industry Approach to Phase 
I Combination Trials in Oncology. Statistical Methods in Drug Combination Studies: 
Chapman & Hall.
O’Brien SFR, Coutre S, Flinn I, et al (2016) Five-Year Experience With Single-Agent 
Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory Chronic 
Lymphocytic Leukemia/Small Lymphocytic Leukemia. Blood (sup), 128, 233.
O’Brien S, Furman RR, Coutre SE, et al (2014) Ibrutinib as Initial Therapy for Elderly 
Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lyphoma: an Open-
Label, Multicentre, Phase 1b/2 trial. Lancet Oncol, 15, 48-58.
O'Brien S, Furman RR, Coutre S, et al (2018) Single-agent ibrutinib in treatment-naive and 
relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood; 131(17):1910-
1919.
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leukemia. Blood, 46(2), 219–234.


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Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol, 25, 4982-4986.
 
 
Shanafelt TD, Borah BJ, Finnes HD, et al (2015) Impact of ibrutinib and idelalisib on the 
pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal 
levels. J Oncol Pract; 11(3):252-258.
Shanafelt TD, Wang V, Kay NE, et al (2018) A Randomized Phase III Study of Ibrutinib 
(PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab 
(FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic 
Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood;
132(Suppl 1):LBA-4-LBA-4.
 
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Health-Care Evaluation. Chichester: John Wiley and Sons.
Tam CS, O'Brien S, Plunkett W, et al. (2014) Long-term results of first salvage treatment in 
CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood, 
124, 3059-3064.
 
van Gent R, Kater AP, Otto SA, et al. (2008) In Vivo Dynamics of Stable Chronic 
Lymphocytic Leukemia Inversely Correlate with Somatic Hypermutation Levels and Suggest 
No Major Leukemic Turnover in Bone Marrow. Cancer Res, 68, 10137-10144.
Wiczer TE, Levine LB, Brumbaugh J, et al (2017) Cumulative incidence, risk factors, and 
management of atrial fibrillation in patients receiving ibrutinib. Blood Adv; 1(20):1739-1748.
 
Woyach JA, Furman RR LiuT-M, Ozer HG, et al. (2014b) Resistance Mechanisms for the 
Bruton's Tyrosine Kinase Inhibitor Ibrutinib. New England Journal of Medicine, 370, 2286-
2294.
Woyach JA, Ruppert AS, Guinn D, et al. (2016) BTKC481S-Mediated Resistance to Ibrutinib 
in Chronic Lymphocytic Leukemia. Journal of Clinical Oncology, 0, JCO.2016.70.2282.


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Woyach JA, Ruppert AS, Heerema NA, et al (2018) Ibrutinib Regimens versus 
Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med; 379(26):2517-
2528.
 
 
 


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14
Appendices
14.1
Appendix 1 – Guidelines for NCI CLL Working Group 2018
(IWCLL)
This appendix refers to Hallek et al 2018.
Table 14-1
Response definition after treatment for patients with CLL
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical 
trials or by physical examination in general practice).
†Spleen size is considered normal if <13 cm. There is not firmly established international consensus of the size of 
a normal liver; therefore, liver size should be evaluated by imaging and manual palpation in clinical trials and be 
recorded according to the definition used in a study protocol.
CR, complete remission (all of the criteria have to be met); PD, progressive disease (at least 1 of the criteria of 
group A or group B has to be met); PR, partial remission (for a PR, at least 2 of the parameters of group A and 1 
parameter of group B need to improve if previously abnormal; if only 1 parameter of both groups A and B is 
abnormal before therapy, only 1 needs to improve); SD, stable disease (all of the criteria have to be met; 
constitutional symptoms alone do not define PD).
GroupParameter
CR
PR
PD
SD
A
Lymph nodes
None ≥1.5 cm
Decrease ≥50% 
(from baseline)*
Increase ≥50% from 
baseline or from 
response
Change of −49% to 
+49%
Liver and/or 
spleen size†
Spleen size <13 cm; 
liver size normal
Decrease ≥50% 
(from baseline)
Increase ≥50% from 
baseline or from 
response
Change of −49% to 
+49%
Constitutional 
symptoms
None
Any
Any
Any
Circulating 
lymphocyte 
count
Normal
Decrease ≥50% from 
baseline
Increase ≥50% over 
baseline
Change of −49% to 
+49%
B
Platelet count
≥100 × 109/L
≥100 × 109/L or 
increase ≥50% over 
baseline
Decrease of ≥50% 
from baseline 
secondary to CLL
Change of −49 to 
+49%
Hemoglobin
≥11.0 g/dL 
(untransfused and 
without erythropoietin)
≥11 g/dL or increase 
≥50% over baseline
Decrease of ≥2 g/dL 
from baseline 
secondary to CLL
Increase <11.0 g/dL 
or <50% over 
baseline, or 
decrease <2 g/dL
Marrow
Normocellular, no CLL 
cells, no B-lymphoid 
nodules
Presence of CLL 
cells, or of B-
lymphoid nodules, or 
not done
Increase of CLL 
cells by ≥50% on 
successive 
biopsies
No change in 
marrow infiltrate


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Table 14-2
Grading scale for hematologic toxicity in CLL studies
Grade*
Decrease in platelets† or Hb‡ (nadir) from pretreatment 
value, %
Absolute neutrophil count/μL§
(nadir)
0
No change to 10%
≥ 2000
1
11%-24%
≥ 1500 and < 2000
2
25%-49%
≥ 1000 and < 1500
3
50%-74%
≥ 500 and < 1000
4
≥ 75%
< 500
* Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as grade 5. † Platelet counts must be below normal levels for 
grades 1 to 4. If, at any level of decrease, the platelet count is < 20 × 109/L (20000/μL), this will be considered 
grade 4 toxicity, unless a severe or life-threatening decrease in the initial platelet count (eg, 20 × 109/L [20000/μL]) 
was present pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts.
‡ Hb levels must be below normal levels for grades 1 to 4. Baseline and subsequent Hb determinations must be 
performed before any given transfusions. The use of erythropoietin is irrelevant for the grading of toxicity but 
should be documented.
§ If the absolute neutrophil count (ANC) reaches < 1 × 109/L (1000/μL), it should be judged to be grade 3 toxicity. 
Other decreases in the white blood cell count, or in circulating neutrophils, are not to be considered because a 
decrease in the white blood cell count is a desired therapeutic endpoint. A gradual decrease in granulocytes is not 
a reliable index in CLL for stepwise grading of toxicity. If the ANC was < 1 × 109/L (1000/μL) before therapy, the 
patient is not evaluable for toxicity referable to the ANC. The use of growth factors such as G-CSF is not relevant 
to the grading of toxicity, but should be documented.
References
Hallek, M, Cheson, BD, Catovsky, D, et al (2018). iwCLL guidelines for diagnosis, 
indications for treatment, response assessment, and supportive management of CLL. Blood, 
131, 2745-2760.


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14.2
Appendix 2 – BLRM, prior, hypothetical dose escalation 
scenarios and operating characteristics
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, the results of the Bayesian analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study of the operating characteristics of the model.
14.2.1
Statistical model 
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part. DLT of the first cycle (28 days) data is used 
in the model. Due to the different administrations and frequency from historical data for the 
VAY736 treatment group (as prior data below), the total cycle 1 dose (mg/kg) is used for the 
VAY736 treatment group in the model.  The daily dose (mg) is used for the Ibrutinib treatment 
group in the model. 
14.2.1.1 Single agent parts 
The study is planned to administer VAY736 Q2W and Ibrutinib daily with 28-day dosing 
schedule and DLTs are assessed for the first cycle (28 days).
Let () be the risk of DLT of the first cycle for VAY736 given as a single agent at total 
cycle 1 dose (Q2W VAY736 dose mg/kg ∗2); () be the risk of DLT of the first cycle   
for Ibrutinib given as a single agent at daily dose  (mg) .  These single agent dose-DLT 
models are logistic:
VAY736
logit() = log() + ! log( 
∗
⁄
)                                      (1)
Ibrutinib:
logit() = log() + ! log( 
∗
⁄
)
                           (2)
where   
∗= 3.0 mg/kg total cycle 1 dose (1.5mg/kg ∗2) and 
∗= 420 mg daily are used 
to scale the doses of VAY736 and Ibrutinib, respectively.  Hence,  and  (>0) are the single-
agent odds of a DLT of the cycle 1 at 3.0 mg/kg  total cycle 1 dose and  420 mg daily, 
respectively; and  ! and !  are the increase in the log-odds of a DLT by a unit increase in 
log-dose.
14.2.1.2 Interaction 
Under no interaction, the risk of a DLT at dose  of VAY736 and dose  of Ibrutinib is:

. (, ) = 1 −1 −()1 −()
To allow for interaction between VAY736 and dose  of Ibrutinib, an odds multiplier is 
introduced. The risk of DLT for combination dose (, ) is then given by:
odds(, ) = exp(1 ×  
∗
⁄
×  
∗
⁄
) × odds
. (, )
where odds() =  (1 −)
⁄
; and 1 is the log-odds ratio between the interaction and no 
interaction model at the reference doses. i.e.,  3.0 mg/kg(1.5 mg/kg ∗2)  of  total cycle 1 
VAY736 and 420 mg of  daily Ibrutinib.  Here 1 = 0 corresponds to no interaction, with 1 > 0
and 1 < 0 representing synergistic and antagonistic toxicity respectively.


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14.2.2
Prior specifications 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log(), log(!) for VAY736,  log(), log(!) for 
Ibrutinib, and the interaction parameter 1.  A meta-analytic-predictive (MAP) approach was 
used to derive the prior distribution for the single-agent model parameters for VAY736. 
A weakly-informative prior is derived for the single-agent model parameters for ibrutinib. 
14.2.2.1 Prior distribution for the logistic parameters 
14.2.2.1.1
Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
log(∗), log(!∗) of the new trial using DLT data from historical studies. 
Let 567 and 867 be the number of patients with a DLT, and the total number of patients at dose 
 in historical study VAY736Y2101 and each of the four autoimmunity clinical program 
historical studies, i.e., s=1,2,3,4,5  represent data from VAY736Y2101, and autoimmunity 
historical studies VAY736X2101, VAY736X2201, VAY736X2202, and VAY736X2203, 
respectively. The corresponding probability of a DLT is 67.  The model specifications are as 
follows:
567 | 67 ~ Bin(67, 867)
logit(67) = log(7) + !7 log(/∗)
;<=(7), ;<=(!7) > ?, @A(7) ~ BVN?, @A(7),
s = 1, … ,5
;<=(∗), ;<=(!∗) > ?, @ ~ BVN(?, @)
The parameter ? = (?, ?)  is the mean for the logistic parameters, and @A is the between-
trial covariance matrix for exchangeability group = = 1,2.  Covariance matrix @A is defined by 
the standard deviations A, A, and correlation (a common value for is used across all 
groups).  The parameters A and A quantify the degree of between trial heterogeneity for 
exchangeability group =.  With different prior distributions for the parameter sets A, A it 
is possible to allow for differential discounting for the historical strata.  In this way the quality 
and relevance of historical data can be accounted for in the meta-analysis.  The following priors 
will be used for these parameters:  

normal priors for ? and ?, 

log-normal priors for A and A, and 

a uniform prior for .
The MAP prior for single-agent model parameters in the new trial, ;<=(∗), ;<=(!∗), is the 
predictive distribution 
;<=(∗), ;<=(!∗) > (567, 867 ∶F = 1, … , 5)


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Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution.  This is implemented using JAGS version 4-6. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions. BVN 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster 1977).  The optimal number of 
components of the mixture is then identified using the Akaike information criterion (AIC) 
(Akaike 1974).
14.2.2.1.2
Single agent VAY736 
For the MAP model for VAY736, total cycle 1 reference dose ∗= 3.0 mg/kg is used; data 
from G = 5 historical studies is available; and  H = 2 exchangeability groups are assumed.
Weakly informative priors are assumed for ? and ?, with means corresponding to a risk of 
DLT at the reference dose of 9.3% (  i.e.,  based on the assumed 3.6% DLT at the starting dose 
from the model (1) above) , and a tripling in dose leading to a doubling in the odds of the risk 
of a DLT.  For the 2 exchangeability groups the priors for A, A are assigned such that 
(1) their medians correspond to small and moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014).  The prior distributions for the model used for deriving the MAP 
priors are specified in Table 14-3.
Table 14-3
Prior distributions for the parameters of the MAP model used to derive 
the prior for single-agent VAY736 model parameters
Exchangeable group
Parameter
Prior distribution
?
N(mean = logit(0.093), sd = 2)
?
N(mean = log(log(2)/log(3)), sd = 1)

uniform(-1,1)
1 small heterogeneity

lognormal(mean = 0.125, sd = log(2)/1.96)

lognormal(mean = 0.0625, sd = log(2)/1.96)
2 moderate heterogeneity

lognormal(mean = 0.25, sd = log(4)/1.96)

lognormal(mean = 0.125, sd = log(4)/1.96)
Historical data
Autoimmunity 
clinical 
studies
VAY736X2101, 
VAY736X2201, 
VAY736X2202, 
VAY736X2203 (Assigned to exchangeability group 2) and study VAY736Y2101 (Assigned to 
exchangeability group 1) subject exposures to VAY736 and DLTs are presented in the 
Table 14-4 below.  
A review of AE records of the patients in autoimmunity clinical studies did not indicate any 
significant toxicity in the historical studies presented in Table 14-4 below.  VAY736 was well 
tolerated, only few SAEs were observed and none of the SAEs were drug related. In addition 
those few SAEs that occurred in autoimmunity studies are irrelevant to current CLL patients.
For VAY736Y2101 there was one patient reported as dose limiting toxicity and SAE (grade 3 
hemolytic autoimmune anemia), however this patient had baseline autoimmune anemia.


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Substantial heterogeneity is assumed due to the difference in population, indication and dosing 
schedule from autoimmune studies to current study; Small heterogeneity is expected between 
VAY736Y2101 and current study. Therefore two exchangeability groups are assigned as below. 
The new trial is assigned to exchangeability group 1.
Table 14-4
Historical DLT data from Studies VAY736X2101, VAY736X2201, 
VAY736X2202, VAY736X2203 and VAY736Y2101
Historical studies/ 
Exchangeability groups
(G)
Total cycle 1 dose 
(<mg/Kg>)
#of DLTs/# of evaluable pts
VAY736X2101/2
.0003
0/3
.001
0/3
.003
0/3
.01
0/4
.03
0/3
.1
0/3
.3
0/9
.86
0/12
1
0/9
3
0/3
10
0/3
VAY736X2201/2
3
0/6
10
0/17
VAY736X2202/2
10
0/8
VAY736X2203/2
3
0/7
10
0/5
VAY736Y2101/1
.008
1/3
Notes: 
1. The data is based on Investigators Brochure released on 29-Aug-2016 and safety cut-off date on 30-Jun-2016.
2. .The total cycle 1 dose (mg/kg) for VAY736 treatment is used to incorporated data from different 
administrations. 
3. DLT presented in the VAY736Y2101 is within cycle 1( 28 days window); DLT presented in the autoimmunity 
studies are within study duration which may occurs beyond cycle 1, which can be deemed as conservative 
estimate for counting AEs to occur within the first cycle of VAY736 treatment. 
To make the prior more robust, an additional mixture component corresponding to a high 
toxicity scenario is added to the MAP prior. For this component, the median probability of DLT 
at the total cycle 1 reference dose 3.0 mg/kg  is 12%; the median for the prior distribution of 
log(β) is set to log(log(2)/log(3)) at the reference dose which assumes a tripling dose leads to a 
doubling of the odds of DLT. The median DLT rates of total cycle 1 doses 0.6 mg/kg, and 4.0 
mg/kg are approximately 3.3%, and 15.4%, respectively. Standard deviations for log(α) and 
log(β) are set to 2 and 1 respectively, with correlation I = 0.
The weight assigned to the 3 components of the MAP prior is 0.80 in total, and the weight 
assigned to the high toxicity prior component is 0.20. The mixture components are weighted 
based upon a priori assessment of their relevance to the toxicity of combination of VAY736 
and Ibrutinib in humans. The prior distribution is described in full in Table 14-3.


