A Phase Ib/II Study of Ibrutinib in Combination With GA101 - Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients Over 65 Years of Age or With Comorbidities That Preclude the Use of Chemotherapy Based Treatment
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Sponsor: University of California, San Diego

CONFIDENTIAL 
This is a University of California San Diego document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and must not be disclosed 
to any other party.  This material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from University of California San 
Diego.  
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
1 
PROTOCOL 
 
TITLE: 
A PHASE IB/II STUDY OF IBRUTINIB IN 
COMBINATION WITH GA101 - OBINUTUZUMAB 
IN 
PREVIOUSLY 
UNTREATED 
CHRONIC 
LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS > 65 
YEARS OF AGE OR WITH COMORBIDITIES 
THAT 
PRECLUDE 
THE 
USE 
OF 
CHEMOTHERAPHY BASED TREATMENT. 
STUDY NUMBER: 
01 
VERSION NUMBER:  
8.0 – September 19th, 2019  
   7.0 – December 3rd, 2018 
   6.0- June 26th, 2017  
5.0 – April 18th, 2017 
4.0 – February 6th, 2017 
3.0 – July 27th, 2016 
2.0 – December 10th, 2015 
1.31 - October 17th, 2014 
TEST PRODUCTS: 
 
 Ibrutinib 
 
 
 GA101 – Obinutuzumab 

CONFIDENTIAL 
This is a University of California San Diego document that contains confidential 
information.  It is intended solely for the recipient clinical investigator(s) and must not be disclosed 
to any other party.  This material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from University of California San 
Diego.  
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
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INVESTIGATORS: 
 
 Thomas Kipps, M.D., PhD 
Moores Cancer Center - University of California, 
San Diego 
Telephone:  858- 543 5400 
Fax:  858- 543 5400 
E-mail:  tkipps@ucsd.edu 
SUB-INVESIGATORS:   
  
Michael Choi, M.D. 
Moores Cancer Center - University of California, 
San Diego 
SUPPORT PROVIDED BY:  Pharmacyclics LLC 
The University of California, San Diego 
 

Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
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TABLE OF CONTENTS 
TABLE OF CONTENTS………………………………………............................................. 3  
LIST OF IN-TEXT TABLES………………………………………………………………....    9 
LIST OF IN-TEXT FIGURES………………………………………………………………..   10  
LIST OF APPENDICES……………………………………………………………………..   10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS…………………………….   11 
SYNOPSIS .................................................................................................................... 14 
1. 
INTRODUCTION ................................................................................................... 24 
1.1 
Chronic Lymphocytic Leukemia ...................................................... 24 
1.1.1 
Natural History and Current Management of Chronic 
Lymphocytic Leukemia .................................................................. 24 
1.1.1.1 Natural History ............................................................................... 24 
1.1.1.2 Current Management ..................................................................... 24 
1.2 
Ibrutinib Background ...................................................................... 26 
1.2.1 
Structure and Mechanism of Action of Ibrutinib .............................. 26 
1.2.2 
Summary of Pharmacokinetic and Pharmacodynamic 
Data for Ibrutinib ............................................................................ 28 
1.2.3 
Clinical Experience with Ibrutinib .................................................... 28 
1.2.3.1 Tolerability and Efficacy of Ibrutinib in Chronic 
Lymphocytic Leukemia .................................................................. 28 
1.2.4 
Overview of Safety of Ibrutinib ........................................................ 32 
1.2.4.1 Monotherapy Studies ..................................................................... 32 
1.2.4.2 Combination Therapy Studies ........................................................ 33 
1.2.4.3 Treatment Discontinuations ........................................................... 34 
1.2.4.4 Hemorrhagic Events ...................................................................... 34 
1.2.4.5 Cardiac .......................................................................................... 35 
1.2.4.6 Rash .............................................................................................. 35 
1.2.4.7 Other Malignancies ........................................................................ 35 
1.2.4.8 Infection ......................................................................................... 35 
1.2.4.9 Myelosuppression .......................................................................... 35 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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1.2.4.11 Embryo-Fetal Toxicity .................................................................. 36 
1.2.4.12 Treatment-related Lymphocytosis ................................................ 36 
1.3 
GA101 - Obinutuzumab Background .............................................. 37 
1.3.1 
Structure and Mechanism of Action of GA101 - 
Obinutuzumab ............................................................................... 37 
1.3.2 
Clinical Experience with GA101 - Obinutuzumab ........................... 38 
1.3.2.1 Tolerability and Efficacy of GA101 - Obinutuzumab in 
Chronic Lymphocytic Leukemia ..................................................... 38 
1.3.3 
Overview of Safety of GA101 - obinutuzumab ................................ 41 
1.3.4 
Risks Associated with GA101 - Obinutuzumab 
Therapy ......................................................................................... 43 
1.3.4.1 Infusion Reactions and Hypersensitivity Reactions 
(including Anaphylaxis) .................................................................. 43 
1.3.4.2 Tumor Lysis Syndrome .................................................................. 44 
1.3.4.3 Thrombocytopenia and Neutropenia .............................................. 44 
1.3.4.4 Hepatitis B Reactivation ................................................................. 44 
1.3.4.5 Worsening of Pre-Existing Cardiac Conditions ............................... 45 
1.3.4.6 Infection ......................................................................................... 45 
1.3.5 
Summary of Pharmacokinetic and Pharmacodynamic 
Data for GA101 - Obinutuzumab .................................................... 45 
1.4 
Study Rationale .............................................................................. 46 
2. 
OBJECTIVES ........................................................................................................ 47 
2.1 
Primary ........................................................................................... 47 
2.2 
Secondary ...................................................................................... 47 
3. 
STUDY DESIGN ................................................................................................... 48 
3.1 
Description of the Study ................................................................. 48 
3.1.1 
Phase II .......................................................................................... 48 
3.2 
Outcome Measures ........................................................................ 49 
3.2.1 
Phase IB Outcome Measures: ........................................................ 49 
3.2.2 
Phase II Outcome Measures: ......................................................... 49 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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4. 
STUDY POPULATION .......................................................................................... 50 
4.1 
Inclusion Criteria ............................................................................ 50 
4.2 
Exclusion Criteria ........................................................................... 52 
5. 
TREATMENT PLAN .............................................................................................. 54 
6. 
STUDY MEDICATIONS ........................................................................................ 55 
6.1 
IBRUTINIB ..................................................................................... 55 
6.1.1 
Formulation .................................................................................... 55 
6.1.2 
Dosage and Administration ............................................................ 55 
6.2 
GA101 - Obinutuzumab .................................................................. 56 
6.2.1 
Formulation .................................................................................... 56 
6.2.2 
Storage .......................................................................................... 56 
6.2.3 
Preparation..................................................................................... 56 
6.2.4 
Dosage and Administration ............................................................ 57 
6.2.5 
Premedication Requirements ......................................................... 58 
6.2.6 
Split Dosing .................................................................................... 59 
6.2.7 
Dosage Modification/Toxicity Management .................................... 61 
6.2.8 
Assessment of Hematologic Toxicities ........................................... 61 
6.2.9 
Administration of Granulocyte Colony-Stimulating 
Factor ............................................................................................ 61 
6.2.10 
Hepatitis B Virus Reactivation ........................................................ 62 
6.2.11 
Management of Infusion-Related Reactions and 
Anaphylaxis ................................................................................... 63 
6.2.12 
Prophylaxis Tumor Lysis Syndrome ............................................... 64 
6.3 
Dose Modifications and Delays for Ibrutinib and 
GA101 – obinutuzumab .................................................................. 65 
6.3.1 
Dose Hold, Reduction, or Discontinuation of Ibrutinib ..................... 65 
6.3.2 
Dose Modifications for Ibrutinib for Hepatic Impaired 
Subject .......................................................................................... 66 
6.3.3 
Ibrutinib Overdose .......................................................................... 67 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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6.3.4 
Dose Modifications and delays for GA101 – 
Obinutuzumab ............................................................................... 67 
6.4 
Concomitant, Excluded Therapies and drug-drug 
interactions ..................................................................................... 69 
6.4.1 
Permitted Concomitant Medications ............................................... 69 
6.4.2 
Medications to be used with Caution .............................................. 70 
6.4.2.1 CYP3A- Inhibitors/Inducers ............................................................ 70 
6.4.2.2 Drugs That May Have Their Plasma Concentrations 
Altered by Ibrutinib ......................................................................... 70 
6.4.2.3 QT Prolonging Agents .................................................................... 70 
6.4.2.4 Antiplatelet Agents and Anticoagulants .......................................... 71 
6.4.3 
Prohibited Concomitant Medications .............................................. 71 
6.4.4 
Concomitant Therapy during the study treatment ........................... 71 
6.5 
Guidelines for Ibrutinib Management with Surgeries 
or Procedure .................................................................................. 72 
6.5.1 
Minor Surgical Procedures ............................................................. 72 
6.5.2 
Major Surgical Procedures ............................................................. 72 
6.5.3 
Emergency Procedures .................................................................. 72 
7. 
CRITERIA FOR SUBJECT DISCONTINUATION .................................................. 72 
8. 
CRITERIA FOR STUDY DISCONTINUATION ...................................................... 73 
9. 
CLINICAL AND LABORATORY EVALUATIONS ................................................... 73 
9.1 
Evaluations Pretreatment ............................................................... 73 
9.1.1 
Study Entry..................................................................................... 73 
9.1.2 
Screening ....................................................................................... 74 
9.1.2.1 Screening History and Physical Examination ................................. 74 
9.1.2.2 Screening Laboratory Tests ........................................................... 74 
9.1.2.3 Screening Diagnostic Tests ........................................................... 75 
9.1.2.4 Pretreatment Cumulative Illness Rating Scale (CIRS) .................... 75 
9.1.2.5 Research Studies .......................................................................... 75 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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9.2 
Evaluations During Study Treatment & Follow-Up .......................... 76 
9.3 
Evaluation of response to treatment ............................................... 77 
9.4 
Evaluations Every 3 Months for Nine Months after 
Response Assessment ................................................................... 78 
9.5 
Evaluation Every 6 Months until progression or 
withdrawal from the study ............................................................... 78 
9.6 
Evaluations At the End of Study ..................................................... 79 
10. STATISTICAL CONSIDERATIONS AND RATIONALE ......................................... 80 
10.1 
Statistical Model ............................................................................. 80 
10.1.1 
Demographic and Background Characteristics ............................... 80 
10.1.2 
Laboratory Variables ...................................................................... 80 
10.1.3 
Concomitant Medications ............................................................... 81 
10.1.4 
Estimated Time to Complete Enrollment ........................................ 81 
10.1.5 
Data Analysis ................................................................................. 81 
10.2 
Statistical Considerations for the Phase Ib ..................................... 81 
10.2.1 
Subject Evaluability for the Phase Ib .............................................. 81 
10.2.2 
Safety Analysis ............................................................................... 81 
10.2.3 
Clinical Adverse Events .................................................................. 81 
10.2.4 
Definition of Dose Limiting Toxicity (DLT) ....................................... 81 
10.2.5 
Dose Escalation / De-escalation Based on AE - DLT ..................... 82 
10.2.6 
Statistical Operating Characteristics of the Phase IB ...................... 83 
10.3 
Statistical Considerations for the Phase II ...................................... 84 
10.3.1 
Clinical and Laboratory Variables ................................................... 84 
10.3.2 
Efficacy Population ......................................................................... 84 
10.3.3 
Efficacy Analysis ............................................................................ 84 
10.3.4 
Statistical Operating Characteristics of the Phase II ....................... 84 
10.4 
Replacement of Subjects ................................................................ 85 
10.5 
Trial Stopping and Holding Rules Based on DLT and 
Lack of Efficacy .............................................................................. 85 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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10.6 
Planned Efficacy Evaluations ......................................................... 86 
10.7 
Primary Efficacy Variables .............................................................. 86 
10.8 
Secondary Efficacy Variables ......................................................... 86 
11. REPORTING OF ADVERSE EVENTS .................................................................. 86 
11.1 
Assessment of Safety ..................................................................... 86 
11.2 
Adverse Events .............................................................................. 87 
11.2.1 
Serious Adverse Events ................................................................. 88 
11.2.2 
Severity Criteria .............................................................................. 89 
11.2.3 
Causality (Attribution) ..................................................................... 89 
11.2.4 
Unexpected Adverse Events .......................................................... 90 
11.3 
Documenting and Reporting of Adverse Events and 
Serious Adverse Events by Investigators. ...................................... 90 
11.3.1 
Assessment of Adverse Events ...................................................... 90 
11.3.2 
Adverse Event Reporting Period .................................................... 91 
11.3.3 
Adverse Events of Special Interest (AESI) ..................................... 92 
11.3.4 
Expediting 
Reporting 
Requirements for Serious 
Adverse Events ............................................................................... 93 
11.3.5 
Reporting to Regulatory Agencies: ................................................. 94 
11.4 
Procedures for Eliciting, Recording, and Reporting 
Adverse Events .............................................................................. 94 
11.4.1 
Procedures ..................................................................................... 94 
11.4.1.1 All Adverse Events ....................................................................... 94 
11.4.2 
Eliciting Adverse Events ................................................................. 95 
11.4.3 
Specific Instructions for Recording Adverse Events ........................ 95 
11.4.3.1 Diagnosis versus Signs and Symptoms ....................................... 95 
11.4.3.2 Deaths ......................................................................................... 95 
11.4.3.3 Preexisting Medical Conditions .................................................... 95 
11.4.3.4 Hospitalizations for Medical or Surgical Procedures ..................... 95 
11.4.3.5 Post-Study Adverse Events ......................................................... 96 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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11.4.3.6 Safety Reconciliation ................................................................... 96 
11.4.3.7 Adverse Events of Special Interest (AESIs) ................................. 96 
11.4.3.8 Special Reporting Situations ........................................................ 97 
11.4.3.9 Prohibitions and Restrictions ........................................................ 97 
11.4.4 
Adverse Event Reporting to Pharmacyclics .................................... 98 
11.4.4.1 Additional reporting requirements to Pharmacyclics 
include the following: .................................................................................... 98 
11.4.4.2 Follow-Up Information .................................................................. 99 
11.4.5 
Data Safety and Monitoring Board (DSMB) .................................. 100 
11.5 
Study Close-Out ........................................................................... 100 
12. RETENTION OF RECORDS ............................................................................... 100 
13. PROTOCOL AMENDMENTS .............................................................................. 100 
14. PUBLICATION OF STUDY RESULTS ................................................................ 101 
15. STUDY DISCONTINUATION .............................................................................. 101 
16. BIBLIOGRAPHY .................................................................................................. 102 
 
 
LIST OF TABLES 
Table 1 
GA101 - Obinutuzumab Dosing Schedule ............................................ 60 
Table 2 
Management of Hepatitis B Reactivation .............................................. 62 
Table 3 
Management of Infusion-Related Symptoms ........................................ 63 
Table 4 
Dose Modifications or Discontinuation Actions for Ibrutinib… ............... 65 
Table 5 
Child-Pugh Score.. ............................................................................... 65 
Table 6 
Dose Modifications for Hepatic Impaired Subjects................................ 66 
Table 7    
Dose Modification for Cytopenias ......................................................... 68 

TABLE OF CONTENTS (CONT.) 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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Table 8 
Operating Characteristics of the Phase IB Procedure.. ........................ 82 
 LIST OF FIGURES 
Figure 1 Treatment Schema……………………………………………………………........ 53 
Figure 2 Recommended Premedication to Reduce Infusion-related Reactions……..… 58 
 
LIST OF APPENDICES 
Appendix 1 
CDC Guideline for Interpretation of Hepatitis B Serology Test 
Results ............................................................................................... 107 
Appendix 2 
Study Flowchart ................................................................................. 108 
Appendix 3 
IWCLL Guideline for Grading Scale for Hematological Toxicity in 
CLL Studies ....................................................................................... 112 
Appendix 4 
Cairo-Bishop Clinical Grading and Laboratory Definition of Tumor 
Lysis Syndrome ................................................................................. 113 
Appendix 5 
Inhibitors or Inducers of CYP3A4/5 .................................................... 114 
Appendix 6 
Cumulative Illness Rating Scale-Geriatric (CIRS Score)..................... 115 
Appendix 7 
Current NCI Common Terminology Criteria for Adverse Events 
(CTCAE) ............................................................................................ 117 
Appendix 8 
FDA MedWatch 3500 Form ................................................................ 118 
Appendix 9 
Safety Reporting Fax Cover Sheet ..................................................... 119 

 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ABC 
activated B cell 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
anti-HBc 
antibody to hepatitis B core antigen 
aPTT 
activated partial thromboplastin time 
BM 
bone marrow 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration−time curve 
BSA 
body surface area 
CDC 
complement-dependent cytotoxicity 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum   concentration observed 
CNS 
central nervous system 
CR 
complete response or complete remission 
Cru 
unconfirmed complete response 
CSR 
Clinical Study Report 
D 
day 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
F 
phenylalanine 
FACS 
fluorescent-activated cell sorter 
FcγR 
leukocyte receptors for the Fc portion of IgG 
FDA 
Food and Drug Administration 
18F-FDG 
18F-fleurodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded  

 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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Abbreviation 
Definition 
FISH 
fluorescence in situ hybridization 
GCB 
germinal center B cell 
GCP 
Good Clinical Practice 
GCSF 
granulocyte-colony stimulating factor 
GEP 
G 
gene expression profiling 
GA101 
G-FC 
GA101 in combination with fludarabine and cyclophosphamide 
HAHA 
human anti-human antibodies 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HD 
high dose 
HTLV 
human T-cell leukemia virus 
ICH 
International Conference on Harmonization 
Ig 
immunoglobulin  
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
IMC 
Internal Monitoring Committee 
IRR 
infusion-related reaction 
IV 
intravenous 
IL 
interleukin  
IPI 
International Prognostic Index 
IVRS 
interactive voice response system 
LD 
low dose 
LVEF 
left ventricular ejection fraction 
LVS. D 
left ventricular systolic dysfunction 
MCL 
mantle-cell lymphoma 
MUGA 
multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NONMEM 
Non-Linear Mixed Effect Model 
ORR 
overall response rate 
OS 
overall survival 

 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
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Abbreviation 
Definition 
PD 
progressive disease  
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response or partial remission 
R-CHOP 
rituximab in combination with cyclophosphamide, doxorubicin, 
vincristine, prednisone 
SAE 
serious adverse event 
SD 
stable disease 
SDI 
shorter duration of infusion 
SLL 
small lymphocytic lymphoma 
SOC 
Scientific Oversight Committee 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
U.S. 
United States 
V 
valine  
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 

 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
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SYNOPSIS 
Study Title 
A phase IB/II study of Ibrutinib in combination with 
GA101 – Obinutuzumab in previously untreated chronic 
lymphocytic leukemia (CLL) patients > 65 years of age or 
with comorbidities that preclude the use of chemotherapy 
based treatment. 
Study Phase 
IB/II 
Study Duration 
24 months 
Investigational 
Products 
Ibrutinib will be supplied as hard gelatin 140-mg 
capsules for oral (PO) administration. Pharmacyclics will 
provide Ibrutinib during the course of the 6 cycles and after 
cycle 6, during the following 3 years. 
GA101 – Obinutuzumab will be supplied as vial of 
1,000mg/40Ml for IV infusion. GA101 – Obinutuzumab will 
be requested to be covered by the insurance as a Standard 
of Care treatment for previously untreated subjects.  
Objectives 
Primary Objective 
• 
The primary objective of the phase IB is to evaluate 
the safety, tolerability and dose limiting toxicity (DLT) 
of 
Ibrutinib 
in 
combination 
with 
GA101 
- 
Obinutuzumab in previously untreated CLL subjects.  
• 
The primary objective of the phase II is to determine 
the overall response rate (partial response + 
complete response rate) of Ibrutinib in combination 
with GA101 - Obinutuzumab in previously untreated 
subjects with CLL. 
Secondary Objective 
• 
To 
determine 
progression-free 
survival 
(PFS), 
treatment-free survival (TFS) and overall survival 
(OS) in previously untreated CLL subjects that will 

 
Ibrutinib + GA101 – Obinutuzumab. University of California, San Diego 
Protocol 01, Version 8.0, Amendment 6 – September 19, 2019 
 
 
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receive treatment with Ibrutinib in combination with 
GA101 – Obinutuzumab. 
• 
To determine the percentage of CLL subjects treated 
with Ibrutinib plus GA101 – Obinutuzumab that 
achieve negative minimal residual disease (MRDneg) 
in the bone marrow or peripheral blood using 
multiparameter flow cytometry (4 colors).  
• 
To evaluate correlative studies in samples collected 
from previously untreated CLL subjects treated with 
Ibrutinib / GA101 – Obinutuzumab combination 
regimen including but not limited to the following: 
assessment of the chemokine and cytokine profile 
using plasma samples from the subjects and 
correlation of the results with the presence of 
Infusion-Related Reactions (IRRs). 
Hypothesis 
We hypothesize that Ibrutinib in combination with 
GA101 – Obinutuzumab is well tolerated and will induce 
higher response rates than the response rate observed in 
the CLL11 Study (Goede et al., 2014). 
Study Design 
This is an open label phase IB/II clinical trial 
designed to determine the safety and clinical activity of 
Ibrutinib in combination with GA101 – Obinutuzumab. 
Safety, tolerability and dose-limiting toxicities (DLTs) will be 
evaluated during the initial cycle of treatment (Cycle 1; Day 
1-28) as part of the phase IB of this study (safety run-in). 
In the phase II the response rate will be determined 
in all subjects that have received treatment. The study will 
enroll 32 subjects previously untreated who have active 
disease requiring treatment (as defined by IWCLL 2008 
criteria for initiation of therapy) (Hallek et al., 2008). The 
study will include a Screening Phase, a Treatment Phase, 
and a Follow-up Phase. The Screening Phase assessments 
will be performed within 28 days prior to treatment. The 
Treatment Phase will extend from first dose until completion 
of all planned cycles of treatment (#6) or study drug 
discontinuation.  

 
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All subjects will receive Ibrutinib 420 mg (3 x 140-mg 
capsules) orally once daily for up to 6 cycles. The treatment 
with Ibrutinib will continue after cycle 6 for the following 3 
years until disease progression, unacceptable toxicity or 
other reason for treatment discontinuation. 
 
