Conditions: Richter Syndrome
Keywords: leukemia richter
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
This research study studies the combination of ibrutinib and obinutuzumab with or without the standard chemotherapy regimen of CHOP to see how well these drugs work in treating patients with a diagnosis of Richter's Transformation or Richter's Syndrome. The Bruton's Tyrosine Kinase (BTK) inhibitor, ibrutinib, may stop growth of cancer cells by blocking the signal needed for cell growth. The monoclonal antibody obinutuzumab may block cancer growth by targeting cells present in Richter's Transformation. Giving ibrutinib with obinutuzumab may be a better treatment for patients with Richter's Transformation. Depending on fitness, the patients may receive ibrutinib and obinutuzumab in combination with a regimen known as CHOP (C= cyclophosphamide, H= hydroxydaunorubicin (also called doxorubicin), O= oncovin (also called vincristine, and P= prednisolone or prednisone (corticosteroids).

Detailed description:

Arms:
arm 1: ibrutinib and obinutuzumab in combination with the CHOP regimen arm 2: ibrutinib and obinutuzumab

Interventions: intervention 1: Obinutuzumab intervention 2: Ibrutinib intervention 3: CHOP
Intervention descriptions: intervention 1: 100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2-6 intervention 2: 560mg po daily intervention 3: cyclophosphamide, doxorubicin, vincristine, and prednisone

Protocol document:
Prot_SAP_000.pdf: 
Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
Page 1 
 
NCT03145480 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
Page 2 
IST PROTOCOL 
 
 
TITLE: 
Two-arm phase II trial exploring the use of the targeted agents 
ibrutinib and obinutuzumab for the treatment of patients with a 
diagnosis of Richter’s Transformation (RT) or Richter’s Syndrome 
(RS) 
PROTOCOL NUMBER: 
 20016 
STUDY DRUG: 
Ibrutinib (PCI-32765), Obinutuzumab (GA101)  
INVESTIGATOR 
SPONSOR: 
 
Jacqueline Barrientos, MD 
DATE FINAL: 
DATE AMENDED #1: 
April 03, 2017 
21-Jun-2018 
 
 
 
 
 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
Page 3 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................7 
LIST OF IN-TEXT TABLES AND FIGURES ...........................................................................7 
SYNOPSIS ......................................................................................................................................8 
ABBREVIATIONS ......................................................................................................................15 
1. 
BACKGROUND ...................................................................................................................16 
1.1. 
Disease/Histology ..............................................................................................................16 
1.1.1. 
Treatment Options .......................................................................................................18 
1.1.2. 
Role of BTK in Disease/Histology ..............................................................................19 
1.2. 
Investigational Product Name and Description .................................................................19 
1.3. 
Summary of Nonclinical Data ...........................................................................................20 
1.3.1. 
Pharmacology ..............................................................................................................21 
1.3.2. 
Toxicology ...................................................................................................................21 
1.3.2.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................21 
1.4. 
Summary of Clinical Data .................................................................................................22 
1.4.1. 
Pharmacokinetics and Product Metabolism .................................................................22 
1.5. 
Summary of Clinical Safety ...............................................................................................23 
1.5.1. 
Risks .............................................................................................................................25 
1.5.2. 
Bleeding-related events ................................................................................................25 
1.5.3. 
Atrial Fibrillation .........................................................................................................25 
1.5.4. 
Cytopenias....................................................................................................................25 
1.5.5. 
Diarrhea........................................................................................................................26 
1.5.6. 
Infections......................................................................................................................26 
1.5.7. 
Non-Melanoma Skin Cancer........................................................................................26 
1.5.8. 
Rash..............................................................................................................................26 
1.5.9. 
Lymphocytosis and Leukostasis ..................................................................................26 
1.5.9.1. 
Tumor Lysis Syndrome..........................................................................................27 
1.5.9.2. 
Interstitial Lung Disease (ILD) ..............................................................................27 
1.6. 
Obinutuzumab Background ...............................................................................................28 
1.6.1. 
Structure and Mechanism of Action of Obinutuzumab ...............................................28 
1.6.2. 
Clinical Experience with Obinutuzumab .....................................................................28 
1.6.2.1. 
Tolerability and Efficacy of Obinutuzumab in Chronic Lymphocytic Leukemia .28 
1.6.3. 
Overview of Safety of Obinutuzumab .........................................................................32 
1.6.4. 
Risks Associated with Obinutuzumab Therapy ...........................................................35 
1.6.4.1. 
Hepatitis B Virus Reactivation ..............................................................................35 
1.6.4.2. 
Progressive Multifocal Leukoencephalopathy .......................................................36 
1.6.4.3. 
Infusion-Related Reactions ....................................................................................36 
1.6.4.4. 
Tumor Lysis Syndrome..........................................................................................36 
1.6.4.5. 
Infection .................................................................................................................37 
1.6.4.6. 
Neutropenia ............................................................................................................37 
1.6.4.7. 
Thrombocytopenia .................................................................................................37 
1.6.5. 
Summary of Pharmacokinetic and Pharmacodynamic Data for Obinutuzumab .........37 
1.7 
Overview of Safety of CHOP ............................................................................................38 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
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Risks and side effects related to Cyclophosphamide include: .......................................................38 
(Table Version Date: May 28, 2013) .............................................................................................38 
Risks and side effects related to Doxorubicin include: ..................................................................39 
(Table Version Date: October 24, 2013)........................................................................................39 
Risks and side effects related to Vincristine include: ....................................................................40 
(Table Version Date: May 28, 2013) .............................................................................................40 
Risks and side effects related to Prednisone include: ....................................................................41 
(Table Version Date: June 24, 2013) .............................................................................................41 
REPRODUCTIVE RISKS: .........................................................................................................41 
1.8. 
Study Rationale ..................................................................................................................42 
2. 
STUDY OBJECTIVE ...........................................................................................................43 
2.1. 
Primary Objective ..............................................................................................................43 
2.2. 
Secondary Objectives.........................................................................................................43 
2.3. 
Exploratory Objective(s) ....................................................................................................43 
3. 
STUDY DESIGN AND TREATMENT ..............................................................................44 
3.1. 
Overview of Study Design .................................................................................................44 
3.1.1. 
Study Schema and Design Overview ...........................................................................45 
3.2. 
Study Design Rationale......................................................................................................45 
4. 
SUBJECT SELECTION ......................................................................................................47 
4.1. 
Inclusion Criteria ...............................................................................................................47 
4.2. 
Exclusion Criteria ..............................................................................................................48 
5. 
TREATMENT OF SUBJECTS ...........................................................................................50 
5.1. 
Study treatment ..................................................................................................................50 
5.2. 
Study Medication ...............................................................................................................50 
5.2.1. 
Ibrutinib........................................................................................................................50 
5.2.1.1. 
Dose and Administration .......................................................................................51 
5.2.1.2. 
Overdose ................................................................................................................51 
5.2.1.3. 
Dose Modification for Adverse Reactions .............................................................51 
5.2.2. 
Obinutuzumab ..............................................................................................................53 
5.2.3. 
Obinutuzumab ..............................................................................................................53 
5.2.3.1. 
Formulation ............................................................................................................53 
5.2.3.2. 
Storage ...................................................................................................................53 
5.2.4. 
Dosage and Administration..........................................................................................54 
5.2.4.1. 
Premedication Requirements .................................................................................55 
5.2.4.2. 
Obinutuzumab Dosing ...........................................................................................56 
CYCLE AND DAY OF ADMINISTRATION ..........................................................................56 
DOSE OF OBINUTUZUMAB ...................................................................................................56 
CYCLE 1.......................................................................................................................................56 
5.2.5. 
Dosage Modification/Toxicity Management ...............................................................57 
5.2.5.1. 
Assessment of Hematologic Toxicities ..................................................................57 
5.2.5.2. 
Dosage Modifications ............................................................................................57 
5.2.5.3. 
Administration of Granulocyte Colony-Stimulating Factor ..................................57 
5.2.5.4. 
Hepatitis B Virus Reactivation ..............................................................................58 
5.2.5.5. 
Management of Infusion-Related Reactions and Anaphylaxis ..............................58 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
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5.3. 
Concomitant and Excluded Therapies ...............................................................................59 
5.3.1. 
Concomitant Therapy...................................................................................................59 
5.3.1.1. 
Prophylaxis for Tumor Lysis Syndrome ................................................................59 
5.3.1.2. 
Infections Prophylaxis ...........................................................................................59 
5.3.1.3. 
Other Concomitant Medications ............................................................................60 
5.4. 
Criteria for Permanent Discontinuation of Study Drug .....................................................60 
5.5. 
Obinutuzumab-Specific Criteria ........................................................................................60 
5.6. 
General Criteria ..................................................................................................................60 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES ......................................................60 
6.1. 
Permitted Concomitant Medications ..................................................................................60 
6.2. 
Medications to be Used with Caution ................................................................................61 
6.2.1. 
CYP3A- Inhibitors/Inducers ........................................................................................61 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib .................63 
6.2.3. 
QT Prolonging Agents .................................................................................................63 
6.2.4. 
Antiplatelet Agents and Anticoagulants ......................................................................64 
6.3. 
Prohibited Concomitant Medications ................................................................................64 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedure ..................................64 
6.4.1. 
Minor Surgical Procedures ..........................................................................................64 
6.4.2. 
Major Surgical Procedures ...........................................................................................64 
6.4.3. 
Emergency Procedures.................................................................................................65 
7. 
STUDY EVALUATIONS ....................................................................................................65 
7.1. 
Screening/Administrative ..................................................................................................65 
7.1.1. 
Informed Consent.........................................................................................................65 
7.1.2. 
Confirm Eligibility .......................................................................................................65 
7.1.3. 
Prior and Concomitant Medications ............................................................................65 
7.1.4. 
Adverse Events ............................................................................................................65 
7.1.5. 
Physical Examination...................................................................................................66 
7.1.6. 
ECOG ...........................................................................................................................66 
7.1.7. 
Vital Signs ....................................................................................................................66 
7.2. 
Clinical Laboratory Assessments .......................................................................................66 
7.2.1. 
Hematology ..................................................................................................................66 
7.2.2. 
Chemistry (Serum) .......................................................................................................66 
7.2.3. 
Coagulation Studies .....................................................................................................66 
7.2.4. 
Hepatitis Serologies .....................................................................................................67 
7.2.5. 
β2 -microglobulin ........................................................................................................67 
7.2.6. 
Pregnancy Test .............................................................................................................67 
7.2.7. 
Flow cytometry surface membrane phenotype ............................................................67 
7.2.8. 
IGHVDJ Rearrangement DNA Sequencing ................................................................67 
7.3. 
Diagnostics/Procedures ......................................................................................................67 
7.3.1. 
ECG..............................................................................................................................67 
7.3.2. 
Pathological Diagnosis and Bone Marrow Sampling ..................................................68 
7.4. 
Biomarkers .........................................................................................................................68 
7.4.1. 
Genetic and Molecular Prognostic Markers ................................................................68 
7.5. 
Efficacy Evaluations ..........................................................................................................70 
7.5.1. 
Radiographic Imaging ..................................................................................................70 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
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7.5.1.1. 
Radiographic Assessment ......................................................................................70 
7.6. 
Sample Collection and Handling .......................................................................................71 
8. 
STUDY PROCEDURES ......................................................................................................71 
8.1. 
Screening Phase .................................................................................................................71 
8.1.1. 
Screening Visit .............................................................................................................71 
8.2. 
Treatment Phase .................................................................................................................71 
8.2.1. 
Cycle 1 Day 1...............................................................................................................71 
8.2.2. 
Cycle 1 Day2................................................................................................................72 
8.2.3. 
Cycle 1 Day 3...............................................................................................................72 
8.2.4. 
Cycle 1 Day 8...............................................................................................................72 
8.2.5. 
Cycle 1 Day 15.............................................................................................................72 
8.2.6. 
Cycle 1 Day 28.............................................................................................................73 
8.2.7. 
Cycle 2 Day 1...............................................................................................................73 
8.2.8. 
Cycle 2 Day 28.............................................................................................................74 
8.2.9. 
Cycles 3 – 6, Day 1 ......................................................................................................74 
8.2.10. 
Cycles 3-7, Day 1 (±3days) .........................................................................................74 
8.2.11. 
Cycles 3-7, Day 15 (±3days) .......................................................................................75 
8.2.12. 
Cycles 8-12, Day 1 (±3days) .......................................................................................75 
8.2.13. 
Suspected PD Visit ......................................................................................................75 
8.2.13.1. 
End-of-Treatment Visit ..........................................................................................76 
8.3. 
Follow-up Phase.................................................................................................................76 
9. 
SUBJECT WITHDRAWAL FROM TREATMENT OR STUDY ..................................77 
9.1. 
Withdrawal from Study Treatment ....................................................................................77 
9.2. 
Withdrawal from Study......................................................................................................77 
10. STATISTICAL METHODS AND ANALYSIS .................................................................78 
10.1. General Consideration .......................................................................................................78 
10.2. Subject Information - Assignment to ARM A vs. ARM B................................................78 
10.3. Endpoints ...........................................................................................................................78 
10.3.1. 
Primary Endpoint .........................................................................................................78 
10.3.2. 
Secondary Endpoints ...................................................................................................79 
10.3.3. 
Exploratory Endpoints .................................................................................................80 
10.4. Sample Size Determination................................................................................................80 
10.5. Safety Analysis ..................................................................................................................80 
11. DATA AND SAFETY MONITORING PLAN (DSMP) ...................................................80 
11.1. Risk Assesssment ...............................................................................................................81 
11.2. Ibrutinib Risk Assessment .................................................................................................81 
11.3. Obinutuzumab Risk Assessment........................................................................................81 
12. ADVERSE EVENT REPORTING .....................................................................................82 
12.1. Definitions .........................................................................................................................82 
12.1.1. 
Adverse Events ...........................................................................................................82 
12.1.2. 
Serious Adverse Events .............................................................................................84 
12.1.3. 
Severity Criteria (Grade 1-5) ....................................................................................84 
12.1.4. 
Causality (Attribution) ..............................................................................................85 
12.2. Expected and Unexpected Adverse Events ....................................................................86 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
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12.3. Procedures for Eliciting,  Documenting and Reporting of Adverse Events and 
Serious Adverse Events by Investigators ...................................................................................86 
12.3.1. 
Eliciting Adverse Events..............................................................................................86 
12.3.2. 
Specific Instructions for Recording Adverse Events ...................................................87 
12.3.2.1. 
Diagnosis versus Signs and Symptoms..................................................................87 
12.3.3. 
Assessment of Adverse Events ..................................................................................87 
12.3.4. 
Adverse Event Reporting ..........................................................................................87 
12.3.5. 
Adverse Event Reporting Period ..............................................................................87 
12.3.6. 
Pregnancy ...................................................................................................................88 
12.3.7. 
Other Malignancies ....................................................................................................89 
12.3.8. 
Eye-Related Adverse Events .....................................................................................89 
12.3.9. 
Adverse Events of Special Interest (AESI) ..............................................................89 
12.3.9.1. 
Major Hemorrhage- Ibrutinib Adverse Event of Special Interest ..........................90 
12.3.10. 
Reporting Requirements for Serious Adverse Events ............................................90 
12.3.10.1. 
Post-Study Adverse Events .................................... Error! Bookmark not defined. 
12.3.10.2. 
Reconciliation ........................................................ Error! Bookmark not defined. 
12.4. Safety Reporting Requirements for IND Exempt Studies .................................................92 
13. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ......................92 
13.1. Protocol Amendments ........................................................................................................92 
13.2. Publication of Study Results ..............................................................................................92 
13.3. Study Discontinuation ........................................................................................................92 
13.4. Study Close-Out ................................................................. Error! Bookmark not defined. 
14. RETENTION OF RECORDS .............................................................................................93 
15. REFERENCES .....................................................................................................................94 
16. APPENDICES .....................................................................................................................101 
 
LIST OF APPENDICES 
Appendix 1.  Schedule of Assessments  ..................................................................................... 102 
Appendix 2.  ECOG Status Scores ............................................................................................. 107 
Appendix 3.  Inhibitors and Inducers of CYP3A ........................................................................ 100 
Appendix 4.   Guidelines for Establishing Response to Treatment ............................................ 101 
Appendix 5. Correlative Studies……………………………..……………………….……... 104 
Appendix 6. Child-Pugh Score……………………………………………………………….. 105 
Appendix 7. Cumulative Illness Rating Score ……………………………………………….. 106 
Appendix 8. FACIT Fatigue Questionnaire …………………………………………………..113 
LIST OF IN-TEXT TABLES AND FIGURES 
Tables 
Table 1. Ibrutinib Dose Modifications ………………………………………………………….45  


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
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Table 2. Obinutuzumab Dosing Schedule ………………………………………………………45 
Table 3. Management of Hepatitis B Reactivation ……………………………………………..49 
 
Figures 
Figure 1. Study Design…………………………………………………………………………38 
SYNOPSIS 
Study Title: 
Two-arm phase II trial exploring the use of the targeted agents 
ibrutinib and obinutuzumab for the treatment of patients with a 
diagnosis of Richter’s Transformation (RT) or Richter’s 
Syndrome (RS)  
Protocol Number: 
 20016 
Study Phase: 
2 
Study Duration: 
2 years 
Investigational Product 
and Reference Therapy: 
• Ibrutinib will be supplied as 140 mg hard gelatin capsules 
for oral (PO) administration. 
Additional Drug: 
• Obinutuzumab (GA-101)  
Objectives: 
Primary Objective: 
• To determine the efficacy of combining Ibrutinib with 
obinutuzumab (with or without “CHOP” chemotherapy 
regimen) as measured by overall response rate (ORR). 
Secondary Objectives: 
• To assess the safety of Ibrutinib in combination with 
obinutuzumab as measured by the incidence of prolonged 
hematologic toxicity in cycle 1 in subjects with a diagnosis 
of 
Richter's 
Transformation 
(RT), 
hematologic 
improvement, progression-free survival (PFS), overall 
survival (OS), and health-related quality of life (HRQL) 
measures. 
• To identify and correlate potential markers predictive of 
response to the combination therapy and associate 
pharmacogenetic findings to response and toxicity. 
 
Study Design: 
We propose a design to evaluate two study arms, a “fit” and a 
“frail” cohort. Each group will follow an independent but parallel 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
Page 9 
design. This is a nonrandomized open-label Phase II study of 
Ibrutinib 560mg daily in combination with Obinutuzumab, 100 mg 
on day 1 and 900 mg on day 2 of Cycle 1, and 1000 mg on days 8 
and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2–6 in subjects 
with RT. The addition of the chemotherapy regimen known as 
“CHOP” (i.e., cyclophosphamide, doxorubicin, vincristine, and 
prednisone) will depend on the fitness of the subject. 
The primary objective of the study is to determine the efficacy of 
this combination regimen in patients with a diagnosis of Richter’s 
Transformation (RT). RT patients are a subtype of chronic 
lymphocytic leukemia (CLL) patients that develop a more rapidly 
progressive disease with extremely poor outcomes when treated 
with chemoimmunotherapy regimens. There is currently no 
standard of care to treat this condition once a Richter’s 
transformation occurs as life expectancy is only a matter of months 
once the diagnosis is established.  
Efficacy for this combination regimen will be assessed by 
measuring overall response rate (ORR), progression-free survival 
(PFS), and overall survival (OS). 
Patients who have no evidence of progressive disease after cycle 3 
will be treated for up to three additional 28-day cycles of the 
infusion regimen based on tolerability and lack of evidence of 
progressive disease. 
Ibrutinib will be continued indefinitely until progression of disease 
or until unacceptable toxicity develops, similar to its current 
approved usage in CLL and lymphoma patients.  
Response rates will be reported following completion of all 
therapy, but the primary efficacy endpoint is ORR following at 
least 2 cycles of treatment.  
Up to 50 subjects will be screened for enrollment in the 
combination treatment groups:  
▪ Up to 20 patients will receive the combination ibrutinib and 
obinutuzumab alone (frail patients) and  
▪ 
Up to 23 patients will receive ibrutinib and obinutuzumab in 
combination with the CHOP regimen (fit patients). 
All enrolled subjects will receive up to 6 cycles of infusion therapy 
(Obinutuzumab with or without CHOP). Ibrutinib will be given 
daily continuously until progression of disease or toxicities as it is 
approved for use in patients with a CLL diagnosis.  
Population: 
This is a two-arm trial with two cohorts of patients based on their 
ability to tolerate therapy:  
 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
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Arm A – Fit cohort: 
Age ≤80, CIRS<6 with adequate renal function (estimated creatinine 
clearance ≥30 ml/min), to be treated with the combination of 
ibrutinib, 
obinutuzumab, 
cyclophosphamide, 
doxorubicin, 
vincristine, and prednisone; i.e. “IG-CHOP” 
Arm B – Frail or unfit cohort: 
Age ≤80 years, estimated Creatinine Clearance ≥30 ml/min (Cockcroft-
Gault) or with a score on the Cumulative Illness Rating Scale (CIRS) ≥6 
for coexisting illnesses not related to CLL, to be treated with ibrutinib (I) 
and obinutuzumab (G), i.e. “IG”. 
Centers: 
Northwell Health/CLL Research and Treatment Program  
Inclusion Criteria: 
1. 
Refer to Section 
4.0 
for 
the 
complete 
and 
detailed 
list 
of 
inclusion/exclusio
n criteria. 
• 
Subjects ≥ 18 and ≤80 years of age 
• 
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status of ≤2 
• 
Histologically confirmed Richter’s transformation in 
CLL/SLL patients. Patients can be treatment-naive or have 
been previously treated 
• 
Regimen-specific inclusions: 
Fit Group: Patients with prior BTK agent exposure 
(including Ibrutinib) may be included on the FIT arm.  
Frail Group: Patients who have had prior BTK 
inhibitors (including Ibrutinib) should not be included on 
the Frail arm. 
• 
Patients may have had prior exposure to alternative B-cell 
signaling receptor agents including prior exposure to a 
Phosphoinositide 3-Kinase Delta (PI3Kd) inhibitor, and a 
Spleen tyrosine kinase (SYK) inhibitor.   
• 
Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local subject privacy 
regulations) 
• 
Willing and able to participate in all required evaluations 
and procedures in this study protocol 
• 
Adequate hematologic function defined as:  
→ Absolute 
neutrophil 
count 
≥1000 cells/mm3 
(1.0 x 109/L).   
→ Platelet count ≥50,000 cells/mm3 (50 x 109/L).   