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14.2.2.1.3
Single agent Ibrutinib 
Based on clinical toxicology data (Section 1.2.4.1) a weakly informative prior is derived for 
which the median probability of DLT at dose 420 mg daily is assumed to be 8%.  The review 
of historical safety data were summarized in the Table 14-5 below. The observed historical rate 
of discontinued from study due to adverse events is approximately 4% at 420 mg ibrutinib daily.  
Due to the lack of precise DLT data from historical studies, the current 8% DLT for cycle 1 is 
assumed to be conservative.
The median for the prior distribution of log(!) was set to 0, to correspond to a doubling of dose 
leading to a doubling of the odds of DLT. The standard deviation for log() is derived 
assuming that there is 90% probability that the DLT rate is lower than 33% at 420 mg daily 
reference dose. The standard deviation for log(!) is 1. The correlation between the log() and 
log(!) is I = 0. The prior distribution is described in full in Table 14-6.
Table 14-5
Historical data for ibrutinib
Study #
Dose of ibrutinib (daily)
# of discon. due to AEs / # of evaluable  
patients (%)
(Byrd et al 2013)
420mg
2/51(4%)
840mg
4/33(12%)
(Byrd JC et al 2015)
420mg
8/195(4%)
14.2.2.2 Prior distribution for the interaction parameters 
Although no interaction is expected for the two agents, uncertainty remains.  Therefore, a 
normal prior for the log-odds multiplier centered at 0 is used that allows for both synergistic 
and antagonistic toxicity.
-
1 is normally distributed, with mean 0, and standard deviation 0.858
-
At the total cycle 1 starting dose of 0.6 mg/kg (0.3 mg/kg *2) the corresponding 
distribution for the odds ratio has mean 1.000 and a 97.5th percentile of 1.4, i.e. 1.4-fold 
increase in odds of DLT due to interaction compared to no interaction.


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14.2.2.3 Summary of prior distributions 
The prior distributions of the model parameters are summarized in Table 14-6. Prior summaries 
for DLT rates for are summarized in Table 14-7.
Table 14-6
Prior distribution for the model parameters 
Parameter
Mean
Standard 
Deviations (SD)
Correlation
Weight
Single agent VAY736 MAP prior, total cycle 1 reference dose 3.0 mg/kg
BVN mixture log(), log(!)
Three-
component 
MAP prior
Component 1
(-4.795,  -1.876)
(0.908,   0.665)
-0.137
0.355
Component 2
(-4.035  -1.443)
(0.645,   0.490)
-0.017
0.347
Component 3
(-3.770, -2.310)
(0.540,   0.668)
0.299
0.098
High-tox 
component
Component 4 
( -1.992, -0.461)
(2, 1)
0
0.200
Single agent Ibrutinib weakly-informative prior, reference dose 420 mg
BVN log(), log(!)
(-2.442, 0)
(1.353, 1)
0
N/A
Interaction parameter 1
Normal
1
0
0.858
N/A
N/A
Table 14-7
Summary of prior distribution of DLT rates
VAY736
dose (mg/kg) 
Q2W
Prior probabilities that 
P(DLT) is in the interval:
Mean
SD
Quantiles
[0, 
0.16)
[0.16, 
0.33)
[0.33,1]
2.5%
50%
97.5%
In combination with Ibrutinib 420mg  daily
0.1
0.665
0.206
0.129
0.156
0.156
0.013
0.101
0.600
0.3
0.650
0.212
0.139
0.164
0.163
0.014
0.106
0.628
1.0
0.606
0.218
0.176
0.186
0.188
0.013
0.117
0.725
2.0
(intermediate)
0.561
0.195
0.245
0.223
0.236
0.007
0.129
0.861
3.0
0.534
0.163
0.303
0.260
0.282
0.003
0.137
0.945
- The grey shaded rows indicate dose combinations not meeting the EWOC criterion, that there is ≥25% 
chance of excessive toxicity, i.e. DLT rate in [0.33, 1]. 
- The starting dose level is highlighted in bold. Total cycle 1 VAY736 dose is used in the BLRM. i.e., 2 * mg/Kg 
Q2W.
Change in dose schedule
In the case that additional dosing schedules for VAY736 are explored during dose-escalation, 
a BLRM of the same functional form will be used to estimate the dose-DLT relationship for 
each new schedule.  Data from previous, or concurrently explored schedules will be used to 
inform the dose escalation for the new schedule. At each time the decision is taken to explore a 
new schedule, the model to be used to guide escalation in that schedule will be constructed.  
The model will be finalized prior to first patient treated under the new schedule, and will be 
documented in full in CSR Section 16.1.9. 


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14.2.3
Hypothetical on-study data scenarios
To illustrate the performance of the Bayesian model used to guide dose escalation, hypothetical 
dose escalations scenarios following the provisional dose levels specified in Table 14-8 are 
displayed.  In each case, the maximum dose that can be used in the next cohort of patients is 
shown.  This maximum dose is determined using the model based assessment of the risk of 
DLT in future patients and the dose escalation rules as described in Section 6.2.3.  In practice a 
dose below the maximum might be chosen based on additional safety, PK or PD information 
(Section 6.2.1.1).
Table 14-8
Hypothetical dose escalation scenarios 
Scenario
Dose
Number of
Next dose combination
Ibrutinib 420 mg 
daily +
VAY736 (mg/kg) 
Q2W
Patients
DLTs
Ibrutinib 420 mg 
daily +
VAY736 (mg/kg) 
Q2W
Median 
P(DLT)
P(excessive 
toxicity)
1
0.3
3
0
1.0
0.076
0.065
2
0.3
3
1
0.3
0.173
0.192
3
0.3
3
2
stop
4
0.3
4
1
1.0
0.163
0.191
5
0.3
1.0
3
4
0
0
3.0
0.052
0.111
6
0.3
1.0
3
4
0
1
1.0
0.124
0.072
7
0.3
1.0
3
6
0
1
3.0 
0.131
0.233
8
0.3
1.0
3
6
0
2
1.0
0.185
0.147
9
0.3
1.0
4
5
0
1
1.0
0.105
0.044
10
0.3
1.0
4
6
0
1
3.0
0.122
0.218
11
0.3
1.0
4
5
1
0
3.0
0.082
0.145
14.2.4
Operating characteristics 
A simulation study is used to illustrate the long run performance of the Bayesian dose escalation 
model.  Several example scenarios were investigated (Section 14.2.4.1), and in each case 1000 
trials were simulated, with results summarized in Section 14.2.4.1.1.


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14.2.4.1 Scenarios 
Table 14-9 shows three dose-DLT scenarios as follow:
-
Scenario 1 represents the situation in which the true probability of DLT is in line with the 
prior, i.e. P(DLT) = prior median.
-
Scenario 2: the odds of DLTs are1.5-fold larger than the ones of scenario 1.
-
Scenario 3: the odds of DLTs increases steeper and rapidly early as dose goes higher, 
where the DLT rate at 1.0 mg/kg bi-weekly is approximately 55%.
Table 14-9
True probability of DLT for simulation scenarios 
Test 
scenarios
Dose of VAY736(bi-weekly) in combination with 
Ibrutinib 420 (mg daily)
Note
0.1 mg/kg
0.3 mg/kg
1.0 mg/kg
3.0 mg/kg
1
0.101
0.106
0.117
0.137
True dose-DLT relationship based on prior 
median  rates
2
0.152
0.159
0.176
0.206
1.5-fold odds increased from scenario 1
3
0.101
0.180
0.550
0.700
More toxic  and steeper than scenario 1
14.2.4.1.1
Simulation details 
Data for 1000 trials are simulated for each scenario and the total minimum number of DLT to 
control the declaration of MTD is fixed to one. The starting dose combination is set to 420 mg 
daily Ibrutinib and 0.3mg/kg Q2W VAY736 and follows the protocol specifications 
(Section 6.2.3). At each dose escalation, the highest VAY736 dose in combination with 
ibrutinib 420 mg daily satisfying the EWOC criterion is chosen for the next cohort.
The number of patients to enroll in each cohort and stopping rules used to declare MTD are 
defined as:

Cohort size: 3-6

Minimum number of patients enrolled: 15

Maximum number of patients enrolled: 40

Minimum number of patients enrolled at a given dose combination in order to declare 
MTD: 6
Simulation results 
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were:

Metric I: Average proportion of patients in target dose region (>=16% - 33%).

Metric II: Average proportion of patients in over dose region (>= 33%).

Metric III: Average proportion of patients in under dose region (< 16%).

Metric IV: Proportion of trials with MTD in target dose region (>= 16% - 33%). 


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
Metric VI: Proportion of trials with MTD in under dose region (< 16%).

Stopped: Proportion of trials stopped with no MTD identified.

Ave N: Average number of patients dosed.

Ave DLT: Average number of DLTs observed.
Table 14-10
Summary of simulation results 
Scenario
Metrics (%)
I
II
III
IV
(Target 
MTD)
V
(Overdose
MTD)
VI
(Under-
dose 
MTD)
Stopped
Ave N
Ave DLT
1
  0
  0
100
0
0
91.4
8.6
18.8
2.3
2
62.2
  0
  37.8
66.3
0
15.6
18.1
17.3
3.0
3
54.8
39.0
    6.2
39.9
7.7
0.2
52.2
14.4
4.7
The operating characteristics show that the BLRM with the derived informative prior perform 
reasonable under the three hypothetical scenarios investigated. In scenario 1 all patients are 
treated in under dose region due to the low assumed true DLT rate in all dose levels (less than 
13%). The proportion of patients treated in the target dose region is about 62% (Metric I) in 
scenario 2. 
The probabilities to identify a MTD in the target dose region (Metric IV) are approximately 66% 
for scenario 2 and 40% for scenario 3, respectively. The chance of identifying a MTD that is in 
fact excessively toxic is controlled at 8% for scenario 3.
Approximately 9-19% of the trials stopped in Scenario 1 and 2. Even the lowest dose has a 
considerable DLT rate of above 10-15% at the starting dose even though the whole dose cure 
are both relatively flat. In the scenario 3, the chance of stopping without identifying a MTD is 
52% due to the relative high toxicity at the starting dose, resulting in a high probability of seeing 
DLTs early in the dose escalation.  
The average number of patients needed are between 14 to 19, and approximately 2-5 DLT’s are 
expected.


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References
Akaike H. (1974) A new look at the statistical model identification. IEEE Transactions on 
Automatic Control, AC-19. 716–723
Byrd JC, Furman RR, Coutre S E, et al. (2015) Three-year follow-up of treatment-naive and 
previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, 125, 
2497-2506.
Byrd JC, Furman RR, Coutre SE, et al. (2013) Targeting BTK with ibrutinib in relapsed 
chronic lymphocytic leukemia. N Engl J Med, 369, 32-42.
Dempster AP, Laird M, Rubin DB (1977) Journal of the Royal Statistical Society. Series B 
(Methodological), Vol 39, 1-38.
Neuenschwander B, Matano A, Tang Z, et al. (2014) A Bayesian Industry Approach to Phase 
I Combination Trials in Oncology. Statistical Methods in Drug Combination Studies: 
Chapman & Hall.


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14.3
Appendix 3 – Drugs which are prohibited or to be used with 
caution
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 ibrutinib.
The following lists are based on the Novartis PK Sciences DDI List (v01 released in January 
2018 ).  The FDA’s Guidance for Industry Drug Interaction Studies – Study Design, Data 
Analysis and Implications for Dosing and Labeling (2017) is the basis of the Novartis PK 
Sciences DDI List, and it was supplemented with Indiana University (IU) Flockhart TableTM. 
and University of Washington (UW) Drug Interaction Database.
The list of medications in Table 14-11 is meant to provide guidance only and it is not a 
comprehensive list. If a patient is required to take a medication that is not in the list, but there 
may be a risk of DDI, please contact the Novartis clinical study team for further advice.
Please contact the Novartis Medical monitor with any questions.
Table 14-11
Drugs prohibited while on study
Category
Drug Names
Strong inhibitors of CYP3A
VIEKIRA PAK1, indinavir/ritonavir1, tipranavir/ritonavir1, ritonavir, 
cobicistat  ,indinavir, ketoconazole, troleandomycin, telaprevir, 
danoprevir/ritonavir1, elvitegravir/ritonavir1, saquinavir/ritonavir1, 
lopinavir/ritonavir1, itraconazole, voriconazole, mibefradil, , clarithromycin, 
posaconazole, telithromycin, grapefruit juice2, conivaptan, nefazodone, 
nelfinavir, , idelalisib, boceprevir, atazanavir/ritonavir1, darunavir/ritonavir1
Moderate inhibitors of 
CYP3A4/5
aprepitant, amprenavir, atazanavir, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, faldaprevir, 
fluconazole, grapefruit juice2, imatinib, isavuconazole, netupitant, nilotinib, 
tofisopam, Schisandra sphenanthera (nan wu wei zi)3, asafoetida resin (Ferula 
asafoetida)3, verapamil Seville oranges or products containing Seville oranges 
(e.g. Marmalades)2. 
Strong inducers of 
CYP3A4/5
carbamazepine, enzalutamide, lumcaftor, phenobarbital, phenytoin, rifabutin, 
rifampin, mitotane, St. John’s wort (Hypericum perforatum)3
Combination therapy. (in some cases combinations with ritonavir have been listed as moderate inhibitors of 
CYP3A in the UW database, the have all been listed as strong in the DDI guide to avoid any potential 
confusion)
Food product.
Herbal product.
FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and Implications for 
Dosing and Labeling (2017) 
(/fdagov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf),
Indiana University (IU) Flockhart Table™ (/drug-interactions.medicine.iu.edu/),
University of Washington (UW) Drug Interaction Database (/druginteractioninfo org/),
Novartis PK Sciences DDI List (Drug-Drug Interactions (DDI) and Co-medication Considerations for Novartis 
Clinical Trials, Novartis PK Sciences Internal Memorandum, v01 released in 2018 January).