All subjects will receive GA101 – Obinutuzumab by 
IV infusion for up to 6 cycles (28-day cycles) as follow: 
 
• On Cycle 1, Day 1, 100 mg GA101-Obinutuzumab 
will be administered. 
• On Cycle 1, Day 2, 900 mg of GA101-Obinutuzumab 
will be administered.  
• On Cycle 1, Days 8 and 15, 1,000 mg of GA101-
Obinutuzumab will be administered.  
• On Cycles 2 − 6, Day 1, 1,000 mg of GA101-
Obinutuzumab will be administered. 
Subjects will undergo response assessment two months 
after completion of the study treatment. The initial follow-up 
evaluations will be made (after the response assessment) 
every 3 months during 9 months and later every 6 months 
until initiation of new treatment for CLL, consent withdrawal 
or death. During the long-term follow-up phase, subjects will 
be followed for survival (PFS, TFS and OS). The long-term 
follow-up phase will continue until disease progression, 
death, loss to follow up, consent withdrawal, or study end, 
whichever occurs first.  
An evaluation of the End of Study will be performed due 
to initiation of new treatment for CLL or withdrawal of 
consent. 
Population 
Males and females with previously untreated chronic 
lymphocytic leukemia (CLL): 
• > 65 years of age, or  
• < 65 years that refuse to be treated with 

 
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chemotherapy or subjects that are not candidates for 
treatment with chemotherapy agents. 
Center 
UCSD Moores Cancer Center 
Key Inclusion Criteria: 
 
Refer to Section 4.1 for 
the complete and 
detailed list of inclusion 
criteria. 
Subjects must meet the following criteria for study 
entry: 
1. Diagnosis of CLL 
2. Indication for treatment as defined by the IWCLL 
Guidelines. 
3. No previous treatment for CLL.  
4. Males and females 65 years of age and older. 
Subjects < 65 years of age that meet any of the 
following criteria: A. Documented refusal to be 
treated with chemotherapy agents. B. Subjects that 
are not candidates for treatment with chemotherapy 
based on poor performance status (ECOG ≥ 2), 
Cumulative Illness Rating Scale (CIRS score) ≥ 6 or 
creatinine clearance <70 mL/min. 
5. Laboratory parameters as specified below:  
• 
Hematologic: Hemoglobin > 8 g/dL (may be 
post-transfusion); platelet count > 40 x103/mm3 
(may be post-transfusion). Absolute neutrophil 
count > 1.0 × 109 cells/L (Growth factor use is 
allowed). 
• 
Hepatic:  Total Bilirubin < 3 x ULN, and ALT and 
AST < 3 x ULN 
• 
Renal: Creatinine clearance > 30 mL/min 
(Calculated according to institutional standards 
or using Cockcroft–Gault formula. Subjects with 
requirement of hemodialysis will be excluded).   

 
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6. Anticipated survival of at least 6 months. 
7. Effective contraception is required while receiving 
Ibrutinib in combination with GA101 - Obinutuzumab.  
For women of childbearing potential and men, 
effective contraception is required while receiving 
GA101 – Obinutuzumab and for 365 days (12 
months) after the last dose of the study drug. 
8. Ability to understand the requirements of the study, 
provide written informed consent and authorization of 
use and disclosure of protected health information, 
and agree to abide by the study restrictions and 
return for the required assessments. 
9. Subjects must give written informed consent to 
participate in this trial. 
Key Exclusion Criteria: 
 
Refer to Section 4.2 for 
the 
complete 
and 
detailed list of exclusion 
criteria. 
Subjects who meet any of the following criteria will 
be excluded from study entry: 
1. Pregnant or nursing women. 
2. Treatment 
with 
chemotherapy, 
monoclonal 
antibodies, or biological agents (e.g. lenalidomide) 
other than the investigational agents during the time 
of participation in this trial. 
3. Grade 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification. 
4. Severe or debilitating pulmonary disease (dyspnea 
at rest, significant shortness of breath, COPD) 
5. Participation in any investigational drug study within 
28 days prior to initiation of treatment within this 
protocol. (Subject must have recovered from all 
acute 
effects 
of 
previously 
administered 
investigational agents). 
6. History of second malignancy, other than non-

 
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melanoma skin cancer or in situ carcinoma of the 
cervix or the breast, unless the tumor was 
successfully treated at least 2 years before trial entry 
and with no evidence of relapse or active cancer.  
7. Active symptomatic fungal, bacterial and/or viral 
infection including evidence of infection with human 
immunodeficiency virus (HIV). 
8. Evidence of active acute or chronic Hepatitis B 
(HBV). 
9. Evidence of active Hepatitis C (HCV):  subjects with 
positive hepatitis C serology and positive HCV RNA 
test. 
10. Any illness or condition that in the opinion of the 
Investigator may affect safety of treatment or 
evaluation of any the study’s endpoints. 
11. History of severe allergic or anaphylactic reactions to 
monoclonal antibody therapy  
12. Known hypersensitivity to any of the study drugs.  
13. Major surgery (within 4 weeks prior to the start of 
Cycle 1), except for procedures that are performed 
for diagnostic purposes. 
14. Men or women of childbearing potential who refuse 
to use an adequate measure of contraception (oral 
contraceptives, 
intrauterine 
device, 
or 
barrier 
method 
of 
contraception 
in 
conjunction 
with 
spermicidal jelly) unless they have past medical 
history of surgical sterilization. 
15. Vaccination with a live vaccine within 28 days of the 
initiation of treatment. 
16. Concomitant use of warfarin or other Vitamin K 
antagonists. 

 
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17. Subjects who received a strong cytochrome 
P450 (CYP) 3A inhibitor within 7 days prior to the 
first dose of Ibrutinib or subjects who require 
continuous treatment with a strong CYP3A inhibitor. 
18. Subjects with chronic liver disease with hepatic 
impairment (Child-Pugh class B or C) 
Dosage and 
administration  
Ibrutinib 420 mg (3 x 140 mg capsules) will be 
administered orally once daily beginning on Day 1 of the 
Treatment Phase. The first dose of Ibrutinib 420 mg will be 
administered in the clinic on Day 1, no more than 72 hours 
after enrollment, after which Ibrutinib will be self-
administered by the subjects on an outpatient basis. 
 
GA101 - Obinutuzumab must be administered in a 
clinical setting (inpatient or outpatient) by IV infusion for up 
to 6 cycles (28-day cycles): on cycle 1, GA101 – 
Obinutuzumab will be administered 100 mg on day 1, 900 
mg on day 2 and 1,000 mg on days 8 and 15. On Cycles 
2 − 6, Day 1, 1,000 mg of GA101 - Obinutuzumab will be 
administered (See Table 1 – Section 6.2.6). 
Statistical Methods 
Refer to Section 10 for 
the 
complete 
and 
detailed 
Statistical 
rationale. 
 
For this open-label study, all demographic, disease 
and relevant clinical characteristics will be summarized 
using descriptive statistics. Continuous variables will be 
reported using appropriate measures of dispersion and 
central tendency (means, medians, ranges and standard 
deviations) while categorical variables (e.g., gender) will be 
summarized as number and percentage [proportions and 
95% confidence intervals (CI)] of the total Registry cohort. 
Each phase of this study will be analyzed separately. All 
tables, figures and listings will therefore be separated by 
study phase. 
 
Determination of the Sample size for the Phase IB 
The phase IB will be performed as a safety run-in 
with the first 6 subjects enrolled in the study. The sample 
size of 6 subjects is considered to be sufficient to support 
preliminary safety, tolerability and DLTs assessments 

 
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(Goede et al., 2013). On this group of subjects, we will 
evaluate safety, tolerability and dose-limiting toxicities 
(DLTs) during the first cycle of treatment (4 weeks; Day 1 - 
28), 
Subjects will be enrolled at least one week apart to 
avoid overlapping time of observation during the first week 
of treatment when infusion reactions are expected to be 
higher.  
• If 0 to 1 DLTs (See DLT definition – Section 
10.2.4) are observed in the first 3 subjects, we will 
proceed to enroll 3 additional subjects.  
• If 0 to 1 DLTs are observed in the first 6 subjects, 
we will proceed to the phase II of the study.  
• If > 2 DLTs are observed, we will hold enrollment 
and revise the study design with the sponsor. 
 
Determination of the Sample size for the Phase II 
Our sample size calculation will use an ORR 
endpoint comparison based on the ORR achieved with the 
Ibrutinib and GA101 - Obinutuzumab combination. We 
hypothesize that Ibrutinib in combination with GA101 – 
Obinutuzumab would induce an ORR of 94%, which is 16% 
higher than the ORR observed in the study published by 
Goede et al. (Goede et al., 2014). 
Based on this, we will use a Simon's two-stage 
optimal design in this study (Simon, 1989). The null 
hypothesis that the true overall response rate is 78% will be 
tested against a one-sided alternative. In the first stage, 10 
subjects will be accrued. If there are 8 or fewer responses in 
these 10 subjects, the study will be stopped. Otherwise, 22 
additional subjects will be accrued for a total of 32. The null 
hypothesis will be rejected if 29 or more responses are 
observed in 32 subjects. This design yields a type I error 
rate of 5% and power of 80% when the true response rate is 
94%. 

 
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Safety 
and 
Efficacy 
Evaluations/Outcomes 
 
Safety Outcomes 
Phase IB Outcome Measures: 
The safety and tolerability of Ibrutinib in combination with 
GA101 - Obinutuzumab will be assessed using the following 
primary safety outcome measures: 
- 
Type, Incidence, nature, and severity of AEs. 
- 
The relationship of AEs to Ibrutinib and/or GA101 – 
Obinutuzumab 
- 
Serious adverse events 
- 
Incidence 
of 
adverse 
events 
leading 
to 
Ibrutinib/GA101 - Obinutuzumab discontinuation or 
dose delays. 
- 
Incidence of adverse events of special interest 
- 
Clinical laboratory abnormalities 
- 
Deaths and cause of death 
- 
Dose limiting toxicity (DLT): DLTs will include 
possibly related or related events that are Grade > 3 
that do not resolve to Grade < 1 within 14 days of 
initiation despite appropriate medical management.  
Some exceptions will apply (See section 10.2.4). 
 
Efficacy Outcomes 
Phase IB Outcome Measures: 
Safety of the treatment study will be determined by: 
adverse events (AE), laboratory tests and dose limiting 
toxicity (DLT) vital signs, and performance status (See 
section 3.2). 
 
Phase II Outcome  Measures: 
Response assessment will be performed by physical 
examination, CT scan evaluation and bone marrow 
biopsy/aspirate at 2 months after completion of the study 
treatment using the International Workshop in CLL 
Guidelines (IWCLL) (Hallek et al., 2008). 
 
• 
Primary outcome measures: 
- Overall response rate (ORR): defined as the 
proportion of subjects who achieve complete 
response (CR), complete response with incomplete 

 
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marrow recovery (CRi), nodular partial response 
(nPR), or partial response (PR) per IWCLL 2008 
criteria over the course of the study. 
- Progression Free Survival (PFS): Time measured 
from initiation of therapy until clinical or laboratory 
evidence of CLL progression.  
- Treatment Free Survival (TFS): Time measured from 
initiation of therapy until next treatment for CLL.  
- Overall Survival (OS): Time measured from initiation 
of therapy until death from any cause. 
• 
Secondary outcome measures: 
- Rate of MRDneg CRs in the bone marrow or 
peripheral 
blood 
using 
multiparameter 
flow 
cytometry (4 colors). 
- Clinical, laboratory and radiological evidence of 
response to administration of Ibrutinib plus GA101 – 
Obinutuzumab based in the International Workshop 
in CLL Guidelines (IWCLL) (Hallek et al., 2008). 
 
 
 
 
 
 
 
 
 
 

 
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1. 
INTRODUCTION 
1.1 
CHRONIC LYMPHOCYTIC LEUKEMIA 
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that 
accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin’s 
lymphomas (NHLs).  In 2010, there were approximately 14,900 new cases in the United 
States (U.S.: American Cancer Society 2010).  The median age at diagnosis is 72 years 
(Hallek, 2010).  CLL is a disease of B-cell origin, with a characteristic immunophenotype 
(CD5 positive, CD23 positive, weak surface expression of CD19, CD20, CD79b, and IgM 
or IgD) and blood smear morphology (mature lymphocytes, Gumprecht shadows also 
known as smudge cells). 
1.1.1 
Natural History and Current Management of Chronic Lymphocytic 
Leukemia 
1.1.1.1 
Natural History 
CLL often is an indolent disease that does not need treatment for many years.  
Many CLL subjects initially present with lymphocytosis in the absence of other 
symptoms. However, when the disease advances, there is the appearance of 
lymphadenopathy, hepatomegaly or splenomegaly, and bone marrow failure.  
B-symptoms (i.e., fever, night sweats, and weight loss), general fatigue, and recurrent 
infections are common in subjects with late-stage CLL but can occasionally be found 
earlier in the course of the disease. 
The individual survival time of CLL subjects is highly variable, with a range of 
less than 2 years to 20 years or more. There are two clinical staging systems (Rai and 
Binet) currently in use for CLL that allow a rough division of subjects into three 
prognostic groups:  good, intermediate, and poor prognosis.  In the Rai staging system, 
the low-risk (Rai Stage 0) group accounts for 31% of all subjects with CLL, and these 
subjects have a median survival of more than 10 years (Dighiero and Binet, 2000). 
Intermediate-risk (Rai Stages I and II) subjects (61% of all CLL subjects) have a median 
survival of 7 to 9 years. High-risk (Rai Stages III and IV) subjects (8% of all CLL 
subjects) have a median survival of 5 years (Hallek et al., 2008a). In the Binet staging 
system, CLL is divided into three stages of A, B, and C (Binet, 1999) 
1.1.1.2 
Current Management 
B-cell lymphoproliferative disorders describe a heterogeneous group of 
malignancies, and include slow-growing indolent and incurable diseases (such as 
follicular lymphoma or chronic lymphocytic leukemia [CLL]) with a median survival of 8-
10 years. Despite the availability of various agents for the treatment of NHL and CLL, 
there is an ongoing need for development of safe and effective therapies to prolong 
remission in subjects. 

 
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Because there is no survival benefit associated with early intervention (Hallek 
and Pflug, 2011), asymptomatic subjects with early-stage CLL (Rai I, II , Binet Stages A 
and B) are usually not treated but are followed with a “watch and wait” approach.  
Treatment is usually initiated when subjects become symptomatic or progress to late 
stage; 50% of CLL subjects ultimately require therapy. In the recent past, first-line 
treatment of CLL has evolved from single-agent therapy with alkylating drugs (e.g., 
chlorambucil -Clb) to combination therapy incorporating purine analogues (i.e., 
fludarabine, pentostatin, and cladribine) and monoclonal antibodies (i.e., rituximab and 
alemtuzumab) (Johnson et al., 1996) ; (Rai et al., 2000); (Eichhorst et al., 2006); (Flinn 
et al., 2007); (Hillmen et al., 2007); (Hallek et al., 2010). 
Currently, fludarabine, cyclophosphamide, and rituximab (FCR) are considered a 
standard chemoimmunotherapy combination for previously untreated subjects with CLL 
requiring treatment (Hallek et al., 2010). However, the favorable outcome of FCR 
treatment has been reported only for subjects not suffering from other medical 
impairments.   
Major comorbidities are present in 46% of unselected subjects with newly 
diagnosed CLL and advanced age (Thurmes et al., 2008). Immunochemotherapy with 
FCR is often withheld from medically unfit subjects because co-morbid conditions and 
age-related changes of the organ function may facilitate the occurrence and increase the 
severity of sustained cytopenia, T-cell depletion, and opportunistic infections.   
In December of 2013 GA101 - Obinutuzumab in combination with chlorambucil 
was approved for previously untreated CLL subjects based on data from study BO21004 
(CLL11; NCT01010061) (Phase III) – discussed below. This treatment constitutes an 
alternative for previously untreated subjects, specially the elderly and those with 
comorbidities 
that 
will 
prevent 
them 
from 
receiving 
treatment 
with 
FCR 
chemoimmunotherapy. However, it is important to note that the current FDA approval for 
GA101 - Obinutuzumab does not have restrictions in terms of age or the presence of 
comorbidities. Therefore, based on the current FDA approvals, the current standard 
treatment for untreated CLL subjects could include FCR or GA101 - Obinutuzumab / 
Chlorambucil. A selection between those regimens is entirely based on clinician 
assessment or the subject status, comorbidities and potential toxicities of each regimen. 
In February of 2014, Ibrutinib was approved for the treatment of subjects with 
CLL who have received at least one prior therapy.  The approval in CLL was based on 
the results of a multi-center, single-arm trial of 48 subjects with previously treated CLL. 
All subjects had a baseline ECOG performance status of 0 or 1. The median time since 
diagnosis was 6.7 years and the median number of prior treatments was 4 (range, 1 to 
12 treatments). Ibrutinib was administered orally at 420 mg once daily until disease 
progression or unacceptable toxicity. 

 
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The efficacy results demonstrated a 58.3% overall response rate (95% CI: 43.2, 
72.4) as assessed by an independent review committee. The response duration ranged 
from 5.6 to 24.2 months; the median was not reached. The safety profile of ibrutinib for 
subjects with previously treated CLL was consistent with observations in the mantle cell 
lymphoma clinical trial. 
 
Additional treatment options for relapse / refractory subjects or those who are 
older 
than 
65 
or 
with 
significant 
comorbidities 
include 
the 
following:  
chemoimmunotherapy with chlorambucil or bendamustine with or without rituximab. 
Monoclonal antibody based therapy with Ofatumumab, rituximab or alemtuzumab.  
Corticosteroids including high dose methylprednisolone in combination with rituximab 
(Castro et al., 2009) - (National Comprehensive Cancer Care Network, CLL/SLL 
Guidelines, 2013) and the newly approved Bruton’s tyrosine kinase (BTK) inhibitor 
(Ibrutinib)(Byrd et al., 2013). Typically, with any of those regimens the progression free 
survival is expected to be less than 3-4 years and ultimately subjects relapse requiring 
additional treatment. Moreover, Ibrutinib requires continuous administration increase 
cumulative cost of treatment, does not induce complete responses, induces side effects 
and toxicities in 40-50% of the subjects, there are cases reported of subjects developing 
resistance due to BTK mutations and the long term side effect from chronic 
administration at this time are unknown.  
Ultimately, the choice of treatment and its intensity at any particular point in the 
management of subjects with CLL is largely dependent upon subject age, comorbidities, 
ability to tolerate treatment, presence of poor-risk molecular features, cumulative 
toxicities, and in salvage therapy, the duration of the response to prior therapy. 
1.2 
IBRUTINIB BACKGROUND 
1.2.1 
Structure and Mechanism of Action of Ibrutinib 
Ibrutinib (IMBRUVICA ™) has been approved   by the U.S. Food and Drug 
Administration (FDA) for the treatment of subjects with chronic lymphocytic leukemia 
(CLL) or mantle cell lymphoma (MCL) who have received at least one prior therapy. 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor 
of Bruton’s tyrosine kinase (BTK) (Rushworth et al., 2013). Inhibition of BTK blocks 
downstream B-cell receptor (BCR) signaling pathways and thus prevents B-cell 
proliferation (Honigberg et al., 2010). In vitro, Ibrutinib inhibits purified BTK and selected 
members of the kinase family with 10-fold specificity compared with non-BTK kinases.   
B cells are lymphocytes with multiple functions in the immune response, 
including antigen presentation, antibody production, and cytokine release. B-cells 
express cell surface immunoglobulins comprising the BCR, which is activated by binding 

 
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to antigen.  Antigen binding induces receptor aggregation and the clustering and 
activation of multiple tyrosine kinases, which in turn activate further downstream 
signaling pathways (Bishop GA et al., 2003). 
The process of B-cell maturation, including immunoglobulin chain rearrangement 
and somatic mutation, is tightly regulated. It is thought that B-cell lymphomas and CLL 
result from mutations and translocations acquired during normal B-cell development (AL. 
et al., 2002, Shaffer et al., 2002). Several lines of evidence suggest that signaling 
through the BCR is necessary to sustain the viability of B-cell malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human 
genetic immunodeficiency disease X-linked agammaglobulinemia and the mouse 
genetic disease X-linked immunodeficiency, both caused by a mutation in the BTK gene.  
These genetic diseases are characterized by reduced BCR signaling and a failure to 
generate mature B-cells. The BTK protein is expressed in most hematopoietic cells with 
the exception of T-cells and natural killer cells, but the selective effect of BTK mutations 
suggests that its primary functional role is in antigen receptor signaling in B-cells 
(Satterthwaite and Witte, 2000). 
 
Treatment of activated CLL cells with Ibrutinib resulted in inhibition of BTK 
tyrosine phosphorylation and also effectively abrogated downstream survival pathways 
activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, Ibrutinib 
inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided 
externally to CLL cells from the microenvironment including soluble factors (CD40L, 
BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact (Herman 
et al., 2011) (de Rooij et al., 2012). 
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the 
chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at 
the B cell receptor. Together, these data are consistent with a mechanistic model 
whereby Ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts 
cell migration and adherence to protective tumor microenvironments (Ponader et al., 
2012) (de Rooij et al., 2012) 
 
In early clinical studies, the activity of Ibrutinib has been described to include a 
rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, 
suggesting that the drug might have direct effects on cell homing or migration to factors 
in tissue microenvironments (Byrd et al., 2012). Data from Study PCYC-04753 
demonstrates that although Ibrutinib is rapidly eliminated from the plasma after oral 
administration, once daily dosing with Ibrutinib is adequate to sustain maximal 
pharmacodynamic activity for 24 hours post-dose at dose levels ≥2.5 mg/kg. In Study 
PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts 

 
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and for the 560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours 
after drug administration. 
 
1.2.2 
Summary of Pharmacokinetic and Pharmacodynamic Data for 
Ibrutinib 
 
Following oral administration of Ibrutinib at doses ranging from 1.25 to 12.5 
mg/kg/day as well as fixed dose levels of 420, 560, and 840 mg/day, exposure to 
Ibrutinib increased as doses increased with substantial intersubject variability. The mean 
half-life (t1/2) of Ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median 
time to maximum plasma concentration (Tmax) of 2 hours. Administration of 420 mg 
Ibrutinib with a high-fat breakfast in subjects with CLL approximately doubled the mean 
systemic exposure compared to intake after overnight fasting with median time to Tmax 
delayed from 2 to 4 hours. Ibrutinib is metabolized by hepatic cytochrome P450 (CYP) 
3A enzymes and to a minor extent by CYP2D6. Metabolism is the major route of 
elimination. Ibrutinib is metabolized to the dihydrodiol metabolite PCI-45227, a reversible 
inhibitor of BTK, with approximately 15 times lower inhibitory potency compared to 
Ibrutinib. The metabolite-to-parent AUC ratio ranged from 0.7 to 3.4. Steady-state 
exposure of Ibrutinib and PCI-45227 was less than 2-fold of first dose exposure. 
The results of human mass balance study of [14C]-Ibrutinib conducted in six 
healthy male subjects demonstrated that less than 10% of the total dose of [14C]-Ibrutinib 
is renally excreted, whereas approximately 80% is recovered in feces. Subjects with mild 
and moderate renal insufficiency (creatinine clearance > 30 mL/min) were eligible to 
enroll in Study PCYC-1102-CA in which pharmacokinetic (PK) assessments were 
included.  No dose adjustment is needed for mild or moderate renal impairment (greater 
than 30 mL/min creatinine clearance). There is no data in subjects with severe renal 
impairment or subjects on dialysis.  The study of ibrutinib in hepatic impaired subjects is 
currently in progress. 
1.2.3 
Clinical Experience with Ibrutinib 
1.2.3.1 
Tolerability and Efficacy of Ibrutinib in Chronic Lymphocytic 
Leukemia 
The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-
naive (TN) Chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a 
phase Ib/II Study. 
 
  
A multi-cohort Phase IB/II trial evaluated 2 doses of single-agent P in both TN 
and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts was 
reported. Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated 
with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until 
disease progression (PD). Response was evaluated according to 2008 IWCLL criteria.  
 

 
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31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort 
was terminated after comparable activity and safety between doses was shown in R/R 
pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline 
cytopenias (Hgb < 11g/dl or plts <100,000). Unmutated IgVH was present in 43% of pts. 
The majority of AEs have been Gr<=2 in severity, most commonly diarrhea, nausea, and 
fatigue. Gr >3 non-heme AEs potentially related to P in 19% of pts. 10% of pts 
experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 
mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial 
responses (PR) and 8% complete remissions with no morphologic evidence of CLL on 
marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with 
lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 
2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% 
of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) 
and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg 
cohort is 93%.  
 
PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high 
ORR, including marrow clearance and very low PD rate with the single agent suggests 
that P warrants further study as a first-line treatment approach in elderly pts (Byrd et al., 
2012). 
 
A Phase 1B/II Fixed-dose Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, 
PCI-32765, in Chronic Lymphocytic Leukemia (NCT01105247). 
 
This was a phase 1b–2 multicenter study to assess the safety, efficacy, 
pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765) in subjects with 
relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 subjects, the 
majority of whom were considered to have high-risk disease, received ibrutinib orally 
once daily; 51 received 420 mg, and 34 received 840 mg. 
 
Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, 
fatigue, and upper respiratory tract infection; thus, subjects could receive extended 
treatment with minimal hematologic toxic effects. The overall response rate was the 
same in the group that received 420 mg and the group that received 840 mg (71%), and 
an additional 20% and 15% of subjects in the respective groups had a partial response 
with lymphocytosis. The response was independent of clinical and genomic risk factors 
present before treatment, including advanced-stage disease, the number of previous 
therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free 
survival rate was 75% and the rate of overall survival was 83%. 
 

 
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Ibrutinib was associated with a high frequency of durable remissions in subjects 
with relapsed or refractory CLL and small lymphocytic lymphoma, including subjects with 
high-risk genetic lesions (Byrd et al., 2013). 
 
Ibrutinib in combination with Rituximab (IR) is well tolerated and induced a 
high rate of durable remissions in patients with high-risk chronic lymphocytic 
Leukemia (CLL): New, update results of a phase II trial in 40 patients. 
 
Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed 
CLL, based on the Phase 1/2 experience. To accelerate and improve responses to 
ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; this was a Phase 2 
single-center clinical trial with a median follow-up of 14 months. 
 
Subjects were treated with ibrutinib 420 mg PO daily continuously throughout the 
study Rituximab (375 mg/m2) was administered weekly for the first four weeks  (cycle 1), 
then  monthly  until cycle 6 at which point subjects continued on ibrutinib monotherapy. 
Study inclusion required high-risk disease (del17p or TP53 mutation [treated or 
untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL 
with del11q. 
 
Characteristics of the 40 subjects enrolled included median age of 65 (range 35–
82) with a median of 2 prior therapies.  There were14 female and 26 male subjects.  20 
subjects had del17p or TP53 mutation (4 without prior therapy), and 13 subjects had 
del11q. 32 subjects had unmutated IGHV, only one subject mutated IGHV, the 
remaining subjects had inconclusive IGHV results. The median β2 microglobulin was 4.2 
mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 subjects continue on 
therapy (16 out of 20 with del17p or TP53 mutation) without disease progression.  
 
39 subjects were evaluable for response assessment per 2008 IWCLL 
guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete 
remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow 
cytometry, The ORR in the 20 subjects with del17p or TP53 mutation was 90% (16 PR, 
2 CR). Among the 8 subjects that came off study, 3 subject died from unrelated 
infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from 
unrelated respiratory and cardiovascular failure. Two subjects came off study because of 
possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one 
subject had progressive disease, and one proceeded to stem cell transplantation. 
Treatment generally was well tolerated, with infectious complications (6 cases of 
pneumonia and 3 cases of upper respiratory infections) being the most common 
complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and 
peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 
subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or 

 
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diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality 
of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which 
coincided with a significant weight gain at 3 and 6 months. 
 
Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-
risk CLL subjects, which induces high rates of durable responses. Responses were 
associated with significant improvements in QOL. Compared to ibrutinib monotherapy, 
the redistribution lymphocytosis resolves more rapidly and completely, and consequently 
the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into 
longer progression-free and overall survival will be addressed in an upcoming larger, 
randomized trial of ibrutinib versus IR in relapsed/refractory CLL (Burger et al., 2013). 
 
A Multicenter, Open-label, Phase 3 Study of the Bruton’s Tyrosine Kinase 
Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with 
Treatment-naïve 
Chronic 
Lymphocytic 
Leukemia 
or 
Small 
Lymphocytic 
Lymphoma (RESONATETM-2) (PCYC-1115-CA; NCT01722487) 
 
This is a randomized, multicenter, open-label, Phase 3 study designed to 
compare the safety and efficacy of PCI-32765 versus chlorambucil in treatment-naive 
subjects 65 years or older who have CLL or SLL. Eligible subjects were randomized in a 
1:1 ratio to Treatment Arm A or B: 
• 
Treatment Arm A: Oral chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day 
cycle; the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on 
Day 1 of each cycle to a maximum of 0.8 mg/kg; subjects receive a minimum of 3 
and a maximum of 12 cycles, in the absence of progressive disease or 
unacceptable toxicity 
• 
Treatment Arm B: Oral PCI-32765 420 mg/day Randomization will be stratified 
on Eastern Cooperative Oncology Group (ECOG) performance status (0,1 
versus 2); presence of advanced Rai stage (yes/no), advanced being defined as 
Stages 3-4; and geographic region: US versus non-US. 
 
The primary endpoint of this study is PFS as assessed by IRC review according to 
IWCLL 2008 criteria with modification for treatment-related lymphocytosis. All enrolled 
subjects have completed at least 12 months of treatment and/or follow-up and either (a) 
81 progression or death events have been observed or (b) 15 months have elapsed after 
the last subject is randomized, whichever occurs first.  
 
Secondary endpoints (efficacy and safety) will be collected for 12 months of 
treatment and/or follow-up and either (a) 81 progression or death events have been 

 
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observed or (b) 15 months have elapsed after the last subject is randomized whichever 
occurs first.  
 
This study is ongoing, but not recruiting participants. 
 
A Multicenter Phase 2 Study of PCI-32765 (Ibrutinib) in Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic 
Lymphoma with 17p Deletion (PCYC-1117-CA; NCT01744691) (Phase II). 
 
This is a multicenter, international, open-label, single arm, Phase 2 study 
designed to evaluate the efficacy and safety of PCI-32765 in subjects with 
relapsed/refractory CLL or SLL with del 17p. All subjects will receive PCI-32765 until 
disease progression or unacceptable toxicity occurs. 
 
The primary outcome measures: Overall Response Rate (Time Frame: 6 -12 
months after last subject enrolled). Secondary outcome measures: duration of Response 
(Time Frame: 18 months after last subject enrolled), and safety parameters: number and 
type of adverse events (Time Frame: 18 months after last subject enrolled. 
 
Other Outcome Measures: progression-free survival (Time Frame: 18 months after last 
subject enrolled), and overall survival (Time Frame: 18 months after last subject 
enrolled). 
 
This study is ongoing, but not recruiting participants. 
 
1.2.4 
Overview of Safety of Ibrutinib 
Safety data are available for 1741 subjects treated in 13 company-sponsored 
monotherapy and 4 combination therapy studies, as discussed below (Investigator’s 
brochure Version 10, dated February 28, 2017).  
1.2.4.1 
Monotherapy Studies 
Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy in 13 
studies that have completed primary analysis or final analysis as of the 31 May 2016 
cutoff date for the current IB update in B-cell malignancies are summarized below.   
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects 
receiving ibrutinib as monotherapy (N = 1318): 

 
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Most frequently reported 
TEAEs ≥ 15% a 
Most frequently reported 
Grade 3 or 4 TEAEs ≥ 3% b  
Most frequently reported 
Serious TEAEs ≥ 2% c  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia 
Hypertension   
 
Anemia  
Diarrhea  
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract 
infection 
 
 
Thrombocytopenia    
 
 
Edema peripheral    
 
 
a Source is Table 6 of IB (v10), b Source is Table 8 of IB (v10), c Source is Table 9 of IB 
(v10). 
 
1.2.4.2 
Combination Therapy Studies 
Pooled safety data from a total of 423 subjects treated with various therapies in 
combination with ibrutinib from 4 studies conducted in subjects with B-cell malignancies, 
are briefly summarized below. Therapies used in combination with ibrutinib in these 
studies, 
included 
BR 
(bendamustine 
and 
rituximab), 
FCR 
(fludarabine, 
cyclophosphamide, 
and 
rituximab), 
ofatumumab, 
and 
R-CHOP 
(rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone).  
The most frequently reported TEAEs in subjects receiving ibrutinib in combination 
therapy (N = 423): 

 
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Most frequently reported 
TEAEs ≥ 20% a   
Most frequently reported 
Grade 3 or 4 TEAEs ≥ 3% b  
Most frequently reported 
Serious TEAEs ≥ 2% c  
Neutropenia 
Neutropenia 
Pneumonia  
Diarrhea 
Thrombocytopenia 
Febrile neutropenia  
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anemia 
Anemia 
 
Pyrexia 
Fatigue 
 
 
Hypertension 
 
 
Diarrhea 
 
a Source is Table 10 of IB (v10), b Source is Table 12 of IB (v10), c Source is Table 13 of 
IB (v10). 
 
1.2.4.3 
Treatment Discontinuations 
As of 6 April 2013, 71/636 subjects discontinued treatment due to an adverse 
event, across the monotherapy and combination therapy ibrutinib studies (excluding 
Study PCYC-1103-CA); 62 subjects receiving monotherapy population and 9 subjects 
receiving combination therapy.  The most frequently reported adverse events that led to 
treatment discontinuations were pneumonia (13 subjects), respiratory failure (4 
subjects), and cardiac arrest and Richter’s Syndrome (3 subjects each).   
1.2.4.4 
Hemorrhagic Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both 
with and without thrombocytopenia. These include minor hemorrhagic events such as 
contusion, epistaxis, and petechiae; and major hemorrhagic events, some fatal, 
including gastrointestinal bleeding, subdural intracranial hemorrhage, and hematuria. 
Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. Subjects with congenital bleeding 
diathesis have not been studied. See Section 6.4 for guidance on concomitant use of 
anticoagulants, antiplatelet therapy and/or supplements. See Section 6.5 for guidance 
on ibrutinib management with surgeries or procedures.  In an in vitro platelet function 
study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were 
observed. 
 

 
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1.2.4.5 
Cardiac  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a 
previous history of atrial fibrillation. Subjects who develop arrhythmic symptoms (eg, 
palpitations, lightheadedness) or new onset of dyspnea should be evaluated clinically, 
and if indicated, have an ECG performed. For atrial fibrillation which persists, consider 
the risks and benefits of ibrutinib treatment and follow the protocol dose modification 
guidelines.  
 
1.2.4.6 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib 
or in combination with chemotherapy. Most rashes were mild to moderate in severity. 
Isolated cases of severe cutaneous adverse reactions (SCARs) including Stevens-
Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib. Subjects 
should be closely monitored for signs and symptoms suggestive of SCAR including SJS. 
Subjects receiving ibrutinib should be observed closely for rashes and treated 
symptomatically, including interruption of the suspected agent as appropriate. In 
addition, hypersensitivity-related events including erythema, urticaria, and angioedema 
have been reported. 
. 
1.2.4.7 
Other Malignancies 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor 
subjects for the appearance of non-melanoma skin cancer  
 
1.2.4.8 
Infection  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in 
subjects treated with ibrutinib therapy. Some of these reported infections have been 
associated with hospitalization and death. Consider prophylaxis according to standard of 
care in subjects who are at increased risk for opportunistic infections. Although causality 
has not been established, cases of progressive multifocal leukoencephalopathy (PML) 
have occurred in patients treated with ibrutinib. Subjects should be monitored for 
symptoms (fever, chills, weakness, confusion) and appropriate therapy should be 
instituted as indicated.  
 
1.2.4.9  
Myelosuppression 
Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of subjects. These 
included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor 
complete blood counts monthly. 

 
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1.2.4.9 
Embryo-Fetal Toxicity 
Based on findings in animals, Ibrutinib can cause fetal harm when administered 
to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times 
those reported in subjects receiving the ibrutinib dose of 560 mg per day. Reduced fetal 
weights were observed at lower exposures. Advise women to avoid becoming pregnant 
while taking Ibrutinib. If this drug is used during pregnancy or if the subject becomes 
pregnant while taking this drug, the subject should be apprised of the potential hazard to 
a fetus. 
 
 
As of 6 April 2013, 71/636 subjects discontinued treatment due to an adverse 
event, across the monotherapy and combination therapy ibrutinib studies (excluding 
Study PCYC-1103-CA); 62 subjects receiving monotherapy population and 9 subjects 
receiving combination therapy. The most frequently reported adverse events that led to 
treatment discontinuations were pneumonia (13 subjects), respiratory failure (4 
subjects), cardiac arrest (3 subjects) and Richter’s Syndrome (3 subjects). 
 
1.2.4.10 
Treatment-related Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% 
increase from baseline and an absolute count >5000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects with CLL/small 
lymphocytic lymphoma (SLL) treated with ibrutinib. This effect has also been observed in 
some subjects with MCL treated with ibrutinib. This observed lymphocytosis (increase in 
the number of circulating lymphocytes eg, >400,000/µL) is a pharmacodynamic effect 
and should not be considered progressive disease in the absence of other clinical 
findings. In both disease types, lymphocytosis typically occurs during the first few weeks 
of ibrutinib therapy and typically resolves within a median of 8.0 weeks in subjects with 
MCL and 14 weeks in subjects with CLL/SLL. This pharmacodynamic effect was less 
prominent or not observed in other indications. 
 
There were isolated cases of leukostasis reported in subjects treated with 
ibrutinib. A high number of circulating lymphocytes (>400,000/µL) may confer increased 
risk. For subject and ibrutinib management guidance..  
A high number of circulating malignant cells (>400000/mcL) may confer 
increased risk; these subjects should be closely monitored. Administer supportive care 
such as hydration and/or leukophoresis as indicated. Ibrutinib may be temporarily held, 
and medical monitor should be contacted.  

 
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1.2.4.11 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with 
ibrutinib. Monitor subjects for pulmonary symptoms indicative of ILD. Should symptoms 
develop follow the protocol dose modification guidelines. 
1.2.4.12 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy. Subjects at risk of TLS are 
those with comorbidities and/or risk factors such as high tumor burden prior to treatment, 
increased uric acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky 
disease at baseline, and pre‐existing kidney abnormalities. 
1.2.4.13 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy 
and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe. Should symptoms be 
severe or prolonged follow the protocol dose modification guidelines. 
1.2.4.14 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor 
subjects for new onset of hypertension or hypertension that is not adequately controlled 
after starting ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-
hypertensive treatment as appropriate. 
 
1.3 
GA101 - OBINUTUZUMAB BACKGROUND 
1.3.1 
Structure and Mechanism of Action of GA101 - Obinutuzumab 
Obinutuzumab (GA101, RO5072759), is a glycolengineered, humanized, type II 
anti-CD20 monoclonal antibody (mAb).  GA101 - Obinutuzumab was derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering 
leading to the following characteristics (Beers et al., 2010):  high antibody-dependent 
cellular cytotoxicity (ADCC); high affinity binding to the CD20 antigen; low complement-
dependent cytotoxicity (CDC) activity; and antibody dependent cellular phagocytosis 
(ADCP) through recruitment of FcγRIII positive immune effector cells such as natural 
killer (NK) cells, macrophages and monocytes; and high direct cell death induction. 
Given the direct cell death inducing properties of GA101-Obinutuzumab and the 
significantly enhanced ADCC in preclinical assays, it is possible that GA101-

 
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Obinutuzumab may have greater efficacy than the widely used anti-CD20-mAb rituximab 
(Rituxan).  
1.3.2 
Clinical Experience with GA101 - Obinutuzumab 
1.3.2.1 
Tolerability and Efficacy of GA101 - Obinutuzumab in Chronic 
Lymphocytic Leukemia  
 
Phase I Study of RO5072759 (GA101) in Relapse/Refractory Chronic 
Lymphocytic Leukemia. (Study BO20999; GAUGUIN; NCT00517530) 
BO20999 was an open-label, multicenter, Phase I/II study to explore GA101 - 
Obinutuzumab safety and activity in subjects with CD20+ malignant disease. Thirteen 
CLL subjectswere enrolled and received GA101 - Obinutuzumab at doses with a range 
of 400−2,000 mg (given as a flat dose) across four cohorts. There were no dose-limiting 
toxicities (DLTs) and no requirement for dose reductions.  Infusion-related reactions 
(IRRs) occurred in all CLL subjects and were characterized predominantly by National 
Cancer Institute Common Terminology Criteria (NCI-CTC) Grade 1−2 toxicities:  
chills, nausea, vomiting, fever, pyrexia, hypertension, hypotension, dyspnea, and 
dizziness.  Two subjects experienced four NCI-CTC Grade 3 toxicities:  sweats, flushing, 
asthenia, and hepatic cytolysis (Morschhauser et al., 2009).  
Although the safety profile appears otherwise similar between NHL and CLL in 
the BO20999 study, there was an increase in NCI-CTC v3.0 Grade 3−4 neutropenia 
noted in CLL subjects, which were observed in 9 subjects across the four dose levels 
administered.  Five subjects experienced NCI-CTC Grade 4 neutropenia and 4 subjects 
experienced NCI-CTC Grade 3 neutropenia as the maximum severity.  Of the 9 subjects, 
7 had one NCI-CTC Grade 3−4 event and 2 subjects experienced more than one event.  
Granulocyte colony-stimulating factor (G-CSF) support was administered to 6 of the 9 
subjects, and these subjects responded quickly to G-CSF support.  For the 3 subjects 
who did not receive G-CSF, neutrophil counts normalized spontaneously.  Furthermore, 
it is important to note that these neutropenia events did not appear to be accompanied 
by a higher incidence of infections.  No deaths were reported in Phase I of this study for 
CLL. 
As assessed by the International Workshop on CLL (IWCLL) criteria, the 
end-of-treatment response rate with GA101 - Obinutuzumab monotherapy was 62% 
(8 of 13 subjects with partial response – PR) (Morschhauser et al., 2009). 
Study BO21003 (GAUSS; NCT00576758) (Phase I) 
BO21003 is an open-label, dose-escalating, multicenter Phase I/randomized 
Phase II study in subjects with relapsed/refractory CD20+ malignant disease.  In Study 
BO21003, 5 CLL subjects have been administered GA101 - obinutuzumab.  The fifth 

 
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subjects withdrew at Cycle 1, Day 1 because of a Grade 4 IRR, which occurred minutes 
after the start of infusion in the setting of high tumor burden.  Efficacy assessments are 
available for only the 4 subjects who completed treatment (received 4 cycles of infusion).  
The end-of-treatment response in subjects with CLL receiving GA101-Obinutuzumab 
monotherapy in this study included 3 stable disease and 1 progressive disease subjects 
(Sehn et al., 2012). 
Study GAO4768g / GAGE / NCT01414205 (Phase II) 
GAO4768g is an open-label, randomized, multicenter, Phase II study evaluating 
the efficacy and safety of GA101-Obinutuzumab administered at 1,000 mg versus 2,000 
mg in subjects with previously untreated CLL. Study GAO4768g is ongoing so data 
provided here are preliminary.  As of July 2012, 51 previously untreated CLL subjects 
were exposed to GA101-Obinutuzumab in this study. Of these, 38 subjects (75%) have 
been exposed to treatment for more than 4 weeks, but less than 6 months and one 
subject (2%) has been exposed for ≥ 6 months.  
A total of 41 subjects (80%) have experienced AEs, and SAEs have been 
reported in 5 subjects (10%). The SAEs include febrile neutropenia, neutropenia, 
thrombocytopenia, pyrexia, urosepsis, IRR, depressed level of consciousness, hypoxia 
and hypotension.  Twenty-two subjects (43%) have experienced a Grade 3−4 AE, of 
which 15 subjects (29%) had a Grade 3−4 blood and lymphatic system disorder.  AEs of 
special interest included 37/51 subjects (73%) with AEs of any grade associated with 
study drug infusion, 13/51 subjects (26%) with infections, 14/51 subjects (28%) with 
neutropenia, 7/51 subjects (14%) with thrombocytopenia, and 1/51 subjects (2%) with 
TLS. 
Four subjects (8%) have discontinued from the study treatment due to AEs:  
sneezing and chills; IRR, vomiting, hypotension, depressed level of consciousness, and 
hypoxia; neutropenia; and thrombocytopenia. No deaths have been reported in this 
study.  
No efficacy data are available yet for study GAO4768g. 
Study GAO4779g (GALTON; NCT01300247) (Phase II) 
GAO4779g is an open-label, non-randomized, multicenter Phase II study GA101-
Obinutuzumab in combination with FC (G-FC) or bendamustine (G-B) in previously 
untreated subjects with CLL. Study GAO4779g is ongoing so data provided here are 
preliminary.  In this study, a safety run-in analysis was conducted in each treatment arm 
for the first three subjects per arm treated through Day 28 of Cycle 1 before additional 
subjects were exposed to treatment. 