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
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→ Hemoglobin >8.0 g/dL 
• 
Adequate hepatic and renal function defined as: 
→ Serum aspartate transaminase (AST) or alanine 
transaminase (ALT) ≤ 2.5 x upper limit of normal 
(ULN). 
→ Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-
Gault) 
→ Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to 
Gilbert’s syndrome or of non-hepatic origin) 
→ PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN 
(unless abnormalities are unrelated to coagulopathy or 
bleeding disorder). When treated with warfarin or other 
vitamin K antagonists, then INR≤3.0) 
Exclusion Criteria: 
• 
Regimen-specific exclusions: 
o Fit Group: known hypersensitivity to any of the 
agents in the combination regimen or having a 
comorbidity that may affect patient’s ability to 
tolerate the therapy at the investigator’s discretion. 
Patients with prior BTK agent exposure (including 
Ibrutinib) may be included on the FIT arm.  
o Frail Group: Known grade 4 hypersensitivity, 
severe allergy, or anaphylactic reaction to a 
monoclonal antibody. 
Patients who have had prior BTK inhibitors (including 
Ibrutinib) should not be included on the Frail arm. 
• 
Inability to swallow capsules or any of the following: 
uncontrolled malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach 
or small bowel, symptomatic inflammatory bowel disease or 
ulcerative colitis, or partial or complete bowel obstruction 
• 
Unwilling or unable to participate in all required study 
evaluations and procedures 
• 
Unable to understand the purpose and risks of the study and to 
provide a signed and dated informed consent form (ICF) and 
authorization to use protected health information (in 
accordance with national and local subject privacy regulations) 
• 
Lactating, pregnant or unwilling to follow precautions to avoid 
an unintended pregnancy 
• 
Concomitant use of warfarin or other Vitamin K antagonists 
• 
Subjects who received a strong cytochrome P450 (CYP) 3A4 
inhibitor within 7 days prior to the first dose of ibrutinib or 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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subjects who require continuous treatment with a strong 
CYP3A inhibitor (see Appendix 3) 
• 
Chemotherapy 21 days prior to first administration of study 
treatment 
• 
Biologic immunotherapy 10 days prior to first administration 
of study treatment 
• 
BCR inhibitors 24 hours days prior to first administration of 
study treatment 
• 
Major surgery, excluding diagnostic tissue biopsies required to 
diagnose Richter’s transformation, within 4 weeks of first dose 
• 
History of other malignancies, except:  
o Malignancy treated with curative intent and with no known 
active disease present for ≥2 years before the first dose of 
study drug and felt to be at low risk for recurrence by treating 
physician 
o Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease 
o Adequately treated carcinoma in situ without evidence of 
active or residual disease 
• 
Unresolved toxicities from prior anti-cancer therapy, defined 
as having not resolved to Common Terminology Criteria for 
Adverse Event (CTCAE, version 4), grade 0 or 1, or to the 
levels dictated in the inclusion/exclusion criteria with the 
exception of alopecia. 
• 
Any life-threatening illness, medical condition, or organ 
system dysfunction that, in the investigator’s opinion, could 
compromise the subject’s safety or put the study outcomes at 
undue risk. 
• 
Recent infection requiring systemic treatment that was 
completed ≤14 days before the first dose of study drug. 
• 
Known history of human immunodeficiency virus (HIV) or 
active with hepatitis C virus (HCV) or hepatitis B virus (HBV). 
Subjects who are positive for hepatitis B core antibody or 
hepatitis B surface antigen or Hepatitis C antibody must have 
a negative polymerase chain reaction (PCR) result before 
enrollment.  Those who are PCR positive will be excluded. 
• 
Any uncontrolled active systemic infection. 
• 
Known bleeding disorders (e.g., von Willebrand’s disease) or 
hemophilia. 
• 
History of stroke or intracranial hemorrhage within 6 months 
prior to enrollment. 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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• 
Currently active, clinically significant cardiovascular disease, 
such as uncontrolled arrhythmia or Class 3 or 4 congestive 
heart failure as defined by the New York Heart Association 
Functional Classification; or a history of myocardial 
infarction, unstable angina, or acute coronary syndrome within 
6 months prior to randomization.  
• 
Currently active, clinically significant hepatic impairment 
Child-Pugh class  C according to the Child Pugh classification 
• 
Vaccinated with live, attenuated vaccines within 4 weeks of first 
dose of study drug. 
 
Study Treatment: 
Ibrutinib (PCI-32765), Obinutuzumab (GA101) plus or minus 
CHOP 
 
Concomitant Therapy: 
Refer to Section 6 for information on concomitant therapy. 
 
Safety Plan: 
 
Refer to Section 11 for information on safety follow up measures. 
Statistical Methods and 
Data Analysis: 
Primary Efficacy Analysis: 
The primary endpoint variable is the overall response rate evaluated 
following at least two months after start of therapy.  ORR conforms 
to the published Revised Response Criteria for malignant 
lymphoma   
 
Secondary Efficacy Analysis: 
Secondary endpoints include: incidence of prolonged hematologic 
toxicity in cycle 1 in subjects with a diagnosis of Richter's 
Transformation (RT), hematologic improvement, progression-free 
survival (PFS), overall survival (OS), and health-related quality of 
life (HRQL) measures 
 
Exploratory Efficacy Analysis:   
Peripheral blood, lymph node and/or bone marrow samples 
(depending on the site of disease activity) will be obtained pre-
therapy.   
In addition, peripheral blood and possibly lymph node and bone 
marrow samples (depending on the site of disease activity) will be 
obtained on C1D15, C1D28, C2D28 of therapy and at the end of 
the study or at the time of disease progression.  


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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These samples will be tested to determine correlation with observed 
outcomes. 
 
Sample Size 
Determination 
Simon's two-stage design (Simon, 1989) will be used for each of 
the two study groups (fit and frail groups). 
 
For the frail group, the study will be designed to test the ORR at 
55% (the alternative hypothesis) against the estimated true 
response rate of 30% (the null hypothesis).  In the first stage, 8 
patients will be accrued. If there are 2 or fewer responses in these 
8 patients, the study will be stopped. Otherwise, 12 additional 
patients will be accrued for a total of 20. The null hypothesis will 
be rejected if 9 or more responses are observed in 20 patients. 
This design yields a type I error rate of alpha=0.1 and power of 
80% when the true response rate is 55%. 
 
For the fit group, the study will be designed to test the ORR at 
60% (the alternative hypothesis) against the estimated true 
response rate of 35% (the null hypothesis).  In the first stage, 10 
patients will be accrued. If there are 4 or fewer responses in these 
10 patients, the study will be stopped. Otherwise, 13 additional 
patients will be accrued for a total of 23. The null hypothesis will 
be rejected if 11 or more responses are observed in 23 patients. 
This design yields a type I error rate of alpha=0.1 and power of 
80% when the true response rate is 60%. 
 
For the frail (fit) group, the null hypothesis will be rejected if 
there are 9 (11) or more responses in the 20 (23) patients, 
9/20=45% (11/23=48%). Therefore, the study will require a total 
of 20+23=43 patients (fit and frail groups). 
 
 
 


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ABBREVIATIONS 
Include all abbreviations used in the text. If a term is used less than 3 times, it should be spelled out on 
each use. Each term should be spelled out the first time it is used in the Synopsis, and again the first time 
it is used in the text. Refer to AMA Manual of Style for standard abbreviations. 
CRF 
case report form (paper or electronic as appropriate for this study) 
DCF 
data clarification form 
DMC 
Data Monitoring Committee 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders (4th edition) 
ECG 
Electrocardiogram 
ECOG 
eDC 
Eastern Cooperative Oncology Group 
electronic data capture 
EQ-5D-5L 
FACT-Leu 
GCP 
EuroQoL Five-Dimension utility measure 
Functional Assessment of Cancer Therapy: Leukemia questionnaire 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
HRQL 
IAC 
health-related quality of life 
Interim Analysis Committee 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LC-MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PQC 
Product Quality Complaint 
PRO 
patient-reported outcome(s) 
RS 
RT 
USP 
Richter’s Syndrome 
Richter’s Transformation 
United States Pharmacopeia 
 
 


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1. BACKGROUND 
1.1. 
Disease/Histology 
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the 
United States and Europe. According to the SEER database, the annual incidence is ~15,000 new 
cases with a median age at diagnosis of 72. Clinically, CLL is characterized by a marked degree 
of heterogeneity, ranging from patients that harbor highly stable disease who do not require 
treatment to patients with a rapidly progressive disease that require immediate intervention after 
diagnosis due to the presence 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 patients with late-stage CLL but can occasionally be found 
earlier in the course of the disease (Gribben 2011). While clinical staging systems have been 
developed to risk stratify CLL patients (Rai 1975, Binet 1981), the outcome for a given patient 
ultimately depends on complex relationships between the characteristics of the patient (age, 
gender, comorbidity, performance status), the disease (burden, kinetics and biology of the tumor), 
as well as sensitivity of the disease to treatment. Thus, clinical staging is only one of the parameters 
in this complex interaction (Montserrat 2006). As previously described by our research group, the 
observed clinical heterogeneity extends to the molecular biology of CLL clones as CLL cases can 
be divided into two subgroups based on the presence or absence of significant numbers of IGHV 
somatic mutations (Fais 1998). This molecular distinction has been found to correlate with the 
heterogeneity in clinical course and survival observed in CLL patients (Damle 1999, Hamblin 
1999). 
 
The use of chemoimmunotherapy for CLL as initial therapy is associated with high 
response rates, with the most active combination being the three-drug regimen of fludarabine, 
cyclophosphamide, and rituximab (FCR) (Keating 2005, Hallex 2010). Despite excellent 
responses and remission durations obtained with this regimen, patients with cells that use an 
unmutated IGHV gene (UM-CLL) have inferior rates of survival compared with those that use a 
mutated IGHV gene (M-CLL) (Damle 1999, Hamblin 1999), due to a significantly shorter 
complete remission duration in the UM-CLL group (Lin 2009). The worse prognosis predicted by 
unmutated IGHV genes is conceivably due to the enrichment of some genetic lesions that confer 
higher aggressiveness (e.g., mutations of TP53 or NOTCH1) among UM-CLLs, as well as to the 
greater predisposition of UM-CLLs, compared with M-CLLs, to undergo clonal evolution 
(Shanafelt 2006, Stilgenbauer 2007, Fabbri 2011, Puente 2011, Rossi 2012). 
 
The excellent clinical activity of a regimen such as FCR is counterbalanced by its 
significant toxicities including persistent cytopenias, infections, and the development of therapy-
related secondary malignancies (Fischer 2013). Novel treatment strategies have been developed 
for use in CLL patients that are not appropriate candidates for this regimen due to their co-existing 
medical comorbidities. Agents such as bendamustine, alemtuzumab, and ofatumumab have shown 
activity in CLL (Knauf 2009, Hillmen 2007, Wierda 2010) and have been approved by the FDA 
for use in CLL as monotherapy or in combination regimens. Over the past few months, two new 
targeted agents with unprecedented activity and safety have been approved for use in CLL patients: 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
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the Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib and the monoclonal antibody targeting 
CD20, obinutuzumab. The activity and duration of remission for both agents was also observed in 
patients that were traditionally excluded from participation in clinical trials due to their known 
inability to tolerate intensive regimens. 
While the availability of agents such as FCR and ibrutinib and obinutuzumab has improved 
clinical outcomes in CLL, therapy is not curative. The clinical course for the majority of patients 
with CLL has been predictable, with a response to initial treatment, eventual recurrence, reduced 
likelihood for response with subsequent treatments, and shorter duration of response with each 
remission (Wierda 2006). Retreatment typically yields progressively less satisfactory responses 
than the prior treatment, eventually leading to refractory disease. The predisposition to clinical 
progression of CLL is influenced by the genetic lesions of the leukemic clone. At the time of CLL 
diagnosis, mutations such as TP53 disruption, ATM deletion, NOTCH1, and SF3B1, have all been 
shown to predict a worse outcome (Gaidano 2012). Currently available treatment options for 
relapsed disease tend to have increased toxicity and decreased anti-neoplastic activity with each 
subsequent therapy, hence the need for the development of agents that target different pathways 
that can overcome the acquired resistance that stems from clonal evolution. 
Despite all the recent advances in therapeutic interventions for CLL patients, a subset of 
CLL patients will eventually transform into a high-grade Diffuse Large B-Cell Lymphoma 
(DLBCL), a type of Non-Hodgkin’s lymphoma (NHL). When transformation occurs, it is known 
as a Richter’s Transformation (RT) or Richter’s syndrome (RS) (referred to in this document as 
RT). Incidence has been reported to be approximately 2-8% of CLL patients (Tsimberidou 2006), 
though a single institution experience reported on the outcomes of 185 previously untreated CLL 
patients and found a cumulative incidence of RT at 5 and 10 years after CLL diagnosis at 13% and 
16%, respectively, higher than historical records (Rossi 2008).  Since RT diagnosis requires a 
pathological assessment, heterogeneity in biopsy policies among institutions could represent a 
major factor influencing the reported rate in different CLL series. In this respect, the high rate of 
RT in this particular cohort may reflect the intensive biopsy policy, hence the need for biopsies to 
determine whether the clinical presentation is a Richter’s transformation vs relapsed/refractory 
CLL. The clinical manifestations of RT include a rapid increase in size of lymphadenopathy, 
splenomegaly, worsening “B” symptoms (fevers, night sweats, and weight loss of over 10%) 
accompanied by a rise in lactic acid dehydrogenase (Tsimberidou 2006), though as mentioned 
above, these symptoms could also be attributed to relapsed or refractory CLL. The mechanism by 
which this transformation to an aggressive lymphoma occurs is still poorly understood. Most 
importantly, we currently lack predictors of transformation and prognostic markers to determine a 
response to treatment (Tsimberidou 2005). TP53, NOTCH1, and MYC abnormalities are the most 
frequent recurrent genetic lesions observed in patients that develop RT. Because these 
abnormalities are frequently acquired at the time of transformation (Rossi 2011), next-generation 
ultra-deep sequencing studies can aid in the identification of additional genetic lesions acquired at 
the time of transformation from CLL to RT. The high prevalence of TP53 mutation in RT suggests 
clonal selection driven by previous CLL treatments. Nevertheless, despite morphologic and 
phenotypic similarities with non-germinal center (non-GC) de novo DLBCL (a more benign and 
responsive form of DLBCL), the molecular profile of genomic abnormalities in RT is different. 
Most genetic changes that are observed in de novo DLBCL are rare or absent in RT. The increased 
frequency of unmutated IGHV genes observed in RT is in sharp contrast with the genetic 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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Richter’s Syndrome (RS)/ PCYC-20016 
 
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characteristics of de novo DLBCL, which show mutated IGHVs in virtually all cases. This disparity 
could reflect differences in the cell of origin or the microenvironment. 
 
1.1.1. 
Treatment Options 
Once a CLL patient develops RT, there are no consensus guidelines on its therapy and there 
is currently no standard of care management recommendations. If the patient is fit and able to 
tolerate chemotherapy, treatments for a Richter’s transformation include the use of aggressive 
lymphoma combination regimens, such as CHOP, ESHAP, and Hyper-CVAD or CVXD in 
combination with the anti-CD20 monoclonal antibody rituximab, although the response rates to 
these are poor and short lived.  
In a single institution study, Hyper-CVXD regimen was used in 49 patients (31 patients 
with RT with a median interval to diagnosis of RT from CLL diagnosis of 52 months (range 0-112 
months) and 19 patients with fludarabine-refractory CLL). Nine of 49 patients (19%) achieved a 
complete remission (CR) and 11 (22%) patients achieved a partial remission (PR) for an overall 
response rate of 41% and a median survival of 8.5 months.  Nevertheless, patients with fludarabine-
refractory CLL had a significantly higher survival rate compared with patients who had RT when 
a 2-month landmark analysis was performed (RT 12/25 deaths, CLL 1/11 deaths). Most currently 
available regimens have a high risk of a serious toxicity despite the use of multiple prophylactic 
and supportive agents, as evidenced by early treatment mortality of 18% and 4% during the first 
and second cycle of therapy, respectively (Tsimberidou 2003).  
Another phase I/II study looking at a combination regimen of oxaliplatin, fludarabine, 
cytarabine, and rituximab (OFAR) showed overall response rate of 50% (10/20 patients responded) 
but a sixmonth overall survival of only 59% (Tsimberidou 2008). As expected, patients who 
achieve a CR or PR have a longer survival than patients whose disease fails to respond to therapy.  
A recent single institution study reported the outcomes of 16 RT patients following 
progression after ibrutinib failure in patients participating on ibrutinib clinical trials: with a median 
follow-up of 16 months (<1-42months), 6 patients received no additional therapy and died within 
a month of transformation. The remaining 10 patients were treated with R-EPOCH, R-CHOP, R-
ICE, or OFAR; the reported median survival from date off ibrutinib study was 120 days (Woyach 
2014).   
Given that CLL is considered a “disease of the elderly”, a significant number of patients 
who develop RT are not able to tolerate intensive regimens and die without the ability to receive 
any salvage therapy. Furthermore, patients with RT continue to be excluded from clinical trials. 
RT patients have a reported median overall survival of 5 to 8 months (Tsimberidou 2005), even in 
younger patients that would be better fit to tolerate current multidrug chemotherapy regimens. It 
is clear that there is an unmet need to study the activity of the recently approved agents that are 
showing remarkable activity as monotherapy or in combination in CLL and NHL. 
 
Kinase inhibitors affecting signaling of the B-cell antigen receptor (BCR) have shown 
significant promise in patients with CLL and NHL. Ibrutinib is an orally bioavailable, potent 
inhibitor that covalently binds to the cysteine-481 amino acid of the Bruton’s tyrosine kinase 
(BTK) enzyme, leading to irreversible inhibition of activity (Honigberg 2010). In vitro studies 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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June 21, 2018 
 
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demonstrate BTK inhibition in CLL cells blocks BCR-related survival signals, thereby leading to 
apoptosis. Ibrutinib has demonstrated single-agent activity in a variety of relapsed or refractory B-
cell malignancies with excellent tolerability (Advani 2013). A recent phase1b–2, open-label, 
multicenter study testing single agent ibrutinib in patients with relapsed CLL (including patients 
with high risk disease) showed an overall response rate, based on standard criteria of 71% in two 
different cohorts (420-mg QD and 840-mg QD cohort). In addition, 10 patients in the 420-mg QD 
cohort (20%) and 5 patients in the 840-mg QD cohort (15%) had a partial response with persistent 
lymphocytosis. Blood lymphocytosis peaked at a median of 4 weeks and then slowly declined. 
Lymphocytosis occurred concomitantly with a notable reduction in lymph node and spleen sizes, 
along with frequent improvement of baseline cytopenias in a time-dependent manner. Irrespective 
of dose, treatment with ibrutinib provided durable responses. The 26-month estimated rate of 
progression-free survival was 75%, and the rate of overall survival was 83% (Byrd 2013). As 
required by clinical trial protocols, patients with a diagnosis of RT were excluded from 
participation in these initial trials. 
Obinutuzumab is an anti-CD20 monoclonal antibody (mAb) that differs from previous 
anti-CD20 mAbs in its glycoengineered Fc region and type 2 CD20-binding mode. Anti-CD20 
antibodies have two main binding sites and downstream effects on target cells: type 1 binding 
results in the formation of lipid rafts containing the antibody bound target that cluster the target 
antigen on the cell surface; type 2 binding does not produce the same lipid-raft clustering but may 
transduce signals into the cell that add to the usual complement-mediated and antibody-dependent 
cell-mediated cytotoxicity and phagocytosis mechanisms. Glycoengineering increases the binding 
affinity of the Fc portion of obinutuzumab to Fcγ receptor III on innate immune effector cells 
(natural killer cells, macrophages, and neutrophils), which in turn leads to enhanced antibody-
dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis. The 
consequence of type 2 CD20 binding (as compared with type 1 binding with the other available 
drugs, i.e. rituximab and ofatumumab) is mainly different B-cell signaling downstream of CD20 
engagement, which leads to increased direct cell death (through a caspase-independent 
mechanism) and reduced internalization and degradation of monoclonal antibody–bound 
membrane CD20 molecules (Mössner 2010, Honeychurch 2012).  The type 2 binding feature of 
obinutuzumab as well as its glycoengineered constant region of immunoglobulin has translated 
into an impressive improvement over other antibody therapies targeting CD20 (Goede 2014). 
We propose the use of ibrutinib in combination with obinutuzumab with and without a 
commonly used chemotherapy regimen used in Richter’s patients known as CHOP (i.e. 
cyclophosphamide, doxorubicin, vincristine, and prednisone).  Given the outstanding responses 
from these recently approved agents (ibrutinib and obinutuzumab) reported in both CLL and NHL, 
we expect an improved clinical activity when these agents are used in patients that develop RT. 
 
1.1.2. Role of BTK in Disease/Histology 
1.2. 
Ibrutinib Background – Investigational Product Name and Description 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally-administered, covalently-
binding inhibitor of Bruton’s tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-
cell receptor (BCR) signaling pathways and thus prevents B-cell proliferation. In vitro, ibrutinib 
inhibits purified BTK and selected members of the kinase family with 10-fold specificity compared 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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with non-BTK kinases.  Ibrutinib (IMBRUVICA®) is approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of 1) mantle cell lymphoma (MCL) in patients who have 
received at least one prior therapy based on overall response rate, 2) chronic lymphocytic leukemia 
(CLL) in patients who have received at least one prior therapy, and 3) CLL in patients with 17p 
deletion, and 4) Waldenström’s Macroglobulinemia.  Ibrutinib is currently under investigation in 
various other indications.   
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 that comprise the antigen-binding portion of the B-cell receptor (BCR), which 
is activated by binding 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 2003).  
The process of B-cell maturation, including immunoglobulin variable (IGHV), diversity 
(IGHD) and joining (IGHJ) region gene rearrangement and somatic mutation, is tightly regulated.  
It is thought that B-cell lymphomas and CLL result from translocations and mutations, 
respectively, acquired during normal B-cell development (Shaffer 2002) or subsequently during 
germinal center reactions in secondary lymphoid tissues.  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. 
Although the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells (Satterthwaite 2000), the enzyme also is critical for the 
function of other receptors such as the chemokine receptor, CXCR4.   
Data from Study PCYC-04753 demonstrate 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 and for the 
560 mg continuous dosing cohort, were all above 90% at both 4 and 24 hours after drug 
administration. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib 
background, safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of 
ibrutinib, refer to the latest version of the ibrutinib Investigator's Brochure. 
1.3. 
Summary of Nonclinical Data 
For the most comprehensive nonclinical information regarding ibrutinib, refer to the 
current version of the Investigator's Brochure.  