SAP_001.pdf: 
Clinical Development 
VAY736 
CVAY736Y2102 / NCT03400176
Phase Ib open-label study of VAY736 and ibrutinib in 
patients with chronic lymphocytic leukemia (CLL) on 
ibrutinib therapy 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Amendment 1  
Release date: 
27-Feb-2024
Number of pages: 
58 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis  
Template Version 4.0, Effective from 23-Apr-2021 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
27-
Feb-
2024 
Prior 
to DB 
Lock 
Creation 
of 
Amendment 1 
Changes 
to 
dose 
expansion arm and 
study design 
Section 1.1 Study design 
Section 2.1 Data analysis and 
information 
 
 
 
Section 1.1 Study design 
Section 1.2 Study objectives and 
endpoints 
Section 2.3.2 Demographic and 
background data 
Section 2.8.1 Efficacy analysis 
 
 
Section 3.1.2 Dose-expansion part 
 
 
 
Update 
secondary 
efficacy objective to 
include CRi in rate 
of CR/CRi at C9  
Section 1.2 Study objectives and 
endpoints 
Section 2.8.1 Efficacy analysis 
Section 3.1.2 Dose-expansion part 
 
 
 
Update 
imputation 
rule 
for 
prior 
antineoplastic 
therapies 
Section 2.3.4.4 Partial-date 
imputation rules for prior 
antineoplastic therapies 
 
 
 
Add 
section 
for 
diagnosis and extent 
of cancer imputation  
Section 5.1.5 Diagnosis and extent 
of cancer imputation 
 
 
 
Remove 
statement 
regarding 
TTP 
analysis 
with 
censoring rules 
Section 2.8.1 Efficacy analysis 
 
 
 
Clarify 
summaries 
and listings for lab 
parameters 
Section 2.8.2.3.3 Data analysis  
 
 
 
 
Update PK analysis 
set 
to 
observing 
vomit after ibrutinib 
Section 2.2.1 Analysis sets 
Table 2-1 Classification based on 
PDs and non-PD criteria 


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SAP Amendment 1 
 
Study No. CVAY736Y2102 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
dosing to 4 hours 
from 8 hours 
 
 
 
 
Add 
clarifications 
for visits/timepoints 
to be used in efficacy 
analyses 
Section 2.8.1 Efficacy analysis 
 
 
 
 
 
Section 1.2 Study objectives and 
endpoints 
 
 
 
 
 
 
Add AESI reporting 
criteria 
Section 2.8.2.2 
 
 
 
 
 
 
 
 
 
Add definitions for 
immunogenicity  
Section 2.2.1 Analysis sets 
Section 2.2.2 Subject classification 
Section 2.8.4.5.1 Sample ADA 
Status 
Section 2.8.4.5.2 Patient ADA 
Status 
 
 
 
Remove histological 
grade, predominant 
and 
additional 
histology/cytology 
summary and listing 
Section 2.3.5 Diagnosis and extent 
of cancer 
 
 
 
Update to include 
new guidelines for 
IWCLL for disease 
response 
assessments for CLL 
and censoring rules  
Section 5.2  Guidelines for efficacy 
analysis for chronic lymphocytic 
leukemia (CLL) studies 
 
 
 
Update 
and 
add 
literature cited in 
SAP to reference 
section 
Section 2.6.1.1 Statistical 
hypothesis, model, and method of 
analysis 


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SAP Amendment 1 
 
Study No. CVAY736Y2102 
 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
Section 2.8.4.4 Dose 
proportionality  
Section 5.2 Guidelines for NCI 
CLL Working Group 2018 
(IWCLL) 
 
 
 
 
Section 6 References 
 
 
 
Add 
changes 
to 
protocol 
specified 
analyses 
Section 4 Change to protocol 
specified analyses  
 
 
 
Add 
missing 
acronyms 
List of Abbreviations 
 
 
 
Correct 
minor 
typographical errors 
All 


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SAP Amendment 1 
 
Study No. CVAY736Y2102 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................................. 11 
2 
Statistical methods ............................................................................................................. 14 
2.1 
Data analysis general information ......................................................................... 14 
2.1.1 
General definitions ................................................................................ 15 
2.2 
Analysis Set/ Subject Classification/ Withdrawal of ICF/ Subgroups .................. 17 
2.2.1 
Analysis sets .......................................................................................... 17 
2.2.2 
Subject Classification ............................................................................ 19 
2.2.3 
Withdrawal of Informed Consent.......................................................... 20 
2.2.4 
Subgroup of interest .............................................................................. 20 
2.3 
Subject Disposition / Demographics / Other Baseline Characteristics .................. 20 
2.3.1 
Subject disposition ................................................................................ 20 
2.3.2 
Demographic and background data ....................................................... 21 
2.3.3 
Medical History ..................................................................................... 21 
2.3.4 
Prior antineoplastic therapy................................................................... 21 
2.3.5 
Diagnosis and extent of cancer ............................................................. 22 
2.4 
Protocol deviations ................................................................................................ 22 
2.5 
Treatments (study treatment, concomitant therapies, compliance) ....................... 22 
2.5.1 
Study treatment ..................................................................................... 22 
2.5.2 
Prior, concomitant and post therapies ................................................... 25 
2.5.3 
Compliance ........................................................................................... 26 
2.6 
Analysis of the primary objective .......................................................................... 26 
2.6.1 
Reports of DLT analysis ....................................................................... 26 
2.6.2 
Handling of missing values/censoring/discontinuations ....................... 29 
2.6.3 
Supportive and sensitivity analyses ...................................................... 29 
2.7 
Analysis of the key secondary objective ............................................................... 29 
2.8 
Analysis of other secondary objective(s) ............................................................... 29 
2.8.1 
Efficacy analysis ................................................................................... 29 
2.8.2 
Safety analyses ...................................................................................... 30 
2.8.3 
Other safety data ................................................................................... 35 
2.8.4 
Pharmacokinetic analysis ...................................................................... 35 
2.9 
Interim analysis ...................................................................................................... 39 


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Study No. CVAY736Y2102 
 
3 
Sample size calculation ..................................................................................................... 40 
3.1.1 
Dose-escalation part .............................................................................. 40 
3.1.2 
Dose-expansion part .............................................................................. 40 
4 
Change to protocol specified analyses .............................................................................. 41 
5 
Appendix ........................................................................................................................... 42 
5.1 
Imputation rules ..................................................................................................... 42 
5.1.1 
Study drug ............................................................................................. 42 
5.1.2 
AE date imputation ............................................................................... 42 
5.1.3 
Concomitant medication date imputation ............................................. 43 
5.1.4 
Prior and post antineoplastic therapies date imputation ........................ 43 
5.1.5 
Other imputation ................................................................................... 43 
5.2 
Guidelines for efficacy evaluation in chronic lymphocytic leukemia (CLL) 
studies1 .................................................................................................................. 44 
5.2.1 
Introduction ........................................................................................... 44 
5.2.2 
Efficacy assessment .............................................................................. 44 
5.2.3 
Data collection ...................................................................................... 50 
5.2.4 
Derivation of efficacy endpoints ........................................................... 52 
5.3 
CTC grades for laboratory values in Novartis Oncology (based on CTCAE 
v4.03 – June 2010) ................................................................................................. 55 
6 
References ......................................................................................................................... 58 


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List of abbreviations  
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
 
 
 
 
BLRM 
Bayesian Logistic Regression Model 
CLL 
Chronic Lymphocytic Leukemia 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Drug Administration Record 
DDI 
Drug-Drug Interaction 
DDS 
Dose Determining Set 
DI 
Dose Intensity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IG 
Immunogenicity 
IGHV 
Immunoglobulin Heavy Chain 
IGIS 
Immunogenicity Incidence Set 


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IGPS 
Immunogenicity Prevalence Set 
IV 
Intravenous(ly) 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
JAGS 
Just Another Gibbs Sampler 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MRD 
Minimum Residual Disease 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
 
 
ORR 
Overall Response Rate 
OS 
Overall Survival 
Q2W 
Once Every Two Weeks 
Q4W 
Once Every Four Weeks 
PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamic(s) 
PDS 
Programming Datasets Specifications 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PPS 
Per-Protocol Set 
PR 
Pulse Rate 
PT 
Preferred Term 
qd 
Qua’que di’e / once a day 
RAP 
Report and Analysis Process 
RD 
Recommended Dose 
RDE 
Recommended Dose for Expansion 
RDI 
Relative Dose Intensity 
 
 
SAP 
Statistical Analysis Plan 
 
 
SCr 
Serum Creatinine 
SOC 
System Organ Class 


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SS 
Safety Set 
SSD 
Study Specifications Document 
TFLs 
Tables, Figures, Listings 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1 
Introduction 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study VAY736Y2102 that will be presented in the Clinical Study Report (CSR). 
The output shells accompanying this document can be found in the Tables, Figures and Listings 
(TFL) shells document. The specifications for derived variables and datasets can be found in 
the Programming Datasets Specifications (PDS) document. This version of the SAP is based on 
the Protocol Version 06 released on 20-Oct-2021. 
All required changes to the planned analysis described in this document will be made through 
an amendment or addendum, depending on whether the change is made before or after database 
lock (DBL), respectively. Note that obvious corrections will be made at the time of analysis to 
address minor formatting or spelling mistakes present in the TFL shells document, without the 
need to amend. 
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., maximum-tolerated dose (MTD) or recommended 
dose for expansion (RDE) declaration, Investigator’s Brochure (IB) updates, abstracts, posters, 
presentations, manuscripts, and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance. 
The CVAY736Y2102 trial has been endorsed for early termination by the ICDB on 22-Sep-
2023, due to business purposes and not safety concerns. 
1.1 
Study design 
This Phase Ib, multi-center, open-label study has two parts: a dose-escalation part and a dose-
expansion part. The purpose of the dose-escalation part is to characterize the safety and 
tolerability of VAY736 in combination with ibrutinib in patients with relapsed, refractory 
chronic lymphocytic leukemia (CLL). The dose-escalation part will be guided by a Bayesian 
Logistic Regression Model (BLRM) to estimate the MTD and/or RDE of the combination.  
Upon identification of the MTD or RDE, a dose-expansion part will be opened to patient 
enrollment to further characterize the safety, pharmacokinetics (PK), and pharmacodynamics 
(PD), if available, and preliminary anti-tumor efficacy of the combination.   
Both the dose escalation and dose expansion parts will enroll patients with CLL who are 
currently receiving ibrutinib therapy following relapse on another approved therapy AND have 
either failed to achieve a CR after > 1 year of ibrutinib treatment OR who have developed a 
resistance mutation to ibrutinib without clinical relapse at any time during treatment. The dose 
expansion part of the study will also include patients who have received ibrutinib either alone 
or in combination (or have received ibrutinib continuously with multiple sequential 
combination partners) as first-line therapy and have either failed to achieve a complete response 
after 1 year of therapy or have developed a resistance mutation to ibrutinib. Approximately 15-
20 patients will be enrolled to the dose escalation part of the study. In the expansion part, 
approximately 40 patients will be enrolled to two arms (approximately 20 patients in each arm).  
One arm will enroll patients who have been on ibrutinib treatment for more than one year with 
evidence of residual disease which places them at risk for clinical relapse; the other arm will 
enroll patients with acquired resistance mutations to ibrutinib who have not yet demonstrated 


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clinical relapse, see Figure 1-1. All patients with acquired resistance mutations will be enrolled 
in Arm B, irrespective of ibrutinib treatment duration.  
As of Protocol Version 06, enrollment to Arm B (patients with BTK inhibitor resistance 
mutation) is closed due to slower than anticipated enrollment.  
Figure 1-1 
Study design 
 
1.2 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 


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Table 1-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 2.6  
To determine the MTD and/or RD of the combination 
of VAY736 with ibrutinib 
 
To characterize the safety and tolerability of the 
combination of VAY736 and ibrutinib 
Safety 
Escalation only: 
• 
Incidence of DLTs in cycle 1 (28 days) 
Escalation and expansion: 
• 
Incidence and severity of AEs and SAEs, 
including changes in laboratory parameters and 
vital signs 
Tolerability 
Dose interruptions, reduction, and dose intensity 
 
Secondary  
 
Refer to Section 2.8  
To assess any preliminary antitumor activity of the 
combination 
Rate of patients with CR/CRi assessed by 
investigators per IWCLL at cycle 9 day 1 
 
Overall response rate (ORR) assessed by 
investigators per IWCLL criteria and Time To 
Progression (TTP) 
 
Clearance of ibrutinib resistance mutations (BTKC481 
and/or PCLγ2 hotspot), defined as less than 1% 
mutation bearing alleles (Arm B only). 
 
To characterize the PK of VAY736 and ibrutinib when 
used in combination therapy 
Plasma concentration of VAY736 and ibrutinib, and 
derived parameters 
 
To assess immunogenicity (IG) following one or more 
intravenous infusions of VAY736 
Presence of anti-VAY736 antibodies 
 


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Objective 
Endpoint 
Analysis 


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2 
Statistical methods 
2.1 
Data analysis general information 
Study data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated SAS® version in the GPS environment. For Bayesian modeling, R (version 3.2.3) 
and/or JAGS (version 4.6.0) will be used. PK parameters will be calculated using non-
compartmental methods available in Phoenix WinNonlin version 8.3 (or latter version if 
available). 
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred) 
based on all patients’ data from the dose escalation and dose expansion parts up to the time 
when all patients have completed at least six cycles of combined treatment with VAY736 and 
ibrutinib and two cycles of ibrutinib alone or have discontinued the study. The primary CSR 
will include all outputs planned within the TFL shell document. Additional data for patients 
continuing to receive study treatment past the data cutoff date of the primary CSR, as allowed 
by the protocol, will be reported once all patients have discontinued the study. However, only 
a selection of key outputs (indicated in the TFL shell document) for which additional data was 
collected will be provided for the final report. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements. All relevant 
pharmacokinetic (PK) measurements will also be summarized. The summaries will use 
descriptive statistics for quantitative data and contingency tables (frequencies and percentages) 
for qualitative data. 
In case of intra-subject dose escalation, patient’s data from before and after the change in dose 
will be listed and summarized together under the originally intended dose level/treatment group. 
A treatment is defined by the dose level (corresponding to a single combination of doses of 
VAY736 and ibrutinib) and regimen. During the initial dose-escalation phase of the study, in 
which the dose of VAY736 will be escalated in combination with a fixed dose of ibrutinib, 
cohorts of patients with the same treatment will be pooled into one single treatment group. Thus, 
a treatment group may consist of more than one cohort. Patients receiving the same dose of 
VAY736 under different regimens, Q2W or Q4W, belong to different treatment groups. 
Specific plans regarding a change in dosing regimen are discussed in Section 2.6.1.1 of the SAP.  
Patients treated with the same dose level and schedule of VAY736 will be pooled, for all safety 
analyses including PK and ADA, into a single treatment group (which may include patients 
from both the dose-escalation and dose-expansion parts).  
For efficacy analyses, data will also be summarized by study part, and within each study arm 
of the dose expansion part. If multiple dose regimens are observed, summaries will also be 
produced within each treatment regimen as follows: 
• Study parts: dose escalation, dose expansion  
• Study arms:  


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o Dose expansion part: 
 Study arm A (~20 pts): patients with advanced CLL who have been on 
ibrutinib treatment for more than one year with evidence of residual 
disease and which places them at risk for clinical relapse. 
 Study arm B (~20 pts): patients with acquired resistance mutations to 
ibrutinib who have not yet demonstrated clinical relapse. 
2.1.1 
General definitions  
2.1.1.1 
Investigational drug and study treatment 
Investigational treatment will refer to the combination VAY736 + ibrutinib. The term 
investigational treatment may also be referred to as study treatment.  For consistency across 
studies, the term study treatment will be used throughout this document.  
The expression combination therapy may also be used to refer to the investigational treatment 
VAY736+ibrutinib, as defined in the protocol. 
Investigational drug will refer to VAY736 and ibrutinib. The terms investigational drug 
and study drug are used interchangeably.  For consistency across studies, the term study drug 
will be used throughout this document. 
2.1.1.2 
Date of first/last administration of study treatment 
In the combination arm, the date of first (last) administration of study treatment is derived as 
the first (last) date when a non-zero dose of either VAY736 or ibrutinib was administered and 
recorded on the Dose Administration Record (DAR) eCRFs.  
• First and last dose of VAY736 will be as recorded on the Study Treatment - VAY736) 
eCRF.  
• First dose of ibrutinib will be as recorded on the Study Treatment - PK - Ibrutinib eCRF, 
and 
• Last dose of ibrutinib will be as recorded on the Study Treatment – Ibrutinib eCRF.  
2.1.1.3 
Study day 
The study day for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the event (onset date of an event, assessment date etc.) and the start of study 
treatment plus 1. The first day of study treatment is therefore study day 1. Example: if start of 
study treatment is on 05-Jan-2014 and start date of an adverse event is on 09-Jan-2014 then the 
study day of the adverse event onset is 5. For safety assessments before start of study treatment, 
the study day is negative and derived by (date of event – start date of study treatment). For 
example: if start of study treatment is on 05-Jan-2014 and date of lab measurement is on 02-
Jan-2014 then the study day of the laboratory abnormality is -3. Note, the day of start of study 
treatment is day 1, and the day before the date of first study treatment is day – 1, not day 0. 
The study day for other assessments (e.g., efficacy, 
etc.) will be calculated the same 
way as safety assessments. 