 
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As of July 2012, 41 previously untreated CLL subjects had been exposed to 
GA101-Obinutuzumab + FC or GA101-Obinutuzumab + bendamustine with a median 
follow-up time of 11.9 months. The most common adverse events (AEs) (any grade) 
occurring in ≥ 9 subjects in the G-FC arm were GA101 infusion–related reactions (IRRs) 
(91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the 
G-B arm, they were GA101 IRRs (90%), nausea (65%), neutropenia (55%), diarrhea 
(50%), and pyrexia (45%). In both cohorts, Gr 3/4 GA101 IRRs only occurred with the 
1st dose. Fourteen subjects experienced serious AEs (6 subjects in G-FC, 8 subjects in 
G-B), with events including febrile neutropenia (n=5 events); infections (n=4); IRRs 
(n=3); nausea, vomiting, pyrexia (n=2 each); and diarrhea, fatigue, tachycardia, tumor 
lysis syndrome, syncope, mental status changes, neutropenia, face swelling, and 
hypertension (n=1 each). Nine subjects (7 in G-FC, 2 in G-B) had AEs leading to 
treatment discontinuation, including Gr 3/4 neutropenia (3 in G-FC [1 of 3 subjects also 
had Gr 4 cellulitis], 2 in G-B), Gr 3 thrombocytopenia (2 in G-FC), Gr 4 pancytopenia (1 
in G-FC), and Gr 4 AST/Gr 3 ALT elevation (1 in G-FC). 
The overall response rate was 62% (2 CR, 3 CRi, 8 PR) in the G-FC arm, and 
90% (4 CR, 5 CRi, 9 PR) in the G-B arm, including 6 subjects (4 in G-FC, 2 in G-B) not 
evaluable due to inadequate response evaluation. Four subjects in the G-FC arm (0 in 
G-B) had stable disease during and after therapy. No subject progressed during the 
study (Brown et al., 2013). 
Study BO21004 (CLL11; NCT01010061) (Phase III) 
This is an open-label, multicenter, three-arm randomized, Phase III study to 
compare the efficacy and safety of GA101-Obinutuzumab +  chlorambucil (GClb), 
rituximab + GClb (RClb), or Clb alone in previously untreated CLL subjects with 
comorbidities.  The data from this study were pivotal for the FDA approval of GA101-
Obinutuzumab in previously untreated subjects with CLL.  
BO21004 enrolled 781 subjects and an additional 6 subjects during a safety run-
in period before randomization.  An analysis based on data collected by the data cutoff 
date for these 6 subjects accrued from December 2009 until February 2010 for the 
BO21004 safety run-in phase showed that all 6 subjects completed 6 cycles of treatment 
but two subjects had significant dosing delays.  IRRs occurred in 5 subjects, all were 
Grade 1 or 2, with no severe IRRs.  All 6 subjects experienced neutropenia, 5/6 subjects 
reported Grade 3 − 4 afebrile neutropenia with no febrile neutropenia. All 6 reported 
thrombocytopenia with one case of Grade 3 − 4 thrombocytopenia. No subject died 
during the safety run-in period.  Given that none of the pre-defined stopping criteria were 
met during this safety run-in period, Study BO21004 opened to randomization in April 
2010 (Goede et al., 2013). Study BO21004 includes two separate stages evaluating 

 
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efficacy and the primary endpoint is progression-free survival (PFS).  Stage 1 evaluated 
GA101-Obinutuzumab + chlorambucil compared to chlorambucil alone.   
Stage 1 of Study BO21004 met its primary endpoint (Goede et al., 2013).  
Compared to chlorambucil, both GA101 - Obinutuzumab +  chlorambucil and rituximab  + 
 chlorambucil demonstrated statistically significant PFS benefit compared to chlorambucil 
alone.  Median PFS of chlorambucil vs. GA101 - Obinutuzumab +  chlorambucil were 
11.1 vs. 26.7 months respectively (HR: 0.18, 95% CI: 0.13  − 0.24, p  < 0.001).  The 
difference in PFS was smaller between chlorambucil and rituximab + chlorambucil; 
median PFS were 11.1 vs. 16.3 months, respectively (HR: 0.44, 95% CI: 0.34 − 0.57, p 
 < 0.001) (Goede et al., 2014).  
Treatment with GA101 – Obinutuzumab + chlorambucil, as compared with 
chlorambucil alone, prolonged overall survival (HR for death, 0.41; 95% CI, 0.23 to 0.74; 
P = 0.002). Treatment with GA101 – Obinutuzumab + chlorambucil, as compared with 
rituximab + chlorambucil, resulted in prolongation of progression-free survival (HR: 0.39, 
95% CI: 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) 
and molecular response. Infusion-related reactions and neutropenia were more common 
with Obinutuzumab–chlorambucil than with rituximab–chlorambucil, but the risk of 
infection was not increased (Goede et al., 2014). 
1.3.3 
Overview of Safety of GA101 - Obinutuzumab 
GA101 - Obinutuzumab has been administered to approximately 1310 subjects 
with CD20-positive malignancies. Both in subjects with NHL and with CLL, IRR were the 
most common AE in clinical trials conducted to date. They were predominantly 
associated with the first infusion, generally occurring early during the infusion, shortly 
after, or in some cases up to 24 hours after the completion of the infusion with GA101 - 
obinutuzumab.  The incidence and intensity of IRRs decreased with subsequent 
infusions of GA101 - Obinutuzumab.   
In a few subjects, concurrent signs of tumor lysis syndrome (TLS) were 
observed.  Other frequently observed AEs include infections, neutropenia and 
thrombocytopenia.  These events appeared to be more common in subjects with CLL 
compared to NHL. 
In trials investigating the combination of GA101-Obinutuzumab and CHOP, FC, 
chlorambucil or bendamustine, the incidence of AEs in the treatment arms with 
combined use was consistent with the known safety profiles of the individual study 
drugs.  So far, no maximum tolerated dose, no dose-limiting toxicities, and no clear 
dose-related trends in the incidence of AEs have been determined. 

 
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A pooled analysis of safety data for GA101-Obinutuzumab collected during the 
monotherapy studies BO20999 and BO21003 was conducted in subjects with NHL 
(aggressive [aNHL] and indolent []iNHL]) or CLL who participated in those two studies 
(both Phase I and Phase II) and received monotherapy treatment with GA101-
Obinutuzumab and included a total 205 subjects with NHL (49 aNHL and 156 iNHL 
subjects) and 38 subjects with CLL. 
In the group of 38 subjects with CLL, the majority of subjects (25 [66%]) were 
treated for ≥  4 weeks to <  6 months.  Eleven subjects (29%) were exposed for 6 to  < 12 
months, and two subjects (5%) were exposed for 12 months or longer. Eight of 38 
subjects (21%) with CLL were withdrawn during the treatment phase; 4 subjects (11%) 
were withdrawn due to AEs, which indicates that AEs were mostly manageable.  Almost 
all subjects (37/38 [97%]) experienced an IRR. The number of subjects with Grade 3−4 
IRRs was 11/38 (29%). As is typical for subjects with CLL, blood and lymphatic system 
disorders were among the most frequently reported AEs, in particular neutropenia 
(13/38 subjects [34%]), febrile neutropenia (5/38 subjects [13%]), and thrombocytopenia 
(7/38 subjects [18%]). 
Infections and infestations were common AEs, occurring in 21/38 subjects (55%).  
Infections reported in more than one subject were nasopharyngitis (6 subjects), 
bronchitis and sinusitis (4 subjects each), influenza and lung infection (3 subjects each), 
and herpes zoster and oral herpes (2 subjects each). 
Thirteen subjects (34%) died, 8 of these due to disease progression. One subject 
died from an unspecified cause after withdrawal from the study for lack of response.  
This subjects had received subsequent experimental therapies and had stable CLL at 
the time she died.  For 4 additional subjects, the cause of death was reported as colon 
cancer, lung adenocarcinoma, metastasis, and septic shock, and all were considered not 
to be related to treatment. 
In the two studies investigating GA101-Obinutuzumab as monotherapy, 
BO20999 and BO21003, subjects with CLL appeared to be at a higher risk of 
experiencing an AE of special interest than subjects with NHL.  The largest difference in 
the incidences was seen for neutropenia (occurring in 47% of subjects with CLL [18/38] 
vs. 8% of subjects with aNHL [4/49] and 8% of subjects with iNHL [13/156]) and 
treatment-related AEs associated with the infusion (100% [38/38] vs. 80% (39/49) and 
83% [129/156]). 
To date, a very small number of subjects have experienced TLS (six in total); four 
subjects in the aNHL population (population including MCL) and one subjects each in 
the CLL and iNHL populations. 

 
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Infections have been reported in 20/49 aNHL subjects (41%), 74/156 iNHL 
subjects (47%), and 21/38 CLL subjects (55%). One iNHL subjects was withdrawn from 
the study because of an infection.  In addition, one CLL subject and one iNHL subject 
died from an infection (septic shock in both cases) during survival follow-up 671 days 
and 494 days after last dose of treatment, respectively. 
Three CLL and 3 iNHL subjects were withdrawn from treatment due to an AE of 
special interest, all for IRRs.  An additional subject in the iNHL group discontinued 
treatment because of an infection.  This indicates that these events were generally 
manageable. 
In Study BO21004 (CLL11), 6 previously untreated CLL subjects received 
GA101-Obinutuzumab in combination with chlorambucil (GA101 – Obinutuzumab 1,000 
mg on Days 1, 8, and 15 of Cycle 1, then 1,000 mg on Day 1 for Cycles 2 − 6; 
chlorambucil 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 − 6).  All 6 subjects 
completed six cycles on treatment, 2 with significant dosing delays.  Five of 6 subjects 
experienced an IRR with no severe IRRs. All 6 subjects experienced neutropenia with no 
febrile neutropenia, and all 6 subjects reported thrombocytopenia with one case of 
severe thrombocytopenia. 
Most IRRs were associated with the first GA101-Obinutuzumab infusion.  Their 
frequency and intensity decreased with subsequent infusions. 
The safety plan for subjects receiving GA101-Obinutuzumab is based on the 
toxicities observed in nonclinical studies and the clinical experience with this molecule in 
completed and ongoing studies.   
The potential safety issues anticipated in this trial, as well as measures intended 
to avoid or minimize such toxicities, are outlined below. 
1.3.4 
Risks Associated with GA101 - Obinutuzumab Therapy 
No evidence available at the time of the approval of this protocol indicates that 
special warnings or precautions are appropriate other than those noted in the following 
sections. 
1.3.4.1 
Infusion Reactions and Hypersensitivity Reactions (including 
Anaphylaxis) 
In Phase I/II clinical trials of GA101 - Obinutuzumab, the most common AEs were 
mild or moderate IRRs.  To date, the commonly experienced IRRs are characterized, 
among other symptoms, by fever, chills, nausea, vomiting, hypotension, and fatigue.  

 
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Respiratory 
infusion-related 
symptoms 
such 
as 
hypoxia, 
dyspnea, 
bronchospasm, larynx and throat irritation, and laryngeal edema have also been 
reported. These IRRs were mostly mild or moderate (NCI-CTC, v3.0, Grade 1−2), 
occurring predominantly during the first hour or shortly after the first infusion, 
and resolved with the slowing down or the interruption of the infusion and with supportive 
care where appropriate. In some subjects, some IRRs occurred up to 24 hours after 
receiving the first infusion. The incidence and severity of IRRs decreased with 
subsequent infusions. Cases of tumor flare have also been reported with GA101 - 
Obinutuzumab. Extensive tumor burden, predominantly localized in the blood circulation 
(e.g., high peripheral lymphocyte count in CLL subjects), may be a predisposing factor 
for the development of IRRs. 
The mechanism of IRRs is unclear, but it is potentially linked to the process of 
B-cell depletion by ADCC and the rapidity of apoptosis. IRRs may be clinically 
indistinguishable from IgE-mediated allergic or anaphylactic reactions. 
For the management of IRRs, see Section 6.1.12, For dose delay and 
modification instructions, see Section 6.1.4.  
1.3.4.2 
Tumor Lysis Syndrome 
Cases of TLS have been reported with GA101-Obinutuzumab administration.  To 
date, no subject has required hemodialysis for renal failure.  subjects with a high tumor 
burden, including subjects with a lymphocyte count of ≥ 25 × 109/L (particularly, subjects 
with B-cell CLL and MCL), are at increased risk for TLS and severe IRRs.  
1.3.4.3 
Thrombocytopenia and Neutropenia 
Cases of Grade 3 or 4 thrombocytopenia and neutropenia, including febrile 
neutropenia, have been reported with GA101-Obinutuzumab administration. Grade 3 or 
4 neutropenia has been observed predominantly in subjects with CLL. Subjects who 
experience Grade 3 or 4 neutropenia or thrombocytopenia should be monitored until 
neutrophil and platelet values return to at least Grade 2. The use of myeloid growth 
factors has been found to result in a rapid normalization of neutrophils, similar to what 
has been observed in subjects treated with rituximab. 
1.3.4.4 
Hepatitis B Reactivation 
Due to the potential for hepatitis B reactivation to occur with anti-CD20 therapy, 
all subjects should be screened for hepatitis B virus (HBV) prior to initiation treatment 
with GA101 - Obinutuzumab. Subjects with positive serology may be referred to a 
hepatologist or gastroenterologist for appropriate monitoring and management. subjects 
with active HBV disease should not be treated with GA101 - Obinutuzumab. 

 
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1.3.4.5 
Worsening of Pre-Existing Cardiac Conditions 
GA101 - Obinutuzumab treatment can result in arrhythmias such as atrial 
fibrillation and tachyarrhythmia, angina pectoris, acute coronary syndrome, myocardial 
infarction, and heart failure in subjects with underlying cardiac disease. These events 
may occur as a part of an infusion reaction and can be fatal.  subjects with a history of 
cardiac disease should be monitored closely and should be hydrated with caution in 
order to prevent a potential fluid overload. 
1.3.4.6 
Infection 
On the basis of its anticipated mode of action resulting in profound B-cell 
depletion, GA101 - Obinutuzumab may be associated with an increased risk of 
infections.  Infections have been reported in subjects receiving GA101 - Obinutuzumab.  
Therefore, GA101-Obinutuzumab should not be administered to subjects with active 
severe infections.  
Serious infections, including fatal, bacterial, fungal, and new or reactivated viral 
infections (e.g., cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster 
virus, West Nile virus, and hepatitis B and C) have been reported with the 
B cell-depleting antibody rituximab, mainly in subjects who had received the drug in 
combination with chemotherapy or as part of a hematopoietic stem-cell transplant. 
One case of progressive multifocal leukoencephalopathy (PML), which was fatal, 
has been observed during treatment with GA101 – Obinutuzumab. Physicians should be 
aware of symptoms suggestive of PML and consider the diagnosis of PML in any subject 
presenting with new-onset neurologic manifestations. Evaluation of PML includes but is 
not limited to consultation with a neurologist, brain magnetic resonance imaging (MRI), 
and lumbar puncture. Discontinue GA101-Obinutuzumab and consider discontinuation 
or reduction of any concomitant chemotherapy or immunosuppressive therapy in 
subjects who develop PML.  
There may be additional potential health risks, including hitherto unknown risks, 
derived from exposure to GA101 – Obinutuzumab. 
1.3.5 
Summary of Pharmacokinetic and Pharmacodynamic Data for GA101 
- Obinutuzumab 
A two-compartment model comprising a time-varying clearance pathway and a 
linear clearance pathway provides an adequate description of the pharmacokinetics of 
GA101-Obinutuzumab following intravenous (IV) administration in Studies BO20999 and 
BO21003.  Following the infusion of GA101 – Obinutuzumab, the elimination appears to 
be characterized by a clearance pathway that is dependent on time (i.e., starting at a 
typical value of 630 mL/day and then gradually decreasing to an asymptote of 60 mL/day 

 
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at steady state) and a linear clearance pathway. Tumor burden may potentially 
contribute significantly to the clearance of GA101 - Obinutuzumab, especially at the 
beginning of treatment when CD20-positive tumor cells are most abundant. As tumor 
burden decreases, the clearance reaches an asymptote, which is believed to be 
primarily a function of the proteolytic metabolic clearance.  Consequently, some subjects 
with a high tumor burden may appear to clear the drug from the plasma faster than do 
subjects with a low tumor burden because GA101-Obinutuzumab binds to the CD20-
positive tumor cells and is effectively removed from the plasma. Therefore, the clearance 
of the drug will vary with time, since repeated treatments with GA101-Obinutuzumab will 
reduce the quantity of CD20-positive tumor cells. Consequently, the number of GA101-
Obinutuzumab administrations during the first cycle of treatment may be expected to 
reduce the number of CD20-positive tumor cells, thus minimizing the impact of the time 
varying clearance pathway on GA101-Obinutuzumab exposure. 
Treatment with GA101-Obinutuzumab resulted in extensive B-cell depletion, with 
all subjects showing a reduction in cell count to absolute zero at some stage of their 
treatment cycle. Overall, there has been no notable increase in complement levels 
before and after infusion, but changes have been observed in the levels of interleukin 
(IL)-6 and IL-8 before and after infusion. 
 
1.4 
STUDY RATIONALE 
Standard treatment for subjects with chronic lymphocytic leukemia (CLL) is 
rapidly evolving and gradually has incorporated the use of monoclonal antibodies and 
targeted therapy with small molecules. Based on the data from the CLL-11 study (Goede 
et al., 2014), GA101 - Obinutuzumab was approved in 2013 for front line treatment of 
CLL subjects. In addition, Ibrutinib has been recently approved in February 2014 by the 
FDA, as a single agent for treatment of subjects with relapse refractory CLL. There is no 
data available testing the combination of Ibrutinib with GA101 – Obinutuzumab, but their 
separate mechanism of action and non-overlapping adverse events makes them ideal 
for administration together with an expected synergistic effect.  
The CLL-11 study demonstrated that GA101 – Obinutuzumab in combination 
with Chlorambucil induce higher overall and complete responses, and conferred a 
statistically significant benefit in terms of progression free and overall survival compared 
to subjects receiving single agent chlorambucil. These data provided the support for the 
FDA approval on November 1, 2013. This and other studies using chlorambucil 
combination strategies (Hillmen et al., 2013) have shown that the benefit of adding 
chlorambucil to these combination regimens is questionable and it is likely that, instead 
of providing additive or synergistic interaction, it may increase the rate of adverse events 
including cytopenias and infections. Similarly, single agent Ibrutinib has shown to be 

 
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effective in previously untreated subjects including those that are older than 65 or 
considered unfit to receive chemotherapy based combinations (O'Brien et al., 2014). The 
response rate (Overall response of 71% and complete response of 13%) could be higher 
in subjects receiving Ibrutinib but the mobilization of lymphocytes, which is typically 
asymptomatic, decreases the response rate due to lack of complete fulfillment of IWCLL 
criteria. Ibrutinib-induced lymphocytosis could be ameliorated by using a monoclonal 
antibody therapy as shown by Burger et al. In this study, when Ibrutinib was 
administrated in combination with Rituximab, lymphocytosis resolved more rapidly and 
completely, and consequently the overall response rate was higher (90-95%) (Burger et 
al., 2013).  
There is no data available assessing the combination of Ibrutinib with GA101 – 
Obinutuzumab in the elderly population (> 65 years old) or in those subjects < 65 years 
of age where the chemotherapy based agents is contraindicated. We hypothesize that 
Ibrutinib in combination with GA101 – Obinutuzumab will be well tolerated and will 
induce higher response rates than the response rate observed in the CLL11 Study 
(Goede et al., 2014). 
2. 
OBJECTIVES 
2.1 
PRIMARY 
• 
Primary Objective Phase IB: 
o To evaluate the safety, tolerability and dose limiting toxicity (DLT) of 
Ibrutinib in combination with GA101 - Obinutuzumab in previously 
untreated CLL subjects. 
• 
Primary objective Phase II: 
o To determine the overall response rate (partial response + complete 
response rate) of Ibrutinib in combination with GA101 - Obinutuzumab in 
previously untreated subjects with CLL. 
2.2 
SECONDARY 
• 
To determine progression-free survival (PFS), treatment-free survival (TFS) and 
overall survival (OS) in previously untreated CLL subjects that will receive treatment 
with Ibrutinib in combination with GA101 – Obinutuzumab. 
 
• 
To determine the percentage of previously untreated CLL subjects treated with 
Ibrutinib plus GA101 – Obinutuzumab that achieve negative minimal residual 
disease (MRDneg) in the bone marrow or peripheral blood using multiparameter flow 
cytometry (4 colors).  

 
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• 
To evaluate correlative studies in samples collected from previously untreated 
CLL subjects treated with Ibrutinib / GA101 – Obinutuzumab combination regimen 
including but not limited to the following: assessment of the chemokine and cytokine 
profile using plasma samples from the subjects and correlation of the results with 
the presence of Infusion-Related Reactions (IRRs). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open label phase IB/II clinical trial to determine the safety, tolerability 
and clinical activity of Ibrutinib in combination with GA101 - Obinutuzumab. 
Pharmacyclics will provide Ibrutinib during the course of the 6 cycles and after cycle 6, 
during the following 3 years. GA101 – Obinutuzumab will be requested to be covered by 
the insurance as a Standard of Care treatment for previously untreated subjects. Phase 
Ib 
We will evaluate safety, tolerability and dose-limiting toxicities (DLTs) during the 
first cycle of treatment (4 weeks; Day 1 – 28). The phase IB will be performed as a 
safety run-in in the first 6 subjects enrolled. The sample size of 6 subjects is considered 
to be sufficient to support preliminary safety, tolerability and DLTs assessments (Goede 
et al., 2013). For additional statistical considerations see section 10.2.6. 
Subjects will be enrolled at least one week apart to ovoid overlapping time of 
observation during the first week of treatment when infusion reactions are expected to 
be higher.  
If no more than one of six subjects experiences DLTs, we will proceed to the 
Phase II described below. 
3.1.1 
Phase II 
In the phase II we will determine response rate in all subjects that have received 
treatment. This study will enroll 32 subjects and the sample size has been calculated 
using a Simon two-stage design (Simon, 1989). In the first stage, 10 subjects will be 
enrolled. If 8 or fewer responses are observed at the end of this stage, then the study 
will be terminated for futility. If at least 9 responses are observed, an additional 22 
subjects will be enrolled in a second stage, for a total of 32 subjects.  If at least 29 
responses are observed among the 32, then efficacy of the treatment will be concluded. 
For additional statistical considerations see section 10.3.4. 
Response assessments will be evaluated based on the International Workshop in 
CLL Guidelines (IWCLL) (Hallek et al., 2008). 

 
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The estimated accrual time from first to last subject enrolled in the study will be 
24 months (including the safety run-in of the phase Ib) 
3.2 
OUTCOME MEASURES 
3.2.1 
Phase IB Outcome Measures: 
The safety and tolerability of Ibrutinib in combination with GA101 - Obinutuzumab will 
be assessed using the following primary safety outcome measures: 
- 
Type, Incidence, nature, and severity of AEs. 
- 
The relationship of AEs to Ibrutinib and/or GA101 – Obinutuzumab 
- 
Serious adverse events 
- 
Incidence of adverse events leading to Ibrutinib/GA101 - Obinutuzumab 
discontinuation or dose delays. 
- 
Incidence of adverse events of special interest 
- 
Clinical laboratory abnormalities 
- 
Deaths and cause of death 
- 
Dose limiting toxicity (DLT): DLTs will include possibly related or related events 
that are Grade > 3 that do not resolve to Grade < 1 within 14 days of initiation 
despite appropriate medical management. Some exceptions will apply (See 
section 10.2.4). 
 
3.2.2 
Phase II Outcome Measures: 
Response assessment will be performed by physical examination, CT scan 
evaluation and bone marrow biopsy/aspirate at completion of therapy using the 
International Workshop in CLL Guidelines (IWCLL) (Hallek et al., 2008).  
• Primary: 
- 
Overall response rate (ORR): defined as the proportion of subjects who 
achieve complete response (CR), complete response with incomplete marrow 
recovery (CRi), nodular partial response (nPR), or partial response (PR) per 
IWCLL 2008 criteria over the course of the study. 
- 
Progression Free Survival (PFS): Time measured from initiation of 
therapy until clinical or laboratory evidence of CLL progression.  
- 
Treatment Free Survival (TFS): Time measured from initiation of therapy 
until next treatment for CLL.  
- 
Overall Survival (OS): Time measured from initiation of therapy until 
death from any cause. 
• Secondary: 

 
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- 
Rate of MRDneg CRs in the bone marrow or peripheral blood using 
multiparameter flow cytometry (4 colors). 
 
- 
Clinical, 
laboratory 
and 
radiological 
evidence 
of 
response 
to 
administration of Ibrutinib plus GA101 – Obinutuzumab based in the International 
Workshop in CLL Guidelines (IWCLL) (Hallek et al., 2008). 
 
4. 
STUDY POPULATION 
• Previously untreated CLL subjects > 65 years of age or subjects < 65 years that 
refuse to be treated with chemotherapy or that are not candidates for treatment 
with chemotherapy agents. 
 
4.1 
INCLUSION CRITERIA 
Subjects must meet the following criteria for study entry: 
1. 
Diagnosis of CLL: 
• 
Monoclonal B-cells co-expressing > one B-cell marker (CD19, CD20, or 
CD23) and CD5 in peripheral blood or lymph node. 
2. 
Indication for treatment as defined by the IWCLL Guidelines: 
• 
Massive (i.e. > 6 cm below the left costal margin) or progressive/ 
symptomatic splenomegaly OR 
• 
Massive lymph nodes or nodal clusters (i.e. > 10 cm in longest diameter), 
or progressive / symptomatic lymphadenopathy OR 
• 
Presence of disease-related constitutional symptoms: 
− 
Weight loss ≥ 10% over the preceding 6 months 
− 
Significant fatigue (i.e., ECOG PS 2 or worse; inability to work or perform 
usual activities). 
− 
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other 
evidence of infection. 
− 
Night sweats for more than 1 month without evidence of infection. 