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
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1.3.1. Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the Btk (Pan 2007).  In vitro, 
ibrutinib is a potent inhibitor of Btk activity (IC50 = 0.39 nM).  The irreversible binding of ibrutinib 
to cysteine-481 in the active site of Btk results in sustained inhibition of the catalytic activity of 
that Btk molecule and enhanced selectivity over other kinases that do not contain a cysteine at this 
position.  When added directly to human whole blood, ibrutinib inhibits signal transduction from 
the B-cell receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by CD69 
expression after anti-IgM stimulation (Herman 2011)   
Ibrutinib arrested arrests cell growth and induces apoptosis in human B-cell lymphoma cell 
lines in vitro and inhibited tumor growth in vivo in xenograft models (Herman 2011)   Ibrutinib 
also inhibits adhesion and migration of mantle cell lymphoma (MCL) cells in co-culture and 
reduces tumor burden in lymph node and bone marrow in a murine model of MCL dissemination 
and progression (Chang 2013a, Chang 2013b). 
For more detailed and comprehensive information regarding nonclinical pharmacology, 
refer to the current Investigator’s Brochure. 
1.3.2. Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the 
central nervous system or respiratory system in rats at any dose tested.  Further, no treatment-
related corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs.   
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, 
the greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally decreased 
trabecular and cortical bone (rat) and corneal dystrophy (dog).   
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 14 times 
the exposure (AUC) in patients administered the dose of 560 mg daily, respectively.     
1.3.2.1.Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay and was not 
clastogenic in a chromosome aberration assay in mammalian (CHO) cells or in an in vivo bone 
marrow micronucleus assay in mice at doses up to 2000 mg/kg. 


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Fertility studies with ibrutinib have not been conducted in animals. In the general 
toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in 
adverse effects on reproductive organs. 
1.4. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, refer to the current 
version of the Investigator's Brochure.  
1.4.1. Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging 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.  Taking into account the approximate 
doubling in mean systemic exposure when dosed with food and the favorable safety profile, 
ibrutinib can be dosed with or without food. Ibrutinib is extensively metabolized primarily by 
cytochrome P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not considered 
clinically relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first 
dose exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 
patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or 
patients on dialysis have not been studied. Following single dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects 
with normal liver function.  A higher proportion of Grade 3 or higher adverse reactions were 
reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.   
Evaluations of exposure/response using PK/PD modeling of data from 11 completed Phase 2 and 
3 studies have been conducted from a total of 1,306 ibrutinib-treated subjects with B-cell 
malignancies or cGVHD. The results from these analyses are as follows:  
• No meaningful relationship between tumor response (ORR) and systemic exposure to 
ibrutinib was observed for patients with CLL, MCL, MZL, or cGVHD. 
 
• Similarly, there was no meaningful or consistent indication of any potential relationship 
between the safety-related endpoints of treatment-emergent atrial fibrillation, neutropenia, or 
liver function test abnormalities and ibrutinib systemic exposure. 
 
• The integrated exposure-response exploration for the 9 studies in CLL/SLL and MCL 
combined suggested that the incidence of major hemorrhage events was minimally 
increased with increasing systemic ibrutinib exposure. A more detailed analysis by 
indication and approved clinical doses indicated that this effect was most evident among 


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subjects with MCL treated with the 560 mg/day dose. There was no apparent association 
of major hemorrhage events with ibrutinib exposure in subjects with CLL assigned the 
420 mg/day dose. 
 
1.5. 
Summary of Clinical Safety  
For combination therapy studies:  
Integrated safety data for a total of 422 subjects treated with B-cell malignancies from 4 
combination therapy studies that have completed primary analysis or final analysis included in 
the CSR as of 31 July 2017, 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=422): 


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Most frequently reported 
TEAEs 10% a   
Most frequently reported Grade 
3 or 4 TEAEs 2% a  
Most frequently reported 
Serious TEAEs 1% b  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anemia 
Anemia 
Sepsis 
Pyrexia 
Fatigue 
Neutropenia 
Infusion related reaction 
Diarrhea 
Tumor lysis syndrome 
Upper respiratory tract infection 
Hypertension 
Urinary tract infection 
Constipation 
Pyrexia 
 
Vomiting 
Cellulitis 
 
Rash 
Leukopenia 
 
Headache 
Tumor lysis syndrome 
 
Cough 
Atrial fibrillation 
 
Muscle spasms 
Hyperuricaemia 
 
Pneumonia 
Urinary tract infection 
 
Oedema peripheral 
White blood cell count 
decreased 
 
Arthralgia 
 
 
Decreased appetite 
 
 
Contusion 
 
 
Insomnia 
 
 
Chills 
 
 
Peripheral sensory neuropathy 
 
 
Stomatitis 
 
 
Febrile neutropenia 
 
 


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Abdominal pain 
 
 
Back pain 
 
 
Bronchitis 
 
 
a Source is Table 7 of IB (v11), b Source is Table 8 of IB (v11) 
 
1.5.1. Risks 
1.5.2. Bleeding-related 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, intracranial hemorrhage and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.  
Initially, subjects were excluded from participation in specific ibrutinib Phase 2 and 3 
studies if they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K 
antagonists should not be administered concomitantly with ibrutinib unless specified in the 
protocol. Supplements such as fish oil and vitamin E preparations should be avoided. 
 
Subjects with congenital bleeding diathesis have not been studied. See section 6 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.4 for guidance on ibrutinib management with surgeries or procedures.  
1.5.3. Atrial Fibrillation  
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. Periodically monitor subjects clinical for atrial fibrillation. Subjects 
who develop arrhythmic symptoms (e.g., 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.  Ventricular tachyarrhythmia has also been reported. Abnormal rapid 
and/or irregular heart rhythm that starts from the lower chambers (ventricles) of the heart 
(ventricular tachyarrhythmia). 
1.5.4. Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) 
were reported in subjects treated with ibrutinib. 


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1.5.5. 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 and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged follow the protocol dose 
modification guidelines (see Section 5.2.1.3). 
1.5.6. Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated 
with ibrutinib. Some of these 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. At least 25% of subjects with MCL and 35% of subjects with CLL had 
Grade 3 or greater infections per NCI Common Terminology Criteria for Adverse Events 
(CTCAE). The most commonly reported infections include pneumonia, cellulitis, urinary tract 
infection and sepsis. Although causality has not been established, cases of progressive multifocal 
leukoencephalopathy (PML) and hepatitis B reactivation have occurred in patients treated with 
ibrutinib. Subjects should be monitored for signs and symptoms (fevers, chills, weakness, 
confusion, vomiting and jaundice) and appropriate therapy should be instituted as indicated.  
1.5.7. Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor 
patients for the appearance of non-melanoma skin cancer.  
1.5.8. Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or 
in combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. 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 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.  
1.5.9. Lymphocytosis and Leukostasis 
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. Consider 
temporarily holding ibrutinib. Subjects should be closely monitored. Administer supportive care 


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including hydration and/or cytoreduction as indicated. For subject and ibrutinib management 
guidance, refer to Sections 5.2.1 and 6.4. 
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥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 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 months 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.  
A large increase in the number of circulating lymphocytes (e.g., >400,000/µL) has been observed 
in some subjects. Lymphocytosis was not commonly observed in subjects with Waldenström’s 
macroglobulinemia treated with ibrutinib. Lymphocytosis appeared to occur in lower incidence 
and at lesser magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy. 
1.5.9.1. 
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 tumor lysis syndrome are 
those with comorbidities and/or risk factors such as high tumor burden prior to treatment, increased 
uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre‐existing kidney 
abnormalities.  
1.5.9.2. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD. Should symptoms develop, 
interrupt ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and 
benefits of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 
5.2.1.3). 
1.5.9.3  
Inflammation 
Inflammation of the fatty tissue underneath the skin (panniculitis). 
 
1.5.9.4  
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. 


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Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as 
appropriate. 
 
 
1.6. 
Obinutuzumab Background 
1.6.1. 
Structure and Mechanism of Action of Obinutuzumab 
Obinutuzumab (GA101, RO5072759), is a glycoengineered, humanized, type II anti-CD20 
monoclonal antibody (mAb).  Obinutuzumab was derived by humanization of the parental B-Ly1 
mouse antibody and subsequent glycoengineering leading to the following characteristics (Beers 
et al. 2010; Mössner 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 FcRIII 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 obinutuzumab and 
the significantly enhanced ADCC in preclinical assays, it is possible that obinutuzumab may have 
greater efficacy than the widely used anti-CD20-mAb rituximab (Rituxan).  
1.6.2. 
Clinical Experience with Obinutuzumab 
For the most up-to-date information on obinutuzumab, please refer to the current version 
of the Investigator’s Brochure. 
1.6.2.1. 
Tolerability and Efficacy of Obinutuzumab in Chronic Lymphocytic 
Leukemia  
 
Study BO20999 (GAUGUIN; NCT00517530) (Phase I) 
BO20999 was an open-label, multicenter, Phase I/II study to explore obinutuzumab safety and 
activity in relapsed/refractory NHL and CLL.  Thirteen CLL patients have received obinutuzumab 
at doses with a range of 400−2000 mg (given as a flat dose) across four cohorts 
(Morschhauser et al. 2009).  There were no dose-limiting toxicities (DLTs) and no requirement for 
dose reductions.  Infusion-related reactions (IRRs) occurred in all CLL patients 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 patients experienced four NCI-CTC Grade 3 toxicities:  sweats, 
flushing, asthenia, and hepatic cytolysis.  
Although the safety profile appears otherwise similar between NHL and CLL, there was 
an increase in NCI-CTC v3.0 Grade 3/4 neutropenia noted in CLL patients, which were observed 
in 9 patients across the four dose levels administered.  Five patients experienced NCI-CTC Grade 
4 neutropenia and 4 patients experienced NCI-CTC Grade 3 neutropenia as the maximum severity.  
Of the 9 patients, 7 had one NCI-CTC Grade 3/4 event and 2 patients experienced more than one 
event.  Granulocyte colony-stimulating factor (G-CSF) support was administered to 6 of the 9 
patients, and these patients responded quickly to G-CSF support.  For the 3 patients 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. 


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As assessed by the International Workshop on CLL (IWCLL) criteria, the end-of-treatment 
response rate with obinutuzumab monotherapy was 62% (8 of 13 patients with partial response 
[PR]) (Morschhauser et al. 2009). 
Study BO20999 (GAUGUIN; NCT00517530) (Phase II) 
Twenty patients with relapsed/refractory CLL have received 1000 mg of obinutuzumab.  
The most commonly reported adverse event (AE) during the treatment period was IRR, reported in 
19 (95%) of 20 patients.  Fifteen patients experienced Grade 3/4 AEs of whom 14 patients had 
treatment-related Grade 3/4 AEs (investigator assessment).  Treatment-related Grade 3/4 AEs were 
IRR (6 patients), neutropenia (4 patients), lymphopenia (2 patients), thrombocytopenia (2 patients), 
and anemia, pure red cell aplasia, pancytopenia, febrile neutropenia, herpes zoster, and interstitial 
lung disease (1 patient each).  Eleven serious adverse events (SAEs) in 9 patients were reported 
during treatment, 9 of which were assessed by the investigator as related to obinutuzumab:  IRR 
(4 patients) and febrile neutropenia, pancytopenia, pure red cell aplasia, interstitial lung disease and 
pyrexia (1 patient each).  Three patients withdrew from further study treatment after the first 
infusion due to IRR.  One death has been reported during follow-up from colon cancer.  The most 
common AE in follow-up was nasopharyngitis, reported in 2 patients.  End-of-treatment response 
assessment showed that four patients (20%) achieved a clinical response, with a best overall 
response rate (ORR) of 25% in evaluable patients (Salles et al. 2011). 
Study BO21003 (GAUSS; NCT00576758) (Phase I) 
BO21003 is an open-label, dose-escalating, multicenter Phase I/randomized Phase II study 
in patients with relapsed/refractory CD20+ malignant disease.  In Study BO21003, 5 CLL patients 
have been administered obinutuzumab.  The fifth patient 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 patients who completed treatment (received 
4 cycles of infusion).  The end-of-treatment response in patients with CLL receiving obinutuzumab 
monotherapy in this study included 3 stable disease and 1 progressive disease patients (Sehn, et al. 
2009). 
Study GAO4768g / GAGE / NCT01414205 (Phase II) 
GAO4768g is an open-label, randomized, multicenter, Phase II study evaluating the 
efficacy and safety of obinutuzumab administered at 1000 mg versus 2000 mg doses in patient 
with previously untreated CLL.  The results of the GAGE study were recently presented at the 
2014 annual meeting of the American Society of Clinical Oncology.  
Eighty patients were randomized and stratified based on Rai stage and tumor mass.   
For patients who received the 1000-mg doses, obinutuzumab was administered with three 
1000-mg doses in the first 21-day cycle (the first 1000-mg dose was administered over 2 days:  
100 mg administered on Day 1, 900 mg administered on Day 2; 1000 mg was administered on 
both Days 8 and 15).  In the subsequent cycles (2 − 8), 1000 mg of obinutuzumab was administered 
on the first day of each cycle. 
For patients who received the 2000-mg doses, obinutuzumab was administered as follows:  
100 mg on Cycle 1, Day 1; 900 mg on Day 2; and 1000 mg on Day 3.  On Days 8 and 15 of Cycle 
1, 2000 mg was administered on each day.  For Cycles 2 − 8, 2000 mg of obinutuzumab was 
administered on Day 1 of each cycle. 


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ORR was assessed at 2 months post-therapy according to the IWCLL criteria.  The ORR 
for the 1000 mg and 2000 mg obinutuzumab treatment arms were 49% compared with 67%, 
respectively; 2-sided p = 0.0779.  Complete response/complete remission with incomplete blood 
count recovery (CR/CRi) were achieved by 5% of patients (2/41) in the 1000-mg arm compared 
with 21% of patients (8/39) in the 2000-mg arm. In study GAO4768g in previously untreated 
patients with CLL, 44% and 46% of the patients achieved a PR in the 1000 mg and 2000 mg 
cohorts, respectively. The proportion achieving a CR/CRi was higher in high dose cohort (20.5% 
vs. 4.9%). 
The most common Grade 3/4 AEs were IRRs (23% vs. 11%) and neutropenia (3% vs. 5%) 
for the 1000-mg and 2000-mg arms, respectively (Flynn et al. 2014). 
Study GAO4779g (GALTON; NCT01300247) (Phase II) 
GAO4779g is an open-label, non-randomized, multicenter, Phase II study.  In the 
GALTON study, 41 patients with untreated CLL were treated with obinutuzumab 1000 mg (100 
mg IV on Day 1, 900 mg on Day 2, and 1000 mg on Days 8 and 15 of Cycle 1; 1000 mg on Day 
1 in Cycles 2 − 8) and either fludarabine + cyclophosphamide (G-FC; 25/250 mg/m2 IV on Days 
2 − 4 of Cycle 1, then on Days 1 − 3 of Cycles 2 − 6) or bendamustine G-B; 70 mg/m2 IV on Days 
2 − 3 of Cycle 1, then on Days 1 − 2 of Cycles 2 − 6).   Each cycle was 28 days long.    
The most common AEs (any grade) occurring in the G-FC arm were obinutuzumab-related 
IRRs (91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the G-
B arm, they were obinutuzumab-related IRRs (90%), nausea (65%), neutropenia (55%), diarrhea 
(50%), and pyrexia (45%).  The most common Grade 3/4 AEs were obinutuzumab-related IRRs 
(29%, 10%), neutropenia (43%, 55%), and infections (19%, 5%) for G-FC and G-B, respectively.   
Fourteen patients experienced SAEs (G-FC, n = 6; G-B, n = 8), with events including 
febrile neutropenia (5 events); infections (4 events); IRRs (3 events); nausea, vomiting, pyrexia (2 
events each); and diarrhea, fatigue, tachycardia, tumor lysis syndrome, syncope, mental status 
changes, neutropenia, face swelling, and hypertension (1 event each).  Nine patients (G-FC, n = 7; 
G-B, n = 2) had AEs leading to treatment discontinuation, including Grade 3/4 neutropenia (3 
patients in G-FC [1 of these 3 patients also had Grade 4 cellulitis] and 2 patients in G-B), Grade 3 
thrombocytopenia (2 patients in G-FC), Grade 4 pancytopenia (1 patient in G-FC), and Grade 4 
aspartate aminotransferase (AST)/Grade 3 alanine aminotransferase (ALT) elevation (1 patient in 
G-FC). 
The ORR was 62% (CR, 2; CRi, 3; PR, 8) in patients who received G-FC and 90% (CR, 4; CRi, 
5; PR, 9) in patients who received G-B, including 6 patients (G-FC, n = 4; G-B, n = 2) not 
evaluable due to inadequate response evaluation.  Four patients in the G-FC arm (0 in G-B) had 
stable disease during and after therapy.  No patient progressed during the study (Brown et al. 
2013). Efficacy data of obinutuzumab administered in combination with chemotherapy are 
available from the Phase II study GAO4779g, from the updated Stage 1a (GClb vs. Clb) and 
primary Stage 2 (GClb vs. RClb) analyses of the randomized Phase III study BO21004, and from 
phase IIIb study subgroup analysis of Cohort 1 (G-Benda) MO28453. In study GAO4779g, 
13/21 patients (62%) with previously untreated CLL treated with G-FC achieved a response (2 


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CR patients, 3 CRi, 8 PR) and 18/20 patients (90%) achieved a response with G-benda (4 CR 
patients, 5 CRi, and 9 PR). 
In study GAO4779g, at the end of treatment 39/41 patients with a B-cell assessment were 
B-cell depleted and all 36 patients with an assessment at the 6-month follow-up visit remained B-
cell depleted. At the 18-24 month assessment, 13/39 patients (33.3%) had B-cell recovery without 
PD and 6/39 patients (15.4%) remained B-cell depleted, at the 30-36 months follow-up assessment 
14/39 patients (35.9%) had B-cell recovery without PD and 4/41 patients (10.3%) remained B-cell 
depleted. The median time to B-cell recovery in the G-FC arm was 542 days (range 1 to 1067 days; 
95% CI for the median 395; not estimated) and 632 days (range 54 to 1079 days; 95% CI for the 
median: 460, not estimated) in the G-benda arm. 
Study BO21004 (CLL11; NCT01010061) (Phase III) 
This is an ongoing, open-label, multicenter, three-arm randomized, Phase III study to 
compare the efficacy and safety of obinutuzumab + chlorambucil (GClb), rituximab + GClb 
(RClb), or Clb alone in previously untreated CLL patients with comorbidities.  BO21004 enrolled 
781 patients and an additional 6 patients during a safety run-in period before randomization.  An 
analysis based on data collected by the data cutoff date for these 6 patients accrued from December 
2009 until February 2010 for the BO21004 safety run-in phase showed that all 6 patients completed 
6 cycles of treatment but two patients had significant dosing delays.  IRRs occurred in 5 patients, 
all were Grade 1 or 2, with no severe IRRs.  All 6 patients experienced neutropenia, 5/6 patients 
reported Grade 3 − 4 afebrile neutropenia with no febrile neutropenia.  All 6 reported 
thrombocytopenia with one case of Grade 3 − 4 thrombocytopenia.  No patient 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 2012). 
Study BO21004 includes two separate stages evaluating efficacy and the primary endpoint 
is progression-free survival (PFS).  Stage 1 evaluated obinutuzumab + chlorambucil compared 
with chlorambucil alone.   
In the Stage 1 analysis, the safety and efficacy of obinutuzumab + chlorambucil or 
rituximab + chlorambucil was compared with chlorambucil alone.  Compared with chlorambucil, 
both obinutuzumab + chlorambucil and rituximab + chlorambucil demonstrated statistically 
significant PFS benefit compared with chlorambucil alone.  Median PFS of chlorambucil vs. 
obinutuzumab + chlorambucil was 11.1 vs. 23 months, respectively, (median observation time, 
14.2 months; hazard ratio [HR], 0.16 [0.11 − 0.24]; p 0.0001; stratified log-rank test) as assessed 
by independent review.  The difference in PFS was smaller between chlorambucil and 
rituximab + chlorambucil; median PFS was 16.3 months with rituximab + chlorambucil vs. 11.1 
months with chlorambucil alone; HR, 0.44; 95% CI, 0.34 − 0.57; p  0.001). 
In the Stage 2 analysis of this study, obinutuzumab + chlorambucil was compared with 
rituximab + chlorambucil.  At the pre-planned interim analysis, the primary endpoint was met 
early and the results were released by the independent data monitoring board.  Median PFS was 
26.7 months vs. 15.2 months for obinutuzumab + chlorambucil vs. rituximab + chlorambucil, 
respectively.  The ORR was 78% vs. 65%, and CR was 21% vs. 7%, respectively. 


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In the comparison of obinutuzumab + chlorambucil vs. chlorambucil alone, the most 
common AEs (all grades, Grades 3 − 4), respectively, were IRRs (69% vs. 0, 21% vs. 0), 
neutropenia (40% vs. 18%, 34% vs. 16%), thrombocytopenia (15% vs. 7%, 11% vs. 3%), anemia 
(12% vs. 10%, 4% vs. 5%), leukopenia (7% vs. 0, 5% vs. 0), pyrexia (10% vs. 7%,   1% vs. 0), 
and cough (10% vs. 7%, 0 vs   1%).  Hematologic laboratory abnormalities (all grades, Grades 
3 − 4) with obinutuzumab + chlorambucil vs. chlorambucil alone, respectively, were neutropenia 
(77% vs. 53%, 46% vs. 27%), lymphopenia (80% vs. 9%, 40% vs. 2%), leukopenia (84% vs. 12%, 
36% vs.   1%), and thrombocytopenia (47% vs. 50%, 14% vs. 11%). 
Non-hematologic 
laboratory 
abnormalities 
(all 
grades, 
Grades 
3 − 4) 
with 
obinutuzumab + chlorambucil vs. chlorambucil alone, respectively, were hypocalcemia (32% vs. 
29%, 3% vs.   1%), hyperkalemia (31% vs. 17%, 5% vs. 2%), hyponatremia (29% vs. 11%, 8% 
vs. 22%), AST (SGOT increased; 28% vs. 12%,   1% vs. 0), creatinine increased (28% vs. 
18%,   1% vs.   1%), ALT (SGPT increased; 25% vs. 14%,   1% vs. 0), hypoalbuminemia 
(22% vs. 14%,   1% vs.   1%), alkaline phosphatase increased (16% vs. 11%, 0 vs. 0), and 
hypokalemia (13% vs. 4%, 1% vs.   1%) (Goede et al. 2014; Obinutuzumab USPI). 
Because Study BO21004 is a pivotal Phase III study in patients with CLL (median age: 73 
years; 44% patients were ≥ 75 years), a sparse serum sampling scheme was implemented which 
involved pre- and post-infusion samples only on each infusion day. Due to this limited sampling 
schedule, derived PK parameters for obinutuzumab could not be obtained by NCA. Mean serum 
obinutuzumab pre (Ctrough) and post-infusion (Cmax) concentrations used in the population PK 
analysis are provided in Table 11 of Investigator’s Brochure Version 11 (dated September 2016). 
The geometric mean post-infusion serum concentrations of obinutuzumab increased from 224 μg 
/mL (Cycle 1, Day 1) to 588 μg /mL (Cycle 1, Day 15). From Cycle 2 to Cycle 6, serum post-
infusion levels remained constant during the course of treatment, ranging from 577 μg /mL on 
Cycle 2 to 529 μg /mL on Cycle 6. Pre-infusion serum concentrations remained constant from 
Cycle 3 (160 μg/mL) to Cycle 6 (182 μg /mL). 
In the Phase III study BO21004, at the safety cutoff date of 04 July 2016, a total of 118 of 
the 212 patients with B-cell assessments (55.7%) in the GClb arm and 45 of the 74 patients with 
B-cell assessments (60.8%) in the RClb arm had B-cell recovery without PD within 48-54 
months of follow-up. The median time to B-cell recovery in the GClb arm was 743 days (range 
64 to 1673 days; 95% CI for median: 608, 763) compared with 393 days (range 85 to 1555 days; 
95% CI for median: 385, 540) in the RClb arm. 
For more information related to safety and efficacy in the CLL indication, please refer to 
the Obinutuzumab Investigator’s Brochure or the Obinutuzumab USPI. 
1.6.3. 
Overview of Safety of Obinutuzumab 
Obinutuzumab has been administered to approximately 1310 patients with CD20-positive 
malignancies.  Both in patients with NHL and with CLL, IRR was the most common AE in clinical 


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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 obinutuzumab.  The incidence and intensity of IRRs decreased 
with subsequent infusions of obinutuzumab.  In a few patients, concurrent signs of tumor lysis 
syndrome (TLS) were observed.  Other frequently observed AEs include infections and 
neutropenia.  These events appeared to be more common in patients with CLL compared to NHL. 
In trials investigating the combination of 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. 
A pooled analysis of safety data for obinutuzumab collected during the monotherapy 
studies BO20999 and BO21003 was conducted in patients 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 obinutuzumab and included a total 205 patients with NHL 
(49 aNHL and 156 iNHL patients) and 38 patients with CLL. 
In the group of 38 patients with CLL treated with obinutuzumab monotherapy, the majority 
of patients (25 [66%]) were treated for   4 weeks to   6 months.  Eleven patients (29%) were 
exposed for 6 to   12 months, and two patients (5%) were exposed for 12 months or longer.  Eight 
of 38 patients (21%) with CLL were withdrawn during the treatment phase; 4 patients (11%) were 
withdrawn due to AEs, which indicates that AEs were mostly manageable.  Almost all patients 
(37/38 [97%]) experienced an IRR.  The number of patients with Grade 3
4 IRRs was 11/38 
(29%).  As is typical for patients with CLL, blood and lymphatic system disorders were among the 
most frequently reported AEs, in particular neutropenia (13/38 patients [34%]), febrile neutropenia 
(5/38 patients [13%]), and thrombocytopenia (7/38 patients [18%]). 
Infections and infestations were common AEs, occurring in 21/38 patients (55%).  
Infections reported in more than one patient were nasopharyngitis (6 patients), bronchitis and 
sinusitis (4 patients each), influenza and lung infection (3 patients each), and herpes zoster and 
oral herpes (2 patients each). 
Thirteen patients (34%) died, 8 of these due to disease progression.  One patient died from 
an unspecified cause after withdrawal from the study for lack of response.  This patient had 
received subsequent experimental therapies and had stable CLL at the time she died.  For 4 
additional patients, 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 obinutuzumab as monotherapy, BO20999 and BO21003, 
patients with CLL appeared to be at a higher risk of experiencing an AE of special interest than 
patients with NHL.  The largest difference in the incidences was seen for neutropenia (occurring 


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in 47% of patients with CLL [18/38] vs. 8% of patients with aNHL [4/49] and 8% of patients 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 patients have experienced TLS (six in total); four patients 
in the aNHL population (population including MCL) and one patient each in the CLL and iNHL 
populations. 
Infections have been reported in 20/49 aNHL patients (41%), 74/156 iNHL patients (47%), 
and 21/38 CLL patients (55%).  One iNHL patient was withdrawn from the study because of an 
infection.  In addition, one CLL patient and one iNHL patient 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 patients were withdrawn from treatment due to an AE of special 
interest, all for IRRs.  An additional patient in the iNHL group discontinued treatment because of 
an infection.  This indicates that these events were generally manageable. 
In the Phase III Study BO21004 (CLL11), comparison of obinutuzumab + chlorambucil to 
chlorambucil alone showed that the most common AEs (all grades, Grades 3 − 4), respectively, 
were IRRs (69% vs. 0, 21% vs. 0), neutropenia (40% vs. 18%, 34% vs. 16%), thrombocytopenia 
(15% vs. 7%, 11% vs. 3%), anemia (12% vs. 10%, 4% vs. 5%), leukopenia (7% vs. 0, 5% vs. 0), 
pyrexia (10% vs. 7%,   1 vs. 0), and cough (10% vs. 7%, 0 vs.   1%). 
The incidence of IRRs was 69% with the first infusion of obinutuzumab.  The incidence of 
Grade 3 or 4 IRRs was 21%, with 8% of patients discontinuing therapy.  The incidence of reactions 
with subsequent infusions was 3%, with the second 1000-mg dose and <1% thereafter.  No Grade 
3 or 4 IRRs were reported beyond the first 1000- mg infusion.  Of the first 53 patients receiving 
obinutuzumab in the trial, 47 (89%) experienced an IRR.  After this occurrence, study protocol 
modifications were made to require pre-medication with a corticosteroid, antihistamine, and 
acetaminophen.  The first dose was also divided into two infusions (100 mg on Day 1 and 900 mg 
on Day 2).  Of the 45 patients for whom these mitigation measures were implemented, 21 patients 
(47%) experienced a reaction with the first 1000-mg dose and <2% thereafter. 
The incidence of neutropenia reported as an AE was 40% in the obinutuzumab-treated arm 
and 18% in the chlorambucil-alone arm, with the incidence of SAEs being 1% and 0%, 
respectively.  Cases of late-onset neutropenia (occurring 28 days after completion of treatment or 
later) were 16% in the obinutuzumab-treated arm and 12% in the chlorambucil-alone arm.  
The incidence of infections was similar between arms.  Thirty-eight percent of patients in 
the obinutuzumab- treated arm experienced an infection, 9% were Grade 3 − 4, and none were 
fatal.  


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The incidence of thrombocytopenia reported as an AE was 15% in the 
obinutuzumab-treated arm and 7% in the chlorambucil-alone arm.  Five percent of patients in the 
obinutuzumab-treated arm experienced acute thrombocytopenia (occurring within 24 hours after 
the obinutuzumab infusion).  
The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the obinutuzumab-treated 
arm vs. 0% in the chlorambucil-alone arm.  
AEs related to musculoskeletal disorders, including pain (System Organ Class), have been 
reported with obinutuzumab with higher incidence than with the comparator (17% vs. 13%, 
respectively) (Goede et al. 2013). 
1.6.4. 
Risks Associated with Obinutuzumab Therapy 
1.6.4.1. 
Hepatitis B Virus Reactivation 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure, and death, can occur in patients treated with anti-CD20 antibodies such as obinutuzumab.  
HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) 
positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) 
positive.  Reactivation has also occurred in patients who appear to have resolved hepatitis B 
infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] 
positive).  HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a 
rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously 
HBsAg negative and anti-HBc positive.  Reactivation of HBV replication is often followed by 
hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver 
failure, and death.  
All patients will be screened for HBV infection by measuring HBsAg and anti-HBc before 
initiating treatment with obinutuzumab. For patients who show evidence of hepatitis B infection 
(HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), 
physicians with expertise in managing hepatitis B will be consulted regarding monitoring, and 
initiation of HBV antiviral therapy will be considered.  
Patients with evidence of current or prior HBV infection will be monitored for clinical and 
laboratory signs of hepatitis or HBV reactivation during and for several months following 
treatment with obinutuzumab.  HBV reactivation has been reported for other CD20-directed 
cytolytic antibodies following completion of therapy.  
In patients who develop reactivation of HBV while receiving obinutuzumab, immediately 
discontinue obinutuzumab and any concomitant chemotherapy, and institute appropriate 
treatment.  Resumption of obinutuzumab in patients whose HBV reactivation resolves should be 
discussed with physicians with expertise in managing hepatitis B.  Insufficient data exist regarding 
the safety of resuming obinutuzumab in patients who develop HBV reactivation.  


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1.6.4.2. 
Progressive Multifocal Leukoencephalopathy  
JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which 
can be fatal, was observed in patients treated with obinutuzumab.  Consider the diagnosis of PML 
in any patient presenting with new onset or changes to pre-existing neurologic manifestations.  
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic 
resonance imaging (MRI), and lumbar puncture.  Discontinue obinutuzumab therapy and consider 
discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in 
patients who develop PML.  
1.6.4.3. 
Infusion-Related Reactions  
Obinutuzumab can cause severe and life-threatening IRRs.  Two-thirds of patients 
experienced a reaction to the first 1000 mg of obinutuzumab infusion.  IRRs can also occur with 
subsequent infusions.  Symptoms may include hypotension, tachycardia, dyspnea, and respiratory 
symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, and laryngeal edema).  
Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, 
pyrexia, and chills.  
Pre-medicate patients with acetaminophen, antihistamine, and a glucocorticoid.  Institute 
medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for IRRs 
as needed.  Closely monitor patients during the entire infusion.  IRRs within 24 hours of receiving 
obinutuzumab have occurred.  
For patients with any Grade 4 IRRs, including but not limited to anaphylaxis, acute life-
threatening respiratory symptoms, or other life-threatening infusion reaction, stop the 
obinutuzumab infusion.  Permanently discontinue obinutuzumab therapy.  
For patients with Grade 1, 2, or 3 IRRs, interrupt obinutuzumab for Grade 3 reactions until 
resolution of symptoms.  Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and 
manage symptoms. 
For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently 
throughout the infusion and the post-infusion period because these patients may be at greater risk 
of experiencing more severe reactions.  Hypotension may occur as part of the obinutuzumab IRR.  
Consider withholding antihypertensive treatments for 12 hours prior to, during, and for the first 
hour after administration of each obinutuzumab infusion until blood pressure is stable.  For patients 
at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their 
hypertensive medication as is suggested here.  
1.6.4.4. 
Tumor Lysis Syndrome  
Acute 
renal 
failure, 
hyperkalemia, 
hypocalcemia, 
hyperuricemia, 
and/or 
hyperphosphatemia from TLS can occur within 12 − 24 hours after the first infusion.  Patients with 
high tumor burden and/or high circulating lymphocyte count (  25  109/L) are at greater risk for 
TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., 


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allopurinol) and hydration beginning 12 − 24 hours prior to the infusion of obinutuzumab.  For 
treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and 
administer supportive care, including dialysis as indicated.  
1.6.4.5. 
Infection  
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following obinutuzumab therapy.  Do not administer obinutuzumab to patients with an active 
infection.  Patients with a history of recurring or chronic infections may be at increased risk of 
infection.  
1.6.4.6. 
Neutropenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% 
of patients in clinical trials.  Patients with Grade 3 to 4 neutropenia should be monitored frequently 
with regular laboratory tests until resolution.  Anticipate, evaluate, and treat any symptoms or signs 
of developing infection.  Neutropenia can also be of late onset (occurring more than 28 days after 
completion of treatment) and/or prolonged (lasting longer than 28 days).  
Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis 
throughout the treatment period.  Antiviral and antifungal prophylaxis should be considered.  
1.6.4.7. 
Thrombocytopenia  
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia 
in 12% of patients in clinical trials.  In 5% of patients, obinutuzumab caused an acute 
thrombocytopenia occurring within 24 hours after the obinutuzumab infusion.  In patients with 
Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution.  
Transfusion of blood products (i.e., platelet transfusion) may be necessary. 
1.6.5. 
Summary of Pharmacokinetic and Pharmacodynamic Data for 
Obinutuzumab 
A two-compartment model comprising a time-varying clearance pathway and a linear 
clearance pathway provides an adequate description of the pharmacokinetics of obinutuzumab 
following intravenous (IV) administration in Studies BO20999 and BO21003.  Following the 
infusion of 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 at steady state) and a linear clearance pathway.  Tumor burden may 
potentially contribute significantly to the clearance of 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 patients with a high tumor burden may appear to clear 
the drug from the plasma faster than do patients with a low tumor burden because 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 obinutuzumab will 


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reduce the quantity of CD20-positive tumor cells.  Consequently, the number of 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 
obinutuzumab exposure. 
Treatment with obinutuzumab resulted in extensive B-cell depletion, with all patients 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. 
1.6.6 
Worsening of Pre-existing Cardiac Conditions 
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and 
tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart 
failure have occurred when treated with obinutuzumab. These events may occur as part of an 
IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored 
closely. In addition, these patients should be hydrated with caution in order to prevent a potential 
fluid overload. 
1.7 Overview of Safety of CHOP 
Risks and side effects related to Cyclophosphamide include: 
(Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, more than 20 and up to 100 may have: 
• Hair loss 
• Nausea, vomiting, loss of appetite 
• Sores in mouth 
• Infection, especially when white blood cell count is low 
• Absence of menstrual period which may decrease the ability to have children 
• Blood in urine 
 
Rev. 1/14,  
6/14


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, from 4 to 20 may have: 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions 
• Loss or absence of sperm which may lead to an inability to father children 
• Stuffy nose 
• Fluid around the heart 
 
RARE, AND SERIOUS 
In 100 people receiving Cyclophosphamide, 3 or fewer may have: 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body 
• Damage to the heart or heart failure which may cause shortness of breath, swelling of 
ankles, cough or tiredness 
• A new cancer including cancer of bone marrow (leukemia) caused by chemotherapy 
• Swelling of the body including the brain which may cause dizziness, confusion 
• Scarring of the lungs 
Risks and side effects related to Doxorubicin include: 
(Table Version Date: October 24, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, more than 20 and up to 100 may have: 
• Hair loss 
• Vomiting 
• Red colored urine, saliva, or sweat  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, from 4 to 20 may have: 
• Heart failure or heart attack which may cause shortness of breath, swelling of ankles, 
cough or tiredness which may occur years after the dose 
• Swelling of the body which may cause shortness of breath 
• Swelling and redness at the site of the medication injection or area of previous radiation 
• Belly pain 
• Sores in the mouth, throat or stomach 
• Nausea, diarrhea 
• Hepatitis which may cause yellow eyes and skin 
Rev. 1/14, 
6/14 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, from 4 to 20 may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Cancer of the bone marrow (leukemia) caused by chemotherapy 
• Damage to organs which may cause infection, bleeding, may require transfusions 
• Darkening of the nail beds or skin or hands and feet 
• Loss of nails 
 
RARE, AND SERIOUS 
In 100 people receiving Doxorubicin, 3 or fewer may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Severe blood infection 
Risks and side effects related to Vincristine include: 
(Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, more than 20 and up to 100 may have: 
• Constipation 
• Hair loss 
• Pain or redness at the site of injection 
• Numbness and tingling of fingers or toes 
• Headache, jaw pain and/or muscle pain 
• Weakness and difficulty walking 
• Swelling of lower legs 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require transfusion 
• Drooping eyelids 
• Hoarseness 
 
RARE, AND SERIOUS 
In 100 people receiving Vincristine, 3 or fewer may have: 
• Seizure 
Rev. 1/14, 
6/14 
Rev. 1/14, 
6/14 


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Risks and side effects related to Prednisone include: 
(Table Version Date: June 24, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, more than 20 and up to 100 may have: 
• In children and adolescents: decreased height 
• Loss of bone tissue 
• Mood swings 
• Skin changes, acne 
• Swelling of the body, tiredness, bruising 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Pain in belly 
• Increased appetite and weight gain 
• Weight gain in the belly, face, back and shoulders 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, from 4 to 20 may have: 
• Cloudiness of the eye, visual disturbances 
• Glaucoma 
• Infection 
• Non-healing wound 
• Diabetes 
• Damage to the bone which may cause joint pain and loss of motion 
• Kidney stones 
• Heartburn 
 
RARE, AND SERIOUS 
In 100 people receiving Prednisone, 3 or fewer may have: 
• Bleeding from sores in the stomach 
• Broken bones 
REPRODUCTIVE RISKS: 
You should not become pregnant or father a baby while on this study because the drugs in this 
study can affect a fetus. Women should not breastfeed a baby while on this study. It is important 
you understand that you need to use birth control while on this study. Check with your doctor 
about what kind of birth control methods to use and how long to use them. Some methods might 
not be approved for use in this study. The long-term effects of lenalidomide and chemotherapy with 


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RCHOP on your ability to have children in the future are unknown. You should discuss fertility 
preservation strategies with your doctor. 
 
 
1.8 Study Rationale   
As discussed in section “1.1.1 Treatment Options”, there are currently no standard of care 
management recommendations for patients that develop RT. Treatments of RT currently include 
the use of aggressive lymphoma combination regimens, but the response rates to these are poor 
and short lived. Given that CLL is considered a “disease of the elderly”, a significant number of 
patients who develop RT are not able to tolerate intensive regimens and die without the ability to 
receive any salvage therapy.  
Despite the advent of promising new drugs to clinical trials of patients with relapsed CLL 
and NHL over the last few years, patients with RT continue to be excluded from clinical trials. RT 
patients have dismal overall survival with a median ranging from five to eight months 
(Tsimberidou 2005), even in younger patients that would be better fit to tolerate current multidrug 
chemotherapy regimens. It is clear that there is an unmet need to study the novel investigational 
agents that are showing remarkable activity as monotherapy or in combination in CLL and NHL.  
Two case reports of ibrutinib monotherapy in RT have been published to date showing 
clinical activity. The first report from Blood Cancer Journal noted Ibrutinib had activity 
highlighted two cases of Richter’s Syndrome patients with activated-B-cell type (ABC) DLBCL. 
One case involved a 60-year old male with Rai stage IV CLL at diagnosis, with no chromosomal 
abnormalities who one month later developed rapidly progressive lymphadenopathy and was 
diagnosed with RS. The other case involved 59-year old male with Rai stage III CLL at diagnosis. 
His disease course was observed for eight years until he developed progressive lymphadenopathy, 
FISH showed trisomy 12 and deletion of p53 chromosomal abnormalities. Both patients were 
treated with chemotherapeutic regimens and neither were candidates for an allogeneic 
hematopoietic stem cell transplant. The first patient demonstrated 70% regression of his disease 
by CT scan one month after starting ibrutinib and 90% regression of disease after 3 months. The 
second patient was refractory to all treatments given prior to ibrutinib. Two months after beginning 
ibrutinib, CT scan showed 100% progression of neck adenopathy. Ibrutinib was discontinued after 
three months due to refractory response. Given the superior response of the first patient in contrast 
to that of the second patient, the data may suggest that ibrutinib is beneficial in RS patients with a 
certain genetic profile. A second report from the Mayo Clinic described the treatment of four 
patients with RS (Giri 2015) All patients experienced improvement in constitutional symptoms 
with two patients achieving a partial response, one patient achieving a complete response and one 
patient showing clinical activity as evidenced by a reduction in lymphadenopathy by physical 
exam (Wilson 2012).  
A recent phase 1b, open-label, non-randomized study was conducted involving 
histologically confirmed CD20-positive B-cell non-Hodgkin lymphoma patients in six centers 
within the USA and France (Younes 2014). The treatment regimen consisted of Ibrutinib plus R-
CHOP. Of the 33 patients enrolled, 32 completed treatment (one patient withdrew). 30 of the 32 
remaining patients achieved an overall response. The maximum tolerated dose was not achieved 


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and the highest dose administered, 560mg per day of Ibrutinib, was recommended for phase 2 
study. In this study, we will administer 560mg po daily of Ibrutinib as it has demonstrated clinical 
activity, safety, and tolerability in NHL patients in combination regimens. 
We propose the use of ibrutinib in combination with obinutuzumab with and without 
CHOP, the chemotherapy regimen traditionally used to treat Richter’s transformation. 
The incorporation of the targeted agents ibrutinib and obinutuzumab in patients with a 
Richter’s transformation may demonstrate improved responses and duration of responses, 
particularly given the outstanding responses from these drugs seen in both CLL and in NHL. This 
is a two-arm trial with two cohorts of patients based on their fitness to tolerate therapy. 
 
2. 
STUDY OBJECTIVE  
2.1. Primary Objective 
To determine the efficacy of combining Ibrutinib with obinutuzumab (with or without CHOP) as 
measured by overall response rate (ORR). 
 
2.2. Secondary Objectives 
• 
To assess the safety of Ibrutinib in combination with obinutuzumab as measured by the 
incidence of prolonged hematologic toxicity in cycle 1 in subjects with a diagnosis of 
Richter's Transformation (RT), hematologic improvement, progression-free survival (PFS), 
overall survival (OS), and quality of life. 
• 
Identify and correlate potential markers predictive of response to the combination therapy 
and associate pharmacogenetic findings to response and toxicity. 
2.3.Exploratory Objective(s)  
• To evaluate patient-reported outcome (PRO) of health-related quality of life by the 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACiT-Fatigue) scale 
• 
Exploratory Biomarker Assessments  
The following biomarker samples will be collected  
• Serum  
• Plasma  
• Blood  
• Archival tumor tissue, when feasible 
• Leftover tissue from Bone marrow biopsies and/or aspirates (if obtained as part of clinical 
disease response assessments and tissue is remaining after clinical analysis, including 
pathology reports), when feasible 
Requests for archival tissue and corresponding pathology report (i.e. samples obtained prior to 
study initiation) should be initiated at Cycle 1 Day 1. 


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• 
Correlative studies, to be performed depending on tissue availability. The following array 
will be performed for samples sent to Cancer Genetics or a local pathology laboratory and 
may be performed more than once. Whole exome sequencing will be done only once. 
o Selective array CGH for 15 distinct chromosomal regions, including 8q24 
(MYC), 18q21 (BCL2), 17p13 (TP53), 9p21 (CDKN2A), and 13q14. 
o Determination of B-cell clonality (by PCR) 
o Immunofluorescence and flow cytometry to characterize surface marker 
phenotype 
o Karyotyping 
o FISH: 
▪ 3q27 (BCL-6 breakpoint) 
▪ t(8;14) (MYC/IGH translocation) 
▪ t(14;18) (IGH translocation/BCL-2 translocation) 
o Immunohistochemistry: 
▪ Distinguish GCB versus non-GCB types of DLBCL 
▪ MYC 
▪ Ki-67  
▪ P53 
▪ Bcl-2 
▪ Bcl-6 
▪ CD30 
▪ EBER 
o Mutation analysis: 
▪ NOTCH1 
▪ SF3B1 
▪ TP53  
▪ MYD88 
 
3. 
STUDY DESIGN AND TREATMENT 
3.1. Overview of Study Design 
This is a nonrandomized open-label Phase II study of Ibrutinib 560mg daily in combination with 
obinutuzumab on days 1, 2, 8, and 15 of cycle 1 and then on day 1 of cycles 2-6 in subjects with 
RT. 


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3.1.1 Study Schema and Design Overview 
 
Figure 1. Study Design 
 
 
3.2.Study Design Rationale 
 
Study Design and Treatment 
 
This is a nonrandomized open-label Phase II study of Ibrutinib 560mg po daily in 
combination with Obinutuzumab, 100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 
8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2–6in subjects with RT. We propose a design 
to evaluate two study arms: fit and frail.  
Ibrutinib 560 mg, PO daily 
+ 
Obinutuzumab 100 mg on day 1 and 
900 mg on day 2 of Cycle 1, 1000 
mg on days 8 and 15 of Cycle 1, and 
1000 mg on day 1 of Cycles 2–6 
+ CHOP
Arm A (Fit) (n = 23) 
Cycle = 28 days 
Key eligibility 
 
•
Arm A, Fit 
•
≤80 yrs, CIRS < 6 
with adequate renal 
function(estimated 
creatinine clearance 
≥30 ml/min) 
•
Arm B, Frail  
•
≤80 yrs, CIRS ≥6  
for coexisting 
illnesses not related 
to CLL, creatinine 
clearance >30 
ml/min 
S 
T 
R 
A 
T 
I 
F   
Y 
 
Ibrutinib to continue until 
intolerance or progressive disease 
 
Two-arm trial with two cohorts of patients 
based on their ability to tolerate therapy 
Ibrutinib 560 mg, PO daily 
+ 
Obinutuzumab 100 mg on day 1 and 
900 mg on day 2 of Cycle 1, 1000 
mg on days 8 and 15 of Cycle 1, and 
1000 mg on day 1 of Cycles 2–6 
Arm B (Frail) (n=20) 


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Up to 50 subjects will be screened in the combination treatment groups: up to 20 patients 
will receive the combination ibrutinib and obinutuzumab alone (frail patients) and up to 23 patients 
will receive ibrutinib and obinutuzumab in combination with the CHOP regimen (fit patients).  
Each group will follow an independent but parallel design and will receive up to 6 cycles of 
infusion therapy.  
The primary objective of the study is to determine the efficacy of combining Ibrutinib with 
obinutuzumab (with or without “CHOP” chemotherapy regimen) as measured by overall response 
rate (ORR), defined as CR PR, or SD.   We plan to estimate the response rate and generate a 95% 
confidence interval (CI). Further development will proceed if the 95% CI will include 50%.  
Secondary objectives include assessment of the safety of Ibrutinib in combination with 
obinutuzumab and determination of progression-free survival (PFS) and overall survival (OS).  
Exploratory analysis will evaluate patient-reported outcome (PRO) health-related quality of life 
by FACiT-Fatigue scores. 
Patients who have no evidence of progressive disease after cycle 3 will be treated for up to 
3 additional 28 day cycles of the infusion regimen based on tolerability and lack of evidence of 
progressive disease. Ibrutinib will be continued indefinitely until progression of disease or toxicity.  
 
All patients will be treated with ibrutinib at a dose of 560 mg orally continuously with 
standard doses of 1000mg obinutuzumab as per package insert guidelines to be given for up to six 
cycles. Obinutuzumab [and CHOP treatment (“G-CHOP”) if in the fit cohort] will be stopped 
sooner than 6 cycles in subjects with unacceptable toxicity, disease progression, or achievement 
of complete remission with no evidence of minimal residual disease. Ibrutinib will be held in 
subjects with unacceptable toxicity.  
If investigator feels the toxicity is from chemoimmunotherapy rather than ibrutinib, patient 
will be allowed to continue on ibrutinib monotherapy while the toxicity from the other agents 
resolves or improves to a grade 1 toxicity. Concomitant chemoimmunotherapy regimen (G-CHOP) 
or immunotherapy (G) can be dose delayed if the toxicity occurs without interruption of ibrutinib 
administration if the investigator considers that ibrutinib is not contributing to or is not a direct 
cause of the toxicity.  
After treatment with obinutuzumab, or G-CHOP, is completed or stopped, patients achieving good 
response with tolerable side effects will continue on ibrutinib until progression of disease or undue 
toxicities. 
 
Toxicities will be scored using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. All adverse clinical experiences will be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and the 
patient’s outcome. To monitor for tumor lysis syndrome and cytopenia(s), the subjects will have 
blood drawn on days 1 through 3 of the first cycle of therapy, then days 8, 15, and 28 during the 
first cycle of therapy. Subjects will also have blood drawn on Day 1 and Day 15 during subsequent 
cycles of therapy. All subjects will receive prophylactic medications (allopurinol, acyclovir, 
bactrim, diflucan, levaquin) as clinically indicated. 


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4. 
 SUBJECT SELECTION 
4.1. Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
inclusion criteria: 
• 
Subjects ≥ 18 and ≤80 years of age 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
• Histologically confirmed Richter’s transformation in treatment-naive and previously treated 
CLL/SLL patients 
• 
Regimen-specific inclusions: 
Fit Group: Patients with prior BTK agent exposure (including Ibrutinib) may be included 
on the FIT arm.  
Frail Group: Patients who have had prior BTK inhibitors (including Ibrutinib) should 
not be included on the Frail arm. 
Patients may have had prior exposure to alternative B-cell signaling receptor agents including prior 
exposure to a Phosphoinositide 3-Kinase Delta (PI3Kd) inhibitor, and a Spleen tyrosine kinase 
(SYK) inhibitor. 
• Prior exposure to anti-CD20 monoclonal antibody 
• Willing and able to participate in all required evaluations and procedures in this study 
protocol 
• Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (in accordance with 
national and local subject privacy regulations) 
• 
Adequate hematologic function defined as:  
o Absolute neutrophil count ≥1000cells/mm3 (1.0 x 109/L).   
o Platelet count ≥50,000 cells/mm3 (50 X 109/L).  
 
o Hemoglobin >8.0 g/dL. 
• 
Adequate hepatic and renal function defined as: 
o Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper 
limit of normal (ULN). 
o Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault) 
o Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin) 
• 
PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN, unless patient has lupus anticoagulant or 
liver impairment due to lymphoma infiltration. 
• 
Documentation of CD20+ status (for B cell malignancies) 
  
• Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 


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history of bilateral oophorectomy). Female subjects of childbearing potential must have a 
negative serum pregnancy test upon study entry. 
• Male and female subjects who agree to use highly effective methods of birth control (e.g., 
implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual 
abstinence, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge 
etc.) during the period of therapy and for 30 days after the last dose of study drug 
 
4.2. Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Regimen-specific exclusions: 
• ARM A:  Fit Group: known hypersensitivity to any of the agents in the 
combination regimen or having a comorbidity that may affect patient’s ability to 
tolerate therapy at the investigator’s discretion. Patients with prior BTK agent 
exposure (including Ibrutinib) may be included on the FIT arm. 
• ARM B:  Frail Group: Known grade 4 hypersensitivity to a monoclonal antibody. 
Patients who have had prior BTK inhibitors (including Ibrutinib) should not be 
included on the Frail arm. 
• Chemotherapy 21 days prior to first administration of study treatment 
• Biologic immunotherapy 10 days prior to days prior to first administration of 
study treatment 
• BCR inhibitors 24 hours days prior to first administration of study treatment 
• Major surgery, excluding diagnostic tissue biopsies, within 4 weeks of first dose 
• Any of the following laboratory abnormalities: 
o Absolute neutrophil count (ANC) < 1000 cells/mm3 (1.0 x 109/L) 
o Platelet count <50,000/mm3 (<50 x 109/L)  
o Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 
>2.5 x upper limit of normal (ULN) 
o Estimated Creatinine Clearance ≤30 ml/min (Cockcroft-Gault) 
o Bilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin) 
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk. 
• History of other malignancies, except:  
o Malignancy treated with curative intent and with no known active disease present 
for ≥2 years before the first dose of study drug and felt to be at low risk for 
recurrence by treating physician. 
o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease. 


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o Adequately treated carcinoma in situ without evidence of disease.  
• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or 
chronic administration [>14 days] of >20 mg/day of prednisone) within 28 days of the first 
dose of study drug. 
• Recent infection requiring systemic treatment that was completed ≤14 days before the first 
dose of study drug. 
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade ≤1, or to the 
levels dictated in the inclusion/exclusion criteria with the exception of alopecia. 
• Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia. 
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or 
hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain 
reaction (PCR) result before enrollment.  Those who are PCR positive will be excluded.  
• Any uncontrolled active systemic infection. 
• Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to randomization. 
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 
• Concomitant use of warfarin or other Vitamin K antagonists. 
• Subjects who received a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to 
the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A 
inhibitor. (see Appendix 3) 
• 
Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal 
infections of nail beds) or any major episode of infection requiring treatment with IV 
antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 
weeks before the start of Cycle 1 
• 
Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia 
virus 1 (HTLV-1) seropositive status 
• 
Women who are pregnant or lactating 
• 
Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an 
adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier 
method of contraception in conjunction with spermicidal jelly. 
• 
Effective contraception is required while receiving obinutuzumab.  For women, effective 
contraception is required to continue for  12 months after the last dose of obinutuzumab.  
For men, effective contraception is required to continue for 3 months after the last dose of 
obinutuzumab treatment. 


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• Currently active, clinically significant hepatic impairment Child-Pugh class  C according to 
the Child Pugh classification (see Appendix 4) 
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug 
 
5. 
TREATMENT OF SUBJECTS  
5.1.Study treatment 
This is a nonrandomized open-label Phase II study of Ibrutinib 560mg daily in combination with 
obinutuzumab  100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 8 and 15 of 
Cycle 1, and 1000 mg on day 1 of Cycles 2–6 in subjects with RT.  Each cycle will consist of 28 
days. 
 
For those subjects accrued to the fit arm (ARM A), they will also receive cyclophosphamide (IV) 
at 750 mg/m² on day 1 of cycles 1-6, hydroxydaunorubicin (IV) at 50 mg/m² on day 1 of cycles 
1-6, oncovin (vincristine) (IV) at 1.4 mg/m² (max. 2 mg) on day1 of cycles 1-6, and prednisone 
or equivalent (PO) at a flat dose of 100mg flat dose per day, or dosage as investigator sees fit on 
days 1-5 of cycles 1-6. Up to 50 subjects will be screened for enrollment in the combination 
treatment groups: up to 20 patients will receive the combination ibrutinib and obinutuzumab 
alone (frail patients) and up to 23 patients will receive ibrutinib and obinutuzumab in 
combination with the CHOP regimen (fit patients). 
 
All patients will be treated with ibrutinib at a dose of 560 mg orally daily with standard doses of 
1000mg obinutuzumab as per package insert guidelines to be given for up to six cycles. 
Obinutuzumab [and CHOP treatment (“G-CHOP”) if in the fit cohort] will be stopped sooner 
than six cycles in subjects with unacceptable toxicity, disease progression, or achievement of 
complete remission with no evidence of minimal residual disease. Ibrutinib will be held in 
subjects with unacceptable toxicity. After treatment with obinutuzumab or G-CHOP is 
completed or stopped, patients achieving good response with tolerable side effects will continue 
on Ibrutinib until progression of disease or undue toxicities. 
5.2.Study Medication 
5.2.1. 
Ibrutinib  
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  All 
formulation excipients are compendial and are commonly used in oral formulations.  Refer to the 
ibrutinib Investigator's Brochure for a list of excipients.  
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drug bottles will be dispensed in child-resistant packaging.   
 


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Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.2.1.1. 
Dose and Administration  
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily. The capsules are to be 
taken around the same time each day 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. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges 
should be avoided for the duration of the study (Appendix 3). 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day.  The subject should not take extra 
capsules to make up the missed dose. 
The first dose will be delivered in the clinic on Day 1, 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 accountability 
records updated at each visit.  Returned capsules must not be re-dispensed to anyone. 
5.2.1.2. 
Overdose 
There is no specific experience in the management of ibrutinib overdose in patients. 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 up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingest more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 11.4 for further information regarding AE reporting.   
5.2.1.3. 
Dose Modification for Adverse Reactions 
If investigator feels adverse reactions are related to chemoimmunotherapy rather than ibrutinib, 
patient will be allowed to continue on ibrutinib monotherapy while the toxicity from the other 
agents resolves. Concomitant chemoimmunotherapy regimen (G-CHOP) or immunotherapy (G) 
can be dose delayed if the toxicity occurs without interruption of ibrutinib administration if the 
investigator considers that ibrutinib is not contributing to or is not a direct cause of the toxicity.  
The dose of the ibrutinib study drug should be modified according to the dose modification 
guidelines in Table 1 if any of the following toxicities occur: 


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• 
Grade 4 ANC (<500/µL) for more than 7 days. The use of neutrophil growth factors is 
permitted per American Society of Clinical Oncology (ASCO) guidelines9  
 
• 
Grade 3 thrombocytopenia (<50,000/µL) for subjects with normal platelet count at 
baseline or, for subjects with baseline thrombocytopenia, a platelet decrease of 50% to 
74% from baseline in the presence of >Grade 2 bleeding  
• 
Grade 4 thrombocytopenia (<25,000/µL) or for subjects with baseline thrombocytopenia, 
platelet decrease of ≥75% from baseline or <20,000/μL, whichever is higher 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy.  
• 
Any other Grade 4 or unmanageable Grade 3 toxicity. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 6.2.4). 
Table 1. Ibrutinib Dose Modifications 
Occurrence 
Action to be Taken 
First 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 
original dose level 
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 
dose level lower (420 mg per day for 560 mg /day dose ) 
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 
dose level lower (280 mg per day for 560 mg /day dose ) 
Fourth 
Discontinue study drug 
 
A high number of circulating malignant cells (>400000/mcL) may confer increased risk of 
leukostasis; 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. 
 
At the Investigator’s discretion, the dose of ibrutinib may be re-escalated after 2 cycles of a dose 
reduction in the absence of a recurrence of the toxicity that led to the reduction. 
 
Dose Modification for Hepatic Impaired Subjects 
 
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 5.2.1.3. Ibrutinib is 
metabolized in the liver and therefore subjects with clinically significant hepatic impairment at 
the time of screening (Child- Pugh class C) are excluded from study participation. Concomitant 
use of strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment. Refer 


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to Appendix 6 for Child-Pugh classification. Please refer to Table 2 for dose modification due to 
hepatic impairment.    
 
Table 2. 
Dose Modification Guidance for Hepatic Impaired Subjects 
 
 
Child Pugh class A 
(Mild hepatic 
impairment)* 
Child Pugh Class B 
(Moderate hepatic 
impairment)** 
Child Pugh class 
C  
(Severe hepatic 
impairment)  
 
Ongoing at 
time of 
enrollment  
Develops 
during 
study  
Ongoing at 
time of 
enrollment  
Develops 
during study  
Develops during 
study  
Ibrutinib 
Dose 
(daily)  
280 mg  
280mg 
140 mg 
140 mg  
Hold until 
improves to 
moderate [Class 
B] or better) 
 
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In 
the event that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity 
until resolution. 
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until 
resolution. 
5.2.2. 
Obinutuzumab 
5.2.3. 
Obinutuzumab 
5.2.3.1. 
Formulation 
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 1000 mg of 
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). 
5.2.3.2. 
Storage 
The recommended storage conditions for the obinutuzumab drug product are between 2C and 
8C, protected from light.  Chemical and physical in-use stability for 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.  Obinutuzumab should not be frozen 


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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. 
Preparation 
Obinutuzumab drug product intended for IV infusion is prepared by dilution of the drug product 
into an infusion bag containing 0.9% NaCl.  
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 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 and discard 4 mL of the sodium chloride.  Withdraw 4 mL of obinutuzumab from a 
single glass vial and inject it into the infusion bag (discard any unused portion of 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 and discard 36 mL of the sodium chloride.  Withdraw 36 mL of obinutuzumab from a 
single glass vial and inject it into the infusion bag (discard any unused portion of 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 1000-mg dose:  The final drug concentration of a 1000-mg dose should be 4 
mg/mL.  Using a 250-mL infusion bag containing 0.9% NaCl, withdraw and discard 40 mL of 
the NaCl.  Withdraw 40 mL of obinutuzumab from a single glass vial and inject it into the 
infusion bag (discard any unused portion of 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 obinutuzumab beyond the expiration date stamped on the carton. 
5.2.4. 
Dosage and Administration 
Obinutuzumab administered by IV infusion for up to 6 cycles (28-day cycles): 
• 
On Cycle 1, Day 1, 100 mg obinutuzumab will be administered 
• 
On Cycle 1, Day 2, 900 mg of obinutuzumab will be administered  


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• 
On Cycle 1, Days 8 and 15, 1000 mg of obinutuzumab will be administered.  
• 
On Cycles 2 − 6, Day 1, 1000 mg of obinutuzumab will be administered (see Table 2) 
 
Obinutuzumab must be administered in a clinical setting (inpatient or outpatient).  Full 
emergency resuscitation facilities should be immediately available, and patients should be under 
close supervision by the investigator at all times.  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 obinutuzumab.  Do not administer as an IV push or bolus.  
After the end of the first infusion, the IV line should remain in place for at least 2 hours in order 
to be able to administer IV drugs if necessary.  If no AEs occur after 2 hours, the IV line may be 
removed.  For subsequent infusions, the IV line should remain in place for at least 1 hour from 
the end of infusion; if no AEs occur after 1 hour, the IV line may be removed. 
If the subject has an infusion-related reaction, the obinutuzumab infusion could be given at a later 
date during the cycle. If the subject doesn’t tolerate the dose of obinutuzumab on Cycle 1, Day 2 
or in the event that the duration of the infusion will last longer than the outpatient facility operating 
hours, the patient may be admitted to the hospital for completion of the infusion without this being 
considered an SAE. 
5.2.4.1. 
Premedication Requirements 
Infusion-Related Reactions 
Since some patients may develop hypersensitivity or other IRRs to obinutuzumab, pre-
medication is recommended to reduce the risk of infusion reactions as outlined below: 
• 
Cycle 1, Days 1 and 2, all patients require pre-medication with:  
• IV glucocorticoid: dexamethasone (20 mg) or methylprednisolone (80 mg) administered 
at least one hour prior to obinutuzumab infusion.  Hydrocortisone should not be used as 
it has not been effective in reducing rates of IRR.  
• An oral acetaminophen (1000 mg) and an antihistamine such as diphenhydramine (50 
mg) administered at least 30 minutes before starting each obinutuzumab infusion. 
• 
Cycle 1, Days 8 and 15 and Cycles 2-6, Day 1:  
• All patients require pre-medication with oral acetaminophen (1000 mg) administered at 
least 30 minutes before starting each obinutuzumab infusion. 
• Patients 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 obinutuzumab infusion. 
• Patients 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 obinutuzumab infusion.  Hydrocortisone 
should not be used as it has not been effective in reducing rates of IRR.  
 


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Hypotension may be expected to occur during obinutuzumab infusions.  Withholding of 
antihypertensive treatments should be considered for 12 hours prior to and throughout each 
obinutuzumab infusion and for the first hour after administration.  Patients at acute risk of 
hypertensive crisis should be evaluated for the benefits and risks of withholding their 
hypertensive medication. 
For TLS prophylaxis, see Section 5.3.1.1. 
5.2.4.2. 
Obinutuzumab Dosing 
The first 1000 mg of obinutuzumab will be administered over 2 days.  During Cycle 1, Day 1, 
100 mg will be administered.  On the following day (Cycle 1, Day 2), 900 mg will be 
administered (see Table 2). 
Table 2 
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 
1000 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 
1000 mg 
Cycles 2−6 
Day 1 
1000 mg 
 
If a patient experiences 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 patient 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 patient does not experience any infusion reaction 
symptoms, infusion rate escalation may resume at the increments and intervals as 
appropriate for the treatment dose. 
 


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5.2.5. 
Dosage Modification/Toxicity Management 
If a patient experiences an IRR of any grade during infusion, adjust the infusion as follows:  
• 
Grade 4 (life-threatening):  Stop infusion immediately and permanently discontinue 
obinutuzumab therapy.  
• 
Grade 3 (severe):  Interrupt infusion and manage symptoms.  Upon resolution of symptoms, 
consider restarting obinutuzumab infusion at no more than half the previous rate (the rate 
being used at the time that the IRR occurred) and, if the patient does not experience any further 
infusion-reaction symptoms, the infusion rate escalation may resume at the increments and 
intervals appropriate for the treatment cycle dose.  Permanently discontinue treatment if a 
patient experiences a Grade 3 infusion-related symptom at re-challenge.  
• 
Grade 1 − 2 (mild to moderate):  Reduce the infusion rate or interrupt infusion and treat 
symptoms.  Upon resolution of symptoms, continue or resume infusion and, if the patient does 
not experience any further infusion-reaction symptoms, infusion rate escalation may resume 
at the increments and intervals appropriate for the treatment cycle dose.  
 
5.2.5.1. 
Assessment of Hematologic Toxicities 
The evaluation of potential treatment-induced toxicity in patients 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 patients 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 
patients would be considered to have Grade 2 − 4 hematologic toxicity at presentation. 
As a consequence, dose modification decisions for patients with cytopenia (below the lower limit 
of the normal range) at baseline will be based on the NCI sponsored Working Group (NCI-WG) 
grading scale for hematologic toxicity in CLL studies (Hallek et al. 2008).  For patients with a 
normal neutrophil count, platelet count, and/or hemoglobin value at baseline, the NCI CTCAE, 
v4.0, will be used. 
5.2.5.2. 
Dosage Modifications 
Consider treatment interruption if a patient experiences an infection, Grade 3 or 4 cytopenia, or 
a   Grade 2 non-hematologic toxicity.  
5.2.5.3. 
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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5.2.5.4. 
Hepatitis B Virus Reactivation 
Positive serology for Hepatitis B is defined as positivity for Hepatitis B surface antigen (HBsAg) 
or Hepatitis B core antibody (anti-HBc).  Patients who are positive for anti-HBc may be 
considered for inclusion in the study by the Medical Monitor on a case-by-case basis if they are 
Hepatitis B viral DNA negative and are willing to undergo ongoing HBV DNA testing by real-
time PCR.  Patients with positive serology may be referred to a hepatologist or gastroenterologist 
for appropriate monitoring and management.   
For the subset of patients 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 3. 
Table 3 
Management of Hepatitis B Reactivation 
Hepatitis B Viral 
DNA Level by Real-
Time PCR 
Guideline 
 100 IU/mL 
• Hold obinutuzumab  
• Begin anti-viral medication and treat for at least 1 year after 
the last dose of obinutuzumab. 
• Immediately refer the patient to a gastroenterologist or 
hepatologist for management. 
• Resume obinutuzumab once Hepatitis B viral DNA levels 
decrease to undetectable levels. 
 100 IU/mL 
while on 
anti-viral 
medication 
Discontinue obinutuzumab. 
29−100 IU/mL 
Retest within 2 weeks. 
If still hepatitis B viral DNA positive: 
• Hold obinutuzumab  
• Begin anti-viral medication and treat for at least 1 year after 
the last dose of obinutuzumab. 
• Immediately refer the patient to a gastroenterologist or 
hepatologist for management 
• Resume obinutuzumab once Hepatitis B viral DNA levels 
decrease to undetectable levels 
 
5.2.5.5. 
Management of Infusion-Related Reactions and Anaphylaxis 
Please refer to Section 5.3.1 for information relating to permitted concomitant medications.  
Medications (including subcutaneous epinephrine, corticosteroids, and intravenous 
diphenhydramine) and resuscitation equipment should be available for immediate use. 


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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, obinutuzumab should be discontinued and no additional 
obinutuzumab should be administered.  Patients who experience any of these reactions should 
receive aggressive treatment of symptoms and will be discontinued from study treatment. 
Tumor Lysis Syndrome 
For patients with evidence of TLS, obinutuzumab should be discontinued and the patient treated 
as clinically indicated.  Following the complete resolution of TLS complications, obinutuzumab 
may be re administered at the full dose during the next infusion in conjunction with prophylactic 
therapy. 
5.3. Concomitant and Excluded Therapies 
5.3.1. 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient 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). 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use.  Effective contraception is required while receiving 
obinutuzumab.  For women, effective contraception is required to continue for  12 months after 
the last dose of obinutuzumab.  For men, effective contraception is required to continue for  3 
months after the last dose of obinutuzumab. 
5.3.1.1. 
Prophylaxis for Tumor Lysis Syndrome 
All patients with peripheral blood lymphocyte counts of  25  109/L or bulky lymphadenopathy 
must receive prophylaxis for TLS prior to the initiation of study treatment.  This includes 
appropriate hydration consisting of a fluid intake of approximately 3 L/day starting 1 to 2 days 
prior to the first dose of obinutuzumab and administration of allopurinol (300 mg/day orally) or a 
suitable alternative treatment starting prior to the first infusion of obinutuzumab (Cycle 1, Day 
1).  All patients should then be carefully monitored during the initial weeks of treatment.  
Patients still considered at risk for TLS because of persistently high tumor burden (i.e., 
peripheral blood lymphocyte counts  25  109/L) before the second and subsequent infusions of 
obinutuzumab should continue TLS prophylaxis with allopurinol and adequate hydration until 
the risk is abated, as determined by the investigator.   
5.3.1.2. 
Infections Prophylaxis 
Pneumocystis jirovecii pneumonia prophylaxis (160 mg trimethoprim/800 mg sulfamethoxazole 
orally twice daily or suitable alternative according to each site’s institutional standards) and anti-


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herpetic viral prophylaxis are recommended for patients with CLL during treatment and for up to 
12 months following treatment as appropriate.  
It is strongly recommended that patients with neutropenia receive antimicrobial prophylaxis 
throughout the treatment period.  Antiviral and antifungal prophylaxis should be considered.     
5.3.1.3. 
Other Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the study 
according to each site’s institutional standards, including the use of growth factors (e.g., 
erythropoietin) if clinically indicated.  G-CSF may be administered as primary prophylaxis in 
each cycle of therapy according to the American Society of Clinical Oncology (ASCO) 
guidelines (Smith et al. 2006) or each site’s institutional standards. 
The use of live viral vaccines is contraindicated.  Responses to inactivated vaccines, recombinant 
vaccines, and cell-wall vaccines are unreliable and suboptimal in CLL patients.  
5.4. Criteria for Permanent Discontinuation of Study Drug 
5.5. Obinutuzumab-Specific Criteria 
Patients who meet the following criteria should be discontinued from the study: 
• 
Active HBV infection or hepatitis 
• 
Severe or life-threatening anaphylaxis or hypersensitivity reaction 
Patients 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. 
5.6. General Criteria 
• 
Inability of patient to comply with study requirements 
• 
Determination by the investigator that it is no longer safe for the patient to continue therapy 
 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
6.1. Permitted Concomitant Medications 
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 2006).  Transfusions may be given in accordance with institutional 
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Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (e.g., 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. 
6.2. Medications to be Used with Caution 
6.2.1. 
CYP3A- Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A. Concomitant use of ibrutinib with drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure. Dose adjustment of 
ibrutinib due to concomitant use of CYP3A inhibitors should follow Table 4.  
Table 4. 
Dose Modification Guidance for CYP3A Inhibitors/Inducers 


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Patient Population 
Co-administered Drug 
Recommended Ibrutinib Dose for the 
Duration of the Inhibitor Usea 
B-Cell 
Malignancies 
Mild CYP3A inhibitors 
420 mg or 560 mg once daily per 
indication. No dose adjustment required. 
Moderate CYP3A inhibitors 
280 mg once daily. 
Voriconazole  
Posaconazole at doses less than or 
equal to suspension 200 mg BID  
140 mg once daily. 
Other strong CYP3A inhibitors 
Posaconazole at higher dosesb  
Avoid concomitant use and consider 
alternative with less CYP3A inhibitory 
potential. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib. 
If the benefit outweighs the risk, and 
long-term dosing with a CYP3A 
inhibitor is required (more than seven 
days), reduce ibrutinib dose to 140 mg 
once daily for the duration of the 
inhibitor use. 
Chronic Graft 
versus Host 
Disease 
Mild CYP3A inhibitors 
420 mg once daily. No dose adjustment 
required. 
Moderate CYP3A inhibitors  
420 mg once daily. No dose adjustment 
required. 
Voriconazole  
Posaconazole at doses less than or 
equal to suspension 200 mg BID  
280 mg once daily. 
Posaconazole at higher dosesb 
140 mg once daily. 
Other strong CYP3A inhibitors 
 
Avoid concomitant use and consider 
alternative with less CYP3A inhibitory 
potential. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib. 
If the benefit outweighs the risk and 
long-term dosing is required (more than 
seven days), reduce ibrutinib dose to 140 
mg once daily for the duration of the 
inhibitor use. 


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a. 
Monitor for adverse reactions to IMBRUVICA and interrupt or modify dose as recommended (see Dosage and 
Administration). 
b. 
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole 
IV injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily).  
 
After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib.  
Avoid concomitant use of strong CYP3A inducers (e.g., 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 3.  A comprehensive 
list of inhibitors, inducers, and substrates may be found at → 
http://medicine.iupui.edu/clinpharm/ddis/main-table/  
This website is continually revised and should be checked frequently for updates. 
6.2.2. 
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), nor other 
major transporters, except OCT2, but is a mild inhibitor (with an IC50 of 2.15 μg/mL) of P-gp 
and breast cancer resistance protein (BCRP).  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 are no clinical data available; therefore, to 
avoid a potential interaction in the GI tract, narrow therapeutic range P-gp or BCRP substrates 
such as digoxin, should be taken at least 6 hours before or after ibrutinib. Ibrutinib may also 
inhibit BCRP systemically and increase the exposure of drugs that undergo BCRP-mediated 
hepatic efflux, such as rosuvastatin. 
Based on preliminary data from the combination studies of ibrutinib and venetoclax, venetoclax 
exposure (area under the concentration-time curve [AUC]) at 400 mg QD appears to be 
approximately 1.6-fold higher with 420 mg ibrutinib (chronic lymphocytic leukemia [CLL], 
N=32) and approximately 2-fold higher with 560 mg ibrutinib (mantle cell lymphoma [MCL], 
N=6) compared with venetoclax single agent exposure. 
 
Within the same dataset, ibrutinib exposures when dosed in combination with venetoclax were 
comparable to those observed at the respective therapeutic dose levels of ibrutinib single agent. 
To date, no new safety signals have been identified in the ongoing combination studies. Patients 
should be closely monitored for signs of toxicity. 
6.2.3. 
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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6.2.4. 
Antiplatelet Agents and Anticoagulants 
  Use ibrutinib with caution in subjects requiring other anticoagulants or medications that inhibit 
platelet function. In an in vitro platelet function study, inhibitory effects of ibrutinib on 
collagen-induced platelet aggregation were observed. Supplements such as fish oil and vitamin E 
preparations should be avoided. Bleeding events of any grade, including bruising and petechiae, 
occurred in subjects treated with ibrutinib. Ibrutinib should be held at least three to seven days 
pre- and post-surgery depending upon the type of surgery and the risk of bleeding (see Section 
6.4) Subjects with congenital bleeding diathesis have not been studied. 
6.3.Prohibited Concomitant Medications 
Any non-study protocol related chemotherapy, anticancer immunotherapy, experimental therapy, 
or radiotherapy are prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying malignancy 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 (e.g., erythropoietin) and neutrophil growth factors (e.g., 
filgrastim and peg-filgrastim) are also prohibited (e.g., initial treatment, DLT assessment 
period). 
6.4. 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:   
6.4.1. 
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.   
6.4.2. 
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.   


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6.4.3. 
Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, or for at least 7 days after the urgent surgical procedure, whichever is longer. 
7. 
STUDY EVALUATIONS 
7.1. 
Screening/Administrative 
All screening clinical and laboratory assessments must be performed within 30 days of first dose 
of study drug and prior to randomization. 
7.1.1. 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed.  In addition, subjects must sign all approved ICF amendments per the 
site IRB/REB/IEC guidelines during the course of the study.  
7.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4).   
The subject’s complete history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis and list of 
all prior anticancer treatments, dates administered, and responses and duration of response to 
these treatments, also will be recorded.  
7.1.3. 
Prior and Concomitant Medications 
All medications from the time of signed consent through 30 days after the last dose of study drug 
will be documented.  After a subject discontinues study treatment, receipt of all subsequent 
anticancer therapies will be collected until death, subject withdrawal of full consent, loss to 
follow-up, or study termination by Sponsor, whichever comes first. 
7.1.4. 
Adverse Events 
The accepted regulatory definition for an adverse event is provided in Section 11.  All medical 
occurrences that meet the adverse event definition must be recorded from the time the ICF is 
signed until 30 days after the last dose of ibrutinib.  Laboratory abnormalities designated 
clinically significant by the Investigator will also be recorded as adverse events.  Additional 


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important requirements for adverse event and serious adverse event reporting are explained in 
Section 11.3.4. 
7.1.5. 
Physical Examination 
The Screening, Week 1, Suspected PD, End-of-Treatment and Follow-Up physical examination 
will include, at a minimum, the general appearance of the subject, height (screening only) and 
weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, nervous system, and lymphatic system. 
A limited symptom-directed physical examination will be required after Week 1 at time points 
specified in the Schedule of Assessments (Appendix 1).  
7.1.6. 
ECOG 
The ECOG performance index is provided in (Appendix 2).  The ECOG performance status will 
be assessed at time points specified in the Schedule of Assessments (Appendix 1).   
7.1.7. 
Vital Signs 
Vital signs will include weight, blood pressure, heart rate, respiratory rate, and body temperature 
and will be assessed at time points specified in the Schedule of Assessments (Appendix 1).  
Blood pressure should be obtained after the subject has been resting in the sitting position for at 
least 3 minutes.  
7.2. 
Clinical Laboratory Assessments  
7.2.1. 
Hematology 
Hematology will be evaluated and will include a complete blood count (CBC) with differential:  
white blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and bands (if reported). 
7.2.2. 
Chemistry (Serum) 
Serum chemistry will be evaluated and include sodium, potassium, chloride, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, 
total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate.     
7.2.3. 
Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening, Week 17 and at the End-Of-Treatment visit using a central 
laboratory.   


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7.2.4. 
Hepatitis Serologies 
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, hepatitis B surface 
antibody, and hepatitis B core antibody and will be evaluated by local laboratory.  PCR must be 
confirmed negative prior to randomization for subjects who are hepatitis B core antibody 
positive, hepatitis B surface antigen positive or hepatitis C antibody positive. 
7.2.5. 
β2 -microglobulin 
Samples will be collected at Screening.  
7.2.6. 
Pregnancy Test 
Serum pregnancy tests are required at Screening by local laboratory only for women of 
childbearing potential.  If positive, pregnancy must be ruled out by ultrasound to be eligible.  
This test may be performed more frequently if required by local regulatory authorities. 
7.2.7. 
Flow cytometry surface membrane phenotype 
To determine the phenotype of malignant cells in patients, blood samples will be collected at 
screening, C1D1, C1D15, C1D28, day 1 of C3-C12. Samples will also be collected at a 
suspected CR visit or at disease progression or discontinuation of treatment. From these samples, 
peripheral blood mononuclear cells (PBMC) will be separated, collected and frozen as viable 
cells that will be analyzed at a future date by flow cytometry, for expression of cell surface 
markers including CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD14, CD16, CD19, 
CD20, CD22, CD25, CD36,  CD38, CD56, IgG, IgM, Kappa, Lambda, and CXCR4.  
7.2.8. 
IGHVDJ Rearrangement DNA Sequencing  
Peripheral blood and/or tissue samples (lymph node, bone marrow) will be collected and sorted 
for surface markers indicating B lymphocytes. DNA and RNA will be extracted from these cells, 
amplified by PCR and subjected to DNA sequencing. These samples will be collected at 
screening and at disease progression, should that occur. 
7.3. 
Diagnostics/Procedures 
7.3.1. 
ECG 
12-lead ECG will be taken in triplicate (≥1 minute apart) at Screening.  Subjects should be in 
supine position and resting for at least 10 minutes prior to the triplicate ECG measurements.  The 
calculated QTcF average of the 3 ECGs must be <470 msec for eligibility.   
The ECGs should be performed prior to any blood samples being collected.  Any clinically 
significant abnormalities noted at Screening should be included in the medical history.   
In addition, a single ECG may be performed, if clinically indicated, at any time during the study.    


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7.3.2. 
Pathological Diagnosis and Bone Marrow Sampling 
Inclusion of the subject in the trial will be based on pathological assessment and histologic 
confirmation of Richter’s transformation in treatment-naive and previously treated CLL/SLL 
patients (including other indolent lymphomas). When feasible, a portion of the BM aspirate will 
be viably cryopreserved for correlative studies. 
 
7.4. 
Biomarkers  
 
7.4.1. 
Genetic and Molecular Prognostic Markers 
Up to four cores of Richter’s Transformed lymph node tissue will be procured at screening or 
pre-dose C1D1.  Half the cores will be snap frozen and the other half will be processed as FFPE. 
Blood samples will be collected if lymphocytosis present, at pre-therapy, on days 15, 28, and 56 
of therapy.  One of the ACD tubes will undergo CD19+ enrichment and half of the enriched cells 
will be stored in RLT buffer and the other half will be viably cryopreserved.  The other ACD 
tube will have the plasma and PBMC isolated and stored.  From the sodium heparin tube a 
portion of the blood will undergo CLL and immune cell subset FACS testing.  The remaining 
blood will have the plasma and PBMC isolated and stored. 
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, flow cytometry and 
secreted protein analyses. Fluids including blood collected during the course of the study may be 
used for, but not limited to, pharmacodynamic, biomarker and pharmacogenomic assessments. 
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, and secreted protein 
analyses C8D1, Suspected PD, and End of Treatment visits. 
7.4.4. Correlative studies 
 
Peripheral blood, lymph node and/or bone marrow samples (depending on the site of 
disease activity) will be obtained pre-therapy.  In addition, peripheral blood and possibly lymph 
node and bone marrow samples (depending on the site of disease activity) will be obtained on 
C1D15, D1D28, and C2D28 of therapy and at the end of the study or at the time of disease 
progression.  
Recent studies have sub-categorized DLBCL arising in the context of a pre-existing CLL as 
either: (1) DLBCL that is “clonally related” to CLL (representing ~80% of cases) or (2) 
development of DLBCL that is “clonally unrelated” to the underlying CLL (remaining 20% 
cases) based on the IGHVDJ rearrangement (Mao 2007). We plan to determine the DNA 
sequence of the IGHVDJ rearrangement at the site of the RT and compare it with the original 


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CLL clone from peripheral blood or bone marrow collected before the diagnosis of RT.  This 
will determine if the new lymphoma arose from the same clone or whether this is a de novo clone 
unrelated to the pre-existing CLL. This information will be correlated with safety/toxicity, 
response to therapy, and outcomes. As routine clinical practice, the CLL clones from all our 
patients are analyzed for IGHV-D-J DNA sequence and IGHV mutation status (UM-CLL and M-
CLL) at the time of the CLL diagnosis or first visit to our clinics. Ibrutinib has shown clinical 
activity in both UM-CLL and M-CLL as a single agent and in combination regimens (Byrd 2013, 
Burger 2013, Brown 2013). 
 
Furthermore, 90-95% of RT in patients with CLL is of the more aggressive activated B-
cell (ABC) subtype (Mao 2007). We will determine ABC subtypes by gene expression profiling 
or immunohistochemistry (when tissue is available) to correlate disease outcomes and identify 
specific genes associated with overall survival. A recent phase 2 multicenter study of ibrutinib 
was performed in patients with relapsed/refractory DLBCL. The objectives were to assess 
whether ibrutinib had differential activity in ABC DLBCL and its role on overall response rate. 
Seventy patients were enrolled with a median age of 64 years and 3 (range 1-7) prior regimens. 
Overall, there were 29 ABC, 20 GCB, and 21 unclassified/unknown patients. Ibrutinib 
monotherapy showed clinical activity in ABC subtype (with a response rate of 41%), however, it 
did not have clinical activity in GCB DLBCL subtype, supporting the role of BCR signaling in 
ABC but not in GCB DLBCL (Mao 2007). 
 
Since additional and possibly different mutations may be needed to generate Richter’s in 
a patient with CLL, especially those that are clonally related to the CLL and those that are not, 
next generation whole exome deep sequencing at the time of RT diagnosis will be carried out to 
identify new mutations that might be mechanistically involved in the evolution from CLL to RT. 
This approach is currently in use in Dr. Chiorazzi’s lab. Our aim is to determine if new mutations 
are generated, if they are derived from the same precursor, or if the Richter’s comes from the 
same CLL clone. 
 
To evaluate the mechanisms whereby new genomic aberrations occur (particularly point 
mutations and gene segment deletion, we will examine the expression of Activation Induced 
Deaminase (AID) and the related apolipoprotein B mRNA editing enzyme, catalytic polypeptide-
like (APOBEC) group of cytidine deaminases in the RT sample and in the preceeding CLL 
clone. mRNA expression will be documented by PCR and protein synthesis also by 
immunofluorescence using flow cytometry for single cells and immunohistochemistry for 
tissues. In addition, we will examine the next generation deep sequencing data for mutation 
signatures of AID/APOBEC, which may arise during transformation and/or development of 
resistance. Dr. Chiorazzi’s group has recently published on AID protein expression in CLL cells 
and documented its ability to lead to IGHV-D-J mutations and isotype class switching (Patten 
2012). AID/APOBEC mutagenic signatures have recently been described in many cancers 
(Alexandrov 2013) and implicated in the evolution of aggressive disease. To our knowledge, this 
has not been studied in RT. 


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Additional correlative data will be obtained by measuring changes in cell surface 
phenotype, surface membrane immunoglobulin density, cytokine/chemokine receptors, and 
ratios of proliferative to resting compartments in peripheral blood and in lymph node and bone 
marrow by flow cytometry. We plan to measure changes in constitutive and induced 
phosphorylation, pre- and post-therapy, and correlate this with changes in lymph node size and 
circulating absolute lymphocyte count and eventually to ibrutinib in combination with 
obinutuzumab with or without chemotherapy. 
7.5. 
Efficacy Evaluations 
Efficacy evaluations will be conducted as outlined in the Schedule of Assessments (Appendix 1).  
Response assessments will be performed using Cheson assessment criteria. 
Nodal and extranodal disease should be evaluated based on the revised criteria for malignant 
lymphoma described in the revised International Working Group for NHL (Cheson 2007).  The 
spleen is considered nodal disease. 
Efficacy evaluation will include the following components: 
7.5.1. 
Radiographic Imaging 
Pre-treatment tumor assessment will be performed up to 28 days before the first dose of study 
drug.  Lesions that have been irradiated cannot be included in the tumor assessment unless 
unequivocal tumor progression has been documented in these lesions after radiation therapy.   
A MRI or PET/CT or CT scans (with contrast, unless contraindicated) of the neck, chest, 
abdomen, and pelvis must be performed.  Information on extranodal involvement will also be 
recorded.   
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the chest without contrast. 
The same imaging method should be used for a given subject throughout the study, when 
feasible.  The same equipment should be utilized for all scans whenever possible.   
7.5.1.1. 
Radiographic Assessment 
Nodal and extranodal disease should be evaluated based on the revised criteria for malignant 
lymphoma described in the revised International Working Group for NHL (Cheson 2007).  The 
spleen is considered nodal disease. 


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7.6. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form.  Refer to the Schedule of Assessments 
(Appendix 1) for the timing and frequency of all sample collections. 
8. 
STUDY PROCEDURES 
8.1. 
Screening Phase 
Screening procedures will be performed up to 30 days prior to Day 1 of Week 1, unless 
otherwise specified.  All subjects must first read, understand, and sign the IRB -approved 
informed consent form before any study-specific screening procedures are performed. 
8.1.1. 
Screening Visit 
A description of all required screening assessments is outlined in Appendix 1 (Schedule of 
Assessments). This will include blood sample collection for correlative studies, including analysis 
of genetic and molecular prognostic markers – TP53, NOTCH1, ZAP-70, MYD88, and SF3B1 
mutation analysis as well as GCB vs. non-GCB subtyping. 
 
8.2. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects 
will be assigned to ARM A (FIT) vs. ARM B (FRAIL).   
Study drug treatment should be continued until disease progression, unacceptable treatment-
related toxicity, or other reasons outlined in Section 9.    
Refer to the Schedule of Assessments (Appendix 1) for a complete list of procedures to be 
performed at each scheduled study visit. 
8.2.1. 
Cycle 1 Day 1 
Subjects who are deemed eligible will return to the clinic on Day 1.  The following procedures 
will be performed: 
Confirmation of eligibility 
FACiT-Fatigue  
Physical Exam, including weight 
Assessment of disease-related symptoms 
ECOG performance status 


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Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Clinical Laboratory Assessments (ideally on Day 1, or up to 7 days preceding Day 1) 
o Hematology to include CBC with differential and platelets (review prior to dosing) 
o Serum chemistry panel to include magnesium and phosphorous 
o Predictive/resistance biomarkers 
o Flow cytometry blood assays  
o Serum Ig and β2-microglobulin 
Review of AEs and concomitant medications 
Dosing and Post-Dose 
Dispense study drug (Ibrutinib) 
Administration of study drug 
Administration of obinutuzumab +/- CHOP  
Review of AEs and concomitant medications  
8.2.2. 
Cycle 1 Day2 
Administration of study drug and obinutuzumab  
Serum chemistry panel to include magnesium, phosphorous 
Review of AEs and concomitant medications 
8.2.3. 
Cycle 1 Day 3 
Serum chemistry panel to include magnesium, phosphorous 
Review of AEs and concomitant medications 
8.2.4. 
Cycle 1 Day 8 
Administration of study drug and obinutuzumab  
Physical Exam, including weight 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Hematology to include CBC with differential and platelets 
Serum chemistry panel to include magnesium, phosphorous 
Review of AEs and concomitant medications 
8.2.5. 
Cycle 1 Day 15 
FACiT-Fatigue  


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Physical Exam, including assessment of disease-related symptoms 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Collect blood samples for the laboratory tests  
• Hematology to include CBC with differential and platelets 
• Serum chemistry panel to include magnesium, phosphorous 
• CD20+ status (for B-cell malignancies) 
• Correlative studies 
• Predictive/resistance biomarkers 
• Flow cytometry surface membrane phenotype 
Review of AEs and concomitant medications 
8.2.6. 
Cycle 1 Day 28 
Physical Exam, including weight 
Assessment of disease-related symptoms 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Collect blood samples for the laboratory tests  
• Hematology to include CBC with differential and platelets 
• Serum chemistry panel to include magnesium, phosphorous 
• Correlative studies 
• Predictive/resistance biomarkers 
• Flow cytometry surface membrane phenotype 
Review of AEs and concomitant medications 
8.2.7. 
Cycle 2 Day 1 
Administration of study drug and obinutuzumab 
Drug accountability 
Physical Exam, including weight  
Assessment of disease-related symptoms 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 


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Hematology to include CBC with differential and platelets 
Serum chemistry panel to include magnesium, phosphorous 
Review of AEs and concomitant medications 
8.2.8. 
Cycle 2 Day 28 
Administration of study drug  
FACiT-Fatigue  
Overall Response Assessment 
• Neck, Chest, Abdomen/Pelvis CT scans or Whole Body MRI or Whole Body 
PET/CT scan 
• Assessment of disease-related symptoms 
• Bone marrow aspirate or biopsy, if applicable 
Collect blood samples for the laboratory tests  
• Correlative Studies 
8.2.9. 
Cycles 3 – 6, Day 1 
Administration of study drug and obinutuzumab 
8.2.10. Cycles 3-7, Day 1 (±3days) 
Drug accountability 
FACiT-Fatigue  
Physical Exam 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Collect blood samples for the following laboratory tests: 
o Hematology to include CBC with differential and platelets 
o Serum chemistry panel to include magnesium, phosphorous  
o Predictive/resistance biomarkers 
o Flow cytometry surface membrane phenotype 
o Serum Ig and β2-microglobulin 
Overall Response Assessment: Cycle 4, Day 1 and Cycle 6 Day 1 
• Neck, Chest, Abdomen/Pelvis CT scans or Whole Body MRI or Whole Body 
PET/CT scan 
• Assessment of disease-related symptoms 


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Review of AEs and concomitant medications 
8.2.11. 
Cycles 3-7, Day 15 (±3days) 
Collect blood samples for the following laboratory tests: 
o Hematology to include CBC with differential and platelets 
o Serum chemistry panel to include magnesium, phosphorous 
8.2.12. 
Cycles 8-12, Day 1 (±3days) 
Drug accountability 
FACiT-Fatigue  
Physical Exam, including weight 
ECOG performance status 
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Hematology to include CBC with differential and platelets 
Serum chemistry panel to include magnesium, phosphorous 
Cycle 8, Day 1 only – Genetic and molecular prognostic markers – TP53, NOTCH1, ZAP-70, 
MYD88, and SF3B1 mutation analysis as well as GCB vs. non-GCB subtyping 
Overall Response Assessment: Cycle 8, Day 1; Cycle 10 Day 1; and Cycle 12 Day 1 
• Neck, Chest, Abdomen/Pelvis CT scans or Whole Body MRI or Whole Body 
PET/CT scan 
• Assessment of disease-related symptoms 
 
8.2.13. 
Suspected PD Visit 
The Suspected PD visit should be performed at any time during the study, if, based on clinical 
and/or laboratory evaluation, the Investigator suspects progressive disease (PD), or if the subject 
discontinues treatment for any other reason.  If possible, the visit should be performed within 
24 hours after the subject’s previous dose.  The following procedures will be performed: 
Complete physical exam, including weight 
ECOG performance status 
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature) 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 


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o Correlative studies 
Tissue and/or bone marrow aspirate or biopsy, if applicable 
Overall Response Assessment: Cycle 4, Day 1 and Cycle 6 Day 1 
• Neck, Chest, Abdomen/Pelvis CT scans or Whole Body MRI or Whole Body 
PET/CT scan 
• Assessment of disease-related symptoms 
Review of AEs and concomitant medications 
8.2.13.1. 
End-of-Treatment Visit 
An End-of-Treatment (EOT) visit should occur 30 days (± 7 days) from the last dose of ibrutinib 
or prior to the start of a new anticancer treatment.  If the subject starts a new anticancer treatment 
less than 7 days after the Suspected PD visit, only those procedures not conducted at the 
Suspected PD visit should be performed at the End-of-Treatment visit.  
The following procedures will be performed at the End-of-Treatment visit: 
Complete physical exam, including weight 
ECOG performance status 
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature) 
Collect blood samples for the following laboratory tests: 
o Hematology to include CBC with differential and platelets 
o Serum chemistry panel to include magnesium, phosphorous 
o Correlative studies 
Review of AEs and concomitant medications 
Bone marrow aspirate or biopsy, if applicable 
Overall Response Assessment: Cycle 4, Day 1 and Cycle 6 Day 1 
• Neck, Chest, Abdomen/Pelvis CT scans or Whole Body MRI or Whole Body 
PET/CT scan 
• Assessment of disease-related symptoms 
Drug accountability 
8.3.Follow-up Phase 
8.3.1 Pre-PD Follow Up 
Physical Exam, including weight 
ECOG performance status 


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Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature 
Assessment of disease-related symptoms 
 
9. 
SUBJECT WITHDRAWAL FROM TREATMENT OR STUDY 
9.1. Withdrawal from Study Treatment 
All study participants may be discontinued from study drug for any of the following reasons: 
 Any subject has the right to discontinue study drug at any time. 
 Any subject who has objective evidence based on progression of disease will discontinue 
study drug. 
 Any subject unable to tolerate a second re-challenge with protocol-described, dose-
modified ibrutinib at Dose Level –2 (see Section 5.2.1.3) should discontinue study drug. 
 Any subject who becomes pregnant or begins breastfeeding should discontinue study 
drug. 
 Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should discontinue study drug. 
 Any subject who chooses to receive an allogeneic hematopoietic stem cell transplant. 
 The investigator may discontinue the study drug if it is not in the subject’s best interest to 
continue. 
9.2.Withdrawal from Study 
Subject study participants will be withdrawn from study due to any of the following reasons: 
 Adverse event. 
 Disease progression. 
 Withdrawal of consent. 
o Withdrawal of consent is the primary reason for study termination only if a 
patient refuses any further contact or follow-up.  
 Significant subject noncompliance with study drug administration, study procedures, or 
study requirements. 
 Initiation of any additional anticancer therapies (other than corticosteroids) including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental 
treatment. 
 Physician’s decision to remove the subject from the study. 
 The subject is lost to follow-up. 
 Death. 
When a patient withdraws before completing the study, the reason for withdrawal must be 
recorded in the source documents. 


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10. STATISTICAL METHODS AND ANALYSIS 
 A general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below. 
10.1. 
General Consideration 
All analyses will be performed based on data up to the timepoint of clinical cutoff.  Long-term 
follow-up data will be summarized separately when the entire study has completed.  Statistical 
inferences will be based on a two-sided Type I rate of 0.1 unless otherwise specified. 
All analyses will be carried out separately for each of the two arms (fit and frail). The fit group 
will be treated with the combination chemotherapy regimen using Ibrutinib (I) with 
Obinutuzumab (G) and CHOP, “IG-CHOP” regimen.  The frail group will use Ibrutinib (I) with 
Obinutuzumab (G), “IG.” 
 
10.2. 
Subject Information - Assignment to ARM A vs. ARM B 
Subjects on the frail or unfit cohort will be ≤80 years of age have an estimated creatinine clearance 
of less than 60 ml per minute, and have a score on the Cumulative Illness Rating Scale (CIRS) of 
≥6 for coexisting illnesses not related to CLL and will be treated with ibrutinib (I) and 
obinutuzumab (G), i.e. “IG”. 
 
Subjects on the fit cohort will have adequate renal function (estimated Creatinine Clearance ≥30 
ml/min), and have a CIRS score of <6 and will be treated with the combination of ibrutinib, 
obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone; i.e. “IG-CHOP”. 
 
10.3. 
Endpoints  
10.3.1. 
Primary Endpoint 
• The primary endpoint of the study is Overall Response Rate, as assessed by 
Cheson 2007 criteria: ORR is defined as the proportion of patients who achieve 
complete response (CR) or partial response (PR) per Cheson 2007 criteria over 
the course of the study 
• To determine the efficacy of combining Ibrutinib with obinutuzumab (with or 
without “CHOP” chemotherapy regimen) as measured by overall response rate 
(ORR), separately for the fit and the frail Richter’s Syndrome patients. 
 
Statistical Methods for the Primary Objective: 


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For each of the two Richter’s groups-fit group (using the IG-CHOP regimen) and frail group 
(using the IG regimen), we will estimate the overall response rate (ORR) using standard methods 
for binomial proportions; corresponding 95% exact confidence intervals will be calculated. 
1.8.1 Secondary Endpoints 
1. To assess the safety of Ibrutinib in combination with obinutuzumab as measured by the 
incidence of prolonged hematologic toxicity in cycle 1 in subjects with a diagnosis of 
Richter's Transformation (RT), hematologic improvement, progression-free survival 
(PFS), overall survival (OS), and health-related quality of life (HRQL) measures.  
2. To identify and correlate potential markers predictive of response to the combination 
therapy and associate pharmacogenetic findings to response and toxicity.  
 
Statistical Methods for the Secondary Objectives: 
The following analyses will be carried out for the outcomes in the secondary objectives: 
 
1. For each of the two groups, fit and frail, we will estimate the rates of prolonged 
hematologic toxicity in cycle 1, and the rates of hematologic improvement, using 
standard methods for binomial proportions; corresponding 95% exact confidence 
intervals will be calculated. 
 
2. Kaplan-Meier (Product-Limit Method) analysis will be used to estimate the overall 
survival (OS) and progression-free survival (PFS) in each of the fit and frail groups.  OS 
and PFS will be estimated from the start of treatment.  Subjects who are alive as of the 
last follow-up will be considered censored for survival. Subjects who have not progressed 
as of the last follow-up will be considered censored for disease progression.   
 
3. For each of the two groups, fit and frail, we will examine patient reported outcome of 
health-related quality of life as measured by the Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACiT-Fatigue).  
 
4. For each of the two groups, fit and frail, biomarkers measured from samples collected in 
patient serum, plasma, blood, tumor tissue, bone marrow biopsies/aspirates as well as 
data from pathology reports and genetic studies will be examined to determine which 
biomarkers are associated with certain genetic characteristics, pathologic features and 
pharmacogenetic findings.  The analyses will be exploratory and descriptive in nature and 
may involve the use of t-tests, chi-square tests, Mann-Whitney/Kruskal-Wallis tests or 
Fisher’s exact tests, as appropriate. 
 
5. If feasible, Cox (proportional hazards) regression will be used to examine factors that 
might be associated with overall survival or progression-free survival.  These factors will 
potentially include biomarkers, genetic characteristics, pathologic features and 
pharmacogenetic findings deemed important from a univariable analysis. 
 
6. For each of the two groups, fit and frail, correlations between biomarker levels measured 
over time will also be examined using analysis of covariance methods (Bland and 


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Altman, 1995). This will allow for the computation of within-subjects correlations where 
the pairs of outcome variables are collected as repeated measures. 
 
10.3.2. 
Exploratory Endpoints 
• Patient-reported outcomes (PRO) measured by the Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACiT-Fatigue)  
• Genetic and molecular characteristics as well as GCB vs. non-GCB subtyping to 
determine which, if any, factors influence ORR to study treatment.  
10.4. 
Sample Size Determination 
Simon's two-stage design (Simon, 1989) will be used for each of the two study groups (fit and 
frail groups). 
 
For the frail group, the study will be designed to test the ORR at 55% (the alternative hypothesis) 
against the estimated true response rate of 30% (the null hypothesis).  In the first stage, 8 patients 
will be accrued. If there are 2 or fewer responses in these 8 patients, the study will be stopped. 
Otherwise, 12 additional patients will be accrued for a total of 20. The null hypothesis will be 
rejected if 9 or more responses are observed in 20 patients. This design yields a type I error rate 
of alpha=0.1 and power of 80% when the true response rate is 55%. 
 
For the fit group, the study will be designed to test the ORR at 60% (the alternative hypothesis) 
against the estimated true response rate of 35% (the null hypothesis).  In the first stage, 10 
patients will be accrued. If there are 4 or fewer responses in these 10 patients, the study will be 
stopped. Otherwise, 13 additional patients will be accrued for a total of 23. The null hypothesis 
will be rejected if 11 or more responses are observed in 23 patients. This design yields a type I 
error rate of alpha=0.1 and power of 80% when the true response rate is 60%. 
 
For the frail (fit) group, the null hypothesis will be rejected if there are 9 (11) or more responses 
in the 20 (23) patients, 9/20=45% (11/23=48%). Therefore, the study will require a total of 
20+23=43 patients (fit and frail groups). 
10.5. 
Safety Analysis 
Safety summaries will include tabulations in the form of tables and listings. The safety analysis 
will be divided between the two treatment cohorts. Patients will be analyzed according to the 
actual treatment received. 
Study drug exposure including duration and dosage as well as dose modifications of study drug 
including dose reduction, dose delay, missed doses, and dose interruption will be summarized. 
 
11. DATA AND SAFETY MONITORING PLAN (DSMP) 


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In accordance with federal guidelines, this study requires a DSMP. The PI will identify 
an independent Safety Officer/Medical Monitor with expertise in Richter’s Syndrome 
who does not have any scientific, financial, or other conflict of interest related to the 
study and who is not responsible for patient care at any of the participating sites. Safety 
will be formerly monitored once yearly by the study team and the Safety Office/Medical 
Monitor throughout the duration of the study. The clinical research team will prepare a 
safety report for these regular reviews comprised of anticipated safety events and actions 
taken. The PI will contact the Safety Officer/Medical Monitor for ad hoc reviews of any 
unanticipated safety events. The study protocol will be carried out in accordance with 
OHRP/FDA/NIH guidelines and requirements. In the event of a serious adverse event 
during the study protocol, it will be reported immediately to the PI, the co-investigators, 
and the Safety Officer/Medical Monitor. It will also be reported to the Northwell Health 
IRB, Pharmacyclics Drug Safety group and to all members of the research team. With the 
approval of the participants and families, the information will be provided to other care 
providers as directed. 
Data will be recorded in RedCap. 
11.1. 
Risk Assessment 
This study involves a minor/major increase above minimal risk to the subjects. The primary 
concern is the risk of development of tumor lysis syndrome, diarrhea, cytopenias, infections, 
atrial fibrillation, non-melanoma skin cancer, rash, lymphocytosis and leukostasis, and bleeding-
related events from ibrutinib and risk of development of tumor lysis syndrome and HBV 
infection from obinutuzumab. 
11.2. 
Ibrutinib Risk Assessment 
• Monitoring: subjects will be monitored for overall risk assessment at screening visit 
and throughout study with laboratory assessments, EKGs, and study visits.  
• Actions: The research team will keep record of adverse events. Table 1 “Ibrutinib 
Dose Modifications” and section 5.2.1.3 define the dose modifications for adverse 
reactions that will incur a dosage change in ibrutinib administered to subjects. 
Additional therapy may administered, as needed. 
11.3. 
Obinutuzumab Risk Assessment 
• Monitoring: subjects will be monitored at screening and each study visit 
• Actions: Subjects will be tested for HBV at screening. Table 3 “Management of 
Hepatitis B Reactivation” describes guidelines for holding and discontinuing 


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obinutuzumab. Section 5.2.5.5 describes management of infusion-related reactions 
and anaphylaxis. Additional therapy may administered, as needed. 
 
12. ADVERSE EVENT REPORTING 
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. Investigators should use correct medical terminology/concepts 
when reporting AEs or SAEs. Avoid colloquialisms and abbreviations. 
12.1. 
Definitions  
12.1.1. 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. 
The term “disease progression” should not be reported as an adverse event term.  As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
o Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
o Any AEs experienced by the subject through the completion of final study procedures. 
o AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
o Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 


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o AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Richter’s Transformation that 
were not present prior to the AE reporting period. 
o Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
o If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
o Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
The following are NOT considered AEs: 
o 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. 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”). 
o 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 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. 
o 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. 
o 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. 
o 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 surgical 


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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: 
o Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
o 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. 
 
12.1.2. 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: 
o Results in death (i.e., the AE actually causes or leads to death). 
o Is life-threatening.  Life-threatening is defined as an AE in which the subject was at 
immediate 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 IND Sponsor believes that an AE meets the definition of life-threatening, it will be 
considered life-threatening. 
o Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
o Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
o Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. 
o 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 outcomes listed above.  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. 
12.1.3. Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.0 
(CTCAE v4.0) will be used for grading the severity (intensity) of non-hematologic AEs.  Refer 


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to 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 subject experience any 
AE not listed in the CTCAE v4.0, the following grading system should be used to assess 
severity: 
o Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities 
o 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 
o 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 
o Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
o Grade 5 (Death related to AE) – experiences which result in subject death 
12.1.4. Causality (Attribution)  
The Investigator is to assess the causal relation (i.e., whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
12.1.4.1 Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the 
obinutuzumab or ibrutinib, and the AE cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 
to the ibrutinib or obinutuzumab; and/or the AE abates or resolves upon discontinuation of the 
ibrutinib or obinutuzumab or dose reduction and, if applicable, reappears upon re-challenge. 
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. 
Related: 
The AE is clearly related to use of the investigational product. 
 


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12.1.4.2 No 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to {study drug} administration (e.g., cancer diagnosed 2 days 
after first dose of study drug). 
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. 
 
 
 
 
12.2. 
Expected and Unexpected Adverse Events 
“Expected” AEs are those AEs that are listed or characterized in the current Investigator's 
Brochure or package insert.  
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. 
12.3. 
Procedures for Eliciting,  Documenting and Reporting of Adverse Events and 
Serious Adverse Events by Investigators 
12.3.1. 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all evaluation timepoints 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?”  


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12.3.2. 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
12.3.2.1. 
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. 
12.3.3. Assessment of Adverse Events 
Investigators will assess the occurrence of adverse events and serious adverse events at all subject 
evaluation time points 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 (i.e., start and 
end dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to the 
investigational product, and any actions taken. 
12.3.4. Adverse Event Reporting 
Any SAE must be reported to the IRB as soon as possible but no later than 5 business days. The 
IRB requires a SAE report to be submitted electronically to Northwell Health IRB at 
irb@northwell.edu and through the electronic IRB portal. The report should be filled out entirely 
and include the following information: 
Principal Investigator 
 
Name: Jacqueline Barrientos, MD 
 
Dept/Div: Medicine 
 
Affiliation: Northwell Health Cancer Institute 
 
Phone #: 516-470-4050 
 
Fax #: 516-470-4250 
 
E-mail: jbarrientos@northwell.edu 
 
The principal investigator’s or sub-investigator’s signature and the date it was signed are 
required on the completed serious adverse event report. 
 
12.3.5. Adverse Event Reporting Period 


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All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is 
obtained and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to prior study treatment. 
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. (See Section 11.1.1) 
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 (e.g., 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.  All deaths that occur during the protocol-
specified AE reporting period (see Section 11.3.3.), 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”. 
 
If a death occurs within 30 days after the last dose of study drug, the death must be reported as a 
serious adverse event.  
12.3.6. 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 30 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 Investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the fetus.   


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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 (or 90 days for male partners) after the last dose of study drug must be reported. Any 
occurrence of pregnancy must be reported to Pharmacyclics Drug Safety, or designee, and 
Northwell Health HRPP 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. Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to the obinutuzumab or ibrutinib should be reported as 
an SAE. 
12.3.7. 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. If 
observed, enter data in the corresponding eCRF.  
12.3.8. Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF. 
12.3.9.  Adverse Events of Special Interest (AESI)  
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor.  These Ibrutinib adverse events of special interest 
(regardless of seriousness) will be reported on the Serious Adverse Event Report Form and sent 
via email or fax to Pharmacyclics Drug Safety, or designee, within 24 hours. 
 
The following AEs are considered of special interest and must be reported to the Sponsor 
expeditiously irrespective of regulatory seriousness criteria:   
• Tumor Lysis Syndrome (serious and non- serious events) 
 
Please note that from Feb/2015, only non-serious TLS is an AESI. 


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The following events can be reported as AESI only when considered SERIOUS by the 
investigator:  
- 
Serious neutropenia 
- 
Serious infection 
- 
Serious Infusion Related Reaction (IRR) 
 
 
Selected events (in clinical trials, these are events for which additional data collection or 
analyses will be performed; no special case handling or follow-up is required):  
• IRRs  
• infections (including PML)  
• neutropenia (including late onset neutropenia - defined as neutrophil count < 1000 
cells/mm3, occurring 28 days or more after obinutuzumab treatment has been completed 
or stopped; prolonged neutropenia - defined as neutrophil count < 1000 cells/mm3, which 
does not resolve after 28 days (without obinutuzumab treatment),  
• thrombocytopenia (including acute thrombocytopenia - events occurring during and within 
24 hours post obinutuzumab infusion)  
• TLS  
• Hepatitis B reactivation  
• cardiac events  
• second malignancies  
• GI perforation. 
 
 
12.3.9.1. 
Major Hemorrhage- Ibrutinib Adverse Event of Special Interest 
Major hemorrhage is defined as any of the following:  
Any treatment-emergent hemorrhagic adverse events 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 according to Section 11.3.7 above. 
12.3.10. 
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) or Suspect Adverse Event Report (CIOMS Form 1) 
IRB Reporting Form and sent via email (AEintakeCT@pcyc.com) or fax (408) 215-


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3500) to Pharmacyclics Drug Safety, or designee, within 24 hours of the event. 
Pharmacyclics may request follow-up and other additional information from the Sponsor 
Investigator.  
 
 
Reporting to Regulatory Agencies: 
Serious adverse events will be forwarded to FDA by the Sponsor according to 21 CFR 312.32. 
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. 
Methods and Timing for Assessing AND Recording Safety variables: 
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 Institutional Review Board (IRBs), in accordance with CFR 312.32 (IND Safety 
Reports).  
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient 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 
 
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 patient identifiers 
(i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief AE 
description, and notation that additional or follow-up information is being submitted (The 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
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patient identifiers are important so that the new information is added to the correct initial 
report) 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
 
 
12.4. 
Safety Reporting Requirements for IND Exempt Studies 
As this is an investigator-sponsored IND exempt study, the investigator will submit safety 
reports in accordance with the reporting requirements set forth in 21 CFR 314.80. 
 
13. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS   
13.1. 
Protocol Amendments 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form 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. 
13.2. 
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. 
13.3. 
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 LLC.  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 patient well-being is identified; or breach of contract. 
Additional grounds for termination are outlined in the IST Agreement. 
 
 


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14. 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and 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, patient 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.  
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must comply 
with the record retention requirements set forth in the U.S. FDA IND regulations and the 
relevant national and local health authorities, whichever is longer. 
 
 
 
 
 


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Wilson WH, Goy A, de Vos S, et al. (2012) The Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib 
(PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse 
large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study 
[abstract] Blood (ASH Annual Meeting Abstracts) 120:686. 
Woyach JA, Ruppert AS, Lozanski G, et al. Association of disease progression on ibrutinib therapy 
with the acquisition of resistance mutations: A single-center experience of 267 patients. J Clin 
Oncol 32:5s, 2014 (suppl; abstr 7010) 
Younes A, Thieblemont C, Morschhauser F, et al. Combination of ibrutinib with rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive 
patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. 
Lancet Oncology 2014; 15(9):1019-1026. 
Younes A, Flinn I, Berdeja JG, et al. Phase Ib study combining ibrutinib with rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-
positive B-cell non-Hodgkin lymphoma (NHL). J Clin Oncol 31, 2013 (suppl; abstr 8502). 
Zelenetz AD, Abramson JS, Advani RH, et al. NCCN clinical practice guidelines in oncology: 
non-Hodgkin lymphoma. J Natl Compr Canc Netw 2010;8:288−334 . 
Zucca E, Conconi A, Martinelli G, et al. Chlorambucil plus rituximab produces better event-free 
survival in comparison with chlorambucil alone in the treatment of MALT lymphoma: 5-year 
analysis of the 2-arms part of the IELSG-19 randomized study [abstract]. Blood 
2010;116:abstract 432. 
 
 
 


Ibrutinib (PCI-32765) Two-arm phase II trial exploring the use of the targeted agents ibrutinib and 
obinutuzumab for the treatment of patients with a diagnosis of Richter’s Transformation (RT) or 
Richter’s Syndrome (RS)/ PCYC-20016 
 
June 21, 2018 
 
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16. APPENDICES 


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Appendix 1.  Schedule of Assessments 


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Study Visits 
Screening 
Phase 
Treatment Phase (1 cycle = 28 days) 
 
Suspected 
PD 
End-of-
Treatment Pre-PD FU 
Cycle 1 
Cycle 2 
Cycles 3–7 
Cycles 
8–12 
D1 
(baseline)a 
D2 
D3 
D8 
D15 
 
D1 
D15 
D1 
D15 
D1 
Any time 
Within 30 
Days after 
treatment 
enddf 
q 4 mos, 
then q 6 
mosk 
Study Visit 
Windows 
-28 days 
 
 
 
 
 
Visits are ± 3 days 
Radiology procedures are ± 7 days 
Any time + 7 days 
± 7 days   
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & 
Demographics 
(including date of 
birth) & Pregnancy 
Test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
and enroll 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
FACiT Fatigue 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
Concomitant 
medications 
x 
x 
 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
Adverse eventsb 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam, vital 
signs, weight, ECOG 
x 
x 
 
 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
CIRS (Cumulative 
Illness Rating Scale) 
Score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment: d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan 
xe 
 
 
 
 
 
 
 
xc 
 
xc 
x 
x 
 
PET/CT scan 
x  
 
 
 
 
 
 
 
xc 
 
xc 
x 
x 
 
Bone marrow 
biopsy/aspiratel 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Disease-related 
symptomsi 
x 
x 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
Overall response 
assessment 
 
 
 
 
 
 
 
 
xc 
 
x 
x 
x 
x 
Hematology 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry j 
x 
x j 
x j 
x j 
x 
x 
x j 
x j 
x j 
x j 
x 
 
xj 
 
EBV PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Visits 
Screening 
Phase 
Treatment Phase (1 cycle = 28 days) 
 
Suspected 
PD 
End-of-
Treatment Pre-PD FU 
Cycle 1 
Cycle 2 
Cycles 3–7 
Cycles 
8–12 
D1 
(baseline)a 
D2 
D3 
D8 
D15 
 
D1 
D15 
D1 
D15 
D1 
Any time 
Within 30 
Days after 
treatment 
enddf 
q 4 mos, 
then q 6 
mosk 
Creatinine clearance 
(Cockcroft-Gault) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlatives:  
Peripheral Blood, 
lymph node, and bone 
marrow n 
x 
 
 
 
 
x 
x 
 
x 
 
 
 
x 
x 
 
 
IGHV mutation at site 
of RT; compare to 
original CLL clone 
from peripheral blood 
or bone marrow d 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hepatitis serologies m 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predictive/resistance 
biomarkerso 
x 
 
 
 
 
 
 
 
 
 
 
x 
xk 
 
Flow cytometry 
surface membrane 
phenotype (including 
CD20+ marker) 
x 
 
 
 
 
 
 
 
 
 
 
 
xk 
 
Serum Ig and β2-
microglobulin 
 
x 
x 
 
 
 
 
 
 
x 
 
xi 
x 
xk 
 
Genetic/molecular 
prognostic factorsp 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
12-lead ECGg 
x 
 
If clinically indicated (e.g., subjects with palpitations, lightheadedness) 
Any new anticancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
xk 
 
 
 
Study Drug Administration and Dispensation 


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Study Visits 
Screening 
Phase 
Treatment Phase (1 cycle = 28 days) 
 
Suspected 
PD 
End-of-
Treatment Pre-PD FU 
Cycle 1 
Cycle 2 
Cycles 3–7 
Cycles 
8–12 
D1 
(baseline)a 
D2 
D3 
D8 
D15 
 
D1 
D15 
D1 
D15 
D1 
Any time 
Within 30 
Days after 
treatment 
enddf 
q 4 mos, 
then q 6 
mosk 
ARM 
A 
IBR 560 mg 
POh + 1000 
mg 
Obinutuzumab 
+ CHOP  
 
 
 
 
 
Ibrutinib is administered daily until PD. 
Obinutuzumab is administered: C1D1 100mg, C1D2 900mg,  
C1D8 and C1D15 1000mg, and then 1000mg on day 1 of 
cycles 2-6 CHOP dose cyclophosphamide D1 of C1-C6 750 
mg/m², hydroxydaunorubicin D1 of C1-C6  50 mg/m² , 
oncovin (vincristine) D1 C1-C6  1.4 mg/m² (max. 2 mg) , and 
prednisone or equivalent  D1 thruD5 of C1-C6 (100mg flat 
dose per day, or dosage as investigator sees fit) 
(FIT population n=23) 
 
 
 
ARM 
B 
IBR 560 mg 
POh + 1000 
mg 
Obinutuzumab  
 
 
 
 
 
Ibrutinib is administered daily until PD. 
Obinutuzumab is administered: C1D1 100mg, C1D2 900mg,  
C1D8 and C1D15 1000mg and then 1000mg on day 1 of 
cycles 2-6  
(FRAIL population n=20) 
 
D = day; Term = treatment termination; d/c = discontinuation; PD = progressive disease; FU = follow-up; (x) = not all visits or all subjects 
a To be collected pre-dose, unless otherwise specified 
b AEs are reported from the time the patient signs the Informed Consent Form until 30 days following last dose of study drug. In addition to all routine AE reporting, all new 
malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events for the duration of the study treatment and 
during any protocol-specified follow-up periods including post-progression follow-up for overall survival. 
c    At 2 months  (ORR, DOR, TTP, PFS); if no evidence or PD at 2 months, give three additional 28 day cycles of Obinutuzumab; Ibrutinib continued indefinitely until PD or 
toxicity. Radiographic assessments (Neck, Chest, Abdomen/Pelvis CT scans OR MRI OR PET/CT scan) will be performed at C2D28, C5D1, C7D1, C9D1, C11D1. 
d   If a patient chooses to undergo an hematopoietic stem cell or bone marrow transplant patients will be censored at that time for statistical analysis of PFS. 
e    Baseline CT scan can be performed up to 28 days prior to C1D1. PET/CT or CT w/contrast (unless contraindicated) of neck/check/abdomen/pelvis or MRI should be 
performed at C2D28, C5D1, C7D1 then every six months. 
f    May be sooner if patient is scheduled to start a new anticancer treatment 
g   ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea.  
h Day 1 dose of Cycle 1 of ibrutinib should be administered at the investigational site.  Subsequent daily doses may be self-administered at home 
i   Disease-related symptoms include weight loss, fatigue, fever, night sweats, abdominal pain/discomfort due to splenomegaly including early satiety, and anorexia. 
j To monitor for tumor lysis syndrome and cytopenia(s), the subjects will have chemistries resulted on days 2 and 3 of the first cycle of therapy, every week during the first cycle 
of therapy and day 1 and day 15 during subsequent cycles of therapy. 
k    Every 4 months for 1 year, then every 6 months thereafter until 2 years. 
l    Bone marrow biopsy and/or aspirate should be performed at Screening or up to 90 days before the first dose of study drug, and as needed to confirm complete 
remission/response (CR) or evaluate cytopenia.  Marrow collected to confirm CR should have minimal residual disease (MRD) assessed by flow cytometry on the 
aspirate; patients confirmed as MRD-negative in the marrow should be followed every 3 months for MRD by peripheral blood flow cytometry (see Section 7.2.7).   


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m    PCR must be confirmed negative prior for subjects who are hepatitis B core antibody positive, hepatitis B surface antigen positive or hepatitis C antibody positive. 
n    When clinically indicated and feasible, peripheral blood should be collected for each correlative studies. When feasible, bone marrow and lymph node samples should be 
collected for analysis of correlative studies as well. 
o    Predictive/resistance biomarkers include those for BTK mutations, other kinases activity and signaling, expression analysis, sequencing, flow cytometry and secreted protein 
analyses. 
p    Genetic/molecular prognostic factors include TP53, NOTCH1, ZAP-70, MYD88, and SF3B1 mutation analysis as well as GCB vs. non-GCB subtyping. Performed at 
screening and suspected PD or End of Treatment visit, if feasible and/or clinically indicated. 


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Appendix 2.  ECOG Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html.   


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Appendix 3.  Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below. Refer to Section 6.2.1 
on instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
INDINAVIR 
Efavirenz 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Aprepitant 
St. John’s Wort 
Erythromycin 
Troglitazone 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 
NOT azithromycin 
 
Chloramphenicol 
 
Boceprevir 
 
Ciprofloxacin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
star fruit 
 
Telaprevir 
 
Troleandomycin 
 
Voriconazole 
 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
 
 
 


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Appendix 4.  Guidelines for Establishing Response to Treatment  
Response 
Definition 
Nodal Masses* 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET 
positive prior to 
therapy; 
mass of any size 
permitted if PET 
negative 
(b) Variably FDG-
avid or 
PET negative; 
regression 
to normal size on CT 
Not palpable, 
nodules 
disappeared 
If infiltrate present at 
screening, infiltrate 
cleared on repeat 
biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should 
be negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in 
SPD of up 
to 6 largest dominant 
masses; 
no increase in size of 
other 
nodes 
(a) FDG-avid or PET 
positive prior to 
therapy; 
≥1 PET positive at 
previously involved 
site 
(b) Variably FDG-
avid or 
PET negative; 
regression 
on CT 
≥50% decrease in 
SPD of nodules 
(for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; 
cell type should be 
specified 
SD 
Failure to attain 
CR/PR or 
progressive disease 
(a) FDG-avid or PET 
positive prior to 
therapy; 
PET positive at prior 
sites of disease, and 
no 
new sites on CT or 
PET 
(b) Variably FDG 
avid or 
PET negative; no 
change 
in size of previous 
lesions on CT 
 
 
 


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Abbreviations: CR=complete remission, CT=computed tomography, FDG=[18F]fluorodeoxyglucose, PET=positron 
emission tomography, PR=partial remission, SD=stable disease, SPD=sum of the product of the diameters 
*Change in target lesion measurement by CT, unless MRI used as the assessment modality for lesions in anatomical 
locations not amenable to CT 
 
Progressive disease for Non-Hodgkin’s lymphoma is characterized by any new lesion or increase 
by ≥50% of previously involved sites from nadir for example: 
• Appearance of a new lesion(s) >1.5 cm in any axis, ≥50% increase in SPD of >1 node, or ≥50% 
increase in longest diameter of a previously identified node >1 cm in short axis 
• Lesions PET positive if FDG-avid lymphoma or PET positive before therapy 
• >50% increase from nadir in the SPD of any previous lesions in the liver or spleen 
• New or recurrent involvement in the bone marrow 
• An increase of ≥50% in blood lymphocytes with ≥5 x 109/L B-cells only in setting of enlarging 
lymph node, liver, or spleen (note: an isolated elevation of white blood cell count by itself will 
not be considered progressive disease unless subject becomes symptomatic from this). 
 
**Reference: Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. Journal of Clinical Oncology 2007;25:579-586. 
 
 
 
 
 
 


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Appendix 5: Correlative Studies 
 
Test 
Collection 
Timepoint 
Site / PI 
Sample 
type 
Collected 
sample 
Processing/Banking 
Site of Analysis  
IGHVDJ 
rearrangement 
Screening 
and 
Suspected 
PD visits, if 
clinically 
indicated 
and feasible 
 
 
 
 
Site/s of RT 
disease 
ABC 
subtyping 
Screening, 
if clinically 
indicated 
and feasible 
 
 
 
 
Site/s of RT 
disease 
mRNA 
expression of 
Activation 
Induced 
Deaminase 
(AID) and 
apolipoprotein 
B mRNA 
editing  
enzyme, 
catalytic 
polypeptide-
like 
(APOBEC) 
 
*Screening  
*Suspected 
PD visit, if 
clinically 
indicated 
and feasible  
 
 
 
Next generation 
clonal evolution 
analysis at site/s 
of RT disease 
PCR 
 
Protein synthesis 
analysis by 
immunofluoresce
nce using flow 
cytometry for 
single cells & 
immunohistoche
mistry  
AID and 
APOBEC 
mutation 
analysis 
*Screening  
*Suspected 
PD, visit if 
clinically 
indicated 
and feasible  
 
 
 
whole exome deep 
sequencing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6.  Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Sources:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of te oesophagus for 
bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 
 
 


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Appendix 7.  Cumulative Illness Rating Score (CIRS) 
Each system is rated as follows: 
Score 
Severity 
Findings 
0= 
NONE: 
No impairment to that organ/system. 
1= 
MILD: 
Impairment does not interfere with normal activity; treatment may or may not be 
required; prognosis is excellent. Easy to control. (Examples could be skin lesions, 
hernias, or hemorrhoids) 
2= 
MODERATE: 
Impairment interferes with normal activity; treatment is needed; prognosis is good. 
Manageable. Requiring daily treatment or first-line therapy (Examples could be 
gallstones, diabetes, or fractures) 
3= 
SEVERE: 
Impairment is disabling; treatment is urgently needed; prognosis is guarded. Hard to 
control. Requiring second-line therapy or multiple medications. (Examples could be 
carcinoma, pulmonary emphysema, or congestive heart failure) 
4= 
EXTREMELY 
SEVERE: 
Impairment is life threatening; treatment is urgent or of an avail; prognosis is grave. 
Poorly manageable. Requiring urgent intervention or resistant to therapy. (Examples 
could be myocardial infarction, cerebrovascular accident, gastrointestinal bleeding, or 
embolus) 
 
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing chronic 
comorbid conditions, classified by 14 organ systems. Using the drop-down lists of organ-specific 
diagnoses, please select any conditions present in the study subject. If the subject has a recurrent or 
ongoing chronic conditions that are not described in the list for a given organ system, please indicate the 
name of the conditions under “other chronic condition” for that organ system. Please take into account 
that CLL-induced discomfort, symptoms, or disability should not be considered. If additional explanation 
would be helpful, text comments may be inserted. 
 
Organ System Diagnosis 
Comment 
Organ System Diagnosis 
Comment 
Organ System Diagnosis 
Comment 
Cardiac 
Chronic heart failure 
Angina pectoris 
Medically relevant arrhythmia 
Valve dysfunction 
Congenital heart disease 
Cardiomyopathy 
Myocarditis 
Chronic pericarditis 
Endocarditis 
Other chronic cardiac condition: 
Other chronic cardiac condition 
 
Vascular 
Hypertension 
Thrombosis 
Peripheral diabetic microvascular 
disease 
Peripheral artery disease 
Aortic aneurysm 
Aortitis 
Raynaud disease 
Vasculitis 
Other chronic vascular condition: 
Other chronic vascular condition 
 


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Hematological/ 
Immunological 
Sickle cell anemia 
Hemoglobinopathy 
Polycythemia 
Thrombocythemia 
Hemophilia 
Paroxysmal nocturnal 
hemoglobinuria 
Thrombotic thrombocytopenic 
purpura 
Dysfibrinogenemia 
HIV 
Other chronic hematological or 
immunological 
condition: 
Other chronic hematological or 
immunological 
condition 
 
Respiratory 
Asthma 
Chronic obstructive pulmonary 
disease 
Cystic fibrosis 
Emphysema 
Chronic bronchitis 
Chronic pleural effusions 
Pulmonary fibrosis 
Sarcoidosis 
Pulmonary embolism 
Pulmonary arterial hypertension 
Lung cancer 
Other chronic respiratory condition: 
Other chronic respiratory condition 
 
Ophthalmological/ 
otolaryngological 
Loss of vision 
Glaucoma 
Cataract 
Macular degeneration 
Diabetic retinopathy 
Loss of hearing 
Otitis/chronic otitis 
Vestibular impairment 
Vertigo 
Temporomandibular disorder 
Sialolithiasis 
Chronic sinusitis 
Laryngeal/pharyngeal disorders 
Other chronic ophthalmological or 
otolaryngological condition: 
 
Upper 
Gastrointestinal 
Chronic esophagitis 
Dysphagia 
Achalasia 
Gastroduodenal ulceration 
Celiac disease 
Irritable bowel syndrome 
Short bowel syndrome 
Malnutrition 
Malabsorption 
Small bowel obstruction 
 


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Hernia 
Pseudomyxoma peritonei 
Upper gastrointestinal cancer 
Other chronic upper gastrointestinal 
condition: 
Other chronic upper gastrointestinal 
condition 
Lower 
Gastrointestinal 
Diverticulitis 
Inflammatory bowel disease 
Volvulus 
Colon cancer 
Other chronic lower gastrointestinal 
condition: 
Other chronic lower gastrointestinal 
condition 
 
Hepatic/ 
Pancreatic 
Chronic hepatitis or hepatic cirrhosis 
Biliary obstructive disorders 
Pancreatitis 
Hepatic, biliary, or pancreatic cancer 
Other chronic hepatic or pancreatic 
condition 
Other chronic hepatic or pancreatic 
condition 
 
Renal 
Chronic kidney disease 
Diabetic nephropathy 
Pyelonephritis 
Renal cancer 
Other chronic renal condition: 
Other chronic renal condition 
 
Gynecological/ 
Urological 
Recurrent/chronic urinary tract 
infection 
Nephrolithiasis 
Bladder dysfunction 
Vaginal/vulvar disease 
Uterine/ovarian disease 
Prostatitis 
Bladder, uterine, ovarian, prostate, 
or other cancer 
Prostate hypertrophy 
Other chronic gynecological or 
urological condition: 
Other chronic gynecological or 
urological condition 
 
Dermatologic/ 
musculoskeletal 
Dermatitis 
Dermatomyositis 
Myopathy 
Gout 
Psoriasis 
Keratosis 
Urticaria 
Scleroderma 
Basal cell carcinoma 
Squamous cell carcinoma 
Melanoma 
Osteomyelitis 
Osteoarthritis 
 


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Rheumatoid arthritis 
Spondyloarthritis 
Temporal arteritis/polymyalgia 
rheumatica 
Polychondritis 
Fibromyalgia 
Osteoporosis 
Systemic lupus erythematosus 
Dermatomyositis 
Sjögren syndrome 
Other chronic dermatological or 
musculoskeletal condition: 
Other chronic dermatological or 
musculoskeletal condition 
Neurological 
Cerebrovascular disease 
(transient ischemic 
attack/stroke/hemorrhage) 
Dementia 
Parkinson disease 
Non-Parkinsonian movement 
disorder 
(eg, ataxia/chorea) 
Leukodystrophic disorders 
Amyotrophic lateral sclerosis 
Multiple sclerosis 
Demyelinating disease 
Guillain-Barré syndrome 
Paralysis (eg, 
paraplegia/quadriplegia/hemiplegia) 
Myelopathy 
Cranial nerve disorder 
Degenerative disk disease with 
nerve root 
compression 
Migraine headaches 
Seizure disorder 
Secondary neuropathy 
(e.g., 
diabetic/alcoholic/autoimmune) 
Neurofibromatosis/tuberous 
sclerosis 
Benign or malignant central nervous 
system tumor 
Other chronic neurological 
condition: 
Other chronic neurological condition 
 
Endocrine/ 
Metabolic 
Diabetes 
Adrenal disorder 
Thyroid disorder 
Parathyroid disorder 
Pheochromocytoma 
Pituitary disorder 
Hemochromatosis 
Porphyria 
Paget's disease 
Endocrine or neuroendocrine tumor 
 


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Other chronic endocrine or 
metabolic condition: 
Other chronic endocrine or 
metabolic condition 
 
Depression 
Anxiety 
Bipolar disorder 
Paranoia 
Schizophrenia 
Neurosis 
Personality disorder 
Substance addiction/abuse 
Posttraumatic stress disorder 
Chronic fatigue syndrome 
Other chronic psychiatric condition: 
Other chronic psychiatric condition: 
 
 
 
 
 
 
 


Ibrutinib (PCI-32765)                                PCYC-20016-CA 
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Appendix 8.  FACIT-Fatigue 
 
 
 
 


Ibrutinib (PCI-32765)                                PCYC-20016-CA 
April 03, 2017 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
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FACIT Fatigue Scale (Version 4) 
 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued
 .......................................................................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 .......................................................................................... 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 .......................................................................................... 
0 
1 
2 
3 
4 
An2 
I feel tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An5 
I have energy
 .......................................................................................... 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 .......................................................................................... 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 .......................................................................................... 
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 .......................................................................................... 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 .......................................................................................... 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to do
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 


Ibrutinib (PCI-32765)                                PCYC-20016-CA 
April 03, 2017 
 
Northwell Health IRB# 16-727     
Proprietary and Confidential 
Page 120 
An16 
I have to limit my social activity because I am tired
0 
1 
2 
3 
4