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2.1.1.4 
Baseline 
Baseline is the result of an investigation describing the “true” state before start of study 
treatment administration. 
The last available assessment on or before the date of start of study treatment is taken as 
“baseline” assessment, unless specified otherwise. Assessments should be done within 21 days 
prior to the start of study treatment apart from baseline efficacy assessments which can be 
conducted within 28 days the date of start of study treatment. Height and virology assessments 
(including HBV and HCV) may also be performed outside of the 21-day window. Other 
assessments taken outside of the above specified assessment window, will not be considered 
for baseline.   
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline. 
For the purpose of VAY736 immunogenicity analysis, the baseline assessment will be defined 
with respect to the date of the first administration of VAY736.  
If patients have no measurement meeting the above criteria, the baseline result will be missing. 
2.1.1.5 
On-treatment assessments 
Safety summaries (tables, figures) include only data from the on-treatment period defined below, 
with the exception of baseline data, which will also be summarized where appropriate (e.g., 
change from baseline summaries). In addition, a separate summary for death, including on-
treatment and post-treatment deaths, will be provided.  Summary tables for AEs will include 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs), as discussed in Section 2.8.2.1.2. 
The overall observation period will be divided, for safety assessments, into three mutually 
exclusive segments as follows:  
Pre-treatment period: from the day of patient’s first informed consent to the day before first 
administration of the study treatment. 
On-treatment period: from date of first administration of study treatment to 30 days after the 
date of last actual administration of VAY736 (including start and stop date).  
Post-treatment period: starting at day 31 after last administration of VAY736.  
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.  
Note that these observational period definitions do not impact the reporting of efficacy 
assessments; all completed efficacy assessments will be summarized, irrespective of their 
timing with regard to the above definitions. 


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2.1.1.6 
Date of last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
date using the last complete date reported among the following as seen in Table 2-1: 
Table 2-1 
Last contact derivation 
Source data 
Conditions 
Last contact date/last date patient was known to be 
alive from Safety Follow-up page 
  
Patient status is reported to be alive, lost to 
follow-up, or unknown 
Start/End dates from further antineoplastic therapy 
Non-missing medication/procedure term 
Start/End dates from treatment page 
  
Non-missing dose. Doses of 0 are allowed 
End of treatment date from end of treatment page 
  
No condition 
Efficacy assessment date if available 
Evaluation is marked as ‘done’ 
Laboratory/Concomitant medication collection dates 
  
Sample collection marked as ‘done’ 
Vital signs date 
  
At least one non-missing parameter value 
Start/End dates of AE 
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely 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. 
2.1.1.7 
Date of start of alternative cancer therapy 
The date of start of alternative cancer therapy is the Start Date of Dose as recorded on the 
Antineoplastic Therapy Since Discontinuation of Study Treatment – Medication eCRF. Note: 
The start date of Ibrutinib is not considered as the start of alternative cancer therapy.  
2.2 
Analysis Set/ Subject Classification/ Withdrawal of ICF/ 
Subgroups 
2.2.1 
Analysis sets 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) and Safety Set (SS) are defined in the same way and comprise all 
patients who received at least one dose of study treatment. Patients will be analyzed according 
to the study treatment received where treatment received is defined as the treatment most 
frequently taken between Study Day 1 and the end of cycle 1 (the first 28 days of dosing), the 
onset of a DLT, or treatment discontinuation, whichever occurs first.  


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Safety Set (SS) 
Same as definition of FAS. 
Per-Protocol Set (PPS) 
Not applicable 
Dose-Determining Set (DDS) 
The Dose-Determining Set (DDS) includes all patients from the FAS (escalation part) who met 
the minimum exposure criterion and had sufficient safety evaluations or experienced a dose 
limiting toxicity (DLT) during cycle 1 (the first 28 days of dosing). 
A patient has met the minimum exposure criterion if the patient takes, during the first 28 days, 
all planned doses of VAY736 and 75% of the planned doses of ibrutinib (i.e., two doses of 
VAY736 Q2W or one dose of VAY736 Q4W, and ≥ 21 of 28 daily doses of ibrutinib). 
Patients who do not experience a DLT during cycle 1 (the first 28 days of dosing) are considered 
to have sufficient safety evaluations if they have been observed for ≥ 28 days following the first 
dose and are considered by both the Sponsor and Investigators to have enough safety data to 
conclude that a DLT did not occur. Patients will be analyzed according to the study treatment 
received as defined for FAS. 
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the DDS and an additional patient may be recruited (see VAY736Y2102-CSP-
Section 7.1.3.1). 
Pharmacokinetic Analysis Set (PAS) 
The Pharmacokinetic Analysis Set (PAS) includes all Patients who provide an evaluable PK 
profile. A profile is considered evaluable if all the following conditions are satisfied: 
• Patient receives one of the planned treatments. 
• Patient provides at least one primary PK parameter (see Table 2-7 for a listing) 
• Patient did not vomit within 4 hours after the dosing of ibrutinib. 
Immunogenicity Prevalence Set (IGPS) 
he IGPS includes all patients in the FAS with a non-missing baseline IG sample or at least 
one non-missing post-baseline IG sample (applicable for VAY736 only) 
Immunogenicity Incidence Set (IGIS) 
The IGIS includes all patients in the IGPS with a non-missing baseline IG sample and at least 
one non-missing post-baseline IG sample (applicable for VAY736 only).  
See Section 2.8.4.5.2 for further definitions.  


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2.2.2 
Subject Classification 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations (PD) entered in the database and/or on specific classification rules defined in Table 
2-2 Classification based on PDs and non-PD criteria.  
Table 2-2 
 Classification based on PDs and non-PD criteria 
 
Analysis set 
Protocol deviations leading 
to exclusion 
Non 
protocol 
deviation 
leading to exclusion 
Full analysis set  
No written informed consent 
(INCL01) 
Patient didn’t receive at least 
one dose of study treatment 
Safety set 
No written informed consent 
(INCL01) 
Patient didn’t receive at least 
one dose of study treatment 
Dose-determining set 
No written informed consent 
(INCL01) 
1. The patient does not 
experience a DLT during the 
first cycle and does not meet 
the 
minimum 
exposure 
criterion. 
2. The patient does not 
experience a DLT during the 
first 
cycle 
but 
has 
no 
sufficient safety evaluation 
(i.e. he has not been observed 
for the full duration of the 
first cycle of treatment, 
and/or  is considered by both 
Novartis and Investigators to 
have not enough safety data 
to conclude that a DLT did 
not occur).  
PK Analysis set 
No written informed consent 
(INCL01) 
1. Patient didn’t receive at 
least one of the planned 
treatments 
2. Patient didn’t provide at 
least 
one 
primary 
PK 
parameter 
3. Patient vomited within 4 
hours after the dosing of 
ibrutinib 
Immunogenicity prevalence 
set 
No written informed consent 
(INCL01) 
Patients 
without 
a 
determinant 
baseline 
IG 
sample or at least one 


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determinant post-baseline IG 
sample 
Immunogenicity 
incidence 
set 
No written informed consent 
(INCL01) 
Patients 
without 
a 
determinant 
baseline 
IG 
sample and at least one 
determinant post-baseline IG 
sample 
2.2.3 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.   
Additional data for which there is a separate informed consent, e.g., PK, 
 etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion. 
2.2.4 
Subgroup of interest 
Not applicable. 
2.3 
Subject Disposition / Demographics / Other Baseline 
Characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS. 
2.3.1 
Subject disposition 
The following will be tabulated: 
• Treatment 1 Disposition/VAY736 Disposition (C1-C6): 
• Number (%) of patients who discontinued treatment with VAY736 and primary 
reasons for discontinuation 
• Treatment 2 Disposition/Ibrutinib Disposition (C1-C9) 
• Number (%) of patients who discontinued treatment with Ibrutinib and primary 
reasons for discontinuation 
• Treatment 3 Disposition/VAY736 Disposition (C7-C9) 
• Number (%) of patients who discontinued treatment with VAY736 and primary 
reasons for discontinuation 
• Post-treatment follow-up 
• Number (%) of patients who discontinued post-treatment follow-up and reasons for 
discontinuation 


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2.3.2 
Demographic and background data 
Demographic data including age, sex, race, ethnicity, height, weight, and ECOG performance 
status will be listed and summarized. In addition, following age categories will be summarized: 
18- <65 years, 65- < 85 years, and ≥ 85 years. Additional baseline characteristics data will be 
included: ibrutinib resistance mutation, the time (in months) from the start of ibrutinib therapy 
to the first study treatment, and the results of direct and indirect Coombs tests. 
2.3.3 
Medical History 
A listing of medical history and current medical conditions will be provided, using the latest 
Medical Dictionary for Regulatory Activities (MedDRA) terminology available at the time of 
reporting.  
2.3.4 
Prior antineoplastic therapy 
All prior antineoplastic medication, radiotherapy and surgery will be listed. The number (%) of 
patients who received any prior antineoplastic medication will be summarized. 
2.3.4.1 
Prior antineoplastic medications 
The summary of prior antineoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting at last treatment, time (in 
months) from last treatment to progression, best hematological response per IWCLL at last 
treatment (defined to be the best response during the last treatment regimens recorded), and 
reason for discontinuation at last treatment. Prior antineoplastic medications will also be 
summarized by Anatomical Therapeutic Chemical (ATC) class, and preferred term. 
2.3.4.2 
 Prior antineoplastic radiotherapy 
The listing of prior antineoplastic radiotherapy will include the radiotherapy locations, 
(including all locations recorded for each patient). 
2.3.4.3 
Prior antineoplastic surgery 
Data collected on prior antineoplastic surgery will be listed.  
2.3.4.4 
Partial-date imputation rules for prior antineoplastic therapies 
The following partial-date imputation rules will apply: 
Start date:  
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used, with the exception of the imputation rule in scenario (B) of Table 2-4, which 
will be replaced by TRTSTD-1.  See Section 2.8.2.1.1. 
End Date:  
Imputed date = min (start date of study treatment, last day of the month), if day is missing; 
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing. 


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If the end date is not missing and the imputed start date is after the end date, use the end date 
as the imputed start date. 
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date. 
2.3.5 
Diagnosis and extent of cancer 
The summary and listing of diagnosis and extent of cancer (disease history) will include stage 
at initial diagnosis, stage at time of study entry, time (in months) since initial diagnosis, time 
(in months) from initial diagnosis to first relapse, time (in months) since most recent 
recurrence/relapse, current extent of disease (metastatic sites).  
2.4 
Protocol deviations 
The full list of protocol deviations will be documented in the Study Specification Document 
(SSD). 
2.5 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.5.1 
Study treatment  
The safety set will be used for all summaries and listings of study treatment.  
2.5.1.1 
Data handling 
2.5.1.1.1 Data analysis 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized separately for each component of study treatment in combination 
therapy. The duration of exposure will also be presented for the study treatment 
(VAY736+ibrutinib). Duration of exposure will be categorized into mutually exclusive time 
intervals; frequency counts and percentages will be presented for the number (%) of patients in 
each interval.  
The number (%) of patients who have dose reductions or interruptions, and the reasons, will be 
summarized by treatment.  
Patient-level listings of all doses administered on treatment along with dose change reasons will 
be produced. 
2.5.1.2 
Duration of exposure to study treatment 
Duration of exposure to study treatment refers to exposure to the combination of ibrutinib and 
the investigational therapy VAY736. The following exposure durations will be calculated:  
(A) Duration of exposure to VAY736 (days) = (last date of exposure to VAY736) – (date of 
first administration of VAY736) + 1 
(B) Duration of exposure to ibrutinib (days) = (last date of exposure to ibrutinib) – (date of first 
administration of ibrutinib) + 1 


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(C) Duration of exposure to study treatment (days) = max(last date of exposure to ibrutinib or 
VAY736) – (date of first administration of ibrutinib) + 1 will be used for the duration of 
exposure to study treatment 
The last date of exposure to ibrutinib is the last date of dose administration.  
The last date of exposure to VAY736 administered Q2W is the last date of administration +13 
days. 
The last date of exposure to VAY736 administered Q4W is the last date of administration +27 
days. 
Table 2-2 
Definition of last date of exposure of investigational drug 
Scenario 
Definition of last date of exposure 
of investigational drug  
Example 
Scenario 1: 
Investigational 
drug with a cyclic 
administration   
The planned end date of the last 
cycle in which the last non-zero 
dose of the investigational drug was 
last administered. 
Note: If the patient died or was lost 
to follow-up before the derived last 
date, the last date of exposure to 
investigational drug is the date of 
death or the date of last contact, 
respectively.  
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff. 
Example 1: In a once-a-week 
administration of an investiga-
tional drug, the last date of 
exposure is the date of 
administration in the last cycle 
+ 6 days. 
Example 2: In a 21-day cycle 
with one or several infusions in 
the beginning of the cycle 
(e.g., 2 weeks on 1 week off), 
the last date of exposure is the 
date of first infusion in the last 
cycle + 20 days. 
Scenario 2: Daily 
administration of 
the investigational 
drug 
Date of last administration of a non 
-zero dose of the investigational 
drug. 
Example 3: A patient had a 
permanent discontinuation of 
the investigational drug 06-
Jan-2013 after being put on a 
temporary interruption since 
01-Jan-2013. In this case the 
last date of exposure is 31-
Dec-2012.  
2.5.1.3 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components, 
VAY736 and ibrutinib, respectively.  


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The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. The planned 
cumulative dose is not summarized/listed. It is used for relative dose intensity calculations.  
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment. For VAY736, this is documented in the VAY736 
Dose Administration eCRF.  
For ibrutinib, the planned and actual dose is the first non-zero dose as recorded on the Study 
treatment – PK - Ibrutinib eCRF. Any periods of dose interruption or reduction are be recorded 
in the change log.  
For patients who did not take any drug, the actual cumulative dose is equal to zero for that drug. 
For VAY736, the actual cumulative dose is the sum of the non-zero doses recorded over the 
dosing period, and the planned cumulative dose is the planned starting dose summed over the 
same dosing period. 
For ibrutinib, the actual cumulative dose is calculated as the planned dose, multiplied by the 
duration of exposure to ibrutinib, accounting for any periods of dose interruptions. The planned 
cumulative dose is the dose is calculated as the planned dose multiplied by duration of exposure 
to ibrutinib. 
2.5.1.4 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (dosing unit / unit of time) = Actual Cumulative dose (dosing unit) / Duration of exposure 
(unit of time). 
For example, the dosing unit for VAY736 is mg/kg and the unit of time is 14 days: 
DI (mg/kg/14 days) = 14 * Actual Cumulative dose (mg/kg) / Actual duration of exposure 
= 14 * Actual cumulative dose (mg/kg) / [Last dosing date – First dosing date + Dose interval 
(14 days)] 
For Ibrutinib the dosing unit is mg, and the unit of time is day (mg/day): 
DI (mg/day) = Actual Cumulative dose (mg) / Actual duration of exposure (day) 
= Actual cumulative dose (mg) / [Last dosing date – First dosing date + Dose interval (1 
day)] 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (dosing unit / unit of time) = Planned Cumulative dose (dosing unit) / Duration of 
exposure (unit of time). 
For example, the dosing unit for VAY736 is mg/kg and the unit of time is 14 days: 
DI (mg/kg/14 days) = 14 * Planned Cumulative dose (mg/kg) / Duration of exposure 
For Ibrutinib the dosing unit is mg, and the unit of time is day (mg/day): 


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DI (mg/day) = Planned Cumulative dose (mg) / Duration of exposure (day) 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).  
As an example, the RDI for VAY736 is defined as: 
RDI = DI (mg/kg/14 days) / PDI (mg/kg/14 days) 
DI and RDI will be summarized separately for each of the study treatment components, using 
the duration of exposure of each of the components. The duration of exposure considered for 
the derivation of the DI and the RDI will be derived from the start date of study treatment to the 
end of the last cycle initiated irrespective of date of death, last contact date for withdraw consent 
and cut-off date. 
RDI will be summarized as a percentage. Summary of RDI may include categorical summaries, 
based on clinically meaningful intervals; see SAP Section 2.5.3. 
2.5.1.5 
Dose reductions, interruptions, or permanent discontinuations 
The number of patients who have dose reductions or interruptions, and the reasons, will be 
summarized separately for each of the study treatment components.  
‘Dose interrupted’ and ‘Dose changed’ fields from the Dosage Administration CRF pages 
(DAR) will be used to determine the dose interruptions and dose changes, respectively. 
Dose reduction: a dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered is lower than the prescribed dose. 
Only dose change is collected in the CRF, number of reductions will be derived 
programmatically based on dose change flag and the change and the direction of the change. 
Dose reduction will be reported for VAY736 only. 
Dose interruption: Actual dose administered equal to zero, between the first and last non-
zero doses, following a non-zero actual dose administered. Dose interruption is collected as 
such in the treatment page eCRF. Number of dose interruptions and corresponding reason will 
be summarized.  
• For VAY736, ‘Dose interrupted’ field from the Dosage Administration CRF pages 
(DAR) will be used to determine the dose interruptions.  
• For ibrutinib, dose interruptions will be captured in the dose change log.  
The corresponding fields ‘Reason for dose change/dose interrupted’ will be used to summarize 
the reasons. For the purpose of summarizing interruptions and reasons, in case multiple entries 
for interruption that are entered on consecutive doses with different reasons, they will be 
counted as separate interruptions. However, if the reason is the same in these mentioned 
multiple entries on consecutive doses, then it will be counted as one interruption. 
2.5.2 
Prior, concomitant and post therapies 
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 


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blood transfusions) administered in the study and are recorded in the Concomitant Medications 
and Prior or Concomitant non-drug therapies/procedures eCRF. These therapies will be coded 
using the WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO 
Anatomical Therapeutic Chemical (WHO ATC) classification system. Significant non-drug 
therapies will use MedDRA coding.  
Any concomitant therapies starting prior to or after the start of study treatment will be listed.  
A separate listing will be provided for instances of concomitant, limited-field palliative 
radiotherapy to non-target lesion(s). Per protocol VAY736Y2102-CSP-Section 6.4, such 
concomitant therapies are allowed, and will be recorded on the Concomitant 
radiotherapy/surgery case report form (CRF) page. 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 2.8.2.1.1 for AE date imputation rules). No imputation will be 
performed for concomitant medication end dates. 
2.5.3 
Compliance 
Compliance to the study treatment will be summarized in terms of the RDI. The predefined RDI 
categories are < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and 
proportion of patients falling in each category will be presented. 
2.6 
Analysis of the primary objective 
The primary objective is to characterize the safety and tolerability of the combination of 
VAY736 with ibrutinib, and to determine the MTD or RDE for the combination. 
The following primary endpoints are of interest in both the dose-escalation and dose-
expansion parts of the study. 
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
• Changes in laboratory parameters and vital signs  
• Dose interruptions, reductions, and dose intensity 
The dose-escalation part will study an additional endpoint: 
• Incidence of DLTs during the first treatment cycle of the investigational treatment. 
For the analysis of safety and tolerability endpoints see VAY736Y2102-CSP-Section 10.5.3, in 
addition to analysis of the DLT rate as below. 
2.6.1 
Reports of DLT analysis 
A dose-limiting toxicity (DLT) is defined as a clinically relevant adverse event or abnormal 
laboratory value or dose reduction due to AE which occur ≤ 28 days following the first 
administration of study treatment as defined in VAY736Y2102-CSP-Section 6.2.4, Table 6-3. 
The MTD (or RD) will be estimated in the dose-escalation part of the study by modeling the 
probability of DLT occurrence in Cycle 1 for patients in the dose-determining set (DDS). This 
probability is estimated by the statistical models in Section 2.6.1.1.  


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The following reports will be produced based on the dose determining set: 
• A plot of posterior interval probabilities will be presented in the body of the CSR;  
• Summary of the DLTs with onset during the evaluation period (dose escalation part only) 
by primary system organ class, preferred term: recommendations at the time of database 
lock will be included in the body of the CSR. Summaries of recommendations from each 
dose escalation meeting (DEM) will be included in Appendix 16.1.9 of the CSR; 
• Listing of inferential results from the BLRM at the time of database lock, will be included 
in Appendix 16.1.9. 
The Bayesian model for DLT rates is described in the next section. 
2.6.1.1 
Statistical hypothesis, model, and method of analysis 
Identification of a recommended dose 
Estimation of the MTD of the treatment will be based upon the estimation of the probability of 
DLT in cycle 1 for patients in the DDS.  A recommended dose below the MTD may be identified 
based on other safety, clinical, PK, and PD data (see VAY736Y2102-CSP-Section 6.2.3). 
Bayesian adaptive approach 
The dose escalation part of this study will be guided by a Bayesian analysis of Cycle 1 dose 
limiting toxicity (DLT) data for VAY736 and ibrutinib. The Bayesian analysis will be based on 
a model with three parts, representing: 
• Single agent VAY736 toxicity 
• Single agent ibrutinib toxicity 
• Interaction  
The single-agent toxicities are modeled as follows. Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT of the first 
cycle for VAY736 given as a single agent at total cycle 1 dose 𝑑𝑑1(Q2W VAY736 dose mg/kg ∗
2); 𝜋𝜋2(𝑑𝑑2) be the risk of DLT of the first cycle   for ibrutinib given as a single agent at daily 
dose 𝑑𝑑2 (mg) .  These single agent dose-DLT models are logistic: 
VAY736: 
logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
(1) 
Ibrutinib: 
logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
(2) 
where   𝑑𝑑1
∗= 3.0 mg/kg  total cycle 1 dose (1.5mg/kg ∗2) and 𝑑𝑑2
∗= 420 mg daily are used 
to scale the doses of VAY736 and ibrutinib, respectively.  Hence, 𝛼𝛼1 and  𝛼𝛼2(>0) are the single-
agent odds of a DLT of the cycle 1 at 3.0 mg/kg  total cycle 1 dose and  420 mg daily, 
respectively; and  𝛽𝛽1 and  𝛽𝛽2 (>0) are the increase in the log-odds of a DLT by a unit increase 
in log-dose. 
Under no interaction, the risk of a DLT at dose 𝑑𝑑1 of VAY736 and dose 𝑑𝑑2 of ibrutinib is: 
𝜋𝜋12
0 (𝑑𝑑1, 𝑑𝑑2) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯ 
To allow for interaction between VAY736 and dose 𝑑𝑑2 of ibrutinib, an odds multiplier is 
introduced. The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2) is then given by: 


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odds൫𝜋𝜋12(𝑑𝑑1, 𝑑𝑑2)൯= exp(𝜂𝜂× 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) × odds൫𝜋𝜋12
0 (𝑑𝑑1, 𝑑𝑑2)൯ 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; and 𝜂𝜂 is the log-odds ratio between the interaction and no 
interaction model at the reference doses. i.e.,  3.0 mg/kg(1.5 mg/kg ∗2)  of  total cycle 1 
VAY736 and 420 mg of daily ibrutinib.  Here 𝜂𝜂= 0 corresponds to no interaction, with 𝜂𝜂> 0 
and 𝜂𝜂< 0 representing synergistic and antagonistic toxicity, respectively. 
Specifications of the prior distributions for 𝛼𝛼1, 𝛼𝛼2, 𝛽𝛽1, 𝛽𝛽2, and 𝜂𝜂 are given in VAY736Y2102-
CSP-Section 14.2.2. 
Assessment of patient risk 
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated.  The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals:  
Under-dosing: 
[0 , 0.16) 
Targeted toxicity: 
[0.16 , 0.33) 
Excessive toxicity: 
[0.33 , 1] 
The escalation with overdose control (EWOC) principle 
Dosing decisions are guided by the escalation with overdose control principle (Rogatko et al 
2007). A combination dose may only be used for newly enrolled patients if the risk of excessive 
toxicity at that combination dose is less than 25%. 
Dose recommendations 
At each dose-escalation meeting, summaries of the posterior distribution of DLT rate will be 
listed for each dose. In particular, the posterior probabilities of the three toxicity intervals will 
be listed for each provisional dose level. Complete guidelines for dose-escalation decision 
making are given in VAY736Y2102-CSP-Section 6.2.3. 
Change in dose schedule 
In the case that additional dosing schedules for VAY736Y are explored during dose-escalation, 
a BLRM of the same functional form will be used to estimate the dose-DLT relationship for 
each new schedule.  Data from previous or concurrently explored schedules will be used to 
inform the dose escalation for the new schedule. At each time the decision is taken to explore a 
new schedule, the model to be used to guide escalation in that schedule will be constructed.  The 
model will be finalized prior to first patient treated under the new schedule and will be 
documented in full in CSR Section 16.1.9. The details may refer to VAY736Y2102-CSP-
Section 14.2.  
In addition, in case VAY736Y Q2W dosing schedule continues, and a new dosing schedule is 
explored during dose-escalation, a BLRM of the same functional form described in 
VAY736Y2102-CSP-Section 14.2 will be used to estimate the dose-DLT relationship for each 
schedule based on a newly derived prior incorporating the historical trial data and the on-study 
data from previous schedule.  


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2.6.2 
Handling of missing values/censoring/discontinuations 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. 
Other missing data will simply be noted as missing on appropriate tables/listings. 
Patients with unknown or missing response and who are treated in the study but provide no 
information on response at the end of treatment will be treated as non-responders and will be 
included in the denominator when calculating CR/CRi rate or ORR. 
2.6.3 
Supportive and sensitivity analyses 
Additional 
 supportive analyses will be conducted, if appropriate, 
 
 
2.7 
Analysis of the key secondary objective 
Not applicable. 
2.8 
Analysis of other secondary objective(s) 
2.8.1 
Efficacy analysis 
Evaluation of anti-tumor activity will be based on investigators’ assessment per IWCLL criteria 
(see VAY736Y2102-CSP-Appendix 1 for details) as documented in the eCRF. The variables 
used to evaluate anti-tumor activity are CR/CRi rate, clearance of ibrutinib resistance mutations, 
overall response rate (ORR), and time to progression (TTP). Analyses of these variables will 
use the FAS, including patients from both the escalation and expansion parts. All analyses will 
be provided by dose level in dose escalation and by two arms in dose expansion. 
Rate of CR/CRi at C9 for expansion arm A and arm B: The proportion of patients with CR 
or CRi assessed by investigators per IWCLL criteria (see VAY736Y2102-CSP-Appendix 1 for 
details) at C9 will be provided.   The rate of CR/CRi at C9 is the primary endpoint for the 
evaluation of anti-tumor activity and will be analyzed for each expansion arm using a Bayesian 
modeling approach. 
A minimally informative beta distribution is used as prior distribution with parameters a=0.25 
and b=1. This assumes, a priori, that the response rate is 20%. 
Posterior summaries for CR/CRi rate (posterior mean, including 90% credible intervals and the 
posterior probability that the true CR/CRi rate falls in the activity intervals defined below) will 
be provided: 
Posterior probability of response rate intervals: 
• [0, 20%) – clinically not meaningful 
• [20%, 40%) – moderate clinical benefit 
• [40%, 100%] – superior clinical benefit 
In addition, exact confidence interval (90% CI) also will be provided. 


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To determine which response assessments occurred at C9, response assessment dates within a 
window of +/- 3 days of patient’s Cycle 9 visit start date or end date will be considered as C9 
responses.  
Clearance of ibrutinib resistance mutation for expansion arm B is defined as less than 1% 
mutation bearing alleles (BTKC481 and/or PCLγ2) during treatment (up to C9). The proportion 
of patients with negative mutation, where negative mutation is defined as having clearance of 
the baseline ibrutinib resistance mutation, will be provided along with corresponding 90% exact 
confidence interval (CI). Note that only R665, S707, A708 and L845 variants will be considered 
as functional PLCγ2 mutations. Other PLC γ2 variants will not be considered for this analysis. 
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
(BOR) of complete response (CR), complete response with incomplete marrow recovery (CRi), 
or partial response (PR), as assessed by investigators per IWCLL criteria (see VAY736Y2102-
CSP-Appendix 1 for details) and will be calculated based on all response evaluations. The ORR 
will be calculated by dose level in dose escalation and by arm in dose expansion, and overall, 
and will be presented along with corresponding 90% exact confidence intervals (CI). 
Assessments taken after the start of alternative cancer therapy will be excluded.  
Time to progression (TTP) is the time from start of treatment to the date of event which is 
defined as the first documented progression (defined as overall disease response assessment of 
PD) or death due to underlying cancer. If a patient has not had an event, time to progression is 
censored at the date of last adequate disease assessment. Assessments taken after the start of 
alternative cancer therapy will be excluded. 
Median TTP (in months) with corresponding 95% CI, 25th and 75th percentiles (Brookmeyer 
and Crowley 1982, Klein and Moeschberger 1997) and Kaplan-Meier estimated probabilities 
(TTP rate) with corresponding 95% CIs (Greenwood’s formula, Kalbfleisch and Prentice 1980) 
at several time points (3, 6, 12, 18 and 24 months) will be presented. The number (%) of 
progressions, deaths and patients censored will also be summarized.  
2.8.2 
Safety analyses 
The Safety Set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used. 
2.8.2.1 
Adverse events (AEs) 
2.8.2.1.1 Data handling and AE date imputation rules 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, respectively.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE 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). 


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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form. 
A missing AE start date will be imputed using the following logic matrix described in Table 2-
3. 
Table 2-3 
Imputation rules for a partially missing AE start date 
 
AEM MISSING 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
No imputation 
No imputation 
No imputation 
No imputation 
AEY < TRTY 
 
(D) 
 
(C) 
 
(C) 
 
(C) 
 
AEY = TRTY 
 
(B) 
 
(C) 
 
(B) 
(A) 
 
AEY > TRTY 
 
(E) 
(A) 
(A) 
(A) 
 
AEM: Month AE started; AEY: Year AE started 
TRTM: Month treatment started; TRTY: Year treatment started 
Table 2-4 is the legend to the logic matrix shown in Table 2-3 and details the relationship of 
AE start date to study treatment start date. 
Table 2-4 
Imputation legend and AE/treatment start date relationship 
 
AE start date relationship 
Imputation 
(A) 
After treatment start or Uncertain 
MAX( 01MONYYYY, TRTSTD+1 ) 
(B) 
Uncertain 
TRTSTD+1 
(C) 
Before treatment start 
15MONYYYY 
(D) 
Before treatment start 
01JULYYYY 
(E) 
After treatment start 
01JANYYYY 
Before treatment start: Partial date indicates AE start date is prior to treatment start date. 
After treatment start: Partial date indicates AE start date is after treatment start date. 
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date. 
No imputation will be performed for AE end dates. 
All events with a start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing. The same rule will be applied to adverse events starting before or on 
the cut-off date and not having a documented end date. No imputation will be performed for 
missing/incomplete AE end dates. 
2.8.2.1.2 Data analysis 
AE Summaries (CSR outputs) 
AE summaries will include only AEs that started or worsened during the on-treatment period, 
the treatment-emergent AEs. All AEs collected in the AE (e)CRF page will be listed along with 


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the information collected on those AEs e.g., AE relationship to study drug, AE outcome etc. 
AEs starting during the post-treatment period will be flagged in the listings.  
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.  
In AE summaries the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational arm.  
The following adverse event summaries will be produced by treatment: 
• Overview of adverse events (number and % of patients with any AE, any SAE any fatal 
SAE, any dose reductions/interruptions, AE leading to discontinuation, AE requiring 
additional therapy); 
The following adverse event summaries will be produced by treatment and maximum grade 
(All grades and Grade >=3): 
• AEs by SOC and PT, regardless of relationship to study treatment and suspected to be 
related to study treatment; 
• Serious adverse events by SOC and PT, regardless of relationship to study treatment and 
suspected to be related to study treatment Leading to treatment discontinuation; 
• AEs leading to dose interruption/adjustment;  
• AEs Requiring additional therapy; 
• Dose limiting toxicities by SOC and PT; 
The following listings will be produced: 
• All adverse events (safety set)  
Deaths (CSR Outputs) 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class (SOC) and preferred term (PT).  
All deaths will be listed for the safety set, and post-treatment deaths will be flagged.  
The death summaries cover patients from the Safety Set.  
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables treatment-
emergent adverse events (30 days after the administration of last study treatment, for definition 
of last study treatment, see Section 2.1.1.2) which are not serious adverse events with an 
incidence greater than 5% and treatment-emergent SAEs and SAEs suspected to be related to 
study treatment will be provided by SOC and PT on the safety set population. 


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If for a single subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness, and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.  
Only disclosure to clinicaltrials.gov is applicable for this trial. As there are no study sites based 
in the European Union (EU), no disclosure to EudraCT will be made. 
DSUR – Development Safety Update Report  
For the purpose of Development Safety Update Report (DSUR) reporting, estimates of overall 
cumulative patient exposure to study treatment by sex and age will be provided for the Safety 
Set, as required. 
2.8.2.2 
Adverse events of special interest/ grouping of AEs 
An adverse event of special interest (AESI) is a grouping of AEs that are of scientific and 
medical concern specific to investigational drug(s) VAY736.  
These groupings are defined using MedDRA terms, SMQs (standardized MedDRA queries), 
high level group terms, high level terms, and PTs. Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. An NMQ is a customized group of search terms which 
defines a medical concept for which there is no official SMQ available or the available SMQ 
does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad. For each specified AESI, number and percentage of patients 
with at least one event of the AESI occurring during on-treatment period will be summarized. 
Selected AEs are described in the VAY736 electronic Case Retrieval Sheet (eCRS) – 
indication: Waiha, itp, cll, nhl. Summaries of these AESIs will be provided by safety topic.   
A listing of all grouping levels down to the MedDRA PTs, based on the electronic Case 
Retrieval Strategy, used to define each AESI will be generated. 
2.8.2.3 
Laboratory data 
2.8.2.3.1 CTC grading for laboratory parameters 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of laboratory 


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CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in the Appendix 5.3 of the 
SAP, Section 5.3. The latest available version of the document based on the underlying CTCAE 
version 4.03 at the time of analysis will be used.  
For laboratory tests where grades are not defined by CTCAE version 4.03 results will be graded 
by the low/normal/high (or other project-specific ranges, if more suitable) classifications based 
on laboratory normal ranges.  
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
The following summaries will be produced separately for hematology and chemistry: 
• For parameters with CTC grades: Shifts from baseline to the worst post-baseline CTC grade, 
• For parameters with no CTC grades defined: Shifts from baseline to the worst post-
baseline using low/normal/high classifications, 
The following listings will be produced: 
• Any laboratory observations with CTCAE grade of 3 or 4.  
Table 2-3 below lists all hematology and chemistry laboratory parameters that will be 
summarized. 
Table 2-3 
Local clinical laboratory parameters to be summarized 
Test category 
Test Name 
Hematology 
Hematocrit, Hemoglobin (Hemoglobin increments will not be 
presented), MCV, Platelets, White blood cells, Differential (Basophils, 
Lymphocytes, Monocytes, Neutrophils) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase 
(LDH), Bicarbonate, Corrected Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Total Bilirubin, Total Protein, Triglycerides, Blood Urea 
Nitrogen (BUN), Uric Acid, Amylase, Lipase, Non-fasting Glucose 
2.8.2.3.2 Imputation rules 
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.  
The following rules will be applied to derive the WBC differential counts and associated normal 
ranges when only percentages are available for Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands, or other differential: 
xxx count = (WBC count) * (xxx %value / 100) 
If normal ranges are not available for certain differentials, then these differentials will not be 
presented. 


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If laboratory values are provided as ‘<X’ (i.e., below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.  
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:  
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]  
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.  
2.8.3 
Other safety data 
2.8.3.1 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters will be collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).  
Notable vital signs collected during the on-treatment period will be summarized. Values 
measured during the post-treatment period will be flagged in the listings.  The number and 
percentage of patients with notable vital sign values (high/low) as seen in Table 2-6 below will 
be presented by treatment arm. 
Table 2-6 
Criteria for notable vital sign values 
Vital sign (unit)  
Notable high value  
Notable low value  
Weight (kg)  
increase >= 10% from 
baseline  
decrease >= 10% from 
baseline  
Systolic blood pressure 
(mmHg)  
>=180 and increase from 
baseline of >=20  
<=90 and decrease from 
baseline of >=20  
Diastolic blood pressure 
(mmHg)  
>=105 and increase from 
baseline of >=15  
<=50 and decrease from 
baseline of >=15  
Pulse rate (bpm)  
>=100 and increase from 
baseline of >25%  
<=50 and decrease from 
baseline of >25%  
Body temperature (°C)  
>= 39.1  
--  
2.8.4 
Pharmacokinetic analysis  
PK parameters will be determined using non-compartmental method(s) for VAY736 and 
ibrutinib. PK parameters such as those listed in Table 2-7 will be estimated and reported, when 
applicable. For ibrutinib, PK parameters determined will be only AUClast, Cmax, Tmax, Tlast, 
and if applicable other PK parameters (eg AUC0-t). The PAS subset of patients will be used in 
all pharmacokinetic data analysis and summary statistics.  


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Table 2-7 
Noncompartmental pharmacokinetic parameters  
AUClast 
The AUC from time zero to the last 
measurable concentration sampling time 
(tlast) (mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x 
time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing 
interval (tau) after first dose and at steady-
state (amount x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, 
blood, serum, or other body fluid drug 
concentration after single dose 
administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, 
blood, serum, or other body fluid drug 
concentration after single dose 
administration (time) 
T1/2 
The elimination half-life associated with the 
terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier 
for other half-lives 
CL/F 
The total body clearance of drug from the 
plasma (volume x time-1) 
Vz/F 
The apparent volume of distribution during 
terminal phase (associated with λz) (volume) 
Racc 
Accumulation ratio should be calculated 
using AUC values obtained from a dosing 
interval 
2.8.4.1 
Data handling principles 
All concentrations below the lower limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of pharmacokinetic parameters, unless 
otherwise stated under the Pharmacokinetic Analysis Set.  
At the time of analysis, concentration data from patients may be removed from the estimation 
of certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Specific time points might be removed from the analysis set if 
technical issues with the sample are reported (e.g., sampling issues, missing information). These 
patients and concentration data points will be identified at the time of analysis. 
2.8.4.2 
Data analysis set 
All pharmacokinetic data analyses and PK summary statistics will be based on PAS. Only PK 
blood samples with date and time and for which the last prior dose dates and times are 
adequately recorded will be included in the PK analyses. 


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2.8.4.3 
Basic tables, figures, and listing 
Descriptive statistics will be presented for all pharmacokinetic parameters, as 
described below.Table 2-8 
Descriptive analysis 
Parameters 
Descriptive statistics 
AUC(1) , Cmax, CL/F, Vz/F, T1/2, Racc 
Mean, standard deviation, CV% mean, geometric mean, 
CV% geo-mean, median, minimum, and maximum.  
 
Tmax, Tlast 
Median, minimum, and maximum. 
(1) Includes AUCtau, AUClast (or all AUC parameters) 
CV% = coefficient of variation (%) = sd/mean*100 
CV% geo-mean = sqrt (exp (variance for log transformed data)-1)*100 
Note: For ibrutinib, PK parameters determined will be only AUClast, Cmax, Tmax, Tlast, and if 
applicable other PK parameters (eg AUC0-t). 
Zero concentrations will not be included in the geometric mean calculations. Tmax will be 
summarized in terms of median values and ranges. Missing concentrations or PK parameter 
values will not be imputed. A listing of derived PK parameters per subject will be produced by 
treatment group. 
2.8.4.4 
Dose proportionality  
The analysis of dose proportionality may be conducted for AUCtau and Cmax of VAY736 
using a power model on log-transformed scale. The log-transformed PK parameters will each 
be regressed onto a fixed factor for log (dose). The 90% confidence interval (CI) of the slope 
for each PK parameter will be computed from the model and presented in the summary table. 
Cmax and AUC will be used for dose proportionality analysis using the power model (Gough 
1995). The power model empirical relationship between a PK parameter and dose is of the form 
( )(
)β
α
dose
Exp
PK =
, 
where “PK” represents the PK parameter AUC or Cmax. For analysis, this equation is log-
transformed (natural log), obtaining the equation 
(
)
(
)
Dose
PK
e
e
log
log
β
α +
=
, 
The slope beta measures the dose-proportionality between Dose and the PK parameter. 
To test for dose proportionality, the confidence interval criteria for assessment of dose 
proportionality from Smith et al. (2000) will be used.  The a priori acceptance range for the 
slope, according to Smith, is given by: 
(
)
(
)
(
)
(
)
ratio
dose
Ln
Ln
ratio
dose
Ln
Ln
_
25
.
1
1
  
  
_
8
.
0
1
+
〈
〈
+
β
 
Where 1.25 and 0.8 are the critical a priori values suggested by regulatory authorities for any 
bioequivalence problem after a data log transformation, and “dose_ratio” is the ratio of the 
largest to the smallest dose.  Dose proportionality can be claimed if the 90% confidence interval 
for the slope is entirely contained within this a priori range.   


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2.8.4.5 
Immunogenicity 
The presence and/or concentration of anti-VAY736 antibodies (Anti-Drug Antibody) will be 
listed by patient and summarized (when sample size is sufficient) using descriptive statistics to 
assess IG following one or more intravenous infusion of VAY736. 
2.8.4.5.1 Sample ADA Status 
Each IG sample is assessed in a three-tiered anti-drug antibody (ADA) testing approach. All IG 
samples are analyzed in the initial screening assay (first tier). Samples testing negative in the 
screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for VAY736 (second tier). The titer of confirmatory positive samples will be 
subsequently determined in the titration assay (third tier). Samples identified as positive in the 
confirmatory assay are considered as ADA positive. Samples can test negative in either the 
screening or confirmatory assay but for analysis purposes they are not differentiated. The 
following properties of each sample will be provided in the source data:  
• Result of assay according to pre-specified confirmatory cut-point: ADA positive (yes) 
or ADA negative (no), or ‘NOT REPORTABLE’. 
• Titer (for positive samples): Numerical representation of the magnitude of ADA 
response. 
Fold titer change (i.e., 4-fold): threshold for determining treatment boosted 
The following definitions apply only to non-missing samples:  
• ADA-negative sample: sample where assay is ADA negative  
• ADA-positive sample: sample where assay is ADA positive.  
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding non-missing baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing:  
• treatment-induced ADA-positive sample: ADA-positive sample post-baseline with ADA-
negative sample at baseline.   
• treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with titer 
that is at least x-fold greater than the ADA-positive baseline titer.  
• treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with titer 
that is less than x-fold greater than the ADA-positive baseline titer.  
The following summaries of ADA sample status (n and %) will be provided using 
Immunogenicity prevalence set:   
• ADA-positive samples (i.e., ADA prevalence), overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of patients at that 
time point with a non-missing sample.  
2.8.4.5.2 Patient ADA Status 
Any IG sample collected after 140 days of the last dose of VAY736 will not be used for 
summaries or derivations and will only be included in the listing. 
Patient ADA status is defined as follows: 


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• Treatment-induced ADA-positive patient: patient with ADA-negative sample at baseline 
and at least one treatment-induced ADA-positive sample.   
• Treatment-boosted ADA-positive patient: patient with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample.   
• Treatment-unaffected ADA-positive patient: patient with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample.   
• Treatment-reduced ADA-positive patient: patient with ADA-positive sample at baseline 
and at least one post baseline sample, all of which are ADA-negative samples.   
• ADA-negative patient: patient with ADA-negative sample at baseline and at least one 
non-missing post baseline sample, all of which are ADA-negative samples.    
• Inconclusive subject: subject who does not qualify for any of the above definitions  
Listings will be provided for patient ADA status using the IGIS. 
The following summaries of ADA patient status (n and %) will be provided using the IGIS: 
• Patients with ADA-negative sample at baseline  
• Patients with ADA-positive sample at baseline  
• ADA-negative Patients  
• Treatment-boosted ADA-positive patients; denominator is the number of patients with 
ADA-positive sample at baseline.   
• Treatment-induced ADA-positive patients; denominator is the number of patients with 
ADA-negative sample at baseline.   
• ADA-negative patients: denominator is the number of patients in Immunogenicity 
incidence set.  
• ADA-inconclusive patients  
• ADA-positive patients (i.e., ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive patients; denominator is the 
number of patients in Immunogenicity incidence set.   
 
 
.  
2.9 
Interim analysis 
No formal interim analyses are planned. However, the dose-escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose escalation part, the next dose of VAY736 in combination with ibrutinib 
has to be chosen depending on the observed data. Details of this procedure and the process for 
communication with Investigators are provided in VAY736Y2102-CSP-Section 6.2.3. 


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3 
Sample size calculation 
3.1.1 
Dose-escalation part 
No formal statistical power calculations to determine sample size were performed for this study. 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD/RDE level, as described in VAY736Y2102-CSP-Section 6.2. Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients 
may be enrolled at any dose level below the estimated MTD/RDE for further elaboration of 
safety and pharmacokinetic parameters as required. Minimum of fifteen patients are expected 
to be treated in the dose escalation part, for the model to have reasonable operating 
characteristics relating to its MTD recommendation. 
3.1.2 
Dose-expansion part 
During dose expansion, additional patients will be enrolled to gain more information about the 
safety and tolerability of VAY736 in combination with ibrutinib, to obtain additional PK/PD 
data and to obtain preliminary anti-tumor activity for two expansion arms.  
VAY736 in combination with ibrutinib will enroll two groups of approximately 20 patients each 
receiving the MTD or RDE study treatment, the probability to detect AEs with a true incidence 
rate of 10% is 87.8% with 20 patients or 98.5% with 40 patients (Table 3-1). 
Table 3-1 
Probability to detect at least one special adverse event of interest 
Special AE of interest incidence rate 
 
20 
30 
40 
2.5% 
0.397 
0.532 
0.637 
5% 
0.642 
0.785 
0.871 
10% 
0.878 
0.958 
0.985 
15% 
0.961 
0.992 
0.998 
In addition, evaluation of CR/CRi rate at Cycle 9 as defined by IWCLL guidelines is the 
secondary objective in dose expansion part. 
Table 3-2 below shows the 90% credible intervals for N=20 for the arm A/arm B in expansion, 
with different response rates using a minimally informative beta distribution as prior 
distribution with parameters a=0.25 and b=1. This assumes a priori response rate of 20%. Note 
that the final interval will depend on the final sample size.  
8 responses observed out of 20 patients will provide 3%, 53%, 44% chance that there is no 
clinical benefit, moderate clinical benefit, and superior clinical benefit as defined above, 
respectively. 


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Table 3-2 
Posterior summaries based on assumed observed responses (CR/CRi 
at C9) and 20% prior assumption 
Observed 
CR/CRi 
(x/N) 
Posterior mean 
(90% credible 
interval) 
Probability of 
no clinical 
benefit 
[0% - 20%] 
Probability of 
moderate clinical 
benefit (20% - 
40%] 
Probability of 
superior clinical 
benefit 
(40%-100%] 
3/20  
.153 (.048,.295)  
.756  
.240 
.005 
4/20 
.200 (.078,.354) 
.544 
.436 
.020 
6/20 
.294 (.147,.464) 
.170 
.687 
.143 
8/20  
.388 (.224,.565)  
.026  
.530  
.443 
10/20 
.482 (.309,.658)  
.002  
.223  
.775 
4 
Change to protocol specified analyses  
1. In protocol v06, one secondary efficacy objective as outlined in Section 10.5.2 is Rate of 
CR at C9 for expansion arm A and arm B. 
• In SAP Sections 2.8.1, 3.1.2,   
2. In protocol v06 Section 10.5.2:  Overall response rate (ORR) is defined as best overall 
response (BOR) of complete response (CR) or partial response (PR), assessed by 
investigators per IWCLL criteria (see Appendix 1 for details). ORR for each expansion 
arm along with corresponding 90% exact confidence interval (CI) will be provided. 
• In SAP Section 2.8.1, based on clinical team discussion, overall response rate (ORR) 
is updated and now defined as the proportion of patients with an overall disease 
response at C9 of complete response (CR), complete response with incomplete 
marrow recovery (CRi), or partial response (PR), as assessed by investigators per 
IWCLL criteria. The rationale is to include the additional response assessment 
category, CRi. 
3. In protocol v06 Section 10.5.4, immunogenicity analyses are discussed to study the 
presence and/or concentration of anti-VAY736 antibodies (Anti-Drug Antibody). 
• SAP Sections 2.2.1, 2.2.2, 2.8.4.5.1 and 2.8.4.5.2 were added and/or modified to 
include the standard definitions for immunogenicity analysis sets, ADA sample status 
and ADA patient status, so that the immunogenicity analyses can be properly defined 
and performed. 
4. 
 
 
 
• In SAP Section 2.9.5, based on clinical team discussion, the definition of 
 
 so this is additionally 
updated. 
5. In protocol v06 Section 14.1 Appendix 1 – Guidelines for NCI CLL Working Group 2018 
(IWCLL), the guidelines consist of four response categories: CR, PR, SD, and PD.  


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• In SAP Section 5.2, the guidelines for efficacy evaluations for CLL studies were 
added. This includes updating the response categories have been updated to include 
two additional responses: complete response with incomplete marrow recovery (CRi) 
and Unknown, because the 2018 IWCLL criteria guidelines specify CRi and 
Unknown as possible responses. The new appendix aligns with TCO standard 
language. It also now specifies TTP censoring rules that were not previously detailed 
in the SAP. 
6. In Protocol v06, Sections 6.6.1.1, 7.2.3.1, and 10.1.5, vomiting within 8 hours of ibrutinib 
administration should be collected, and the time (using the 24-hour clock) of vomiting 
should be recorded in the adverse events eCRF. 
• In SAP, after discussions with clinical and PKS line functions, we have updated this 
to vomiting within 4 hours of ibrutinib administration. The eCRF was not per-
protocol for unknown reasons and instead collected vomiting with 4 hours of dosing. 
PKS confirmed that 4 hours of monitoring should be sufficient for ibrutinib based on 
Tmax half-life and standards. 
7. In Protocol v06, Section 10.1.4, the definition of the Dose-determining analysis set (DDS) 
includes patients from the FAS from both the expansion and escalation parts of the study. 
• In SAP, patients from the expansion parts of the study will not be included as part of 
the definition of the DDS to align with Section 6.2.4 and Section 10.4.1 in the 
Protocol which clearly specify that DLTs will be reported for the escalation part of 
the study.  
8. In Protocol v06, Section 10.4.1, changes in electrocardiograms are considered as part of 
the primary objective.  
• In SAP, reference to ECG monitoring and analysis as part of the primary objective 
was removed to align with Table 3-1 Objectives and related endpoints of the Protocol. 
9. In Protocol v06, Section 10.5.3.4 a listing of ECG evaluations for all patients with at least 
one abnormality should be presented. 
• In SAP, as ECG is not considered part of the study objectives, no ECG data will be 
listed.  
5 
Appendix 
5.1 
Imputation rules 
All imputation rules were defined in previous sections of the SAP, as referenced below. 
5.1.1 
Study drug 
See Section 2.5.1.1. 
5.1.2 
AE date imputation 
See Section 2.8.2.1.1. 


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5.1.3 
Concomitant medication date imputation 
Same as AE date imputation; see Section 2.5.2 for discussion of concomitant medication 
summaries, and Section 2.8.2.1.1 for the imputation rule.  
5.1.4 
Prior and post antineoplastic therapies date imputation 
See Section 2.3.4. 
5.1.5 
Other imputation 
When a date of diagnosis or date of relapse/recurrence/progression or previous progression is 
recorded as a partial date, the missing day is imputed to the 1st of the month (e.g., DEC2021 
imputed to 01DEC2021) and if the day and month are both missing then the missing date is 
imputed to 1st of January of that year (e.g., 2021 imputed to 01JAN2021).  
 
If the imputed date of relapse/recurrence/progression or previous progression is less than the 
date of diagnosis or prior antineoplastic therapy, use the date of diagnosis or the start of prior 
antineoplastic therapy as the imputed date of relapse/recurrence/progression or previous 
progression, respectively. Instances where time to progression is before last antineoplastic 
therapy will not be included in the summary tables. 
 
 
 


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5.2 
Guidelines for efficacy evaluation in chronic lymphocytic 
leukemia (CLL) studies1 
5.2.1 
Introduction 
This document provides the working definitions and specifications for a consistent and efficient 
analysis of efficacy for VAY736 clinical studies in chronic lymphocytic leukemia (CLL). The 
current document is written primarily for the relapse and refractory disease setting. 
Modifications may be indicated for earlier disease settings. 
This document is based on the updated National Cancer Institute (NCI) sponsored response 
guidelines of CLL authored by the International Workshop on CLL (iwCLL) (Hallek et al 2018). 
The objectives of this document are to: 
• Ensure that the definitions of responses in a clinical study protocol correctly reflect the 
above-mentioned guidelines. 
• Provide guidance for the response assessment and clinical monitoring to ensure 
consistency in applying the guidelines. 
Moreover, this document describes data handling and derivation rules. Respective sections may 
be used in the statistical analysis plan (SAP) to provide further details. Relevant sections of this 
document will be copied into individual clinical trial protocols as appendix to the protocol. 
5.2.2 
Efficacy assessment  
5.2.2.1 
Documentation of disease 
For the evaluation of disease at baseline and throughout the study, the following are recorded:  
5.2.2.1.1 Lymphadenopathy 
Throughout this document, a nodal lesion will be called measurable if it can be measured 
accurately in 2 perpendicular dimensions and the long axis is ≥ 1.5 cm, regardless of the length 
of the short axis. A measurable nodal lesion must become < 1.5 cm in long axis to be considered 
normalized. 
Index nodal lesions are selected from the measurable nodal lesions. A minimum of one 
measurable index nodal lesion and maximum of six of the largest dominant nodal lesions should 
be documented at baseline and assessed throughout the study. If a patient has no measurable 
nodal disease at baseline, then it would be acceptable that no index nodal lesions be identified. 
Index nodal lesions should be from disparate regions of the body (e.g., neck, chest, abdomen, 
and pelvis) including mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. Two perpendicular dimensions must be recorded on the corresponding CRF at each 
assessment of a measurable lesion selected to be an index lesion. The response of 
lymphadenopathy is based the sum of the products of diameters (SPD) of all index lesions (up 
to 6) assessed by image and the sum of the longest diameters of all index lesions (up to 6) 
assessed 
by 
physical 
exam. 
One 
CT 
scan 
should 
be 
performed 
before 
randomization/enrollment/start of treatment as baseline and a second CT scan at time of 
establishing response for lymphadenopathy, if abnormal at baseline. Additional CT scan may 


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be required in the protocol. When both CT and physical exam measurements are available for 
a lesion, CT result overrules physical exam measurement. 
5.2.2.1.2 Hepatomegaly and spenomegaly 
The presence of enlarged spleen or liver before randomization/enrollment/start of treatment on 
the basis of CT scan and physical exam should be recorded on the corresponding CRF at 
baseline. If there is hepatomegaly or splenomegaly at baseline, CT scan of the abdomen with 
liver and spleen measurements should be performed at time of establishing complete remission. 
Post-baseline CT may not be needed if no hepatomegaly and/or splenomegaly is detected at 
baseline. Additional CT scan maybe required in the protocol. The radiological responses of 
hepatomegaly and splenomegaly are based on the measurement of the largest diameter. 
5.2.2.1.3 Blood lymphocytes 
Blood lymphocytes will be recorded before randomization/enrollment/start of treatment 
(baseline) and reevaluated at every assessment of response as well as at the end of study. 
5.2.2.1.4 Marrow 
Status of bone marrow involvement by CLL before randomization/enrollment/start of treatment 
will be assessed and collected and subsequent samples can be obtained for comparison (as 
specified in the protocol or as clinically indicated) as well as for confirmation of CR/CRi if 
CR/CRi is indicated by clinical and laboratory evaluations. Bone marrow reports will be 
recorded on the corresponding CRF and should describe cellularity, lymphocyte infiltration, 
and 
. MRD assessments by flow cytometry and/or 
next generation sequencing may be recommended in the protocol. 
5.2.2.1.5 Platelet count, hemoglobin and neutrophils 
Platelet 
count, 
hemoglobin 
and 
neutrophils 
will 
be 
recorded 
before 
randomization/enrollment/start of treatment (baseline) and reevaluated at every assessment of 
response as well as at the end of study. 
5.2.2.1.6 Other (Constitutional symptoms, transfusions, disease transformation) 
Constitutional symptoms should resolve completely in patients who have achieved CR/CRi. 
Constitutional symptoms in patients with CLL are CLL disease related clinical symptoms and 
are not caused by anticancer therapy (or drug toxicity).  
Constitutional symptoms are defined as any of the following disease-related symptoms as 
assessed and reported (present vs. absent) by the Investigator:  
a. Unintentional weight loss of 10% or more within the previous 6 months; 
b. Significant fatigue (i.e., ECOG PS 2 or worse; inability to work or perform usual 
activities); 
c. For patients who are not neutropenic with ANC > 500, fevers equal or higher than 100.5°F 
or 38.0°C for 2 or more weeks without other evidence of infection; or 
d. Night sweats for 1 month or more without evidence of infection. 


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Constitutional symptoms will be recorded before randomization/enrollment/start of treatment 
(baseline) and reevaluated at every assessment of response as well as at the end of study.  
Transfusions (red blood cells, platelets, plasma) received by the patient within 7 days of blood 
response assessments will be noted in the CRF.  
In patients with evidence of transformation, histological evaluation (biopsy of the involved 
lesion) may be recommended for confirmation in the protocol.  
5.2.2.2 
Baseline evaluation 
The following assessments are mandatory at baseline: 
• Peripheral blood for lymphocytes, platelet, hemoglobin, and neutrophils, including 
evaluation of minimal residual disease (Section 5.2.2.1.1 and Section 5.2.2.1.5) 
• Lymphadenopathy (CT plus physical exam) (Section 5.2.2.1.1) 
• Hepatomegaly (CT plus physical exam) (Section 5.2.2.1.2) 
• Splenomegaly (CT plus physical exam) (Section 5.2.2.1.2) 
• Bone marrow aspirate and/or biopsy (Section 5.2.2.1.4) 
• Constitutional symptoms (Section 5.2.2.1.6) 
• 
 
For disease status at baseline, the most current disease assessment for lymph node, liver, spleen, 
bone marrow, constitutional symptoms and blood count within the protocol specified window 
should be used as the baseline reference.  
5.2.2.3 
Post-baseline overall disease response evaluation 
The post-baseline evaluation of overall disease response is a composite of the individual 
responses from peripheral blood count, lymph node, spleen, liver, bone marrow and 
constitutional symptoms etc. 
Treatment discontinuation for any reason not related to new antineoplastic therapy will be 
handled using the treatment policy strategy: Tumor assessment data collected after 
discontinuation of study treatment will be used to derive BOR. 
5.2.2.3.1 Component and timing of overall disease response evaluation 
An overall disease response evaluation must consist of all of the following components: 
• Peripheral blood for lymphocytes, platelet, hemoglobin and neutrophils (Section 5.2.2.1.3 
and Section 5.2.2.1.5).  
• Lymphadenopathy (Section 5.2.2.1.1) 
• Hepatomegaly (Section 5.2.2.1.2) 
• Splenomegaly (Section 5.2.2.1.2) 
Please note post-baseline CT scans for lymph node are required at time of establishing response 
if these sites are abnormal at baseline or as specified per individual protocol. If there is 
hepatomegaly or splenomegaly at baseline, CT scan of the abdomen with liver and spleen 
measurements should be performed at time of establishing complete remission.  


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In addition, 
• Post-baseline bone marrow aspirate and/or biopsies (Section 5.2.2.1.4) for morphologic 
assessment of cellularity, lymphocytic infiltration and 
 are 
required to demonstrate that a patient has achieved response in bone marrow for the first 
time. Following initial achievement of response, a bone marrow biopsy or aspirate will not 
be required unless it is clinically indicated (e.g. improvement from initial response, 
progression, cytopenia of uncertain cause etc.) or as specified per individual protocol. 
 
 
• Evaluation of constitutional symptoms (Section 5.2.2.1.6) is required to demonstrate that a 
patient has achieved CR/CRi without disease-related constitutional symptoms or as 
specified per individual protocol. 
• Lymph node biopsy can be performed to assess the disease transformation to a more 
aggressive histology (e.g., Richter syndrome). 
In order for all components of disease assessments to be qualified as the same response 
evaluation, peripheral blood sample collection, physical exam, CT scan (if needed), bone 
marrow biopsy/aspirate (if needed) and constitutional symptom assessment (if needed) must be 
performed, in general, within 14 days of each other, unless specified otherwise in the protocol. 
In case of a missing measurement of a required component to qualify for a certain response 
category, the overall response at that assessment will be “Unknown”, unless progression was 
seen.  
5.2.2.3.2 Overall disease response criteria 
The general principle of overall disease response determination at a given evaluation is 
described in Table 5-1. Also refer to Hallek et al 2018 for a detailed explanation of each 
response criteria.  
Table 5-1 
Overall disease response classification at a given evaluation time  
Response category 
Definition 
Complete remission (CR) 
All the following criteria in Group A and Group B must be met and 
patients don’t have disease-related constitutional symptoms: 
Group A 
 
      Lymphadenopathy 
• 
None ≥ 1.5 cm (CT is required at time of establishing CR/CRi 
if abnormal at baseline) 
      Hepatomegaly 
• 
Liver size normal (CT is required at time of establishing 
CR/CRi if abnormal at baseline) 
      Splenomegaly 
• 
Spleen size normal (CT is required at time of establishing 
CR/CRi if abnormal at baseline) 
      Blood lymphocytes 


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Response category 
Definition 
• 
< 4000 /μL 
Group B 
      Platelet count 
• ≥ 100,000 /μL 
      Hemoglobin 
• ≥ 11.0 g/dL (without red blood cell transfusions or 
erythropoietin support within 7 days ) 
      Neutrophils  
• ≥ 1500 /μL 
      Marrow 
• Normocellular, no CLL cells, no B-lymphoid nodules  
Complete remission with 
incomplete 
marrow 
recovery (CRi) 
All criteria for CR as defined above are met, except a persistent anemia 
or thrombocytopenia or neutropenia apparently unrelated to CLL. 
Partial remission (PR) 
At least two of the criteria of Group A plus one of the criteria of Group B 
below must be met if abnormal at baseline. If only one parameter of both 
groups A and B is abnormal prior to therapy, only 1 needs to improve. 
Group A 
      Lymphadenopathy 
• 
Decrease ≥ 50% from baseline (CT is required at time of 
establishing PR if abnormal at baseline) or meet CR criteria.  
      Hepatomegaly 
 
• 
Decrease ≥ 50% from baseline of enlargement of liver below 
the costal margin by physical exam or meet CR criteria. 
      Splenomegaly 
• 
Decrease ≥ 50% from baseline of enlargement of spleen 
below the costal margin by physical exam or meet CR criteria. 
      Blood lymphocytes 
• 
Decrease ≥ 50% from baseline or meet CR criteria. 
Group B 
      Platelet count 
• 
≥ 100,000 /μL or increase ≥ 50% from baseline  
      Hemoglobin 
• 
≥ 11.0 g/dL or increase ≥ 50% from baseline (without 
transfusions within 7 days) 
Progressive disease (PD) 
At least one of the criteria in Group A, Group B or Others group is met 
Group A 
      Lymphadenopathy 
• 
Increase ≥ 50% from baseline or from response in greatest 
determined diameter of any previous site, only applicable if 
abnormal at baseline  


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Response category 
Definition 
      Hepatomegaly 
• 
Increase ≥ 50% from baseline or from response, only 
applicable if abnormal at baseline  
      Splenomegaly 
• 
Increase ≥ 50% from baseline or from response , only 
applicable if abnormal at baseline  
      Blood lymphocytes 
• 
Increase ≥ 50% over the course of 2 months from baseline or 
from response with at least 5000 /μL 
 Group B 
      Platelet count 
• 
Decrease ≥ 50% over baseline or best response secondary to 
CLL and unrelated to autoimmune cytopenias 
      Hemoglobin 
• Decrease of ≥ 2 g/dL from baseline or best response 
secondary to CLL and unrelated to autoimmune cytopenias 
      Marrow 
• Increase of CLL cells by ≥ 50% over the nadir 
Others: 
      New lesion 
• 
Appearance of any new lesion such as enlarged lymph nodes 
(≥1.5cm), splenomegaly, hepatomegaly or other organ 
infiltration 
      Disease transformation  
• 
Transformation to a more aggressive histology (e.g., Richter 
syndrome) as documented by lymph node biopsy. 
Stable disease (SD) 
Failure to meet the criteria for CR, PR or PD. SD is equivalent to no 
response (NR) 
Unknown 
“Unknown” is assigned in case the baseline assessment or the response 
assessment is not done, incomplete, indeterminate, or not performed 
within the respective time frame (VAY736Y2101-CSP-Section 16.1.2.2 
and Section 16.1.2.3.1).  
However, if there is any evidence of PD, the overall response will 
considered as PD. 
 
The overall disease responses of CR/CRi must stay the same until PD, with the exception of an 
UNK status. A patient who had a CR/CRi cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more disease component 
reappearing, in which case the status would become a PD. 
Once an overall disease response of PR is observed, the PR response status must be maintained 
or improved over time until PD, with the exception of an UNK status.  That is, after a single PR 


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the overall disease response should still be considered PR (or UNK) until PD is documented or 
the disease totally disappears in which case a CR/CRi assignment is applicable. 
5.2.2.3.3 Establishing CR, CRi, PR and subsequent maintenance of CR, CRi, PR  
with no clinical evidence of progression 
A full response evaluation, including assessments of peripheral blood, bone marrow, lymph 
node, liver, spleen and constitutional symptom, is required at the first time a CR or CRi is 
demonstrated (Section 5.2.2.3.1). Based on iwCLL response guidance, bone marrow 
aspirate/biopsy is not a required criterion for establishing PR. Additional bone marrow 
biopsies/aspirates may be recommended in the protocol.  
Following initial achievement of CR, CRi or PR, if the patient has no evidence of PD as assessed 
on peripheral blood, lymph node, liver, spleen and constitutional symptoms, patients will be 
considered to have maintained a clinical CR, CRi or PR. The maintenance assessment of lymph 
node, liver and spleen can be done via physical exam or CT. 
In order for the best overall disease response to be categorized as CR, CRi or PR, there must be 
no evidence of PD at a minimum of 8 weeks (56 days) after the initial achievement of CR, CRi 
or PR. Please note, if additional assessments (e.g. bone marrow, CT scan or lymph node 
biopsy/aspirate) are performed (Section 5.2.2.3.1) in the same evaluation for disease response 
evaluation purpose, they will also need to show remission status. 
The onset date of CR, CRi or PR will then be derived as the evaluation date of the initial CR, 
CRi or PR assessment. If a patient satisfied CRi at one evaluation and later confirmed as a CR 
in the next evaluation, the patient will be considered as having confirmed CR.  
5.2.2.3.4 Date of overall disease response evaluation 
A complete evaluation of response includes at the minimum the assessments of peripheral blood, 
lymph node, liver and spleen. In addition, bone marrow aspirate/biopsy, constitutional 
symptoms and lymph nodal biopsy/aspirate may be required. All components of disease 
assessments must be performed within the specified time frame (Section 5.2.2.3.1) to be 
qualified as the same response evaluation.  
If the overall disease response is CR, CRi, PR, SD, or Unknown, the evaluation date (i.e. for 
one evaluation number) is defined as the latest of all dates of required measurements at that 
evaluation number. This rule applies also in case of multiple measurements of the same variable. 
PD can be assessed based on a partial evaluation (e.g. a PD is assessed from blood alone). The 
assessment date for PD is calculated as the earliest date of all assessments that reveal a PD. 
5.2.3 
Data collection 
5.2.3.1 
Data sources 
The summary of data sources refers to disease-specific (e)CRF standard modules or data 
transfer specification (DTS) modules. It is not appropriate to deviate from these specifications 
in Table 5-2. 


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Table 5-2 
Data sources 
(e)CRF module 
Specification 
Overall disease response 
Overall disease response and assessments of individual 
components for  
• 
Lymphadenopathy;  
• 
Hepatomegaly; 
• 
Splenomegaly  
• 
Bone marrow; 
• 
Blood lymphocyte; 
• 
Platelet count 
• 
Hemoglobin 
• 
Neutrophils 
• 
B-symptoms 
• 
Disease transformation (e.g., Richter syndrome) 
Nodal lesion (index and new 
lesion) 
Lesion index number, location, evaluation method (CT , Physical 
exam), dimension 
Liver and Spleen assessment 
Evaluation method (CT, Physical exam), result 
Bone marrow biopsy / aspirate 
Cellularity, lymphocyte, B-lymphoid nodule, marrow infiltration 
Blood response 
Blood lymphocyte, platelet, hemoglobin and neutrophils 
B-symptom 
To assess if there are any constitutional symptoms attributable to 
CLL 
Blood component transfusion 
Type and volume of transfusions, timing with respect to disease 
assessment 
Lymph node biopsy/aspirate 
To assess whether disease has transformed to a more aggressive 
histology (e.g., Richter syndrome) 
DTS module 
Specification  
 
 
5.2.3.2 
Recording response evaluation on the (e)CRFs 
The components and timing needed to adequately assess overall disease response is outlined in 
Section 5.2.2.3.1. In practice, disease response evaluation (either a complete assessment or only 
some components) may be performed on both scheduled and unscheduled time points. Also, it 
is not uncommon in oncology trials that disease responses are sometimes assessed at time points 
not matching the scheduled time points. For example, when a patient’s condition prevents 
certain assessments, the scheduled evaluation will have to be delayed to a later time point.  
As a result, the recording of response evaluation is aligned using the “Evaluation number” on 
the (e)CRFs. A new evaluation number should be assigned whenever a scheduled or 
unscheduled disease response assessment is performed, and hence is not necessarily aligned 
with the study visits.  
When progressive disease (PD) can be judge based on any component, e.g., if a PD is observed 
from blood sample alone without bone marrow assessment etc. at any time, it will be recorded 
on the (e)CRFs, with all other assessments as “not done” or “unknown”. See also Section 
5.2.2.3.4 regarding assigning date of the overall response. 


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5.2.4 
Derivation of efficacy endpoints 
5.2.4.1 
Best overall response 
Best overall response will be calculated by patient based on all evaluations. 
The best overall disease response is the best disease response recorded from the start of the 
treatment until PD, death, start of new therapy, withdrawal of consent or end of study, whatever 
comes first. Best response will be assigned according to the following order: 
1. CR 
2. CRi 
3. PR 
4. SD 
5. PD 
6. Unknown 
In case no post-baseline assessment is available or assessments with only unknown response 
status are available, the category “unknown” will be assigned as best overall response. 
Based on the patients’ best overall response during the study, the following rate is calculated: 
Overall response rate (ORR) is the proportion of patients with best overall response of PR or 
better. For the calculation of the ORR, the denominator should include all patients in the 
targeted patient population. Additional analysis sets can be defined in the study protocol. 
5.2.4.2 
Time-to-event endpoints 
General rule for the calculation of the time to event interval is: 
Time to event = end date - start date + 1 (in days) 
When no post-baseline response assessment is available, the date of randomization/start of the 
treatment will be used as end date (duration = 1 day), i.e., time to event variables will never be 
negative. 
Often censoring time is determined based on date of adequate response assessment.  Any 
response assessment is considered to be adequate if the assessment was performed and the 
outcome of the assessment was other than “not done” or “unknown”. 
5.2.4.2.1 Overall survival 
Overall survival (OS) is defined as the time from date of randomization/start of the treatment 
to the date of death due to any cause.  
If a patient is alive or his/her survival status is unknown, OS will be censored at the date of last 
contact.  The derivation of the last contact date, e.g., the variables and data panels to be used, 
should be clearly specified in the statistical analysis plan. 
5.2.4.2.2 Progression-free survival 
Progression-free survival (PFS) is defined as time from date of randomization/start of the 
treatment to date of (1) death due to any cause or (2) PD. 


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If a patient has not had an event, PFS is censored at the last adequate response assessment date. 
5.2.4.2.3 Duration of response 
Duration of response (DOR) is defined as the duration from the first documented onset of PR 
or better response to the date of PD or death due to disease progression.  
In case a patient does not have PD or death due to disease progression, DOR will be censored 
at the date of the last adequate assessment. 
5.2.4.2.4 Time to response 
Time to response (TTR) is defined as the time between date of randomization/start of the 
treatment to the date of first onset of PR or better response. 
Patients without experiencing any PR or better response will be censored according to the 
following events: 
• 
Patients experiencing a PD or death will be censored at maximum follow-up (i.e. date of 
last visit)  
• 
Patients not experiencing PD/death will be censored at their last adequate response 
assessment date 
5.2.4.3 
Event and censoring date, sensitivity analysis 
This section outlines the possible event and censoring dates for PD (Table 5-3), as well as 
addresses the issues of missing response assessments during the study. It is important that the 
protocol and analysis plan specify the primary analysis in detail with respect to the definition 
of event and censoring dates and also include a description of one or more sensitivity analyses 
to be performed. Using the draft FDA guideline on endpoints (Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, April 2005) as a reference, the following analyses 
can be considered: 
Table 5-3 
Options for event dates used in TTP 
Situation 
Options  
(1) 
= 
default 
unless 
specified
differently in the protocol or analysis
plan 
Outcome 
A No baseline or post-baseline assessment  
(1) 
Date 
of 
randomization/start 
of
treatment 
Censor 
B PD or death at scheduled assessment date or 
before next scheduled assessment 
(1) Date of PD (or death) 
(2) Date of next scheduled assessment 
Event 
Event 
C1PD or death after exactly one missing 
assessment 
(1) Date of PD (or death) 
(2) Date of next scheduled assessment1  
Event 
Event 
C2PD or death after two or more missing 
assessments 
(1) Date of last adequate assessment1 
(2) Date of next scheduled assessment2  
(3) Date of PD (or death) 
Censor 
Event 
Event 


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D No PD and no death 
(1) Date of last adequate assessment  
Censor 
E Discontinuation of study treatment due to  PD 
without documented PD, i.e. clinical PD based on 
investigator claim  
(1) N/A 
(2) Date of discontinuation (visit date at
which clinical PD was determined)  
Ignored 
Event 
F New anti-cancer therapy given 
(1) Date of last adequate assessment
prior to start of new anti-cancer therapy 
(2) Date of new anti-cancer therapy 
(3) Date of new anti-cancer therapy 
(4) N/A 
Censor 
Censor 
Event 
Ignored 
1  Date of the last adequate tumor assessment, is the date the last tumor assessment with overall 
lesion response of CR, PR, or SD before an event or censoring occurred.  
2 Date of next scheduled assessment is defined as the date of last adequate tumor assessment 
plus the protocol specified time interval for assessments. 
The primary analysis and the sensitivity analyses must be specified in the Study Protocol. 
Clearly define if and why options (1) are not used for situations C,E, and (if applicable) F.  
Situations C (C1 and C2): PD or death after one or more missing assessments: The primary 
analysis is usually using options (1) for situations C1 and C2, i.e.  
- (C1) taking the actual PD or death date, in the case of only one missing assessment. 
- (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.  
In the case of two or more missing assessments (situation C2), option (3) may be considered 
jointly with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Discontinuation of study treatment due to ‘PD’ without documented PD: By 
default, option (1) is used for situation E as patients without documented PD should be followed 
for PD after discontinuation of treatment.  However, option (2) may be used as sensitivity 
analysis. If PD is claimed based on clinical deterioration instead of response assessment, option 
(2) may be used for indications with high early PD rate or difficulties to assess response due to 
clinical deterioration.  
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
 


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5.3 
CTC grades for laboratory values in Novartis Oncology (based on CTCAE v4.03 – June 2010)  
 


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Note:  For non-fasting glucose Grade 1 and 2 is not assessed.


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6 
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Biometrics, 38, 29-41. 
Gough, K, Hutchison, M, Keene O, et al. (1995) Assessment of Dose Proportionality: Report 
from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working 
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Hallek, M, Cheson, BD, Catovsky, D, et al. (20181) iwCLL guidelines for diagnosis, 
indications for treatment, response assessment and supportive management of CLL.Blood, 
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Kalbfleisch, JD and Prentice, RL (1980) The Statistical Analysis of Failure Time Data. John 
Wiley & Sons, New York. 
Klein, JP and Moeschberger, ML (1997) Survival Analysis Techniques for Censored and 
Truncated Data. Springer-Verlag, New York.  
Rogatko, A, Schoeneck, D, Jonas W, et al. (2007) Translation of innovative designs into 
phase I trials. J Clin Oncol, 25, 4982-4986. 
Smith, BP, Vandenhende, FR, DeSante, KA, et al. (2000) Confidence interval criteria for 
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