 
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• 
Progressive lymphocytes with an increase of ≥ 50% over a 2-month 
period or an anticipated doubling time of less than 6 months. OR 
• 
Evidence of progressive marrow failure as manifested by the 
development of, or worsening of, anemia and / or thrombocytopenia.  
• 
Autoimmune anemia and / or thrombocytopenia poorly responsive to 
corticosteroids or other standard therapy. 
3.  
No previous treatment for CLL.  
4. 
Males and females 65 years of age and older. Subjects < 65 years of age 
that meet any of the following criteria:  
• 
Subjects that refuse to be treated with chemotherapy based agents (This 
should be documented in the consent form). 
• 
Subjects that are not candidates for treatment with chemotherapy agents 
based on any of the following: 
• 
ECOG Performance status ≥ 2 
• 
Cumulative Illness Rating Scale (CIRS score) ≥ 6 (Appendix 6) 
• 
Creatinine clearance <70 mL/min using the Cockcroft-Gault 
Equation. 
5. 
Laboratory parameters as specified below:  
• 
Hematologic: Hemoglobin > 8 g/dL (may be post-transfusion); 
platelet count > 40 x103/mm3 (may be post-transfusion). Absolute 
neutrophil count > 1.0 × 109 cells/L (Growth factor use is allowed). 
• 
Hepatic:  Total Bilirubin < 3 x ULN, and ALT and AST < 3 x ULN 
• 
Renal: Creatinine clearance > 30 mL/min (Calculated according to 
institutional standards or using Cockcroft–Gault formula. Subjects 
with requirement of hemodialysis will be excluded).  
6. 
Anticipated survival of at least 6 months. 
7.  
Effective contraception is required while receiving Ibrutinib in combination 
with GA101 - Obinutuzumab. For women of childbearing potential and men, effective 

 
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contraception is required while receiving GA101 – Obinutuzumab and for 365 days (12 
months) after the last dose of the study drug. 
8.  
Ability to understand the requirements of the study, provide written 
informed consent and authorization of use and disclosure of protected health 
information, and agree to abide by the study restrictions and return for the required 
assessments. 
9.  
Subjects must give written informed consent to participate in this trial. 
4.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following criteria will be excluded from study entry: 
1. 
Pregnant or nursing women. 
2. 
Treatment with chemotherapy, monoclonal antibodies or biological agents 
(e.g. lenalidomide) other than the investigational agents during the time of participation 
in this trial. 
3. 
Grade 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification.  
4. 
Severe or debilitating pulmonary disease (dyspnea at rest, significant 
shortness of breath, COPD). 
5. 
Participation in any investigational drug study within 28 days prior to 
initiation of treatment within this protocol. (Subject must have recovered from all acute 
effects of previously administered investigational agents). 
6. 
History of second malignancy, other than non-melanoma skin cancer or in 
situ carcinoma of the cervix or the breast, unless the tumor was successfully treated at 
least 2 years before trial entry and with no evidence of relapse or active cancer.  
7. 
Active symptomatic fungal, bacterial and/or viral infection including 
evidence of infection with human immunodeficiency virus (HIV). 
8. 
Evidence of active acute or chronic Hepatitis B (HBV):  Subjects with 
acute or chronic active HBV will be defined based on CDC guidelines (Appendix 1). This 
will include subjects with positive serology for hepatitis B surface antigen (HBsAg) or 
hepatitis B core antibody (anti-HBc) associated with HBV-DNA positive test by real time 
quantitative qPCR assessment. Subjects, who are anti-HBc positive and HBsAg 
negative or HBV-DNA test negative, may be enrolled in the study and should undergo 

 
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regular monitoring of HBV viral load using HBV-DNA qPCR. Those subjects may be 
referred to a hepatologist or gastroenterologist for appropriate monitoring and 
management including antiviral therapy. 
9. 
Evidence of active Hepatitis C (HCV):  subjects with positive hepatitis C 
serology and positive HCV RNA test. 
10. 
Any illness or condition that in the opinion of the Investigator may affect 
safety of treatment or evaluation of any the study’s endpoints. 
11. 
History of severe allergic or anaphylactic reactions to monoclonal 
antibody therapy. 
12. 
Known hypersensitivity to any of the study drugs.  
13. 
Major surgery (within 4 weeks prior to the start of Cycle 1), except for 
procedures that are performed for diagnostic purposes. 
14. 
Men or women of childbearing potential who refuse to use an adequate 
measure of contraception (oral contraceptives, intrauterine device, or barrier method of 
contraception in conjunction with spermicidal jelly) unless they have past medical history 
of surgical sterilization. 
15. 
Vaccination with a live vaccine within 28 days of the initiation of 
treatment. 
16. 
Concomitant use of warfarin or other Vitamin K antagonists. 
17. 
Requirement to receive treatment with a strong cytochrome P450 (CYP) 
3A inhibitor. Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 
7 days prior to the first dose of Ibrutinib or subjects who require continuous treatment 
with a strong CYP3A inhibitor. 
18. 
 Subjects with chronic liver disease with hepatic impairment (Child-Pugh 
class B or C). 
 
 
 
 

 
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5. 
TREATMENT PLAN 
Figure 1. Treatment Schema 
 
 
This is a phase IB/II study that will investigate the combination of Ibrutinib with 
GA101 – Obinutuzumab in previously untreated CLL subjects > 65 years of age or 
subjects < 65 years that either refuse to be treated with chemotherapy or that are not 
candidates for treatment with chemotherapy agents. 
 
Treatment will be given up to 6 cycles, each cycle will have duration of 28 days 
(Figure 1 - Appendix 2). 
 
• 
Ibrutinib will be given at 420 mg po daily during the complete study period (6 
cycles) and will continue during the following 3 years until unacceptable toxicity 

 
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or CLL progression in those subjects who respond to treatment. The first dose 
will be delivered in the clinic on Day 1, one to three hours before the GA101 – 
Obinutuzumab infusion, after which the subsequent dosing will be on an 
outpatient basis. 
• 
GA101- Obinutuzumab will be given at 1,000 mg / dose. The first dose given on 
cycle 1 will be split in 2 doses - Day 1 dose of 100mg and Day 2 dose of 900 mg. 
Subsequent doses of GA101 - Obinutuzumab (1,000 mg) will be administered on 
Cycle 1 - Days 8, 15; and on Day 1 of Cycles 2-6 (study days 29, 57, 85, 113, 
141).  
This research study protocol allows the subject to receive up to 8 infusions of 
GA101- Obinutuzumab. Even if the treatment is shown to be of benefit, additional 
infusions of GA101- Obinutuzumab beyond that allowed in the protocol cannot be given 
to the subject while they are participating in this study. 
6. 
STUDY MEDICATIONS 
6.1 
IBRUTINIB  
6.1.1 
Formulation 
Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) 
administration. Pharmacyclics will provide Ibrutinib during the complete study period (6 
cycles) and after cycle 6, during the following 3 years. 
6.1.2 
Dosage and Administration 
Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily with 8 
ounces (approximately 240 mL) of water. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water. Each dose of 
Ibrutinib should be taken approximately at the same time each day. The use of 
CYP3A4/5 inhibitors/inducers, CYP2D6 inhibitors, and grapefruit and Seville oranges 
(due to CYP3A4/5 inhibition) should be avoided for the duration of the study (appendix 
5). 
 
If a dose is missed, it can be taken up to 6 hours after the scheduled time with a 
return to the normal schedule the following day. If the dose is more than 6 hours late, the 
dose should not be taken and the subjects should take the next dose at the scheduled 
time the next day. Missed doses should be recorded by the subjects in the drug diary. 
 
The first dose will be delivered in the clinic on Day 1, one to three hours before 
the GA101 – Obinutuzumab infusion, after which subsequent dosing is typically on an 
outpatient basis. Ibrutinib will be dispensed to subjects in bottles at each visit. Unused 
Ibrutinib dispensed during previous visits must be returned to the site and drug 

 
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accountability records updated at each visit. Returned capsules must not be re-
dispensed to anyone.  
 
After cycle 6, Ibrutinib will be administrated during the following 3 years until 
unacceptable toxicity or CLL progression and will be dispensed in bottles every 3 or 6 
months at each follow-up visit. 
 
6.2 
GA101 - OBINUTUZUMAB 
6.2.1 
Formulation 
GA101 - Obinutuzumab is provided as a single-use vial.  Each vial contains a 
sterile liquid formulation in a 50-mL pharmaceutical-grade glass vial containing a 
nominal dose of 1,000 mg of GA101 - Obinutuzumab (G3 material). The formulated drug 
product consists of 25 mg/mL drug substance formulated in histidine/histidine-HCl, 
trehalose, and poloxamer 188. The vial contains 41 mL (with 2.5% overfill). 
GA101 – Obinutuzumab will be requested to be covered by the insurance as a 
Standard of Care treatment for previously untreated subjects.  
6.2.2 
Storage 
The recommended storage conditions for the GA101-Obinutuzumab drug 
product are between 2°C and 8°C, protected from light.  Chemical and physical in-use 
stability for GA101-Obinutuzumab dilutions in 0.9% sodium chloride (NaCl) at 
concentrations of 0.2 − 20 mg/mL have been demonstrated for 24 hours at 2°C − 8°C 
and an additional 24 hours at ambient temperature and ambient room lighting. The 
prepared diluted product should generally be used immediately.  If not used immediately, 
in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2°C − 8°C unless reconstitution/dilution 
has taken place in controlled and validated aseptic conditions.  GA101 - Obinutuzumab 
should not be frozen or shaken. Mix gently. All transfer procedures require strict 
adherence to aseptic techniques. Do not use an additional in line filter because of 
potential adsorption. 
6.2.3 
Preparation 
Split dosing:  Splitting the first dose of GA101-Obinutuzumab in Cycle 1 is 
mandatory.  The first dose (1,000 mg) must be administered over Days 1 and 2 (100 mg 
on Day 1 and 900 mg on Day 2).   
GA101 - Obinutuzumab drug product intended for IV infusion is prepared by 
dilution of the drug product into an infusion bag containing 0.9% NaCl.  

 
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One vial may be used to prepare both the 100-mg dose (equals 4 mL) and 900-
mg dose (equals 36 mL) following the directions below.  If both bags are prepared at the 
same time, the reconstitution/dilution has to take place in a controlled and validated 
aseptic conditions.  Subsequently store the 900-mg bag for a maximum of 24 hours at 
2°C − 8°C and administer the next day. 
To prepare a 100-mg dose:  The final drug concentration of a 100-mg dose 
should be in the range of 0.4 mg/mL to 4.0 mg/mL. Using a 250-mL infusion bag 
containing 0.9% NaCl withdraw 4 mL of GA101-Obinutuzumab from a single glass vial 
and inject it into the infusion bag (discard any unused portion of GA101-Obinutuzumab 
left in the vial unless reconstitution/dilution has taken place in controlled and validated 
aseptic conditions).  Gently invert the infusion bag to mix the solution.  Do not shake.  
To prepare a 900-mg dose:  The final drug concentration of a 900-mg dose 
should be in the range of 0.4 mg/mL to 4.0 mg/mL.  Using a 250-mL infusion bag 
containing 0.9% NaCl withdraw 36 mL of GA101-Obinutuzumab from a single glass vial 
and inject it into the infusion bag (discard any unused portion of GA101-Obinutuzumab 
left in the vial unless reconstitution/dilution has taken place in controlled and validated 
aseptic conditions).  Gently invert the infusion bag to mix the solution.  Do not shake.  
To prepare a 1,000-mg dose:  The final drug concentration of a 1,000-mg dose 
should be 4 mg/mL.  Using a 250-mL infusion bag containing 0.9% NaCl withdraw 40 mL 
of GA101-Obinutuzumab from a single glass vial and inject it into the infusion bag 
(discard any unused portion of GA101-Obinutuzumab left in the vial). Gently invert the 
infusion bag to mix the solution. Do not shake. 
Administration sets with polyvinyl chloride, polyurethane, or polyethylene as 
product contact surface and IV bags with polyolefin, polypropylene, polyvinyl chloride, or 
polyethylene as product contact surface are compatible and may be used. Use of a port 
or peripherally inserted central catheter line is acceptable. 
Do not use GA101 - Obinutuzumab beyond the expiration date stamped on the 
carton. 
6.2.4 
Dosage and Administration 
GA101 - Obinutuzumab administered by IV infusion for up to 6 cycles (28-day 
cycles): 
• 
On Cycle 1, Day 1, 100 mg GA101-Obinutuzumab will be administered 
• 
On Cycle 1, Day 2, 900 mg of GA101-Obinutuzumab will be administered  

 
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• 
On Cycle 1, Days 8 and 15, 1,000 mg of GA101-Obinutuzumab will be 
administered.  
• 
On Cycles 2 − 6, Day 1, 1,000 mg of GA101-Obinutuzumab will be administered 
(See Table 1). 
GA101 - Obinutuzumab must be administered in a clinical setting (inpatient or 
outpatient).  Full emergency resuscitation facilities should be immediately available, and 
Subjects should be under close supervision by the investigator at all times. GA101-
Obinutuzumab should be given as a slow IV infusion through a dedicated line.  IV 
infusion pumps (such as Braun Infusomat Space) should be used to control the infusion 
rate of GA101-Obinutuzumab. Do not administer as an IV push or bolus. After the end of 
the infusions, the IV line should remain in place for 1 hour + 30 minutes from the end of 
infusion; if no AEs occur after 1 hour + 30 minutes, the IV line may be removed. 
6.2.5 
Premedication Requirements 
Infusion-Related Reactions 
Since some subjects may develop hypersensitivity or other IRRs to GA101 - 
Obinutuzumab, pre-medication is recommended to reduce the risk of infusion reactions 
as outlined below (Figure 2): 
• 
Cycle 1, Days 1 and 2, all subjects require pre-medication with:  
– 
IV glucocorticoid: dexamethasone (20 mg) or methylprednisolone (80 mg) 
administered at least one hour prior to GA101-Obinutuzumab infusion.  
Hydrocortisone should not be used as it has not been effective in reducing rates 
of IRR.  
– 
An 
oral 
acetaminophen 
(975 
mg) 
and 
an 
antihistamine 
such 
as 
diphenhydramine (50 mg) administered at least 30 minutes before starting each 
GA101-Obinutuzumab infusion. 
• 
Cycle 1, Days 8 and 15 and Cycles 2-6, Day 1:  
– 
All subjects require pre-medication with oral acetaminophen (975 mg) 
administered at least 30 minutes before starting each GA101-Obinutuzumab 
infusion. 
– 
Subjects who experience an IRR (Grade 1 or more) with the previous infusion 
will require pre-medication with an antihistamine such as diphenhydramine 
(50 mg) administered at least 30 minutes before starting each subsequent 
GA101-Obinutuzumab infusion. 
– 
Subjects who experience a Grade 3 IRR with the previous infusion or who have 
lymphocyte counts of ≥ 25 × 109/L prior to the next treatment will require pre 
medication 
with 
IV 
glucocorticoid: 
dexamethasone 
(20 
mg) 
or 
methylprednisolone (80 mg) administered at least one hour prior to GA101-

 
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Obinutuzumab infusion.  Hydrocortisone should not be used as it has not been 
effective in reducing rates of IRR.  
Hypotension may be expected to occur during GA101-Obinutuzumab infusions.  
Withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each GA101-Obinutuzumab infusion and for the first hour after 
administration.  Subjects at acute risk of hypertensive crisis should be evaluated for the 
benefits and risks of withholding their hypertensive medication. 
For TLS prophylaxis, see Section 6.2.12 
Figure 2. Recommended Premedication to Reduce Infusion-related 
Reactions. 
 
a  Hydrocortisone is not recommended, as it has not been effective in reducing 
rates of infusion reactions. 
b  Glucocorticoid administration to be completed at least 1 hour prior to GA101 – 
Obinutuzumab infusion. 
c  Acetaminophen and antihistamine at least 30 minutes prior to GA101 - 
Obinutuzumab infusion. 
6.2.6 
Split Dosing 
On Cycle 1, Day 1, 100 mg GA101-Obinutuzumab will be administered.  On 
Cycle 1, Day 2, 900 mg of GA101-Obinutuzumab will be administered.  On Cycle 1, 

 
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Days 8 and 15, and Day 1 of Cycles 2-6, 1,000 mg of GA101-Obinutuzumab will be 
administered (see Table 1). 
Table 1 
GA101 - Obinutuzumab Dosing Schedule 
 
Cycle 
and 
Day 
of 
Administration 
Dose of 
Obinutuzumab 
Rate of Infusion (in the Absence of 
Infusion 
Reactions/ 
Hypersensitivity 
during 
Previous Infusions) 
Cycle 1 
Day 1 
100 mg 
Administer at 25 mg/hour over 4 hours.  Do 
not increase the infusion rate. 
Day 2 
900 mg 
Administer at 50 mg/hour.  The rate of the 
infusion 
can 
be 
escalated 
in 
increments 
of 
50 mg/hour every 30 minutes to a maximum rate of 
400 mg/hour. 
Day 8 
1,000 mg 
Infusions can be started at a rate of 
100 mg/hour 
and 
increased 
by 
100 mg/hour 
increments every 30 minutes to a maximum of 
400 mg/hour. 
Day 15 
1,000 mg 
Cycles 
2−6 
Day 1 
1,000 mg 
 
If a subject experience any grade infusion reaction during infusion, adjust the 
infusion as outlined below: 
• 
Grade 4 (life threatening): Stop infusion and discontinue therapy. 
• 
Grade 3 (severe): Temporarily interrupt infusion and treat symptoms. Upon 
resolution of symptoms, restart infusion at no more than half the previous rate (the 
rate being used at the time that the infusion reaction occurred) and, if subject does 
not experience any infusion reaction symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment dose. 
• 
Grade 1 − 2 (mild to moderate): Reduce infusion rate and treat symptoms.  Upon 
resolution of symptoms, continue infusion and, if subject does not experience any 

 
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infusion reaction symptoms, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment dose. 
 
6.2.7 
Dosage Modification/Toxicity Management 
A number of measures will be taken to ensure the safety of subjects participating 
in this study.  These measures will be addressed through exclusion criteria (see 
Section 4.2) and routine monitoring as follows.   
Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, blood pressure, 
and laboratory measurements. Subjects will be evaluated for AEs (all grades), SAEs, 
and AEs requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study. 
6.2.8 
Assessment of Hematologic Toxicities 
The evaluation of potential treatment-induced toxicity in subjects with advanced 
CLL may be quite difficult and requires careful consideration of both the manifestations 
of the underlying disease, as well as adverse reactions to the therapy under study.  
Some of the conventional criteria for toxicity are not applicable, especially under 
circumstances of progressive bone marrow failure from the CLL itself.  
Dose modifications for hematologic toxicity in subjects with CLL must be made 
with consideration of the increased frequency of hematologic compromise at the 
initiation of therapy.  Therefore, the standard criteria used for solid tumors are difficult to 
be applied directly; many subjects would be considered to have Grade 2 − 4 hematologic 
toxicity at presentation. 
As a consequence, dose modification decisions for subjects with cytopenia 
(below the lower limit of the normal range) at baseline will be based on the International 
Workshop in CLL (IWCLL) guidelines (Hallek et al., 2008). For subjects with a normal 
neutrophil count, platelet count, and/or hemoglobin value at baseline, the NCI CTCAE, 
v4.0, will be used. 
6.2.9 
Administration of Granulocyte Colony-Stimulating Factor 
G-CSF may be administered as primary prophylaxis in each cycle of therapy, as 
per the American Society of Clinical Oncology (ASCO) guidelines or each site’s 
institutional standards. 

 
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6.2.10 
Hepatitis B Virus Reactivation 
Active acute or chronic Hepatitis B (HBV):  Subjects with acute or chronic active 
HBV will be defined based on CDC guidelines (Appendix 1). This will include subjects 
with positive serology for hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb) associated with HBV-DNA positive test by real time quantitative qPCR 
assessment. Subjects who are anti-HBc positive and HBV-DNA test negative, may be 
enrolled in the study and should undergo regular monitoring of HBV viral load using 
HBV-DNA qPCR. Those subjects may be referred to a hepatologist or gastroenterologist 
for appropriate monitoring and management. 
For the subset of subjects who are Hepatitis B viral DNA negative and anti-HBc 
positive and have undetectable Hepatitis B viral DNA levels at screening, Hepatitis B 
viral DNA levels must be followed approximately every 4 weeks. Guidelines for the 
management of hepatitis B reactivation are outlined in Table 2. 
Table 2 
Management of Hepatitis B Reactivation 
Hepatitis B Viral DNA 
Level by Real-Time 
PCR 
 
Guideline 
> 100 IU/mL 
• 
Hold GA101 - Obinutuzumab  
• 
Begin anti-viral medication and treat for at least 1 year 
after the last dose of GA101 - Obinutuzumab. 
• 
Immediately refer the subject to a gastroenterologist or 
hepatologist for management. 
• 
Resume GA101-Obinutuzumab once Hepatitis B viral 
DNA levels decrease to undetectable levels. 
> 100 
IU/mL 
while 
on 
anti-viral 
medication 
Discontinue GA101 - Obinutuzumab. 
29−100 IU/mL 
Retest within 2 weeks. 
If still hepatitis B viral DNA positive: 
• 
Hold GA101 - Obinutuzumab  

 
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• 
Begin anti-viral medication and treat for at least 1 year 
after the last dose of GA101 - Obinutuzumab. 
• 
Immediately refer the subject to a gastroenterologist or 
hepatologist for management 
• 
Resume GA101-Obinutuzumab once Hepatitis B viral 
DNA levels decrease to undetectable levels 
 
6.2.11 
Management of Infusion-Related Reactions and Anaphylaxis 
Please refer to Section 6.4.4 for information relating to concomitant medications.  
Medications (including subcutaneous epinephrine, corticosteroids, and intravenous 
diphenhydramine) and resuscitation equipment should be available for immediate use. 
Life-Threatening Infusion-Related Reactions and Anaphylaxis. 
In the event of a life-threatening IRR (which may include pulmonary or cardiac 
events) or IgE-mediated anaphylactic reaction, GA101-Obinutuzumab should be 
discontinued and no additional GA101-Obinutuzumab should be administered (see 
Table 3). Subjects who experience any of these reactions should receive aggressive 
treatment of symptoms and will be discontinued from study treatment. Subjects will 
continue in follow-up until resolution of reactions or clinical stability. 
Table 3 
Management of Infusion-Related Symptoms 
Infusion-Related 
Symptoms a 
Guidance 
Grades 1−2 
• 
Interrupt or slow the rate of the infusion 
• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume infusion 
rate escalation at the investigator’s discretionc 
 
Grade 3 
• 
Discontinue infusion until resolution of symptoms 

 
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• 
Give supportive treatment b 
• 
Upon symptom resolution, may resume infusion 
rate escalation, at investigator discretion c 
• 
Note:  If the same adverse event recurs with the 
same severity, treatment must be permanently 
discontinued. 
 
Grade 4d 
• 
Discontinue infusion immediately, treat symptoms 
aggressively, and do not restart drug 
a 
Refer to National Cancer Institute Common Terminology Criteria for 
Adverse 
Events, 
v4.0, 
for 
the 
grading 
of 
symptoms 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (Appendix 7) 
b 
Subjects should be treated with acetaminophen and an antihistamine 
such as diphenhydramine if they have not been received these within the previous 4 
hours.  IV saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects 
may require antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or 
equivalent), 
and/or 
bronchodilators. 
For 
hypotension, 
subjects 
may 
require 
vasopressors. 
c 
Upon complete resolution of symptoms, the infusion may be resumed at 
50% of the rate achieved prior to interruption. In the absence of infusion related 
symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 
minutes to a maximum rate of 400 mg/hr. 
d 
Including but not limited to anaphylaxis, acute life-threatening respiratory 
symptoms, or other life-threatening infusion reaction. 
6.2.12 
Prophylaxis Tumor Lysis Syndrome 
All subjects will receive prophylaxis for tumor Lysis syndrome (TLS) in the first 
cycle of treatment and will return to the clinic on day 4 for laboratory assessment in order 
to evaluate the risk for TLS. Diagnosis of TLS and laboratory assessment will be made 
based on the Cairo-Bishop Laboratory definition (Coiffier B et al., 2008) (Appendix 4). 
Prophylaxis for TLS includes: 

 
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• 
Appropriate hydration consisting of a fluid intake of 2- 3 L/day starting 1 to 2 days 
prior to the first dose of GA101 – Obinutuzumab. 
• 
Administration of allopurinol (300 mg/day orally) or a suitable alternative 
treatment starting prior to the first infusion of GA101 - Obinutuzumab (Cycle 1 
Day 1).   
Those subjects with laboratory evidence of TLS will be graded according to the 
NCI-CTCAE grading system (Version 4.0) (Appendix 4) and will return to the clinic on 
the day 4 of the subsequent cycles to continue follow-up of laboratory parameters.  
For subjects with evidence of TLS > Grade 3, GA101 - Obinutuzumab and 
Ibrutinib should be discontinued and the subject treated as clinically indicated.  A dose 
delay of up to 8 weeks is permitted for GA101- Obinutuzumab / Ibrutinib to allow 
recovery of TLS.  Following the complete resolution of TLS complications, Ibrutinib and 
GA101 - Obinutuzumab may be re administered at the full dose during the next infusion 
in conjunction with prophylactic therapy. If the treatment is delayed more than 8 weeks 
because there is no improvement of TLS, treatment will be stopped and the subject will 
continue in follow-up until the beginning of new treatment or death. 
6.3 
DOSE MODIFICATIONS AND DELAYS FOR IBRUTINIB AND GA101 – 
OBINUTUZUMAB 
6.3.1 
Dose Hold, Reduction, or Discontinuation of Ibrutinib 
Treatment with Ibrutinib should be held for any unmanageable, potentially study 
drug-related toxicity that is Grade 3 or higher in severity. Subjects who require 
anticoagulant treatment (eg, heparin and/or warfarin) should have study drug hold until 
stable on anticoagulant therapy. 
 
Ibrutinib may be held for a maximum of 28 consecutive days of toxicity. Ibrutinib 
should be discontinued in the event of a toxicity > Grade 1 lasting > 28 days. 
 
A hematologic AE grading scheme for hematologic toxicity is included in Appendix 3. 
 
The actions in Table 4 should be taken for the following toxicities: 
 
• 
Grade 4 ANC (< 500/μL) for > 7 days (Neutrophil growth factors are permitted 
per ASCO guidelines) (Smith et al., 2006) and use must be recorded in CRF. 
• 
Grade 3 or 4 platelets (< 50,000/μL); or, in subjects with baseline 
thrombocytopenia, a platelet decrease of 50-74% from baseline in presence of 
bleeding. 

 
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• 
Grade 4 Platelets (< 25,000/μL); or, in subjects with baseline thrombocytopenia, 
decrease of > 75% from baseline or < 20,000/μL, whichever is higher. 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy, or any other Grade 4 toxicity and any 
unmanageable Grade 3 toxicity. 
 
Table 4 
Dose modifications or discontinuation actions for Ibrutinib 
 
Occurrence ≥ G3 
AE 
Action 
1st 
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; may restart 
at original dose level 
2nd 
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; restart at 
one dose level lower (280 mg daily) 
3rd 
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; restart at 
one dose level lower (140 mg daily) 
4th 
Discontinue Ibrutinib 
 
6.3.2 
Dose Modifications for Ibrutinib for Hepatic Impaired Subject 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant 
hepatic impairment at the time of screening (Child- Pugh class B or C) are excluded from 
study participation.  
 
Subjects while on study who develop significant clinical and/or laboratory signs 
and/or symptoms of liver dysfunction (e.g., transaminitis, jaundice, etc.) in the opinion of 
the investigator, should be assessed with the Child-Pugh Score (Table 5) to determine a 
dose reduction of Ibrutinib as described in Table 6: 
 
Table 5 
Child-Pugh Score 
The score employs five clinical measures of liver disease. Each measure is 
scored 1–3, with 3 indicating most severe derangement. 
 
Clinical and 
Laboratory 
Criteria 
1 Point 
2 Points 
3 Points 
Hepatic 
encephalopathy 
None 
Mild to moderate 
(grade 1 or 2) 
Severe 
(grade 3 or 4) 
Ascites 
None 
Mild to moderate 
(diuretic 
responsive) 
Severe 
(diuretic 
refractory) 

 
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Total bilirubin 
(mg/dL)  
<2 
2 - 3 
 
>3 
Seum albumin 
(gr/dL) 
>3.5 
2.8 - 3.5 
<2.8 
International 
normalized ratio 
(INR) 
<1.7 
1.7 - 2.3 
>2.3 
Child-Turcotte-Pugh Class obtained by adding score for each parameter (total 
points) 
Class A = 5 – 6 points (mild liver disease) 
Class B = 7 – 9 points (moderate liver disease) 
Class C = 10 – 15 points (severe liver disease) 
 
Table 6 
Dose Modifications for Ibrutinib for Hepatic Impaired Subjects 
 
Child-Pugh Class 
Points 
Dose Reduction for 
Ibrutinib 
A 
5 – 6 
280 mg (two capsules) 
B 
7 – 9 
140 mg (one capsule) 
C 
10 – 15 
Hold Ibrutinib until 
resolved to moderate 
impairment (Child-Pugh 
class B) or better 
Monitor subjects for signs of toxicity and follow dose modification guidance as 
needed. 
 
6.3.3 
Ibrutinib Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose that meet any Serious Adverse 
Event criterion must be reported as a Serious Adverse Event in the appropriate time 
frame and documented as clinical sequelae to an overdose.  
 
There is no specific experience in the management of ibrutinib overdose in 
subjects. No maximum tolerated dose (MTD) was reached in the Phase 1 study in which 
subjects received up to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed 
to up to single dose of 1,680 mg. One healthy subject experienced reversible Grade 4 
hepatic enzyme increases (AST and ALT) after a dose of 1,680 mg. Subjects who 
ingested more than the recommended dosage should be closely monitored and given 
appropriate supportive treatment. Refer to Section 11.4.3.8 for further information 
regarding special reporting situations as a result of overdose 

 
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Dose Modifications and delays for GA101 – Obinutuzumab 
Splitting the first dose of GA101 – Obinutuzumab in Cycle 1 is mandatory. The 
first dose (1,000 mg) must be administered over Days 1 and 2 (100 mg on Day 1 and 
900 mg on Day 2). Infusions should be interrupted or slowed if subjects experience 
infusion reactions (see Section 6.2.11). If a planned dose of GA101 - Obinutuzumab is 
missed, it should be administered as soon as possible and the next cycle should begin 
28 days later.  Do not wait until the next planned dose. 
No reduction in the dose of GA101 - Obinutuzumab is allowed. A dose delay of 
up to 8 weeks is permitted for GA101 - Obinutuzumab to allow recovery of hematologic 
toxicities to < Grade 2 or non-hematologic toxicities to Grade 1 or baseline level. If the 
treatment is delayed for more than 8 weeks because there is no improvement of 
cytopenia to < Grade 2, treatment under this protocol will be discontinued and the 
subject will continue in follow-up until the beginning of new treatment or death. 
If a subject experiences grade 3 or 4 cytopenia, the guidelines for GA101 – 
Obinutuzumab and Ibrutinib dose-delay are outlined in Table 7: 
 
Table 7   Dose Modification for Cytopenias 
Grade 
GA101 - Obinutuzumab 
Ibrutinib 
Grade 3 or 4 
cytopeniaa, c 
Delay dose for a maximum of 8 
weeks. 
If improvement to < Grade 2b, 
administer full dose. 
If delay more than 8 weeks 
because 
there 
is 
no 
improvement of cytopenia < 
Grade 
3, 
subject 
will 
be 
withdrawn 
from 
the 
study 
treatment but will continue in 
follow-up until the beginning of 
new treatment or death. 
Hold Ibrutinib until recovery to Grade 
< 1b; restart Ibrutinib at 420 mg daily. 
For subjects with recurrent episodes 
of grade 3 - 4 AEs a dose 
modification action is described in 
table 4 (see section 6.3.1). 
Ibrutinib may be held for a maximum 
of 28 consecutive days of toxicity. 
Ibrutinib should be discontinued in 
the event of a toxicity lasting > 28 
days 
and 
the 
subject 
will 
be 
withdrawn from the study treatment 
but will continue in follow-up until the 
beginning of new treatment, death or 
assessment of TFS and OS. 

 
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Grade 1 or 2 
cytopeniaa, c 
No dose reduction or delay 
No dose reduction.  
a  In subjects with cytopenia at baseline, dose modifications will be based on 
the IWCLL Guidelines for hematological toxicity in CLL studies (Hallek et al., 2008). For 
subjects with a normal neutrophil count, platelet count, and/or hemoglobin value at 
baseline, the NCI-CTCAE v4.0 grading system will be used.  
b 
Or baseline. 
c Subjects with cytopenia at baseline should have hemoglobin > 8 g/dL, platelets 
count > 40 x103/mm3 and absolute neutrophil count (ANC) > 1.0 × 109 cells/L in order to 
proceed with the study treatment. Transfusion and Growth factors will be permitted and 
must be documented in the medical chart. 
6.4 
CONCOMITANT, 
EXCLUDED 
THERAPIES 
AND 
DRUG-DRUG 
INTERACTIONS 
6.4.1 
Permitted Concomitant Medications 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a subject between the 14 days preceding the study entry 
evaluation and the early study treatment termination visit/study treatment completion 
visit.  All concomitant medications should be reported to the investigator and recorded 
on the appropriate electronic Case Report Form (eCRF). 
Supportive medications in accordance with standard practice (such as for 
emesis, diarrhea, etc.) are permitted.  Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) or red blood cell growth factors (erythropoietin) is permitted per 
institutional policy and in accordance with the ASCO guidelines (Smith et al., 2006).  
Transfusions may be given in accordance with institutional policy.  
Short courses (≤14 days) of steroid treatment for non-cancer related medical 
reasons (eg, joint inflammation, asthma exacerbation, rash, antiemetic use and infusion 
reactions) at doses that do not exceed 100mg per day of prednisone or equivalent are 
permitted. 
The following may be considered: localized hormonal or bone sparing treatment 
for non-B-cell malignancies, and localized radiotherapy for medical conditions other than 
the underlying B-cell malignancies.   
Treatment for autoimmune cytopenias are permitted for <14 days at doses that 
do not exceed 100 mg per day of prednisone or equivalent. 

 
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6.4.2 
Medications to be used with Caution 
6.4.2.1 
CYP3A- Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib and drugs 
that strongly or moderately inhibit CYP3A can increase ibrutinib exposure and therefore 
strong CYP3A inhibitors should be avoided. 
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, 
and posaconazole) must be used, reduce ibrutinib to 140 mg for the duration of 
the inhibitor use or withhold ibrutinib treatment temporarily (for 7 days or less). 
Subjects should be monitored for signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, fluconazole, voriconazole, erythromycin, 
amprenavir, 
aprepitant, 
atazanavir, 
ciprofloxacin, 
crizotinib, 
diltiazem, 
fosamprenavir, imatinib, verapamil, amiodarone, and dronedarone) is indicated, 
reduce ibrutinib dose to 140 mg for the duration of the inhibitor use. 
• 
No dose adjustment is required in combination with mild inhibitors.  
• 
Avoid grapefruit and Seville oranges during ibrutinib treatment as these contain 
moderate inhibitors of CYP3A (see Section 6.1.2). 
 
Avoid concomitant use of systemic strong CYP3A inducers (eg, carbamazepine, 
rifampin, phenytoin, and St. John’s Wort). Consider alternative agents with less 
CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in appendix 5. For further 
information, please refer to the current version of the IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-
table/. This website is continually revised and should be checked frequently for updates. 
 
6.4.2.2 
Drugs That May Have Their Plasma Concentrations Altered by 
Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), 
but is a mild inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have 
systemic drug-drug interactions with P-gp substrates. However, it cannot be excluded 
that ibrutinib could inhibit intestinal P-gp after a therapeutic dose. There is no clinical 
data available; therefore, co-administration of narrow therapeutic index P-gp substrates 
(eg, digoxin) with ibrutinib may increase their blood concentration and should be used 
with caution and monitored closely for toxicity. 
6.4.2.3 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; 
periodic ECG and electrolyte monitoring should be considered.  

 
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6.4.2.4 
Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly with 
Ibrutinib. Supplements such as fish oil and vitamin E preparations should be avoided.  
Use Ibrutinib with caution in subjects requiring other anticoagulants or medications that 
inhibit platelet function. Subjects with congenital bleeding diathesis have not been 
studied.  Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending 
upon the type of surgery and the risk of bleeding (see Section 6.5). 
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than 
warfarin or a vitamin K antagonist) during the course of the study should have treatment 
with ibrutinib/ placebo held, the sponsor’s medical monitor should be contacted, and 
ibrutinib/placebo should not be restarted until the subject is clinically stable and the re-
initiation of ibrutinib/placebo is approved by the sponsor’s medical monitor. Subjects 
should be observed closely for signs and symptoms of bleeding.  No dose reduction is 
required when study drug is restarted. 
6.4.3 
Prohibited Concomitant Medications 
Any 
chemotherapy, 
anticancer 
immunotherapy, 
experimental 
therapy, 
radiotherapy or live viral vaccines are prohibited while the subject is receiving ibrutinib 
treatment.   
Corticosteroids for the treatment of an underlying disease are prohibited.  
Corticosteroids for the treatment of non-cancer related reasons for longer than 14 days 
and/or at doses >100mg of prednisone or its equivalent are prohibited.   
Erythropoietic growth factors (eg, erythropoietin) and neutrophil growth factors (eg, 
filgrastim and peg-filgrastim) are also prohibited during (eg, initial treatment, DLT 
assessment period). 
6.4.4 
Concomitant Therapy during the study treatment 
Subjects who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  Effective contraception is required while 
receiving Ibrutinib in combination with GA101 - Obinutuzumab. For women of 
childbearing potential and men, effective contraception is required while receiving 
GA101 – Obinutuzumab and for 365 days (12 months) after the last dose of the study 
drug. 
All subjects will receive allopurinol 300mg by mouth daily for 3 days prior to and 
during the first cycle of treatment. Allopurinol will be continued for the first cycle until the 
investigator determines there is no longer a concern for hyperuricemia. Subjects allergic 
to allopurinol will not receive allopurinol. 

 
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All subjects will receive premedication with glucocorticoid, acetaminophen and 
diphenhydramine prior to each dose of GA101 – Obinutuzumab as described in section 
6.2.5. 
Anti-viral prophylaxis will be given to subjects with CLL during treatment and for 
up to 2 months after completion of treatment.   
Prophylactic antibiotics to prevent the recurrence of an infection diagnosed 
during treatment may be instituted for any subject if clinically indicated.  
6.5 
GUIDELINES FOR IBRUTINIB MANAGEMENT WITH SURGERIES OR 
PROCEDURE 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The 
following guidance should be applied to the use of ibrutinib in the perioperative period for 
subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib:   
6.5.1 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, 
thoracentesis, or paracentesis) ibrutinib should be held for at least 3 days prior to the 
procedure and should not be restarted for at least 3 days after the procedure. For bone 
marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary 
to hold ibrutinib for these procedures.   
6.5.2 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, 
ibrutinib should be held at least 7 days prior to the intervention and should be held at 
least 7 days after the procedure and restarted at the discretion of the investigator when 
the surgical site is reasonably healed without serosanguineous drainage or the need for 
drainage tubes.   
6.5.3 
Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
7. 
CRITERIA FOR SUBJECT DISCONTINUATION 
Subjects will remain on study for three years after completion of the last cycle of 
treatment or until they have progressive disease requiring further treatment or death.  
Subjects who meet the following criteria should be discontinued from the study: 

 
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• 
HBV Reactivation that is not responding to appropriate management and antiviral 
therapy as described in section 6.2.10, or subjects with evidence of HBV 
associated hepatitis with LFT abnormalities. Subjects who are carriers of 
hepatitis B at the time of discontinuation from study treatment will continue to be 
followed for clinical and laboratory signs of active HBV infection and for signs of 
hepatitis. 
• 
Severe or life-threatening anaphylaxis or hypersensitivity reaction 
• 
Progressive Disease: Subjects with PD will discontinue the study treatment but 
will continue in follow-up until the beginning of new treatment or death.  
• 
Severe life threatening reactions to GA101 – Obinutuzumab or Ibrutinib 
administration.  
• 
Medical Prudence/Non-Compliance: The Principal Investigator may remove a 
subject from study any time deemed medically prudent to do so to assure the 
subject’s health and welfare. A subject will also be removed from study to 
preserve the integrity of the investigation. The latter includes incidents in which 
the subject frequently misses study appointments needed to accurately assess 
response/adverse reactions, or is non-compliant with study directions provided 
by the investigator or study personnel. “Inevaluable” subjects will be replaced to 
meet target accrual. 
8. 
CRITERIA FOR STUDY DISCONTINUATION 
The study will be discontinued due to the following reasons: 
• 
Lack of meeting statistical end point after Stage I accrual. See section 10.3. 
• 
Excessive toxicity of the regimen with > 1 subject death that is considered related 
to the study medications.  
9. 
CLINICAL AND LABORATORY EVALUATIONS 
9.1 
EVALUATIONS PRETREATMENT  
9.1.1 
Study Entry 
Subjects who are interested in participating in this research will have the protocol 
explained to them by the principal investigator / co-principal investigators or one of the 
study coordinators. Potential subjects will be given the opportunity to review the 
informed consent form and have their questions/concerns addressed. After this, if the 

 
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subject chooses to enter the study, a screening date will be arranged by one of the study 
coordinators.  
9.1.2 
Screening 
Screening for this study will occur after the subject has signed the approved 
informed consent form and received a copy of the “Experimental Subject’s Bill of Rights."  
Screening labs, diagnostic tests, and physical examination will be performed four weeks 
prior to beginning treatment. Subjects who do not meet the criteria for study after 
screening will be excluded and will be considered non-evaluable and therefore replaced 
to meet the proposed accrual. 
9.1.2.1 
Screening History and Physical Examination 
• 
Complete medical and surgical history; AND 
• 
Record current medications and past medical history including history of 
previous treatments for CLL; AND 
• 
Record transfusion (PRBC and platelets) and supportive care (IVIG) 
history; AND 
• 
Record history of infections (frequency, severity, treatment); AND 
• 
Physical exam including vital signs (T, P, R, BP); AND 
• 
Measure and record lymph node, spleen, and liver size; AND 
• 
Determine performance status (ECOG) and tumor assessment 
9.1.2.2 
Screening Laboratory Tests  
(To be performed within 28 days prior to treatment start date) 
• 
HBsAg, HbsAb, HBcAb (IgG, IgM), HAAb and Hepatitis CAb. (If HBcAb is 
positive an HBV-DNA viral load qPCR test will be performed) 
• 
HIV serology 
• 
CBC, differential, platelet count, PT, PTT, INR; AND 
• 
comprehensive metabolic panel including: Total bilirubin, AST (SGOT), 
ALT (SGPT), alkaline phosphatase, albumin, creatinine, BUN, total protein, fasting blood 
glucose, calcium, sodium, potassium, chloride, HCO3, phosphorus, LDH and uric acid; 
AND 

 
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• 
Beta-2 microglobulin AND 
• 
Quantitative immunoglobulin levels (IgG, IgA, IgM) AND 
• 
Immunophenotyping of blood mononuclear cells: CD3, CD4, CD5, CD8, 
CD19, CD20. 
• 
Absolute T cell count including CD3+, CD4+, and CD8+ populations; AND 
• 
Serum Pregnancy Test (HcG levels) for FCBP (females of child bearing 
potential)  
9.1.2.3 
Screening Diagnostic Tests 
• 
CT scan or MRI of the chest, abdomen and pelvis will be performed in 
order to assess disease status and confirm Rai stage. Images will be performed within 
28 days of treatment initiation. 
• 
Electrocardiogram (EKG) (within 3 months of treatment start) will be 
performed as clinically indicated, and the investigator will perform an overall 
interpretation. 
• 
Unilateral (minimum) bone marrow aspirate and biopsy for flow cytometry 
and histologic staining (within 90 days of treatment start) to assess leukemia cell 
infiltration and leukemia cell immunophenotype  
• 
FISH and interphase cytogenetics will be performed on all subjects prior 
to therapy to assess for subjects with common and high-risk CLL genetic abnormalities 
within 3 months of treatment start 
• 
Assessment of leukemia cell expression of ZAP-70, CD38 and mutational 
status of IgVH (performed at anytime prior to therapy) 
9.1.2.4 
Pretreatment Cumulative Illness Rating Scale (CIRS) 
The 
Cumulative 
Illness 
Rating 
Scale 
(CIRS) 
(http://eforms.moffitt.org/cirsgScore.aspx) will be assessed prior to therapy or may be 
scored retroactively based on clinic notes and laboratory assessments (Appendix 6) in 
order to meet the Inclusion criteria for participation in the study (See section 4.1). 
9.1.2.5 
Research Studies  
Correlatives Studies will be performed at Dr. Kipps laboratory at different time 
points during the course of cycle #1 in all subjects.  
 

 
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About 40 ml of blood will be collected into BD Vacutainer® Cell Preparation 
Tubes (CPT) on days 1, 2 and 8 of cycle #1 to perform pharmacodynamics studies 
including but not limited to the following: 
• 
Assessment of the chemokine and cytokine profile using plasma samples from 
the subjects and correlation of the results with the presence of Infusion-Related 
Reactions (IRRs). 
   
9.2 
EVALUATIONS DURING STUDY TREATMENT & FOLLOW UP 
• 
Physical examination including vital signs, performance status, lymph 
node, spleen, and liver measurements, adverse event assessment, concurrent 
medications, and transfusion requirements will be recorded prior to each new cycle. 
• 
CBC with differential, platelets, complete metabolic panel with uric acid, 
LDH, albumin, creatinine, BUN, total protein, calcium, sodium, potassium, chloride, 
phosphorus and HCO3 will be performed during the following dates of treatment and 
follow up.  
- Cycle 1 – Day 1,2,4 
- Cycle 1 – Day 8, 15, 22 
- Cycle 2 to 5- Day 1, 8, 15, 22 
- Cycle 6 - Day 1, 8, 15, 22, 28 
- Two months after completion of therapy – Response assessment 
evaluation.  
- After response assessment every 3 months for 9 months.  
- Every 6 months until initiation of new treatment for CLL, consent 
withdrawal or death. 
• 
All subjects will return to the clinic on day 4 of cycle #1 for laboratory 
assessment in order to evaluate the risk for TLS. Those subjects with laboratory 
evidence of TLS will return to the clinic on the day 4 of the subsequent cycles to 
continue follow-up of laboratory parameters.  
• 
Absolute T cell count including CD3+, CD4+, and CD8+ populations will 
be performed on the following dates: 
- At screening or on day 1 of Cycle 1. 

 
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- Two months after completion of therapy – Response assessment 
evaluation.  
- End of study  
• 
Pregnancy monitoring for women of child bearing potential before each 
dose of GA101 – Obinutuzumab (not required more than once monthly). 
9.3 
EVALUATION OF RESPONSE TO TREATMENT  
The response assessment will be performed at 2 months after completion of 
study treatment in order to satisfy IWCLL criteria. This evaluation will include the 
following: 
• 
Physical examination including vital signs, lymph node, spleen and liver 
measurements, 
performance 
status, 
adverse 
event 
assessment, 
concurrent 
medications, and recording of transfusion of blood products; AND  
• 
Liver chemistries: (ALT, AST, total bilirubin and alkaline phosphatase) 
• 
CBC with differential, platelet count, complete chemistry panel with uric 
acid, LDH, albumin, creatinine, BUN, total protein, fasting blood glucose, calcium, 
sodium, potassium, chloride, phosphorus and HCO3. 
• 
Beta-2 microglobulin, and quantitative immunoglobulin levels (IgG, IgA, 
IgM); AND  
• 
Absolute T cell count including CD3+, CD4+, and CD8+ populations 
(frequency should be consistent with standard of care evaluations). 
• 
Chest, abdominal and pelvic CT scan or MRI to assess response.  
• 
Unilateral bone marrow aspirate and biopsy will be performed using 
multiparameter (4 colors) flow cytometry and histologic staining. 
• 
FISH and interphase cytogenetics. 
• 
Serum Pregnancy Test (hCG levels) for FCBP (females of child bearing 
potential).  

 
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9.4 
EVALUATIONS EVERY 3 MONTHS FOR NINE MONTHS AFTER 
RESPONSE ASSESSMENT 
After the response assessment (at 2 months after completion of study treatment), 
the initial follow-up evaluations will be made every 3 months during 9 months. These 
evaluations will include the following: 
• 
Physical examination including vital signs, lymph node, spleen and liver 
measurements, performance status, adverse event assessment, current medications, 
and recording of transfusion of blood products. 
• 
Liver chemistries: (ALT, AST, total bilirubin and Alkaline phosphatase) 
• 
CBC with differential, platelet count, complete metabolic panel with uric 
acid, LDH, albumin, creatinine, BUN, total protein, fasting blood glucose, calcium, 
sodium, potassium, chloride, phosphorus and HCO3.   
• 
Beta-2 microglobulin, and quantitative immunoglobulin levels (IgG, IgA, 
IgM). Continue monitoring of quantitative immunoglobulins (IgG, IgA, and IgM) for up to 
2 years after completion of therapy or until they return to baseline.  
• 
Pregnancy monitoring for women of child bearing potential should 
continue with every follow-up evaluation until 12 months following the last dose of 
GA101 – Obinutuzumab. 
• 
Chest, abdominal and pelvic CT scan or MRI in those subjects with 
clinical or laboratory alterations that suggest disease progression based on IWCLL 
criteria.  
• 
For subjects that maintain a CR, a MRD assessment in peripheral blood 
using multiparameter (4 colors) flow cytometry will be performed at 6 and 12 months in 
order to assess MRD. 
 
9.5 
EVALUATION EVERY 6 MONTHS UNTIL PROGRESSION OR 
WITHDRAWAL FROM THE STUDY 
Long-term follow-up will continue every 6 months until initiation of new treatment, 
consent withdrawal from the study or death, whichever occurs first. These evaluations 
will include the following  
• 
Physical examination including vital signs, lymph node, spleen and liver 
measurements, performance status, adverse event assessment, current medications, 
and recording of transfusion of blood products. 

 
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• 
Liver chemistries: (ALT, AST, total bilirubin and Alkaline phosphatase) 
• 
CBC with differential, platelet count, complete metabolic panel with uric 
acid, LDH, albumin, creatinine, BUN, total protein, fasting blood glucose, calcium, 
sodium, potassium, chloride, phosphorus and HCO3.  
Beta-2 microglobulin, quantitative immunoglobulin levels (IgG, IgA, IgM). 
Continue monitoring of quantitative immunoglobulins (IgG, IgA, and IgM) for up to 2 
years after completion of therapy or until they return to baseline. 
• 
Pregnancy monitoring for women of child bearing potential should 
continue with every follow-up evaluation until 12 months following the last dose of 
GA101 – Obinutuzumab. 
• 
Chest, abdominal and pelvic CT scan or MRI in those subjects with 
clinical or laboratory alterations that suggest disease progression based on IWCLL 
criteria.  
• 
For subjects that maintain a CR (based on clinical and hematological 
assessments), additional CT scans of the chest, abdomen and pelvis will be performed 
after 3 years of completion of study treatment in order to assess response based on 
clinic and radiologic parameters, and discuss the possibility of Ibrutinib discontinuation. 
• 
For subjects that maintain a CR (based on clinical and hematological 
assessments), an additional bone marrow biopsy and aspirate will be performed after 3 
years of completion of study treatment in order to assess MRD and discuss the 
possibility of Ibrutinib discontinuation.  
 
9.6 
EVALUATIONS AT THE END OF STUDY  
An evaluation within 30 days of the end of study will be performed. End of study 
is defined as initiation of new treatment for CLL or withdrawal of consent. This evaluation 
will include the following:  
• 
Physical examination including vital signs, lymph node, spleen and liver 
measurements, 
performance 
status, 
adverse 
event 
assessment, 
concurrent 
medications, and recording of transfusion of blood products; AND: 
• 
Liver chemistries: (ALT, AST, total bilirubin and alkaline phosphatase) 
• 
CBC with differential, platelet count, and complete metabolic panel with 
uric acid, LDH, albumin, creatinine, BUN, total protein, fasting blood glucose, calcium, 
sodium, potassium, chloride, phosphorus and HCO3.  

 
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• 
Beta-2 microglobulin, and quantitative immunoglobulin levels (IgG, IgA, 
IgM).  
• 
Absolute T cell count including CD3+, CD4+, and CD8+ populations. 
• 
Chest, abdominal and pelvic CT scan or MRI in order to confirm CR base 
don IWCLL criteria in subjects that meet clinical and laboratory parameter for CR.  
• 
Unilateral bone marrow aspirate and biopsy will be performed to confirm 
CR (MRD assessment) using multiparameter (4 colors) flow cytometry and histologic 
staining. 
• 
FISH and interphase cytogenetics. 
• 
Serum Pregnancy Test (hCG levels) for FCBP (females of child bearing 
potential).  
10. 
STATISTICAL CONSIDERATIONS AND RATIONALE 
10.1 
STATISTICAL MODEL 
For this open-label study, descriptive statistics will be calculated for demographic 
and baseline characteristics, clinical response variables, immunologic variables and 
safety data. Each phase of this study will be analyzed separately. All tables, figures and 
listings will therefore be separated by study phase. 
10.1.1 
Demographic and Background Characteristics 
The study population will be described in terms of general and background 
characteristics using usual statistics as mean, median, standard deviation and range for 
continuous variables and frequencies for categorical variables. Study conduct will also 
be evaluated by an accurate description of protocol deviations, treatment administration 
and study completion status. 
10.1.2 
Laboratory Variables 
The normal ranges of the local laboratory, including those for liver enzymes, will 
be used as the normal ranges for the respective subject. All laboratory data will be 
converted in the International System of Units (SI units) for the analysis, with the 
exception of the liver enzyme values. For the liver enzymes ALT and AST, the unit U/L 
will be used. The NCI-CTCAE v4.0 grading system will be used for assessing laboratory 
abnormalities. 
 

 
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10.1.3 
Concomitant Medications 
The use of concomitant medications will be recorded at each visit and described 
using descriptive statistics. 
 
10.1.4 
Estimated Time to Complete Enrollment 
The estimated time of accrual of the total number of subjects is 24 months. 
 
10.1.5 
Data Analysis 
The complete analysis of all study data will be contained in the clinical study 
report at the end of the study. 
 
10.2 
STATISTICAL CONSIDERATIONS FOR THE PHASE IB  
The primary objective of the Phase Ib of this clinical study is to evaluate the 
safety, tolerability and DLT of Ibrutinib in combination with GA101 - Obinutuzumab.  
10.2.1 
Subject Evaluability for the Phase Ib  
The first 6 subjects who receive at least one dose of Ibrutinib and/or GA101 – 
Obinutuzumab will be considered evaluable for safety, tolerability and DLTs. 
 
10.2.2 
Safety Analysis 
All subjects who have at least one dose of Ibrutinib and/or one infusion of GA101 
– Obinutuzumab, and a safety follow-up, whether withdrawn prematurely or not, will be 
included in the safety analysis. 
 
10.2.3 
Clinical Adverse Events 
All adverse events, including unrelated adverse events, will be listed and graded 
according to the NCI-CTCAE grading system (Version 4.0) (Appendix 7). The proportion 
of subjects with treatment-related adverse events, overall, and by body system, will be 
tabulated. In addition, subjects with treatment-related adverse events, SAEs, and 
adverse events leading to withdrawal will be listed overall and, if appropriate, 
distributions by body system will be provided. 
10.2.4 
Definition of Dose Limiting Toxicity (DLT)  
Dose limiting toxicity (DLT) is defined as any of the adverse events (AEs) noted 
below that are considered by the investigator to be possibly related or related to Ibrutinib 
/ GA101 - Obinutuzumab treatment. For the purpose of defining DLTs, AE will be 
tabulated and assessed based on the signs and symptoms present during the first cycle 
of treatment (Day 1 - 28). Toxicity will be graded according to the NCI-Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix 7) except for 
hematological toxicities that will be graded according to the IWCLL guidelines (Hallek et 

 
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al., 2008) (Appendix 3) For subjects with a normal neutrophil count, platelet count, 
and/or hemoglobin value at baseline, the NCI-CTCAE v4.0 grading system will be used. 
Dose limiting toxicity will include possibly related or related events that are Grade 
> 3 that do not resolve to Grade < 1within 14 days of initiation despite appropriate 
medical management.  The following exceptions will apply:  
• Non Hematologic:  
- 
> Grade 3 nausea, vomiting, or diarrhea only if uncontrolled by maximal 
antiemetic/antidiarrheal therapy.  
• Hematologic:  
Hematologic toxicity will be graded according to the IWCLL guidelines (Hallek et 
al., 2008) - (Appendix 3), with dose-limiting hematologic toxicity defined as follows:  
- 
> Grade 4 granulocytopenia lasting > 14 days. Note that per IWCLL 
guidelines, subjects are evaluable for toxicity related to granulocytopenia 
only if the pre-treatment ANC is >1.0 x109/L.  
- 
> Grade 4 thrombocytopenia lasting > 14 days or thrombocytopenia 
associated with bleeding. Note that per IWCLL guidelines, subjects are 
evaluable for toxicity related to thrombocytopenia only if the pre-treatment 
platelet count is >20,000/µL.  
• 
Grade > 3 infusion-related reactions to GA101 – Obinutuzumab will be 
considered DLTs under the following circumstances: 
- 
If subjects experience Grade 3 infusion-related reactions at re-challenge 
despite appropriate medical management that leads to permanently 
discontinue GA101 – Obinutuzumab.  
- 
Any Grade 4 infusion reactions, including but not limited to anaphylaxis, 
acute life-threatening respiratory symptoms, or other life-threatening 
infusion reaction.   
10.2.5 
Dose Escalation / De-escalation Based on AE - DLT 
Dose modifications or discontinuation actions for Ibrutinib are described in table 4 
(see section 6.3.1). No dose escalation or de-escalation will occur for GA101 – 
Obinutuzumab. If a subject experiences grade 3 or 4 cytopenia, the guidelines for 
Ibrutinib and GA101 – Obinutuzumab dose-delay are outlined in table 7 (Section 6.3.4). 
 

 
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10.2.6 
Statistical Operating Characteristics of the Phase IB 
The phase IB will be performed as a safety run-in with the first 6 subjects 
enrolled in the study. The sample size of 6 subjects is considered to be sufficient to 
support preliminary safety, tolerability and DLTs assessments (Goede et al., 2013). On 
this group of subjects, we will evaluate safety, tolerability and dose-limiting toxicities 
(DLTs) during the first cycle of treatment (4 weeks; Day 1 - 28),  
Subjects will be enrolled at least one week apart to avoid overlapping time of 
observation during the first week of treatment when infusion reactions are expected to 
be higher.  
• If 0 to 1 DLTs (See DLT definition – Section 10.2.4) are observed in the first 3 
subjects, we will proceed to enroll 3 additional subjects.  
• If 0 to 1 DLTs are observed in the first 6 subjects, we will proceed to the phase 
II of the study.  
• If > 2 DLTs are observed, we will hold enrollment and revise the study design 
with the sponsor. 
 
The table below gives the characteristics of this procedure. For a range of 
underlying dose limiting toxicity rates, the probability that the study will be stopped 
during the Phase IB (i.e. the probability that there are two or more DLT’s within the first 
six subjects) and the expected number of DLT’s are computed.  
Table 8     Operating Characteristics of the Phase IB Procedure 
Toxicity Rate 
Probability of Halting 
Expected # Toxicities 
5% 
3.3% 
0.3 
10% 
11.4% 
0.59 
15% 
22.4% 
0.87 
20% 
34.5% 
1.14 
25% 
46.6% 
1.38 
30% 
58% 
1.61 
35% 
68.1% 
1.8 
40% 
76.7% 
1.98 
45% 
83.6% 
2.13 
50% 
89.1% 
2.25 
 
Thus, when the DLT rate is as high as 30%, the probability of stopping the trials 
will be at least 58%.  Conversely, if the DLT rate is no more than 10%, then the 
chance of stopping the trials during this phase is at most 11.4%. 

 
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10.3 
STATISTICAL CONSIDERATIONS FOR THE PHASE II 
The primary objective of the phase II stage of this clinical trial is to evaluate the 
overall response rate (partial responses + complete responses) in CLL subjects treated 
with Ibrutinib in combination with GA101 – Obinutuzumab. 
All subjects who receive at least one dose of Ibrutinib and/or GA101 – 
Obinutuzumab will be considered evaluable for safety, tolerability and DLT.  
10.3.1 
Clinical and Laboratory Variables 
Clinical and laboratory test will be tabulated after subjects have completed 
treatment under protocol. 
10.3.2 
Efficacy Population 
The Efficacy Population includes all subjects who receive at least one dose of 
study drug and have baseline and at least one post-baseline efficacy assessment. 
10.3.3 
Efficacy Analysis 
Response assessment will be performed by physical examination, CT scan 
evaluation and bone marrow biopsy/aspirate at completion of therapy using the 
International Workshop in CLL Guidelines (IWCLL) (Hallek et al., 2008) (See section 
3.2.2). The ORR will be estimated with an exact 95% confidence interval (CI) for the 
combination regimen of Ibrutinib/GA101 – Obinutuzumab. 
Median PFS, TFS and OS, and their 95% CI will be estimated using the Kaplan-
Meier method. 
10.3.4 
Statistical Operating Characteristics of the Phase II 
The sample size calculation has been made using a comparative overall 
response with GA101 – Obinutuzumab in combination with chlorambucil, which is a 
standard of care regimen for previously untreated CLL subjects. This combination 
regimen can induce an overall response rate (ORR) of 78% in CLL subjects (Goede et 
al., 2014). For the purpose of our sample calculation we will use a true ORR of 78% that 
will be tested against an alternative of 94%, which corresponds to the expected ORR 
that can be achieved when GA101 – Obinutuzumab is administered in combination with 
Ibrutinib.  
 
There is no data available using the combination of Ibrutinib and GA101 - 
Obinutuzumab, therefore we will use as a point of reference for the expected ORR, the 
recently published data of Ibrutinib in combination with Rituximab in relapse/refractory 
CLL subjects. In this publication the ORR was in the 90 – 95% range (Burger et al., 
2013). 
 

 
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Our sample size calculation will use an ORR endpoint comparison based on the 
ORR achieved with the Ibrutinib and GA101 - Obinutuzumab combination. We 
hypothesize that Ibrutinib in combination with GA101 – Obinutuzumab would induce an 
ORR of 94%, which is 16% higher than the ORR observed in the study published by 
Goede et al. (Goede et al., 2014) 
 
Based on this, we will use a Simon's two-stage optimal design in this study 
(Simon, 1989). The null hypothesis that the true overall response rate is 78% will be 
tested against a one-sided alternative. In the first stage, 10 subjects will be accrued. If 
there are 8 or fewer responses in these 10 subjects, the study will be stopped. 
Otherwise, 22 additional subjects will be accrued for a total of 32. The null hypothesis 
will be rejected if 29 or more responses are observed in 32 subjects. This design yields a 
type I error rate of 5% and power of 80% when the true response rate is 94%. 
10.4 
REPLACEMENT OF SUBJECTS 
For the safety run-in, subjects will be replaced if they withdraw from the study 
prior to day 28 of the first cycle for any reason other than withdrawal due to toxicity, 
progressive disease (PD) or death. 
 
In the phase II, up to 3 subjects will be allowed to be replaced if they have not 
completed treatment response assessment and, if they withdraw from the study for any 
reason other than toxicity, progressive disease (PD) or death. 
10.5 
TRIAL STOPPING AND HOLDING RULES BASED ON DLT AND LACK 
OF EFFICACY  
The trial will be stopped or put on hold and the data will be reviewed with the 
sponsor for any of the following reasons: 
• 
If there is ≥ 1 deaths that are considered to be related or possibly related to the 
study medications or procedures related to this clinical trial.  
• 
If the efficacy endpoint is not reached at the end of treatment of the Stage I 
subjects based on Simon II Stage design (Section 10.3.4).  
• 
If > 2 DLTs are observed in the first 6 subjects treated under the phase IB study, 
we will hold enrollment and revise the study design with the sponsor (Section 
10.2.6).  
• 
If the study is put on hold, the decisions regarding continuation of treatment for 
any subjects who have already received therapy will be made on a case-by-case 
basis after discussion with the subject and the principal investigator. All subjects 
will be re-consented.  

 
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• 
All subjects who were on treatment at the time study-stopping criteria were met 
will continue to be followed by the principal investigator for safety until the end of 
the study. 
 
10.6 
PLANNED EFFICACY EVALUATIONS 
• 
Phase IB: We will evaluate AE and determine DLTs as described in Section 
10.2.  
• 
Phase II: All treated subjects will undergo evaluation for response to treatment 2 
months after completion of study treatment. Evaluation tests will include CT / MRI 
of the chest, abdomen and pelvis, CMP, CBC, LDH, bone marrow biopsy 
including immunohistochemistry for pathology analysis, FISH and chromosome 
analysis as well as multiparameter (4 colors) flow cytometry for MRD analysis.  
10.7 
PRIMARY EFFICACY VARIABLES 
• 
Phase Ib: AE that constitute DLT.  
• 
Phase II: Response assessment based on IWCLL (Hallek et al., 2008). 
10.8 
SECONDARY EFFICACY VARIABLES 
• 
PFS, TFS and OS. Clinical parameters that will be measured from initiation of 
treatment until occurrence of the event.  
• 
MRD measured by multiparameter (4 colors) flow cytometry. 
11. 
REPORTING OF ADVERSE EVENTS 
11.1 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and reporting AEs and SAEs that 
are considered related to GA101 – Obinutuzumab and Ibrutinib, all events of death, and 
any study specific issue of concern. 
 
Timely, accurate, and complete reporting and analysis of safety information from 
clinical studies are crucial for the protection of subjects, investigators, and the sponsor, 
and are mandated by regulatory agencies worldwide. The sponsor has established 
Standard Operating Procedures in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of safety information; all clinical studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures. 

 
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11.2 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of an investigational study drug, whether or not 
considered related to the study drug (ICH-E2A, 1995). 
For the purposes of this clinical study, AEs include events which are either new 
or represent detectable exacerbations of pre-existing conditions. 
Disease progression is not an adverse event; rather it may be the cause of an 
adverse event. As an example, “worsening of underlying disease” or the clinical 
diagnosis that is associated with disease progression must be reported as all other 
adverse events. The term “Disease progression” should never be used as an adverse 
event term. 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or 
observed by the Investigator or study staff including laboratory abnormalities of 
clinical significance. 
• 
Any AEs experienced by the subject through the completion of final study 
procedures. 
• 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
CLL/SLL that were not present before the AE reporting period  
• 
Complications that occur as a result of protocol-mandated interventions (eg, 
invasive procedures such as biopsies). 
The following are NOT considered AEs: 
• 
Pre-existing condition: A pre-existing condition (documented on the medical 
history CRF) is not considered an AE unless the severity, frequency, or character 
of the event worsens during the study period. 
 
• 
Pre-planned or elective hospitalization: A hospitalization planned before 
signing the informed consent form is not considered an SAE, but rather a 
therapeutic intervention.  However, if during the pre-planned hospitalization an 
event occurs, which prolongs the hospitalization or meets any other SAE criteria, 
the event will be considered an SAE.  Surgeries or interventions that were under 
consideration, but not performed before enrollment in the study, will not be 

 
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considered serious if they are performed after enrollment in the study for a 
condition that has not changed from its baseline level.  Elective hospitalizations 
for social reasons, solely for the administration of chemotherapy, or due to long 
travel distances are also not SAEs. 
 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be 
reported as AEs or SAEs, but rather the cause for the test or procedure should be 
reported. 
 
• 
Asymptomatic Treatment Related Lymphocytosis: This event should also not 
be considered an AE. Subjects with treatment-related lymphocytosis should 
remain on study treatment and continue with all study-related procedures. 
11.2.1 
Serious Adverse Events 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance 
for Medicinal Products for Human Use is any untoward medical occurrence that at any 
dose: 
• 
Results in death (ie, the AE actually causes or leads to death). 
• 
Is life-threatening.  Life-threatening is defined as an AE in which the subject was 
at risk of death at the time of the event.  It does not refer to an event which 
hypothetically might have caused death if it were more severe.  If either the 
Investigator or the Sponsor believes that an AE meets the definition of life-
threatening, it will be considered life-threatening. 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing 
hospitalization. 
• 
Results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject 
or subject may require intervention to prevent one of the other outcomes listed in 
this definition.  Examples of such events are intensive treatment in an emergency 
department or at home for allergic bronchospasm, blood dyscrasias, or convulsion 
that does not result in hospitalization; or development of drug dependency or drug 
abuse. 
Given that the Investigator’s perspective may be informed by having actually 
observed the event, and the Sponsor is likely to have broader knowledge of the drug and 

 
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its effects to inform its evaluation of the significance of the event, if either the Sponsor or 
the Investigator believes that the event is serious, the event will be considered serious. 
11.2.2 
Severity Criteria 
Definitions found in the Common Terminology Criteria for Adverse Events 
version 4.03 (CTCAE v4.03) will be used for grading the severity (intensity) of AEs. 
Refer to appendix 3 for the grading of hematologic AEs. The CTCAE v4.0 displays 
Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE.  
Should a subjects experience any AE not listed in the CTCAE v4.03, the following 
grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of 
inconvenience or concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic drug 
therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject 
to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death. 
11.2.3 
Causality (Attribution) 
The Investigator is to assess the causal relation (ie, whether there is a 
reasonable possibility that the study drug caused the event) using the following 
definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal 
sequence cannot be established with the onset of the AE and 
administration of the investigational product; or, a causal 
relationship is considered biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates 
that a relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of 
the AE and administration of the investigational product, but 
the AE could also be attributed to concurrent or underlying 
disease, or the use of other drugs or procedures.  Possibly 
related should be used when the investigational product is one 
of several biologically plausible AE causes. 

 
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Related: 
The AE is clearly related to use of the investigational product. 
 
11.2.4 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's 
Brochure/package insert or is not listed at the specificity or severity that has been 
observed.  For example, hepatic necrosis would be “unexpected” (by virtue of greater 
severity) if the Investigator's Brochure referred only to elevated hepatic enzymes or 
hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be 
“unexpected” (by virtue of greater specificity) if the Investigator's Brochure/package 
insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs that are 
mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the study drug under investigation. 
 
11.3 
DOCUMENTING AND REPORTING OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS BY INVESTIGATORS.  
The investigator is responsible for ensuring that all AEs and SAEs, that are 
observed or reported during the study, are collected and reported to the U.S. Food and 
Drug Administration (FDA), appropriate IRB(s), and Pharmacyclics. in accordance with 
CFR 312.32 (IND Safety Reports).  
11.3.1 
Assessment of Adverse Events 
Investigators will assess the occurrence of adverse events and serious adverse 
events at all subject evaluation timepoints during the study. All adverse events and 
serious adverse events whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically 
significant laboratory test, or other means, will be recorded. Each recorded adverse 
event or serious adverse event will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria (if applicable), suspected relationship to the 
investigational product, and any actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
Yes, 
There is a plausible temporal relationship between the onset of the AE and 
administration of the study treatment, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the study treatment; and/or the AE abates or 

 
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resolves upon discontinuation of the study treatment or dose reduction and, if applicable, 
reappears upon re-challenge. 
No, 
Evidence exists that the AE has an etiology other than the study treatment (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to study treatment 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected AEs are those AEs that are listed or characterized in the Package 
Insert or current Investigator Brochure.  
Unexpected AEs are those not listed in the Package Insert (P.I.) or current 
Investigator’s Brochure or not identified.  This includes AEs for which the specificity or 
severity is not consistent with the description in the P.I. or Investigator’s Brochure.  For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or 
Investigator’s Brochure only referred to elevated hepatic enzymes or hepatitis. 
11.3.2 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be captured from the time signed 
and dated ICF is obtained until 30 days following the last dose of study drug.  
Serious adverse events reported after 30 days following the last dose of study 
drug should also be reported if considered related to study drug. Resolution information 
after 30 days should be provided.  
Progressive disease should NOT be reported as an event term, but instead 
symptoms/clinical signs of disease progression may be reported. 
All adverse events, regardless of seriousness, severity, or presumed relationship 
to study drug, must be recorded using medical terminology in the source document. All 
records will need to capture the details of the duration and the severity of each episode, 
the action taken with respect to the study drug, investigator’s evaluation of its 
relationship to the study drug, and the event outcome. Whenever possible, diagnoses 
should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection").  
All deaths should be reported with the primary cause of death as the AE term, as 
death is typically the outcome of the event, not the event itself.  

 
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If a death occurs within 30 days after the last dose of study drug, the death must 
be reported as a serious adverse event.  
11.3.3 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of 
standard safety monitoring activities. These events (regardless of seriousness) will be 
reported to Pharmacyclics Drug Safety per the SAE reporting timelines.   
• 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*.  
• 
Any treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any 
grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as 
Grade 3 or higher AE per CTCAE. 
Events meeting the definition of major hemorrhage will be captured as an event of 
special interest. 
 
• 
Intracranial Hemorrhage 
Any 
intracranial 
hemorrhage 
adverse 
event, 
including 
subdural 
hematoma/hemorrhage, epidural hematoma/hemorrhage, and intracerebral hemorrhage, 
of any grade severity, will be captured as an event of special interest. 
• 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid 
pregnancy. However, should a pregnancy occur in a female study subject, consent to 
provide follow-up information regarding the outcome of the pregnancy and the health of 
the infant until 30 days old will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant 
from the time of consent to 90 days after the last dose of study drug. A male subject 
must immediately inform the Investigator if his partner becomes pregnant from the time 
of consent to 3 months after the last dose of study drug. Any female subjects receiving 
study drug(s) who become pregnant must immediately discontinue study drug. The 

 
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Investigator should counsel the subject, discussing any risks of continuing the pregnancy 
and any possible effects on the fetus.   
Although pregnancy itself is not regarded as an adverse event, the outcome will 
need to be documented. Any pregnancy occurring in a subject or subject’s partner from 
the time of consent to 30 days after the last dose of study drug must be reported. Any 
occurrence of pregnancy must be reported to Pharmacyclics Drug Safety, or designee, 
per SAE reporting timelines. All pregnancies will be followed for outcome, which is 
defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus. 
Pregnancies with an outcome of live birth, the newborn infant will be followed until 30 
days old by completing will need to be reported to Pharmacyclics per SAE reporting 
timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a 
serious adverse event. 
• 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall survival. 
11.3.4 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be 
reported on FDA Medwatch (Form 3500A) (Appendix 8) or Suspect Adverse Event 
Report (CIOMS Form 1) IRB Reporting Form and sent via email or fax to Pharmacyclics 
Drug Safety, or designee, within 15 days of the event. Pharmacyclics may request 
follow-up and other additional information from the Sponsor Investigator.  
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors 
unrelated to                                                                                                                                           
study conduct 

 
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• 
It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow up 
after demonstration of due diligence with follow-up efforts) 
11.3.5 
Reporting to Regulatory Agencies: 
It is the responsibility of the Investigator and the research team to ensure that 
serious adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices (GCP), the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 
11.4 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS  
11.4.1 
Procedures 
11.4.1.1 
All Adverse Events 
All subjects who receive treatment will be considered evaluable for toxicity. All 
adverse events (with the exception of disease progression) and special reporting 
situations, whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until 30 days following the last dose of study drug.  Serious 
adverse events reported after 30 days following the last dose of study drug should also 
be reported if considered related to study drug. Resolution information after 30 days 
should be provided.  All Grade 3 or Grade 4 adverse events considered related to study 
drug must be followed until recovery to baseline or Grade ≤1. Progressive disease 
should NOT be reported as an adverse event, but instead symptoms/clinical signs of 
disease progression may be reported. Otherwise, all events that meet the definition of a 
serious adverse event will be reported as serious adverse events, regardless of whether 
they are protocol-specific assessments. 
All adverse events, regardless of seriousness, severity, or presumed relationship 
to study drug, must be recorded using medical terminology in the source document. All 
records will need to capture the details of the duration and the severity of each episode, 
the action taken with respect to the study drug, investigator’s evaluation of its 
relationship to the study drug, and the event outcome. Whenever possible, diagnoses 
should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse 
event management must be recorded in the source document and reported according to 
sponsor instructions. 

 
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11.4.2 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time-points 
should be adopted.  Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last 
here?”  
11.4.3 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs.  Avoid colloquialisms and abbreviations. 
11.4.3.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, it is acceptable to report the information that is currently 
available.  If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
11.4.3.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 12.2.1), regardless of attribution, will be reported to the appropriate parties.  
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
11.4.3.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  
Such conditions should be reported as medical and surgical history. A preexisting 
medical condition should be re-assessed throughout the trial and reported as an AE or 
SAE only if the frequency, severity, or character of the condition worsens during the 
study. When reporting such events, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
11.4.3.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical or 

 
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surgical procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study. 
11.4.3.5 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject 
has completed or discontinued study participation if attributed to prior Ibrutinib and/or  
GA101 - Obinutuzumab exposure. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived offspring of 
a female subject who participated in the study, this should be reported as an SAE.  
11.4.3.6 
Safety Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Pharmacyclics and 
the Sponsor will agree to the reconciliation periodicity and format, but agree at minimum 
to exchange monthly line listings of cases received by the other party.  If discrepancies 
are identified, the Sponsor and Pharmacyclics will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution. 
11.4.3.7 
Adverse Events of Special Interest (AESIs) 
AEs of special interest (AESIs) are defined as a potential safety problem, 
identified as a result of safety monitoring of the Product  
The following AEs are considered of special interest and must be reported to the 
Sponsor expeditiously (see Section 12.3.2.9 for reporting instructions) irrespective of 
regulatory seriousness criteria:  
• 
TLS (all grades) 
• 
Serious infections 

 
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• 
Serious neutropenia 
• 
Serious infusion related reactions 
• 
Hepatitis B reactivation  
11.4.3.8 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
 
• 
Overdose of a study drug 
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to a study drug 
• 
Medication error involving a product (with or without subject exposure to 
the study drug, eg, name confusion). 
 
Special reporting situations should be recorded in the CRF. Any special reporting 
situation that meets the criteria of a serious adverse event should be recorded on the 
serious adverse event page of the CRF. 
 
11.4.3.9 
Prohibitions and Restrictions 
The following guidance should be applied during the perioperative period for 
subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib: 
• 
For any surgery or invasive procedure requiring sutures or staples for 
closure, Ibrutinib should be held at least 7 days prior to the intervention and 
should be held at least 7 days after the procedure, and restarted at the discretion 
of the investigator when the surgical site is reasonably healed without 
serosanguineous drainage or the need for drainage tubes. 
• 
For minor procedures (such as a central line placement, needle biopsy, 
thoracentesis, or paracentesis) ibrutinib should be held for at least 3 days prior to 
the procedure and should not be restarted for at least 3 days after the procedure. 

 
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For bone marrow biopsies that are performed while the subject is on ibrutinib, it is 
not necessary to hold ibrutinib for these procedures. 
• 
For emergency procedures, ibrutinib should be held after the procedure 
until the surgical site is reasonably healed, for at least 7 days after the urgent 
surgical procedure. 
11.4.4 
Adverse Event Reporting to Pharmacyclics 
The investigator must report all SAEs to Pharmacyclics within the timelines 
specified below. In addition, any protocol specified adverse event reporting requirements 
should be adhered to, including any Adverse Events of Special Interest ("AESI"). 
 
All SAE notifications must be sent to Pharmacyclics via email or fax to the 
following Pharmacyclics Drug Safety Contact Information: 
 
Email: AEintakeCT@pcyc.com 
 
US Fax: 1-408-215-3500 
 
Reporting timeframe: 
The Investigator must report all serious unexpected and suspected adverse 
reaction to Pharmacyclics in parallel to the applicable regulatory agency submissions. 
The notifications to Pharmacyclics will include a cover letter detailing the status of the 
submission to applicable regulatory agency along with submission date. 
 
The Investigator must report all other SAEs and AESIs not meeting the 7 day/15 
day regulatory reporting requirements stated above, to Pharmacyclics as soon as 
possible but no later than 15 calendar days from the Investigator’s first awareness date. 
 
Reporting form: The investigator must report such SAEs using the standard FDA 
Medwatch (Form 3500A) (Appendix 8), Suspect Adverse Reaction Report (CIOMS Form 
1) or IRB Reporting Form. 
 
11.4.4.1 
Additional reporting requirements to Pharmacyclics include the 
following: 
Any reports of pregnancy following the start of administration with Ibrutinib and 
within the follow-up period (for female subjects within one year after the last dose of 

 
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Ibrutinib or the partner of a male subject within three months of completing therapy) will 
be transmitted to Pharmacyclics within 24 hours of the Awareness Date.  
All non-serious AEs originating from the study will be forwarded to 
Pharmacyclics:  
• 
Quarterly after Ibrutinib registration 
Note: Investigators should also report events to their IRB as required. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate subject demographic and suspect 
medication information, the report should include the following information within the 
Event Description (item 5) of the MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each 
investigational product and suspect medication 
11.4.4.2 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of 
the following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-
up 
• 
Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e., D.O.B. initial, subject number), protocol description and number, 
if assigned, brief AE description, and notation that additional or follow-up information is 
being submitted (The subject identifiers are important so that the new information is 
added to the correct initial report) 
Occasionally Pharmacyclics may contact the reporter for additional information, 
clarification, or current status of the subject for whom and AE was reported. For 

 
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questions regarding SAE reporting, you may contact the Pharmacyclics Drug Safety 
representative noted above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Pharmacyclics Drug Safety as soon as it becomes 
available and/or upon request. 
MedWatch 
3500A 
(Mandatory 
Reporting) 
form 
is 
available 
at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm. 
11.4.5 
Data Safety and Monitoring Board (DSMB) 
A Data Safety Monitoring Board (DSMB) will review the safety data once the 
study is opened. Summary reports will be submitted to the DSMB as indicated below: 
 
- After completion of Phase IB and prior to initiation of the Phase II.  
- After the enrollment of the first 10 subjects in the Phase II, i.e., at the point at 
which the decision is made to proceed, or not, to the enrollment of the second 
10 subjects. 
 
The summary reports will be written in a standard DSMB report format and will 
be prepared by the study statistician. 
 
11.5 
STUDY CLOSE-OUT 
Any study report should be submitted to Pharmacyclics. This includes all IND 
annual reports (If applicable) and the Clinical Study Report (final study report).  
Additionally, any literature articles that are a result of the study should be sent to 
Pharmacyclics.   
12. 
RETENTION OF RECORDS 
The ICH Guideline for GCP (see Section 4.9 of the guideline) require that records 
and documents pertaining to the conduct of clinical trials and the distribution of 
investigational drug, subject records, consent forms, laboratory test results, and 
medication inventory records, must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product. All state and local 
laws for retention of records also apply.  
13. 
PROTOCOL AMENDMENTS 
Per the IST Agreement, any amendments to the Protocol or Informed Consent 
Form protocol must be sent to Pharmacyclics for review and approval prior to 
submission to the IRB. Written verification of IRB approval will be obtained before any 
amendment is implemented. 

 
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14. 
PUBLICATION OF STUDY RESULTS 
Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a 
copy of a planned publication (abstract, poster, oral presentation or manuscript) prior to 
the submission thereof for publication or disclosure. Pharmacyclics may provide 
scientific comments and suggestions understanding that the Investigator has sole 
editorial responsibility, and retains the authority to make the final determination on 
whether or not to incorporate Pharmacyclics comments or requests for additional 
information. 
15. 
STUDY DISCONTINUATION 
Per the IST Contract, the Investigator reserves the right to terminate the study at 
any time. Should this be necessary, both the Investigator will arrange discontinuation 
procedures in partnership with Pharmacyclics. In terminating the study, the Investigator 
will assure that adequate consideration is given to the protection of the subjects’ 
interests.  Pharmacyclics may terminate the study for reasons including, but not limited 
to: evidence that the PI or an involved investigator is unqualified to conduct research or 
fulfill sponsor responsibilities (e.g., is listed on a debarment or ineligible investigator list); 
failure to meet timelines or achieve agreed upon milestones; a known or perceived risk 
to subject well-being is identified; or breach of contract. Additional grounds for 
termination are outlined in the IST Agreement. 
 
 

 
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16. 
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in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk 
Lymphoma, 49, 49-56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 1 
CDC Guideline for Interpretation of 
Hepatitis B Serology Test Results 
 
 
 

 
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Appendix 2 
Study Flowchart 
Schedule of Events
Treatment Course
Screening
Visit Number
1
2
3
4
5
6
7
8
9
Day of the cycle
Day 1
Day  2
Day 3
Day 4v
Day 8
Day 15
Day 22
Day 28
Day 1
Day  2
Day 3
Day 4v
Day 8
Day 15
Day 22
Day 28w
Visit window
≤28 days prior to visit 2
±3d
±1d
±1d
±1d
±1d
±1d
±1d
±1d
±3d
±1d
±1d
±1d
±1d
±1d
±1d
±1d
Informed Consent
X
Enrollment Criteria
X
Infectious disease screeninga
X
Medical and CLL history
X
MD PE/VS/Ht and Wt
X
X
X
Nurse Encounter (Infusion Center)
X
X
X
Lymph node and organ examination
X
X
X
RAI stageb
X
X
X
Constitutional Symptoms
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
CBC/Differential/platelets
X
X
X
X
X
X
X
X
X
X
X
X
X
Absolute T cell countc
Xd
PT/PTT/INR
X
Comprehensive Chemistry Panele
X
X
X
X
X
X
X
X
X
X
X
X
X
Electorcardiogramf
X
CT, MRI or PET Scang
X
Adverse Events Screen
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
Obinutuzumab administration (Infusion Center)
X
X
X
X
X
Ibrutinib Dispensingj
X
X
Bone marrow aspirate and biopsy
Xk
MRD assessment in prheripheral blood (Flow cytometry)
Quantitative inmunoglobulinsp
X
β2-microglobulin
X
Cytogenetics/FISHq
X
Full inmunophenotypingr
X
Pregnancy tests
X
X
CLL Prognostic Factors/Correlatives/Data Analysis (Castro's Lab)
Sample Collection/Processing
X
X
X
ZAP-70 Flow Cytometryu
X
VH Immunoglobulin gene mutationr
X
Data Analysis and Statistics
Treatment Period
Cycle 1
Cycle 2 - 6
 

 
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Schedule of Events
Treatment Course
Study Response 
Assessment
End of Study
At 2 months after completion 
of study treatment
Every 3 months for 9 months (after 
response assessment) follow by 
every 6 months until initiation of new 
treatment for CLL, consent 
withdrawal or death.
At 3 years after 
completion of 
study treatment
The evaluation of the end of 
study will be performed 
(within 30 days) due to 
initiation of new treatment for 
CLL or consent withdrawal.
Visit Number
Day of the cycle
Visit window
Informed Consent
Enrollment Criteria
Infectious disease screeninga
Medical and CLL history
MD PE/VS/Ht and Wt
X
X
X
Nurse Encounter (Infusion Center)
Lymph node and organ examination
X
X
X
RAI stageb
X
X
X
Constitutional Symptoms
X
X
X
ECOG Performance Status
X
X
X
CBC/Differential/platelets
X
X
X
Absolute T cell countc
X
X
PT/PTT/INR
Comprehensive Chemistry Panele
X
X
X
Electorcardiogramf
CT, MRI or PET Scang
X
Xh
Xi
X
Adverse Events Screen
X
X
X
Concomitant Medication
X
X
X
Obinutuzumab administration (Infusion Center)
Ibrutinib Dispensingj
X
Bone marrow aspirate and biopsy
Xl
Xm
Xn
MRD assessment in prheripheral blood (Flow cytometry)
Xo
Quantitative inmunoglobulinsp
X
X
X
β2-microglobulin
X
X
X
Cytogenetics/FISHq
X
X
Full inmunophenotypingr
Pregnancy tests
X
Xt
X
CLL Prognostic Factors/Correlatives/Data Analysis (Castro's Lab)
Sample Collection/Processing
ZAP-70 Flow Cytometryu
VH Immunoglobulin gene mutationr
Data Analysis and Statistics
X
X
X
Long Term Follow Up (LTFU)
 

 
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a. HIV-1/2, HAAb, HBsAg, HBsAb, HBcAb (IgG, IgM), HCVAb. (If HBcAb is positive, a HBV-DNA viral load qPCR test will be performed). 
b. RAI staging system includes detailed assessment of liver, spleen, lymph nodes and hematologic laboratories (Hb, Hto and platelets). 
c. Including CD3+, CD4+, and CD8+ populations 
d.  Or on day 1 of cycle 1 
e. Comprehensive Chemistry panel (CMP) that include: ALT, AST, LDH, alkaline phosphatase, total bilirubin, BUN, albumin, creatinine, uric acid, total 
protein, glucose, calcium, sodium, potassium, chloride, HCO3, phosphorus. 
f. 
As clinically indicated. 
g. Of the chest, abdomen and pelvis. 
h. CT, MRI or PET scan in those subjects with clinical or laboratory alterations that suggest disease progression based on IWCLL criteria. 
i. 
For subjects that maintain a CR, we will perform additional CT scans of the chest, abdomen and pelvis after 3 years of completion of study treatment 
in order to assess response based on clinic and radiologic parameters, and discuss the possibility of Ibrutinib discontinuation. 
j. 
Pills will be dispensed to subjects at each monthly visit during the 6 cycles and later, every 3 months during the follow up period. Subjects take 420 mg 
po daily. 
k. Within 90 days of treatment initiation. 
l. 
A unilateral bone marrow biopsy and aspirate will be performed using multiparameter (4 colors) flow cytometry and histologic staining at 2 months after 
completion of study treatment (response assessment) in order to satisfy the IWCLL criteria. 
m. For subjects that maintain a CR, we will perform an additional bone marrow biopsy and aspirate after 3 years of completion of study treatment in order 
to assess MRD and discuss the possibility of Ibrutinib discontinuation.  
n. A unilateral bone marrow biopsy and aspirate will be performed to confirm CR (MRD assessment) using multiparameter (4 colors) flow cytometry and 
histologic staining at the end of study in subjects that meet clinical and laboratory parameters for CR in order to satisfy the IWCLL criteria. 
o. For subjects that maintain a CR, we will perform a MRD assessment in peripheral blood using multiparameter (4 colors) flow cytometry at 6 and 12 
months in order to assess MRD. 
p. IgG, IgA, IgM. 
q. FISH Panel to include 11p, 13q, 17p analysis. 
r. 
Full immunophenotyping of blood mononuclear cells: CD3, 4, 5, 8, 19, 20. 
s. Serum βhCG monthly in women child bearing age. 
t. 
During 12 months after the last dose of GA101 – Obinutuzumab. 
u. Performed at any time prior to therapy. 

 
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v. All subjects will return to the clinic on day 4 of cycle #1 for laboratory assessment in order to evaluate the risk for TLS. The laboratory assessment will 
be made based on the Cairo-Bishop Laboratory definition (Coiffier B et al., 2008) (Appendix 4). Those subjects with laboratory evidence of TLS will 
return to the clinic on the day 4 of the subsequent cycles to continue follow-up of laboratory parameters. 
w. Visit at last day of the study treatment (Day 28, Cycle #6). 

 
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Appendix 3 
IWCLL Guideline for Grading Scale for Hematological 
Toxicity in CLL Studies 
 
 
 
 
 
 
 
 
 

 
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Appendix 4 
Cairo-Bishop Clinical Grading and Laboratory 
Definition of Tumor Lysis Syndrome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 5 
Inhibitors or Inducers of CYP3A4/5 
 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 6 
Cumulative Illness Rating Scale-Geriatric (CIRS 
Score) 
 
http://eforms.moffitt.org/cirsgScore.aspx 
 

 
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Appendix 7 
Current NCI Common Terminology Criteria for 
Adverse Events (CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 8 
FDA MedWatch 3500 Form 
 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm149236.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 9 
Safety Reporting Fax Cover Sheet 
 
PHARMACYCLICS SUPPORTED RESEARCH 
AE/SAE FAX No:   
Alternate Fax No:   
 
Page 1 of ___ 
Pharmacyclics 
Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/ 
/ 
 
 
                 dd / mmm / yyyy 
Follow-up Report Date 
 
 
/ 
/ 
 
 
                 dd / mmm / yyyy 
Subject 
Initials 
(Please enter a 
dash if the subject 
has 
no 
middle 
name) 
____ - ____ -____ 
 
SAE or Safety Reporting questions, contact Pharmacyclics Safety:   
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET.