Conditions: Classical Hodgkin Lymphoma Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This phase II trial evaluates how effective 560 mg of ibrutinib taken by mouth daily is in the treatment of classical Hodgkin lymphoma which recurs or does not respond to initial treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth, by altering the environment around the tumor or by affecting the immune system.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the antitumor efficacy of single agent ibrutinib as measured by the overall response rate in patients with relapsed/refractory Hodgkin's lymphoma who have relapsed or not responded to chemotherapy, immunotherapy and/or radiation.

SECONDARY OBJECTIVES:

I. To assess duration of tumor control including duration of response (DOR) II. To assess progression free survival (PFS). III. To assess the safety and tolerability of 560mg of ibrutinib in Hodgkin lymphoma (HL) patients.

TERTIARY OBJECTIVES:

I. To assess the mechanism(s) by which ibrutinib may be active in patients with classical Hodgkin lymphoma (cHL) by the correlation of potential biomarkers with clinical outcomes.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days then every 9 weeks for 1 year.

Arms:
arm 1: Patients receive ibrutinib PO QD. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
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IST PROTOCOL 
 
IND # 130115 
 
 


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TITLE: 
A phase II multicenter single arm study to evaluate the efficacy 
and safety of single agent Bruton’s tyrosine kinase inhibitor, 
ibrutinib, in patients with relapsed refractory Classical Hodgkin’s 
lymphoma. 
PROTOCOL NUMBER: 
2016-033 
STUDY DRUG: 
Ibrutinib (PCI-32765) 


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PRINCIPAL 
INVESTIGATOR  
 
 
 
 
 
 
CO- INVESTIGATORS  
AT KCI 
 
 
 
 
 
 
CO-INVESTIGATOR AT 
PARTICIPATING SITES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dipenkumar Modi, M.D. 
Assistant Professor of Medicine 
Department of Oncology 
Karmanos Cancer Institute 
4100 John R. Detroit MI 
Detroit, MI 
Tel: 313-576-8739 
Fax: 313-576-8766  
Modid@karmanos.org 
 
Melissa A. Runge-Morris, MD 
Abhinav Deol, MD 
Jeffrey Zonder, MD 
Jay Yang, MD 
Andrew Kin, MD 
Suresh Balasubramanian, MD 
Vijendra Singh, MD 
 
 
Hun Ju Lee MD 
Assistant Professor 
Lymphoma & Myeloma 
MD Anderson Cancer Center 
1515  Holcombe Blvd 
Unit 429, Houston Texas, 77030 
Tel: 713-794-1829 
Fax: 713-794-5656  
hunlee@mdanderson.org 
 
 
Ryan Wilcox, MD 
University of Michigan Health System 
1500 E. Medical Center Drive 
C357 Med Inn / SP 5848 
Ann Arbor, MI 48109 
Tel: 734-615-1482 
rywilcox@med.umich.edu 
 
 
Radhakrishnan Ramchandren, MD 
University of Tennessee 
1926 Alcoa Highway Suite 350 
Knoxville, TN 37920 
Tel: 734-325-3832 
RRamchandren@utmck.edu 


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SPONSOR: 
 
 
 
 
 
LEAD STUDY 
COORDINATOR: 
 
 
 
 
 
 
 
LEAD REGULATORY 
COORDINATOR: 
 
 
 
 
 
 
 
STATISTICIAN: 
 
Karmanos Cancer Institute 
Wayne State University  
4100 John R 
Detroit, MI 48201 
Tel: 313-576-8673 
Fax: 313-576-8767 
 
Erik Carr, CCRP 
Clinical Research Coordinator 
Malignant Hematology 
Karmanos Cancer Institute  
4100 John R  
Mailcode MM03CT 
Detroit, MI 48201  
Tel: 313-576-9758 
carrer@karmanos.org 
 
Kathy Reichel, BS, CCRP 
Clinical Research Coordinator IV | Regulatory 
Malignant Hematology 
Karmanos Cancer Institute | Clinical Trials Office 
87 E Canfield St 
Detroit, MI 48201 
 
Tel: 313-576-9374 
reichelk@karmanos.org 
 
 
Wei Chen, PhD 
Karmanos Cancer Institute 
4100 John R  
Detroit, MI 48201 
Tel: 313-576-8655 
chenw@karmanos.org 
 
 
 
DATE FINAL: 
 
 
25 April 2016 


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AMENDMENT 1: 
AMENDMENT 2: 
AMENDMENT 3: 
1 July  2016 
5 January 2017 
11 September 2018 
AMENDMENT 4: 
14 December 2018 
 AMENDMENT 5:  
  27 March 2020 
 AMENDMENT 6:  
  23 February 2021 
 AMENDMENT 7:  
  25 October 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
LIST OF IN-TEXT TABLES AND FIGURES ...........................................................................8 
SYNOPSIS ......................................................................................................................................9 
1. 
Introduction ........................................................................................................................17 
1.1. 
Disease/Histology ..............................................................................................................17 
1.1.1. 
Treatment Options .......................................................................................................18 
1.1.2. 
Role of BTK in Disease/Histology ..............................................................................18 
1.2. 
Investigational Product Name and Description .................................................................18 
1.3. 
Summary of Nonclinical Data ...........................................................................................19 
1.3.1. 
Toxicology ...................................................................................................................20 
1.3.1.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................20 
1.4. 
Summary of Clinical Data .................................................................................................21 
1.4.1. 
Pharmacokinetics and Product Metabolism .................................................................21 
1.5. 
Summary of Clinical Safety ...............................................................................................21 
1.5.1. 
Risks .............................................................................................................................23 
Bleeding-related events ..................................................................................................................23 
Atrial Fibrillation ...........................................................................................................................23 
Diarrhea ......................................................................................................................................24 
Infections ......................................................................................................................................24 
Non-Melanoma Skin Cancer..........................................................................................................24 
Rash 
......................................................................................................................................24 
Lymphocytosis and Leukostasis ....................................................................................................25 
Tumor Lysis Syndrome..................................................................................................................25 
1.6. 
Study Rationale ..................................................................................................................26 
1.7 
Exploratory Rationale ……………………………………………………………………24 
2. 
STUDY OBJECTIVE ...........................................................................................................27 
2.1. 
Primary Objective ..............................................................................................................27 
2.2. 
Secondary Objective(s) ......................................................................................................27 
2.3. 
Exploratory Objective(s) ....................................................................................................28 
3. 
STUDY DESIGN ..................................................................................................................28 
3.1. 
Overview of Study Design .................................................................................................28 
3.2.      Study Schema (include Figure) ..........................................................................................30 
 
3.3. 
Study Design Rationale......................................................................................................31 
3.3.1. 
Study Population and Treatment ..................................................................................31 
3.3.2. 
Dose Selection .............................................................................................................31 
4. 
SUBJECT SELECTION ......................................................................................................31 
4.1. 
Inclusion Criteria ...............................................................................................................31 
4.2. 
Exclusion Criteria ..............................................................................................................33 
4.3 
Prohibitions and Restrictions----------------------------------------------------------------------32 
5. 
TREATMENT OF SUBJECTS ...........................................................................................35 
5.1. 
Treatment Registration.......................................................................................................35 
5.1.1. 
Study treatment ............................................................................................................36 
5.2. 
Route and schedule ............................................................................................................36 
5.3. 
Study Medication ...............................................................................................................36 


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5.3.1. 
Ibrutinib........................................................................................................................37 
5.3.1.1. 
Formulation/Packaging/Storage .............................................................................37 
5.3.1.2. 
Dose and Administration .......................................................................................37 
5.3.1.3. 
Drug Accountability...............................................................................................38 
5.3.1.4. 
Overdose ................................................................................................................38 
5.3.1.5. 
Dose Modification for Adverse Reactions .............................................................39 
5.4. 
Dose Modification for Hepatic Impaired Subjects ............................................................39 
5.5. 
Criteria for Permanent Discontinuation of Study Drug .....................................................40 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES ......................................................40 
6.1. 
Permitted Concomitant Medications ..................................................................................40 
6.2. 
Medications to be Used with Caution ................................................................................41 
6.2.1. 
CYP3A- Inhibitors/Inducers ........................................................................................41 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib .................42 
6.2.3. 
QT Prolonging Agents .................................................................................................42 
6.2.4.       Antiplatelet Agents and Anticoagulants …………………………………………….39 
6.3. 
Prohibited Concomitant Medications ................................................................................42 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedure …………………….40 
6.4.1.      Minor Surgical Procedures …………………………………………………………..40 
6.4.2.        Major Surgical Procedure ……………………………………………………………40 
7. 
STUDY EVALUATIONS ....................................................................................................43 
7.1 
Description of Procedures ............................................................................................43 
7.1.1. 
Assessments .................................................................................................................43 
7.1.2. 
Pharmacokinetics/Biomarkers .....................................................................................46 
7.2.0 
Efficacy Evaluations ....................................................................................................46 
7.3. 
Evaluations……………………………………………………………………………….43 
7.3.1.         Radiographic Image Assessments …………………………………………………...43 
7.3.2.       Positron Emission Tomography (PET)………………………………………………44 
7.3.3       Definition of Measurable and Assessable Disease ………………………………….44 
7.3.4.       Bone Marrow Assessment…………………………………………………………...45 
7.3.5.       Criteria for Response Categories…………………………………………………….45 
7.4. 
Sample Collection and Handling………………………………………………………...47  
8 
SUBJECT COMPLETION AND WITHDRAWAL .........................................................50 
8.1 
Completion ...................................................................................................................50 
8.2 
Withdrawal from Study Treatment ..............................................................................50 
8.3 
Withdrawal from Study......................................................................................................51 
9. 
STATISTICAL CONSIDERATIONS ................................................................................51 
10.  ADVERSE EVENT REPORTING .....................................................................................53 
10.1.1 
Adverse Events ............................................................................................................54 
10.1.2 
Serious Adverse Events ...............................................................................................55 
10.1.3 
Severity Criteria (Grade 1-5) .......................................................................................55 
10.1.4 
Causality (Attribution) .................................................................................................56 
10.2 
Unexpected Adverse Events ..............................................................................................56 
10.3 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ...................................................................................................................................57 
10.3.1 
Assessment of Adverse Events ....................................................................................57 


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10.3.2 
Adverse Event Reporting Period .................................................................................57 
10.3.3 
Pregnancy .....................................................................................................................58 
10.3.4 
Other Malignancies ......................................................................................................58 
10.3.6 Adverse Events of Special Interest (AESI) .....................................................................58 
10.3.6.1 
Major Hemorrhage ....................................................................................................58 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 10.3.6 above. ...................................................................................59 
10.3.7 
Expediting Reporting Requirements for Serious Adverse Events ........................59 
10.4. Reporting to Regulatory Agencies……………………………………………………….57 
11 STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ......................60 
12  DATA AND SAFETY MONITORING ..............................................................................60 
12.1  Institutional Review Board (IRB), Research Ethics Board (REB) and Independent Ethics 
Committee (IEC) Approval............................................................................................................61 
12.2 
Informed Consent...............................................................................................................61 
12.3 
Protected Subject Health Information Authorization ........................................................61 
12.4 
Study Files and Record Retention......................................................................................62 
12.5 
Study Monitoring/Audit Requirements..............................................................................62 
12.6 
Investigator Responsibilities ..............................................................................................63 
12.7 
Protocol Amendments ........................................................................................................63 
12.8 
Publication of Study Results ..............................................................................................63 
12.9 
Study Discontinuation ........................................................................................................63 
13. REFERENCES .....................................................................................................................65 
14 APPENDICES .......................................................................................................................67 
 
List of Appendices 
Appendix 1.  Schedule of Assessments ........................................................................................ 68 
Appendix 2.  ECOG Status Scores and Formulas......................................................................... 70 
Appendix 3.  Inhibitors and Inducers of CYP3A .......................................................................... 71 
Appendix 4.  Response Criteria .................................................................................................... 72 
Appendix 5.  Data and Safety Monitoring Report Form…………………………………….......74 
Appendix 6. Pill Diary…………………………………………………………...……………....76 
Appendix 7. Child-Pugh Scores……………………………………………………………….…77 
LIST OF IN-TEXT TABLES AND FIGURES 
Figures 
Study Schema ----------------------------------------------------------------------------------------------25 
 
 
 


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SYNOPSIS 
Study Title: 
A phase II multicenter single arm study to evaluate the efficacy 
and safety of single agent Bruton’s tyrosine kinase inhibitor, 
ibrutinib, in patients with relapsed refractory Hodgkin’s 
lymphoma.  
Protocol Number: 
2016-033 
Study Phase: 
2 
Study Duration: 
1 year upon completion of accrual   
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral 
(PO) administration. 
Objectives: 
Primary Objective: 
To determine the antitumor efficacy of single agent ibrutinib as 
measured by the overall response rate in patients with 
relapsed/refractory Hodgkin’s lymphoma ineligible for; or following 
ASCT  
Secondary Objectives: 
To assess duration of tumor control including duration of response 
(DOR and progression free survival (PFS) 
To assess the safety and tolerability of 560mg of ibrutinib in HL 
patients. 
Exploratory Objectives: 
To assess the mechanism(s) by which ibrutinib may be active in patients 
with cHL by the correlation of potential biomarkers with clinical 
outcomes.  
Study Design: 
Phase II multicenter open label single agent study 
Population: 
Relapsed or Refractory Hodgkin’s lymphoma  
Ineligible for autologous stem cell transplant 
Or relapse after autologous/allogeneic stem cell transplant 
Centers: 
Multiple 
Inclusion Criteria: 
Refer to Section 4.0 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
Disease Related           
• Patients with relapsed or refractory Classical HL who 
have previously received autologous stem cell transplant 
and/or allogeneic stem cell transplant. Patients must have 
received prior autologous stem cell transplant at least 12 
weeks (3 months) before the first dose of ibrutinib and/or 
allogeneic stem cell transplant must have been completed 
at least 6 months prior to the first dose of Ibrutinib.   


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• or 
• Patients with relapsed or refractory HL who have received 
at least 2 prior therapies and are not eligible for 
autologous stem cell transplant due to: 
1.  Inability to achieve a CR or PR prior to transplant 
2. Age or comorbid conditions  
3.  Inability to collect stem cells 
• Completion of any prior treatment with radiation, 
chemotherapy, biologics, and/or other investigational 
agents at least 4 weeks prior to the first dose of ibrutinib. 
Patients must have completed any prior immunotherapy 
(e.g., rituximab or PD-1 inhibition) or antibody drug 
conjugate therapy (e.g. brentuximab vedotin) at least 4 
weeks prior to the first dose of ibrutinib. 
• Fluorodeoxyglucose (FDG)-avid disease by PET and 
measurable disease of at least 1.5 cm in minimum 
dimension by CT scan with contrast, as assessed by the 
site radiologist. 
• Prior treatment with at least 2 lines of therapy for HL 
including brentuximab vedotin or individuals who have 
received at least 2 prior therapies and are not candidates 
for brentuximab vedotin therapy.  
• Adequate hematologic function independent of transfusion 
and growth factor support for at least 7 days prior to 
screening and randomization, with the exception of 
PEGylated G-CSF (pegfilgrastim) and darbopoeitin which 
require at least 14 days prior to screening and 
randomization defined as:  
• Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L). 
• Platelet count >50,000 cells/mm3 (50 x 109/L).  
• Hemoglobin >8.0 g/dL. 


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• Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN). 
• Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-
Gault)(see appendix 2) 
• 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. 
Demographic 
• Men and women ≥ 18 years of age. 
• Eastern Cooperative Oncology Group (ECOG) 
performance status of 0, 1 or 2. 
Ethical/Other 
• 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 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., condoms, implants, 
injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], sexual abstinence, or 
sterilized partner) during the period of therapy and for 90 
days after the last dose of study drug 
• Sign (or their legally-acceptable representatives must 
sign) an informed consent document indicating that they 
understand the purpose of and procedures required for the 
study and are willing to participate in the study. 
Exclusion Criteria: 
Disease-Related 


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• Prior allogeneic Stem cell transplant within 6 months.  
• Active GVHD or concurrent treatment with 
immunosuppressive medications as prophylaxis for GVHD 
• Previous therapy with BTK inhibition 
• Known cerebral/meningeal disease 
• Nodular Lymphocyte predominant Hodgkin’s Lymphoma 
Concurrent Conditions: 
• Concurrent therapy with other systemic anti-neoplastic or 
investigational agents 
• Patients with a known hypersensitivity to any excipient 
contained in the drug formulation 
• History of other malignancies, except:  
• 
Malignancy treated with curative intent and 
with no known active disease present for ≥3 
years before the first dose of study drug and 
felt to be at low risk for recurrence by treating 
physician. 
• 
Adequately treated non-melanoma skin cancer 
or lentigo maligna without evidence of disease. 
• 
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. 
• Vaccinated with live, attenuated vaccines within 4 weeks 
of first dose of study drug. 
• Recent infection requiring systemic treatment that was 
completed ≤14 days before the first dose of study drug. 


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• 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 must have a 
negative polymerase chain reaction (PCR) result before 
enrollment.  Those who are PCR positive will be excluded. 
• Any uncontrolled active systemic infection. 
• Major surgery within 4 weeks of first dose of study drug. 
• 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. 
• 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 registration. 
• 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. 


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• Requires treatment with a strong cytochrome P450 (CYP) 
3A4/5 inhibitor. (see Appendix 3) 
• Currently active, clinically significant hepatic impairment 
Child-Pugh class B or C according to the Child Pugh 
classification 
• Lactating or pregnant. 
• 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). 
Study Treatment: 
Ibrutinib 560mg p.o. q.d. until disease progression, unacceptable 
toxicity or patient/clinician choice to discontinue.   
Concomitant Therapy: 
Refer to Section 6 for information on concomitant therapy. 
Safety Plan: 
 
The Barbara Ann Karmanos Cancer Institute, Data and Safety 
Monitoring Committee (DSMC), provides the primary oversight 
of data and safety monitoring for KCI Investigator-initiated trials. 
In Addition monthly investigator teleconferences will occur to 
discuss adverse event and safety issues. 
Statistical Methods and 
Data Analysis: 
All efficacy analyses will be performed using all evaluable participants.  
Primary Efficacy Analysis 
A one-sample binomial test will be used to assess efficacy in terms of 
ORR. The ORR will be reported as a proportion with a one-sided, lower 
95% confidence interval. Assuming p0=30%, pA=50%, power=85% 
and type I error = 10.69% the null hypothesis will be rejected if there 
are 13 or more ORRs. 
Secondary Efficacy Analysis: 
DOR will be reported as median and range. Kaplan-Meier estimate of 
median PFS will be reported with 95% confidence intervals. 
Exploratory Efficacy Analysis: 


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The influence of ibrutinib on T cell behavior and antitumor effect will 
be assessed using a variety of techniques including gene expression and 
mutational analysis.  T cell subset alterations in blood and tumor tissue 
will be analyzed and PD-1 and PD-2 expression will be evaluated by 
FISH and IHC.  
Safety Analysis: 
Frequency of grade 3 or higher adverse events will be tabulated and all 
grade 1 and 2 adverse events will be collected. 
Sample Size 
Determination 
Sample Size Determination 
A study of 31 evaluable participants was deemed feasible. To 
accomplish this with an expected not evaluable rate of 12% a total 
sample population of 35 patients is planned. We specified statistical 
power of 85% to distinguish a null hypothesis value of 30% against 
an alternative value of 50% assuming a binomial test of one 
proportion with a target, one-sided type error of 11%. Under these 
assumptions the null hypothesis will be rejected if there are 13 or 
more ORRs among the 31 participants. 
Accrual Rate, Accrual Duration and Expected Study Duration The 
expected accrual rate across the 4 institutions is 35 participants per 
year. Thus it is expected that the duration of accrual will be one year. 
An additional year is planned for evaluation of the primary, 
secondary and safety endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations 
 
CRF 
DSM 
case report form (paper or electronic as appropriate for this study) 
Data and Safety Monitoring (DSM) Report 
DCF 
data clarification form 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eDC 
electronic data capture 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PQC 
Product Quality Complaint 
PRO 
patient-reported outcome(s) 
USP 
United States Pharmacopeia 
Mos 
Months 
HRS 
Reed Sternberg Cells 
cHL 
KCI 
PCYC 
Classical Hodgkin’s Lymphoma 
Karmanos Cancer Institute 
Pharmacyclics 
 
 
 
 
 
 
 
 
 
 


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OBJECTIVES 
 
 
 
Primary Objective 
 
To determine whether the antitumor efficacy of single agent ibrutinib as measured by the 
overall response rate in patients with relapsed/refractory Hodgkin’s lymphoma ineligible 
for; or following ASCT is sufficient to justify further study.  
 
Secondary Objective 
 
To assess duration of tumor control including duration of response (DOR and progression 
free survival (PFS).  
 
To assess the safety and tolerability of 560mg of ibrutinib in cHL patients. 
 
Safety Objectives 
 
To assess the safety and tolerability of 560mg of ibrutinib in cHL patients. 
 
Exploratory Objectives 
 
To assess the mechanism(s) by which ibrutinib may be active in patients with cHL by the 
correlation of potential biomarkers with clinical outcomes 
 
Background 
1. INTRODUCTION 
Ibrutinib (also referred to as PCI-32765 or JNJ 54179060) is a first-in-class potent, orally-
administered, covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) 
currently being co-developed by  Pharmacyclics LLC and Janssen Research & Development, 
LLC (JRD). It has demonstrated single-agent activity in several B-cell lymphomas, including 
relapsed mantle cell lymphoma (MCL), with an acceptable safety profile. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib, refer to the 
latest version of the ibrutinib (PCI-32765) Investigator’s Brochure and Addenda. 
1.1. 
Disease/Histology 
Classical Hodgkin’s Lymphoma (cHL) is a malignancy of mature (post germinal center) B-
lymphocytes that afflicts almost 20,000 individuals annually in North America and Europe alone. 
Uniquely, the malignant Reed Sternberg (RS) cell in cHL comprises only a fraction of the tumor 
mass in pathologic lymph nodes (LN) with the majority of the tumor composed of activated T 
and B lymphocytes and a variety of other hematopoietic elements. While the majority of patients 
diagnosed with cHL are cured with multi-agent chemotherapy, 15 % of patients are refractory to 
conventional chemotherapy and almost half of patients with high-risk disease relapse.1 For these 
patients few effective therapeutic options exist. Only one agent has been approved in the last 30 
years for relapsed HL and novel therapies are needed.2 


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1.1.1. 
Treatment Options 
Current initial therapy for the treatment of HL includes adriamycin, (doxorubicin) bleomycin, 
vinblastine and dacarbazine (ABVD).  In patients who relapse options include salvage 
chemotherapy followed by autologous stem cell transplant (ASCT) which results in long term 
disease free progression rates of 50%.1 Other options include brentuximab vedotin an antibody 
drug conjugate which has shown significant single agent activity in HL and is approved after 
ASCT or failure of 2 prior lines of therapy.2 
1.1.2. 
Role of BTK in Disease/Histology 
Bruton’s Tyrosine Kinase (BTK) is a member of the TEC family and plays a central role in B-
cell signaling, activation, proliferation and differentiation. BTK is expressed in normal B-cells, 
myeloid cells and macrophages. In addition to activation by the B-cell receptor, several studies 
have shown that BTK has been associated with PI3K, mTOR, FAS and NF-κB signaling. 
Furthermore, BTK can be activated by CD40 ligand binding, chemokines such as IL-6 and 
activation of toll like receptor (TLR) pathways.5,6 Many of these pathways are also known to 
play important roles in the pathologic behavior of HL cells. In particular, CD 40, mTOR NF-kB 
and toll like receptor pathways have been identified as targets for possible therapeutic 
intervention in cHL.1,7  
Recent data has also suggested that T cell cytotoxicity and immune surveillance is important in 
the pathogenesis of cHL. This may be particularly true in patients with high copy numbers of 
chromosome 9p24.1 as determined by fluorescence in situ hybridization.11 Novel therapies have 
taken advantage of this by stimulating native T cells in this population with excellent results in 
relapsed cHL patients.11 Ibrutinib has shown the ability to potentially subvert Th2 immunity 
potentiating Th1 based immune responses through inhibition of ITK.12 This may in turn enhance 
a Th1 dominant cytotoxic immune response against the malignant clone in cHL. 
Lastly, as the RS cell comprises only a fraction of the tumor mass in patients with HL, the tumor 
microenvironment is also likely to be of vital importance. It has been hypothesized that activated 
B-cells, macrophages and other hematopoietic elements provide anti-apoptotic and survival 
signals necessary for the survival of the malignant RS population.7 Therapies directed at the 
tumor microenvironment have previously demonstrated significant and durable responses in 
highly refractory cHL patients.8,10 BTK over activity has been associated with chemokine related 
homing, adhesion and migration by inhibition of CXCR4/5 and CXCL 12/13 in B cells.3,4 
Consequently interruption of the microenvironment by BTK inhibition may result in anti-tumor 
effect. 
1.2. 
Investigational Product Name and Description 
Ibrutinib 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 


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selected members of the kinase family with 10-fold specificity compared 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) including CLL 
with a deletion of the short arm of chromosome 17 (del17p) or a TP53 mutation, and 3) in 
patients with Waldenstrom’s macroglobulinemia.  Ibrutinib is currently under investigation in 
various 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 comprising 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 chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from 
mutations and translocations acquired during normal B-cell development (Shaffer 2002).  
Several lines of evidence suggest that signaling through the BCR is necessary to sustain the 
viability of B-cell malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease X-
linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B-cells.  The BTK 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells (Satterthwaite 2000).   
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 either 4 or 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.  


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In HL cell lines H2 were grown in vitro and incubated with increasing concentrations of ibrutinib 
for 72 hrs. Incubation of the cell line with ibrutinib resulted in a significant reduction in viability 
by trypan blue analysis in a dose dependent manner.  Additionally, apoptotic studies confirmed 
the induction of cell death by BTK inhibition with ibrutinib in both annexin V-FITC assays and 
histone DNA ELISA studies.  Lastly, caspase-3 and PARP cleavage was demonstrated in this 
cell line.  (Azmi A, Ramchandren R unpublished data) 
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 Btk catalytic 
activity 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 anti-IgM stimulation 
followed by CD69 expression (Herman 2011).   
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to 
the current Investigator’s Brochure. 
1.3.1. 
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 420 and 560 mg daily, 
respectively.     
1.3.1.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 


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Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
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. 
1.5. 
Summary of Clinical Safety  
Integrated safety data from a total of 1,523 subjects with B-cell malignancies treated with 
ibrutinib monotherapy in 17 studies that have completed primary analysis or final analysis 
included in the CSR as of the 31 July 2017 cutoff date for the current IB update in B-cell 
malignancies are summarized below.   
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N = 1,523): 


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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  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Pyrexia 
Cough 
Anemia 
Febrile neutropenia 
Pyrexia 
Hypertension   
Sepsis 
Anemia  
Diarrhea  
Cellulitis 
Upper respiratory tract infection 
 Neutropenia  
Atrial fibrillation 
Fatigue 
Pleural effusion 
Dyspnoea 
Oedema peripheral 
Neutrophil count decreased 
Urinary tract infection 
Thrombocytopenia    
Febrile Neutropenia 
Lung infection 
Muscle spasms 
Hyponatraemia 
Abdominal pain 
Constipation 
Hypokalaemia 
Acute kidney injury 
Arthralgia 
 
Anemia 
Vomiting 
 
Respiratory failure 
 
Decrease appetite 
 
 
Dyspnoea 
 
 
Headache 
 
 
Pneumonia 
 
 
Rash 
 
 
Hypertension 
 
 
Abdominal pain 
 
 
Back pain 
 
 
Contusion 
 
 


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Dizziness 
 
 
a Source is Table 5 of IB (v11), b Source is Table 6 of IB (v11) 
For more detailed information refer to the current version of the IB. 
1.5.1. 
Risks 
Long-term safety 
The long-term safety data over 4 years from 1,177 subjects (CLL/SLL n = 807 and MCL n = 
370) treated with ibrutinib were analyzed. The median duration of treatment for CLL/SLL was 
45 months with 70% and 40% of subjects receiving treatment for more than 2 years and 4 years. 
The median duration of treatment for MCL was 11 months with 31% and 14% of subjects 
receiving treatment for more than 2 years and 4 years. The overall known safety profile of 
ibrutinib-exposed subjects remained consistent, other than an increasing prevalence of 
hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater 
hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), and 8% (year 3-4). The incidence 
for the 4-year period was 10%. 
Bleeding-related events 
There have been reports of bleeding events in subjects treated with ibrutinib both with and 
without thrombocytopenia.  These include minor bleeding events such as contusion, epistaxis, 
and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. 
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen‑induced platelet 
aggregation were observed, refer to Section 6.2.4. Use of  either anticoagulant or antiplatelet 
agents comcomitantly with ibrutinib increases the risk of major bleeding. A higher risk for major 
bleeding was observed with anticoagulant than with antiplatelet agents. Consider the risks and 
benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib. Monitor for 
signs or symptoms of bleeding. See Section 6.2.4 for guidance on concomitant use of 
anticoagulants, antiplatelet therapy and/or supplements.  
 
Supplements such as fish oil and vitamin E preparations should be avoided. 
 
Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of 
surgery and the risk of bleeding. See Section 6.3 for guidance on ibrutinib management with 
surgeries or procedures. 
 
Subjects with congenital bleeding diathesis have not been studied. 
 
Cardiac arrhythmias 
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 


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risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness), syncope, chest discomfort or new onset of 
dyspnea) should be evaluated clinically, and, if indicated, have an ECG performed. For cardiac 
arrhythmias which persist, consider the risks and benefits of ibrutinib treatment and follow the 
dose modification guidelines. For cardiac arrythmia which persists, consider the risks and 
benefits of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 
5.4.1.5).  
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly. 
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 5.4.1.5). 
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 (reference Section Error! Reference source not found.). Although 
causality has not been established, cases of progressive multifocal leukoencephalopathy (PML) 
and hepatitis B reactivation have occurred in subjects treated with ibrutinib. Subjects should be 
monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting and jaundice) 
and appropriate therapy should be instituted as indicated. 
Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor subjects 
for the appearance of non-melanoma skin cancer. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 


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of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
For subject and ibrutinib management guidance, refer to Section 5.3.1.5. 
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 
including hydration and/or cytoreduction as indicated. For subject and ibrutinib management 
guidance, refer to Section 5.3.1.5. 
Lymphocytosis 
Upon initiation of single agent treatment with ibrutinib, a reversible increase in lymphocyte 
counts (i.e., ≥50% increase from baseline and an absolute count >5000/mcL), often associated 
with reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL/SLL. 
This effect has also been observed in some subjects (35%) 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 month 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 (range, 0.1 to 104 weeks). 
When ibrutinib was administered in combination with BR or with obinutuzumab in subjects with 
CLL/SLL, lymphocytosis was infrequent (7% with ibrutinib + BR versus 6% with 
placebo + BR and 7% with ibrutinib + obinutuzumab versus 1% with chlorambucil + 
obinutuzumab). Lymphocytosis was not observed in subjects with WM treated with ibrutinib. 
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 high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
 
Interstitial lung disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 


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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 5.3.1.5). 
 
 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
Cerebrovascular Accidents 
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended. 
1.6. 
Study Rationale   
Despite the curability of HL in patients with ABVD, it remains a serious and fatal malignancy in 
patients who relapse after ASCT or cannot undergo intensive therapy.  Due to the young age of 
this population (median 30 yrs.) the number of years of life lost is substantial with a median 
overall survival (OS) of only 3 years if relapse occurs after stem cell transplant1.  In this 
population there is an unmet medical need, particularly for those patients who relapse or become 
refractory to treatment.  The expected survival is progressively shorter with each subsequent 
relapse. Brentuximab vedotin is the only FDA approved agent in the US for patients who have 
received at least 2 prior therapies. However less than 40% of patients achieve a complete 
remission (CR) with this therapy and eventually all patients who receive this therapy will relapse 
with no other approved therapeutic options. As an oral daily treatment, ibrutinib may offer a 
treatment option to this otherwise terminal patient population who are without alternative 
approved treatment options.  Based on the activity of ibrutinib in other B cell malignancies, the 
well-defined toxicity profile and encouraging pre-clinical data, we hypothesize that BTK 
inhibition with ibrutinib may have clinical benefit in patients with Hodgkin’s lymphoma with a 
novel mechanism of action. 
1.7 
Exploratory Rationale 
Gene expression profiling and mutational analysis of laser micro dissected HRS cells will be 
performed to evaluate genes of interest.  This will be performed on archival tissue blocks that 
must be submitted as described in the lab manual. Whenever possible the most recent biopsy 
sample must be sent for evaluation.   If archival tissue is not available a fresh biopsy must be 


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performed prior to treatment with study drug.  An excisional biopsy is preferred in all instances 
however, when an excisional biopsy is not possible a core biopsy will be allowed. If core biopsy 
is utilized then 4-6 cores must be provided for analysis to ensure adequate sample.   In those 
patients who progress or do not respond to therapy, end of study (EOT) testing includes and 
optional, highly recommended tumor biopsy for assessment.   In this instance excisional or core 
biopsy will be acceptable.  
To assess ibrutinib’s influence on T cell behavior and antitumor effect, serial serum samples pre 
and post therapy will be assessed for Th1 ( (IFN-g ) and Th2 cytokines ( IL-10, IL-4 and IL-13) 
at 4 distinct time points (pre-dose, cycle 1 day 2 , day 15, and day 28) .  The cytokine profiles pre 
and post therapy with ibrutinib will be compared to assess modifications in T cell subsets due to 
ibrutinib therapy.12      In addition post treatment T cell populations will be compared with tumor 
microenvironment populations. 
HL has shown sensitivity to T cell immune based anti-neoplastic therapy.11 A potential predictor 
of immune based therapy may be the presence of overexpression of the PDL1 and PDL2 
proteins.  Due to the potential of ibrutinib to alternative immunity through T cell subsets 
correlating responses to T cell alterations and malignant overexpression of PDL1 and PDL2 may 
be beneficial. Consequently, archived tissue will be evaluated by three probe FISH assay for 
relative copy gain or polysomy of chromosome 9p.11. This data will then be correlated with 
clinical activity of ibrutinib in cHL.    
Therefore whenever possible a biopsy (preferably a lymph node excision) performed after the 
most recent therapy is highly recommended. In the event an excisional biopsy is not possible 
then a core tissue biopsy is acceptable with a minimum of 4 cores.  In the event a biopsy cannot 
be obtained upon the completion of their most recent therapy, an archival tissue block must be 
submitted for analysis. The archival tissue must be from the most recent biopsy with adequate 
specimen. 
2. 
STUDY OBJECTIVE  
2.1. 
Primary Objective 
To determine the antitumor efficacy of single agent ibrutinib as measured by the overall response 
rate in patients with relapsed/refractory Hodgkin’s lymphoma ineligible for, or post ASCT 
2.2. 
Secondary Objective(s) 
• To assess duration of tumor control including duration of response (DOR) and progression 
free survival (PFS)  
• To assess the safety and tolerability of 560mg of ibrutinib in HL patients. 


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2.3. 
Exploratory Objective(s)  
• To assess the mechanism(s) by which ibrutinib may be active in patients with cHL by the 
correlation of potential biomarkers with clinical outcomes. 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This is a multicenter, single-arm Phase 2 study to evaluate the efficacy and safety of single-agent 
ibrutinib in subjects with HL who have received at least 2 prior chemotherapy regimens and are 
ineligible for ASCT or have progressed after ASCT. Approximately 35 eligible subjects will be 
enrolled to have 31 evaluable subjects for overall response to treatment.  
Subject participation will include a Screening Phase, a Treatment Phase, and a Posttreatment 
Phase (Figure 1). The Screening Phase will be up to 28 days and include a computed 
tomography (CT), or MRI scan and a positron emission tomography (PET) scan, prior to first 
dose. A formalin-fixed paraffin embedded tumor (FFPE) block must be sent to the central 
laboratory for confirmation of HL and biomarker analysis diagnosis. However, prior to 
enrollment, a report from the local laboratory that contains relevant data documenting HL 
diagnosis is acceptable.  
The Treatment Phase will extend from the administration of the first dose of ibrutinib until the 
completion of the End of Treatment Visit. Subjects will receive 560 mg oral ibrutinib once daily 
on a 28-day cycle until disease progression (or relapse if the subject achieved a CR) or 
occurrence of unacceptable toxicity, whichever occurs first. Regularly scheduled disease 
assessments are required throughout the Treatment Phase to assess Efficacy (See appendix 1). 
PET imaging is required to document complete remission (CR).   PET imaging is to be 
performed after 2 cycles of therapy, at the time of maximal tumor reduction (e.g., CR or 2 
consecutive CT scans showing no further tumor reduction), relapse from CR, and at suspected 
disease progression if new lesion was detected on CT. Tumor (from lymph node biopsies or 
diagnostic biopsy tissue collected during screening), blood, and/or bone marrow aspirate/ biopsy 
will be evaluated to identify markers predictive of response to ibrutinib. Bone marrow biopsy 
will be used to confirm CR if marrow involvement is present at baseline.  During the study, 
safety evaluations will include adverse event monitoring, physical exams (including changes to 
concomitant medications and assessment of lymphoma B-symptoms), and clinical laboratory 
parameters (See Appendix 1). Subjects will be provided a diary card to record study drug intake 
(See Appendix 6).  At each site visit, site personnel will check ibrutinib daily dosing and 
evaluate the subject for toxicity; doses can be held or reduced based on the severity of and the 
recovery from a previous toxicity. Dose re-escalation will ONLY be allowed after discussion 
with medical monitor, otherwise no dose escalation will be permitted. Subjects who discontinue 
from treatment will enter the Posttreatment Phase. Regularly scheduled disease assessments are 
required during the Posttreatment Phase for subjects who discontinue treatment prior to disease 


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progression, until the clinical cutoff.  During the Posttreatment Phase, data on PFS, overall 
survival, and subsequent anti-HL therapies will be collected from all subjects except those who 
explicitly withdraw consent for further follow-up. It is imperative that survival status be assessed 
and that the date of death is documented for each treated subject. 


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Study Schema (include Figure) 
3.2. 
 
Post Treatment Phase 
Post Progressive Disease
Collect data on survival status and subsequent anti-HL 
therapies
Post Treatment Phase
Prior to Progressive Disease
Continue the same efficacy assessments schedule:
- in the first 15 months every 12 weeks;
- then every 24 weeks until disease progression
 
 


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3.3. 
Study Design Rationale 
3.3.1. 
Study Population and Treatment 
Patients with HL who have relapsed after autologous and/or allogeneic stem cell transplant or 
have relapsed after a minimum 2 prior lines of therapy and are transplant ineligible due to: 
inability to tolerate transplant as determined by their treating physician, inability to achieve a 
complete response (CR), comorbidities or age. 
Ibrutinib will be prescribed at a dose of 560mg given orally daily. Patients will be assessed 
weekly during the initial cycle for toxicity and adverse event reporting. Dose interruptions and 
modifications will occur based on standard ibrutinib prescribing guidelines in NHL (see 5.4.1.5). 
Treatment will continue on study until disease progression, patient/investigator discontinuation 
or unacceptable toxicity.  
3.3.2. 
Dose Selection 
Data from Study PCYC-04753 showed 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, greater than 85% of patients who received dosages ≥2.5 mg/kg/day had Day 1 AUC0-24 
values ≥160 ng∙h/mL. The analysis of pharmacokinetic and pharmacodynamic profiles showed 
that BTK active-site occupancy was saturated or near saturated (>95%) at AUC values of ≥160 
ng∙h/mL.15 In study PCYC-1104-CA where ibrutinib was administered to relapsed/refractory 
MCL patients as a fixed dosage of 560 mg/day, 96% of the patients retained steady-state 
ibrutinib AUC values >160 ng∙h/mL.16 This result indicates that the vast majority of patients who 
received a dose of 560 mg/day will achieve exposures yielding full BTK active-site occupancy. 
An interim analysis has confirmed a high rate of response (approximately 70%) with this dose in 
relapsed or refractory MCL with an acceptable toxicity profile. Based on these data, the oral 
daily 560 mg dose has been selected for this study.  Based on these data, and because of the 
modest and acceptable toxicity profile of ibrutinib, subjects in this study will be treated until 
progressive disease or occurrence of unacceptable toxicity, whichever comes first. Patients 
deriving benefit as deemed by the treating physician may continue on study drug until 
progression, or unacceptable toxicity.  
4. 
 SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria. 
Disease Related 


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1. Patients with relapsed or refractory classical HL who have previously received 
autologous stem cell transplant and/or allogeneic stem cell transplant.  Patients must have 
received prior autologous stem cell transplant at least 12 weeks (3 months) before the 
first dose of ibrutinib and/or allogeneic stem cell transplant must have been completed at 
least 6 months prior to the first dose of Ibrutinib.   
or 
Patients with relapsed or refractory HL who have failed at least 2 lines of prior therapy 
and are not eligible for autologous stem cell transplant due to:  
a. Inability to achieve a CR or PR prior to transplant 
b. Age or comorbid conditions 
c. Inability to collect stem cells 
2. Completion of any prior treatment with radiation, chemotherapy, biologics, and/or other 
investigational agents at least 4 weeks prior to the first dose of ibrutinib. Patients must 
have completed any prior immunotherapy (e.g., rituximab or PD-1 inhibition) or antibody 
drug conjugate therapy (e.g. brentuximab vedotin) at least 4 weeks prior to the first dose 
of ibrutinib in the absence of clear disease progression.  
3. Prior treatment with at least 2 lines of therapy for HL including brentuximab vedotin. In 
those patients who cannot receive brentuximab vedotin, treatment with 2 prior therapeutic 
regimens is sufficient.   
4. Fluorodeoxyglucose (FDG)-avid disease by PET and measurable disease of at least 1.5 
cm in minimum dimension by CT scan with contrast, as assessed by the site radiologist. 
PROTOCOL SPECIFIC 
Laboratory 
1. Adequate hematologic function independent of transfusion and growth factor support for 
at least 7 days prior to screening and randomization, with the exception of PEGylated G-
CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening and 
randomization defined as:  
o    Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L).   
o Platelet count >50,000 cells/mm3 (50 x 109/L).   
o Hemoglobin >8.0 g/dL. 
2. Adequate hepatic and renal function defined as: 


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o Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤ 3.0 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) 
3. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN. 
Demographic 
4. Men and women ≥ 18 years of age. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 
 
Ethical/Other 
 
6. 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 history of bilateral oophorectomy). Female subjects of childbearing potential must 
have a negative serum pregnancy test upon study entry. 
7. Male and female subjects who agree to use highly effective methods of birth control (e.g., 
condoms, implants, injectables, combined oral contraceptives, some intrauterine devices 
[IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90 
days after the last dose of study drug 
8. Sign (or their legally-acceptable representatives must sign) an informed consent document 
indicating that they understand the purpose of and procedures required for the study and 
are willing to participate in the study. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Disease-Related 
1.  Prior allogeneic Stem cell transplant within 6 months.  
2. Active GVHD or concurrent treatment with immunosuppressive medications as 
prophylaxis for GVHD 
3. Previous therapy with BTK inhibition 
4. Known cerebral/meningeal disease 
5. Nodular lymphocyte predominant Hodgkin’s Lymphoma subtype 
PROTOCOL SPECIFIC 


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Concurrent Conditions 
1. Concurrent therapy with other systemic anti-neoplastic or investigational agents 
2. Patients with a known hypersensitivity to any excipient contained in the drug formulation 
3. History of other malignancies, except:  
• Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician. 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
• Adequately treated carcinoma in situ without evidence of disease.  
4. 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. 
5. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
6. Recent infection requiring systemic treatment that was completed ≤14 days before the first 
dose of study drug. 
7. 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. 
8. Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia. 
9. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
10. 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 must have a negative polymerase chain reaction (PCR) result 
before enrollment.  Those who are PCR positive will be excluded. 
11. Any uncontrolled active systemic infection. 
12. Major surgery within 4 weeks of first dose of study drug. 
13. 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. 
14. 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. 
15. 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. 
16. Concomitant use of warfarin or other Vitamin K antagonists. 


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17. Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor (see Appendix 
3). 
18. Currently active, clinically significant hepatic impairment Child-Pugh class B or C 
according to the Child Pugh classification (see Appendix 7). 
19. Lactating or pregnant. 
20. Unwilling or unable to participate in all required study evaluations and procedures. 
21. 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). 
 
4.3. Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation. During the study, 
subjects should avoid consuming food and beverages containing grapefruit or Seville oranges as 
these contain certain ingredients that inhibit CYP3A4/5 enzymes. 
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib: 
• For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure, and restarted at the discretion of the investigator when the surgical 
site is reasonably healed without serosanguinous drainage or the need for drainage tubes. 
• For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should 
not be restarted for at least 3 days after the procedure. For bone marrow biopsies that are 
performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures. 
• For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
5. 
TREATMENT OF SUBJECTS  
5.1. 
Treatment Registration 
Consent must be signed before any study specific procedures are performed.   Once a patient is 
consented, the site must email/fax a copy of the consent and the patient pre-registration form to 
the lead personnel at Karmanos Cancer Institute within 24 hours.  Each patient will be assigned a 
unique identification number upon consenting and registration approval by the KCI lead 
coordinator which will be used to track all correlative shipments and study drug dispensation. 
The subject must also be entered into Oncore by the participating site within 24 hours of consent.  
Training for Oncore will be provided during site initiation.  The participating site will provide 


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the registration form, eligibility checklist and all source documents to support patient eligibility 
to Karmanos and sites must receive approval from Karmanos prior to initiating study treatment.  
All subjects will receive the same treatment regimen, single-agent Ibrutinib.   
5.1.1. 
Study treatment   
For the purposes of this study, ‘study drug’ refers to ibrutinib. Treatment will be administered 
until disease progression or relapse after CR, or occurrence of unacceptable toxicity, whichever 
comes first. Patients deriving benefit as deemed by the treating physician may continue on study 
drug until progression, or unacceptable toxicity. 
5.2. 
Route and schedule 
Ibrutinib is to be taken in the morning (around the same time each day) with approximately 8 
ounces (240 mL) of water. All 4 capsules should be taken at the same time. The capsules should 
be swallowed whole and should not be opened, broken, or chewed. The daily self-administered 
home treatment is to be continuous (without interruption). Subjects should avoid consuming food 
and beverages containing grapefruit or Seville oranges for the duration of the study due to CYP 
3A4/5 inhibition. Subject should refrain from taking the study drug on the morning of study 
visits until seen at the site. 
If a dose is missed, 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. Variations in dosing are not considered unsafe if more than 12 hrs of time are 
provided between doses.  If doses occur within 12 hours of each other this will be considered a 
minor deviation.   During the first 15 months, study drug will be dispensed at the beginning of 
each 28-day cycle. Subjects will be provided with 2 days overage each time study drug is 
dispensed to allow for delayed return visits. Unused ibrutinib, dispensed during previous visits, 
must be returned and drug accountability records updated. Returned capsules must be discarded 
and cannot be re-used in this study or outside the study. Study staff will instruct subjects on how 
to store ibrutinib for at-home use as indicated for this protocol. After 15 months of treatment, 
patient site visits may be conducted every 56 days. Sufficient drug supply until next visit will be 
dispensed. 
5.3. 
Study Medication 
Subjects will receive 560 mg oral ibrutinib once per day, continuously during a 28 day treatment 
cycle. Each capsule contains 140 mg of ibrutinib. Subjects will be instructed to take 4 capsules 
for a dose of 560 mg. 


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5.3.1. 
Ibrutinib  
5.3.1.1. 
Formulation/Packaging/Storage  
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 
drugs will be dispensed in child-resistant packaging. Study drug labels will contain information 
to meet the applicable regulatory requirements. 
Drug Storage: The labeled storage condition for ibrutinib is between 15-25°C (59-77°F), with 
excursions permitted up to 30°C. Total cumulative excursions between 25°C and 30°C must not 
exceed 12 months. Temperatures lower than 15°C or greater than 30°C must be reported to 
Pharmacyclics for evaluation of impact on product quality. In storage areas where the 
temperature can exceed or fall below the required storage conditions (e.g., air conditioning, 
heating), measures must be in place to maintain the required temperature. Ibrutinib should be 
kept away from direct sunlight. 
 
Temperature conditions during on-site storage of study drug must be closely monitored and 
recorded (e.g., temperature logs, or data, charts or graphs from temperature monitoring 
equipment or devices). All monitoring equipment must be calibrated in accordance with the 
manufacturer’s recommendations. All documentation/data of the storage temperature must be 
retained in accordance with the records retention policy outlined in the Protocol and applicable 
legal and regulatory requirements. 
 
The storage temperature documentation must identify or link to (e.g., through the serial number 
or unique identifier) the thermometer or temperature monitoring equipment and, if applicable the 
refrigerator/freezer. These logs must be made available to the monitors for review at routine 
interim monitoring visits. 
5.3.1.2. 
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. 


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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 (Section 5.4.1.3) updated at each visit.  Returned capsules must not be re-dispensed to 
anyone. 
5.3.1.3. 
Drug Accountability  
The site specific investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. The dispensing of study drug to the subject, 
and the return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. The subject or their legally acceptable representatives where applicable, 
must be instructed to return all original containers, whether empty or containing study drug. All 
study drug will be stored and disposed of per institution’s protocol. Site staff must not combine 
contents of the study drug containers. Study drug must be handled in strict accordance with the 
protocol and the container label, and must be stored at the study site in a limited-access area or in 
a locked cabinet under appropriate environmental conditions. Unused study drug, and study drug 
returned by the subject, must be available for verification by the lead investigators. When study 
drug supplies are destroyed on site per institutional protocol, a tablet count and disposal method 
should be documented on the drug return form. Study drug should be dispensed under the 
supervision of the investigator or a qualified member of the investigational staff, or by a 
hospital/clinic pharmacist. Study drug will be supplied only to subjects participating in the study. 
Returned study drug (ibrutinib) must not be dispensed again, even to the same subject. Study 
drug may not be relabeled or reassigned for use by other subjects. The investigator agrees neither 
to dispense the study drug from, nor store it at, any site other than the study sites agreed upon 
with the investigating sponsor.  
The investigator will be provided with a drug accountability diary to be provided to patients 
beginning therapy prior to or on day one of treatment.  Patients must be instructed to document 
ibrutinib usage per the diary requirements.  The drug diary should be reviewed by the study staff 
prior to drug dispensation for every cycle.  Discrepancies between the returned drug 
accountability and diary must be evaluated at the beginning of each cycle.  
5.3.1.4. 
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 10 for further 
information regarding AE reporting. 
 


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5.3.1.5. 
Dose Modification for Adverse Reactions 
The dose of study drug should be modified according to the dose modification guidelines in 
Table 1 if any of the following toxicities occur: 
• 
Grade 4 ANC (<500/µL) for more than 7 days. See Section 6 for instructions regarding 
the use of growth factor support.  
• 
Grade 3 thrombocytopenia (<50,000/µL) in the presence of clinically significant bleeding 
events. 
• 
Grade 4 thrombocytopenia (<25,000/µL). 
• 
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 (i.e.  420 mg/day for 560 mg /day dose ) 
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose 
level lower (i.e. 280 mg/day for  420 mg /day dose ) 
Fourth 
Discontinue study drug 
 
A high number of circulating malignant cells (>400,000/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 principal 
investigator should be contacted. 
 
5.4. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant chronic 
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 to Appendix D for Child-Pugh classification. Please refer to Table 2 


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for dose modifications due to hepatic impairment. Monitor subjects for signs of toxicity and 
follow dose modification guidance as needed (Refer to Appendix 7). 
Table 2: Dose Modification due to Hepatic Impairment 
 
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.  
 
5.5. 
Criteria for Permanent Discontinuation of Study Drug 
Study drug may be held for a maximum of 28 consecutive days. Study treatment should be 
permanently discontinued in the event of a toxicity lasting >28 days. Once the ibrutinib dose is 
reduced it cannot be re-escalated without a discussion with the medical monitors (Dr. Modi or 
Dr. Ramchandren). 
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) beginning cycle two day one of therapy.  Transfusions may be 
given in accordance with institutional policy.  
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. 
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 100 
mg per day of prednisone or equivalent. 


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Standard supportive care therapies (e.g., antiemetics, loperamide) needed for the management of 
symptoms are permitted, as clinically indicated, other than anticancer treatment. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A- Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. 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 3. 
Table 3. 
Dose Modification Guidance for CYP3A Inhibitors/Inducers 
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. 
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 systemic CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, 
and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix 3.  A comprehensive 
list of inhibitors, inducers, and substrates may be found at 


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http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised and 
should be checked frequently for updates. 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please 
refer to the current version of the IB. 
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), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There is no clinical data available; therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib. 
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 
For a list of potential medications which may prolong the QT interval please review the 
following link.  If there are additional questions/concerns contact the P.I. Dr. Modi or Dr. 
Ramchandren. 
www.rettsyndrome.eu/wp-content/uploads/2015/10/CombinedList.pdf   
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 during treatment with ibrutinib. Bleeding events of any grade, 
including bruising and petechiae, occurred in subjects treated with ibrutinib. Subjects with 
congenital bleeding diathesis have not been studied. Ibrutinib should be held at least 3 to 7 days 
pre- and post-surgery depending upon the type of surgery and the risk of bleeding (see Section 
6.3). 
6.3. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are 
prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying disease are prohibited.  Corticosteroids for the 
treatment of non-cancer related reasons for longer than 14 days and/or at doses >100mg of 
prednisone or its equivalent are prohibited.   


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Erythropoietic growth factors (eg, erythropoietin) and neutrophil growth factors (eg, filgrastim 
and peg-filgrastim) are also prohibited during the initial cycle (28 days) of treatment 
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, skin or 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.   
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 (except for emergency procedures) 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 serosanguinous drainage or the need for drainage tubes.   
 
 
7. 
STUDY EVALUATIONS  
7.1   Description of Procedures 
The study is divided into 3 phases: a Screening Phase, a Treatment Phase, and a Post treatment 
Phase. Screening occurs from the time of informed consent up to commencement of therapy on 
cycle 1 day 1. Treatment includes the time frame from commencement of therapy including the 
end of treatment visit.  The post treatment phase includes the time from end of treatment until 
progression, death or next therapy. During the Post treatment Phase, subjects will be followed for 
survival and subsequent anti-HL therapy until death, withdrawal of consent, confirmed lost to 
follow-up, or the end of study, whichever occurs first. 
7.1.1. 
Assessments   
• Screening phase 
• All patients must sign an informed consent prior to any study related procedures 
listed below with the exception of CT or PET imaging which can be performed prior 
to informed consent if done within 28 days of Day 1 of therapy. 


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• Screening procedures will be performed up to 28 days before first dose of study drug. 
Subjects must satisfy all of the inclusion and none of the exclusion criteria listed in 
Section 4.1 and Section 4.2, respectively, before receiving the first dose of study 
drug. The results of laboratory tests noted in the inclusion criteria must be within the 
limits specified prior to the first dose of study drug. Testing can be repeated for this 
purpose. The last result obtained prior to start of study treatment will be used to 
determine eligibility 
• During the Screening Phase, eligibility criteria will be reviewed and a complete 
clinical evaluation will be performed (Appendix 1). A complete medical history and 
physical exam (including concomitant medications, vital signs, height, and weight) 
with baseline evaluation of lymphoma B-symptoms, adverse events and ECOG 
performance status (See appendix 2) will be conducted. 
• 12 lead ECG 
• All subjects must undergo a whole body FDG-PET scan and CT scan with contrast. 
Evaluation of other sites of disease, as relevant, may be performed. In instances 
where contrast cannot be utilized a discussion with the principal investigator is 
necessary.  
• Laboratory studies including CBC with differential, Serum chemistries, hepatitis 
serologies, coagulation panels (See Appendix 1) 
• Correlative biomarker analysis MUST be drawn prior to dose on cycle 1 day 1 of 
therapy (See Lab Manual) 
• A fresh tissue biopsy (excisional lymph node biopsy) is highly recommended for 
correlative analysis.  In instances where an excisional lymph node biopsy is not 
obtainable, core needle biopsy (4 cores minimum) is recommended. 
• If fresh tumor biopsy is unobtainable, a formalin-fixed paraffin embedded (FFPE) 
tumor block must be submitted for correlative analysis. (See Lab Manual)   For 
screening, a report confirming the diagnosis of Hodgkin’s lymphoma is required. 
• Subjects must initiate ibrutinib treatment within 28 days of the start of the screening 
phase 
 
• Treatment Phase 
• Throughout the Treatment Phase, the investigator will assess subject response to 
therapy using efficacy measurements and disease response criteria. Subjects will be 
monitored for safety, and adverse event information will be collected using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 4.03. Dose modifications will be made as required according to 
dose-modification rules (Section 5.4). The frequency of study procedures and 
assessment to be conducted during the Treatment Phase are outlined in Appendix 1. 
However, clinical evaluations and laboratory studies may be repeated more frequently 
if clinically indicated 
• During each Day one of therapy a symptom-directed physical exam (including 
lymphoma B-symptoms and performance status will be conducted and the results of 
all laboratory tests will be reviewed. Adverse events and changes to concomitant 
medications will be recorded (see Section 6 for concomitant medications). Subjects 
will be evaluated throughout the Treatment Phase for possible toxicities, and 
modifications in dosing will be made as required according to the criteria in Section 


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3. The investigator will assess subject response to therapy using the efficacy 
measurements and disease response criteria according to the schedule described the 
study calendar (See Appendix 1 notation g and i). For subjects who remain on study 
treatment beyond 15 months from the date of enrollment, site visits may be conducted 
every 56 days. 
• Subjects will be issued diary cards to record study drug dosing. Instructions for 
proper self-administration and study drug storage conditions will be provided. 
Precaution associated with the use of study drug and prohibited concomitant 
medications will be reviewed. The investigator or designated study research staff will 
review the study diary at the beginning of each cycle and provide additional 
instruction to re-educate any patient who has not followed the study treatment 
schedule. Patients on study should refrain from taking the study drug on the morning 
of study visits designated for commencement of a new cycle until seen at the site. 
When all evaluations have been completed, and it has been determined that the 
subject can continue treatment, ibrutinib capsules for 1 cycle of treatment will be 
dispensed.  
• Treatment will continue until progressive disease or unacceptable toxicity occurs. If 
progressive disease is diagnosed the subject will discontinue study drug, complete the 
End of Treatment Visit within 30 days, and enter the Post treatment Phase. 
• To assess ibrutinib’s influence on T cell behavior and antitumor effect, serial serum 
samples pre and post therapy will be assessed for Th1 ( (IFN-g) and Th2 cytokines 
(IL-10, IL-4 and IL-13) at 4 distinct time points (pre-dose cycle 1 day one,  cycle 1 
day 2 , cycle 1 day 15) , and  cycle 2 day 1 (See Appendix 1).  All assessments will 
occur prior to dosing that day.  Patients must be instructed not to swallow study 
drug prior to biomarker evaluation on cycle 1 day 1,  cycle 1 day 2, cycle 1 day 
15, and cycle 2 day 1. 
• An End of Treatment Visit will be scheduled within 30 days after the last dose of 
study drug for all subjects, including those discontinuing treatment for any reason, 
except for those lost to follow-up, death, or withdrawal of consent for study 
participation. Subjects who discontinued from treatment (due to progression, adverse 
event, or other reasons) and enter the Posttreatment Phase should have the End of 
Treatment Visit completed before starting any subsequent anti-HL treatment. If a 
subject is unable to return to the site for the End of Treatment Visit, the subject 
should be contacted to collect adverse events that occur within 30 days after the last 
dose of study drug. 
 
• Follow Up Phase 
• The Posttreatment Phase is the time between the End of Treatment Visit and end of 
study participation or the end of study. The clinical cutoff for primary analysis will 
occur approximately 1 year after the last subject is enrolled. Investigators will be 
informed of the timing of the clinical cutoff. It is imperative that the regularly 
scheduled disease assessments (clinical and radiographic) are performed throughout 
the Posttreatment Phase for subjects who discontinue treatment prior to disease 
progression, as outlined in Section 7.3.1 Evidence of clinical relapse according to the 
Revised Response Criteria for Malignant Lymphoma is to be documented at the time 
at which it is first detected. During this period, assessments will be performed until 


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disease progression, death or study end, whichever comes first. Subjects off treatment 
will be contacted every 9 weeks to obtain data on subsequent anti-HL therapies 
(including treatment regimen, start date, end date, and best response to subsequent 
therapy) and survival status. If the information on subsequent anti-HL therapies and 
survival status is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the subject 
has died, the date and cause of death will be collected and documented on the CRF. 
7.1.2. 
Pharmacokinetics/Biomarkers  
• To assess ibrutinib’s influence on T cell behavior and antitumor effect, serial serum 
samples pre and post therapy will be assessed for Th1 ( (IFN-g ) and Th2 cytokines ( IL-
10, IL-4 and IL-13) at 4 distinct time points (pre-dose cycle 1 day one,  pre-dose cycle 1 
day 2 , pre-dose cycle 1 day 15) , and  pre-dose cycle 2 day 1 (See Appendix 1).  All 
assessments will occur prior to dosing that day.  
7.2.0 Efficacy Evaluations  
The investigator will perform tests that will allow evaluation of response to therapy according to 
the Revised Response Criteria for Malignant Lymphoma.13    An evaluable patient will be defined 
as “any patient receiving study drug for > 1 cycle and having completed at least one radiographic 
(CT with contrast or PET) evaluation. Patients missing > 25% (14 doses) of study drug prior to 
the initial study evaluation (cycle 3 day 1 +/- 7days) will not be evaluable for efficacy but may 
remain on study pending a discussion with the medical monitors Dr. Modi or Dr. Ramchandren.   
Efficacy assessments will be performed as outlined in Appendix 1 and Section 7.3. These 
assessments are to be conducted until disease progression, withdrawal of consent from study 
participation, or the end of study. For subjects who discontinue study drug before disease 
progression is documented, disease assessments will continue in the Posttreatment Phase. The 
determination of disease status for continuation of treatment will be assessed by the investigator 
based on the results of the efficacy assessments. For all subjects, documentation of disease 
progression must be sent within 24 hours to the sponsor’s medical monitor. 
7.3 
Evaluations 
7.3.1 Radiographic Image Assessments  
During the study, disease response will be assessed using whole body FDG-PET scans and CT 
scans with IV contrast of the neck, chest, abdomen, and pelvis and any other location where 
disease was present at screening. Subjects who are intolerant of IV CT contrast agents will have 
CT scans performed with oral contrast. A separate CT scan and PET scan are preferred but, if the 
only available modality is combined/dual PET/CT scanner, then the CT portion of a PET/CT 
may be performed in lieu of a dedicated CT; however, the CT scanning must be done with 
contrast l to ensure that an optimized CT examination is done. Evaluation of other sites of 
disease by radiological imaging, physical examination, or other procedures as necessary (to be 
performed throughout the study using the same method of assessment used to assess disease at 


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baseline), and review of hematology and clinical chemistry results may be performed at the site 
level, as determined by the investigator. Magnetic resonance imaging may be used to evaluate 
sites of disease that cannot be adequately imaged using CT (in cases where MRI is desirable, the 
MRI must be obtained at baseline and at all subsequent response evaluations). For all other sites 
of disease, MRI studies do not replace the required neck, chest, abdomen, and pelvic CT scans. 
Brain MRI and lumbar puncture are required, only if clinically indicated. 
Radiological assessments will be performed at Screening, (PET and CT w/ contrast) upon 
completion of cycle 2 (week 8 PET and CT w/ contrast). Thereafter, CT with contrast will be 
performed every 12 weeks until disease progression, death, or end of study, whichever comes 
first.  Patients who remain on study without progression at 15 mos. may have subsequent 
imaging performed every 24 weeks. A PET scan will be performed at Screening and after cycle 2 
and at CR.  PET scans will also be done at the time of maximal tumor reduction (eg, CR or 2 
consecutive CT scans showing no further tumor reduction), relapse from CR, and at suspected 
disease progression if new lesion was detected on CT. 
Subjects who discontinue treatment prior to disease progression (for other reasons such as an 
adverse event) must continue to have regularly scheduled CT scans/efficacy assessments every 
12 weeks up to 15 months after the start of study drug. Thereafter, scan will be performed every 
24 weeks until disease progression, or death, or the end of the study, whichever occurs first. It is 
important that instances of progressive disease be reported to the lead investigators at Karmanos 
Cancer Institute within 24 hours by means of the tumor response form provided at site initiation. 
7.3.2. Positron Emission Tomography (PET) 
PET using [18F]-fluorodeoxyglucose (FDG) is important for the complete assessment of 
response and progression in subjects with HL. Whole body FDG-PET scan (skull base to the 
proximal femur) should be done at Screening, After 2 cycles of therapy ( week 8),  at the time of 
maximal tumor reduction (eg, CR or 2 consecutive CT scans showing no further tumor 
reduction), relapse from CR, and at suspected disease progression if new lesion was detected on 
CT. 
Assessment of PET results is based on published criteria.14   Visual assessment is considered 
adequate for determining whether a PET scan is positive, and use of the standardized uptake 
value is not necessary. A positive scan is defined as focal or diffuse FDG uptake above 
background in a location incompatible with normal anatomy or physiology, without a specific 
standardized uptake value cutoff. Other causes of false-positive scans should be ruled out. 
Exceptions include mild and diffusely increased FDG uptake at the site of moderate- or large 
sized masses with an intensity that is lower than or equal to the mediastinal blood pool, hepatic 
or splenic nodules 1.5 cm with FDG uptake lower than the surrounding liver/spleen uptake, and 
diffusely increased bone marrow uptake within weeks after treatment. 
7.3.3 Definition of Measurable and Assessable Disease 


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Eligible subjects must have at least 1 measurable site of disease.13 Measurable sites of disease are 
defined as lymph nodes, lymph node masses, or extranodal sites of lymphoma. Each measurable 
site of disease must be greater than 1.5 cm in the short axis regardless of long axis measurement, 
and clearly measurable in 2 perpendicular dimensions. Measurement must be determined by 
imaging evaluation. All other sites of disease are considered assessable, but not measurable. 
Up to 6 measurable sites of disease, clearly measurable in 2 perpendicular dimensions, will be 
followed for each subject. Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease (this includes splenic and extranodal disease). If there are 
lymph nodes or lymph node masses in the mediastinum or retroperitoneum larger than 1.5 cm in 
2 perpendicular dimensions, at least 1 lymph node mass from each region should always be 
included. In addition, selection of measurable lesions should be from as disparate regions of the 
body as possible and PET avid. 
All other sites of disease will be considered assessable. Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures as necessary, but is not measurable as defined above. Examples of assessable disease 
include bone lesions; mucosal lesions in the GI tract; effusions; pleural, peritoneal, or bowel wall 
thickening; disease limited to bone marrow; and groups of lymph nodes that are not measurable 
but are thought to represent lymphoma. In addition, if more than 6 sites of disease are 
measurable, these other sites of measurable disease may be included as assessable disease. 
7.3.4. Bone Marrow Assessment 
Bone marrow aspirate and biopsy are optional at screening and based on investigator’s clinical 
judgment.  However, if there is evidence of marrow involvement at screening, a repeat bone 
marrow evaluation must be performed at the time of CR to confirm remission. This must be done 
within 30 days of initial documentation of CR.   
7.3.5 Criteria for Response Categories 
The response categories being used to assess efficacy are based on the Revised Response Criteria 
for Malignant Lymphoma.13 (See Appendix 4) 
 
Complete Response 
 
For CR determination, all the following criteria must be met: 
 
1. Complete disappearance of all detectable evidence of disease and disease-related 
symptoms. 
2. All lymph nodes and nodal masses must have regressed on CT to normal size (equal to 
or smaller than 1.5 cm in the greatest transverse diameter [GTD] for nodes greater 
than 1.5 cm before therapy, regardless of the short axis). Previously involved nodes 
that were between 1.1 cm and 1.5 cm in the long axis and more than 1.1 cm in the 
short axis before treatment must have decreased to or be equal to 1 cm in the short 


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axis after treatment. All splenic and hepatic nodules and other extranodal disease must 
have disappeared. 
3. PET scan must be negative (for the combined CT+PET assessment of CR). A 
posttreatment residual mass of any size is permitted as long as it is PET-negative. 
4. The spleen and/or liver, if enlarged before therapy on the basis of physical 
examination or CT scan, should not be palpable on physical examination and should 
be considered normal size by imaging studies. 
5. If bone marrow was involved before treatment, the infiltrate must have cleared on 
repeated bone marrow biopsy. If a sample is intermediate by morphology, it should be 
negative by IHC (if bone marrow was involved before therapy and a radiological CR 
was achieved, but with no bone marrow assessment after treatment, the response 
should be classified as a PR.) 
6. No new sites of disease are detected during assessment. 
 
Partial Response 
 
For PR determination, all the following criteria must be met: 
 
1. 1. A ≥ 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses. 
2. No increase should be observed in the size of other nodes, liver, or spleen, meeting the 
criteria for progressive disease. 
3. Splenic and hepatic nodules must regress by ≥ 50% in the SPD or, for single nodules, in 
the GTD. 
4. With the exception of splenic and hepatic nodules, other organs should not have any 
measurable disease. 
5. Bone marrow assessment is not required for PR determination. 
6. No new sites of disease should be observed. 
7. At least 1 PET-positive site of disease (required for the CT+PET assessment of PR). 
 
Stable Disease  
 
1. A subject is considered to have stable disease when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease. 
2. The PET should be positive at 1 or more previously involved sites of disease, with no 
new areas of lymphoma involvement on the posttreatment CT or PET (for the combined 
CT+PET assessment of stable disease). 
 
Progressive Disease or Relapsed Disease 
 
Progressive disease or relapsed disease (after CR) is defined as: 
 
1. Lymph nodes should be considered abnormal if the long axis is ≥ 1.6 cm, regardless of 
the short axis length. If a lymph node has a long axis from 1.1 cm to 1.5 cm, it should be 
considered abnormal, only if its short axis is >1.0 cm. Lymph nodes ≤ 1.0 cm x ≤ 1.0 cm 
will not be considered abnormal for progressive disease/relapsed disease. 


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2. Appearance of any new nodal lesion ≥ 1.6 cm in GTD or ≥ 1.1 cm in short axis during or 
after the end of therapy even if other lesions are decreasing in size. 
3. Appearance of any new unequivocal extra-nodal lesion measuring > 1.0 cm in GTD, not 
thought to be benign by the reviewer, even if other lesions are decreasing in size. 
4. At least a 50% increase from the nadir in the SPD of any previously involved nodes, or in 
a single involved node, or in the size of other lesions (e.g. splenic or hepatic nodules). To 
be considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1 cm must increase by > 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in 
the long axis. 
5. At least a 50% increase from the nadir in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. For the combined CT+PET assessment 
of progressive disease, lesions should be PET-positive or the lesion was PET-positive 
before therapy unless the lesion was too small to be detected with current PET systems 
(smaller or equal to 1.5 cm in the long axis by CT). Any previously involved FDG 
positive site that became negative and subsequently became positive will be considered 
progressive disease. Increased FDG uptake in a previously unaffected site should only be 
considered progressive disease after confirmation with other modalities. For fluid 
collection (ascites, pleural, or pericardial effusions) cytology confirmation for presence of 
lymphoma is required. 
 
7.4 
Sample Collection and Handling 
Correlative studies evaluating blood samples for T cell behavior and cytokine expression as well 
as fluorescence in situ hybridization of tumor samples are required during this study.  For blood 
samples, study kits will be provided with shipping instructions. A detailed description of these 
instructions are noted in the Lab Manual.   
For tissue block submission, a representative amount of tissues in a paraffin embedded block 
should be shipped to the address noted in the Lab Manual.   
The appropriate personnel at the Karmanos Cancer institute (noted on instructions) should 
be notified at least 24 hours prior to shipment.   
8 
SUBJECT COMPLETION AND WITHDRAWAL 
8.1 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost-to-follow up, or has not withdrawn consent before the end of the 
study. 
8.2 
Withdrawal from Study Treatment 
Investigators are encouraged to keep a subject experiencing clinical benefit in the study unless 
significant toxicity puts the subject at risk or routine noncompliance puts the study outcomes at 
risk. 


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If a subject's study treatment must be discontinued this will not result in automatic withdrawal of 
the subject from the study. 
A subject's study treatment should be discontinued if: 
• The subject experiences overt disease progression or relapse 
• Unacceptable toxicity 
• The subject becomes pregnant 
• The subject refuses further treatment with the study drug 
• A serious protocol violation has occurred, as determined by the principal investigator 
 
The investigator must notify the medical monitor within 24 hours if a subject has been 
determined to have disease progression and provide documentation of disease progression. If a 
subject discontinues study treatment before the onset of disease progression, end of treatment 
and posttreatment assessments should be obtained and follow-up of scheduled assessments 
should be continued. 
 
Refer to Section 7.1.1 for instructions regarding the posttreatment efficacy assessments. The 
reason(s) a patient discontinues treatment will be recorded on the CRF. 
8.3 
Withdrawal from Study 
A subject will be withdrawn from the study for any of the following reasons: 
• Lost to follow-up 
• Withdrawal of consent 
 
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. When a subject withdraws before completing the study, 
the reason for withdrawal is to be documented in the CRF and in the source document. Study 
drug assigned to the withdrawn subject may not be assigned to another subject. A subject who 
withdraws will not be replaced. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Objectives 
 
The primary objective is estimation of the overall response rate. Secondary objectives are 
estimation of duration of response and progression free survival. The exploratory objectives are 
identification of genes of interest, estimation of the T cell subset alteration and estimation of the 
association of PDL1 and PDL2 overexpression by FISH with overall response.  
9.2. 
Design 


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This is a multicenter, single arm, single stage phase II study designed to estimate the efficacy of 
ibrutinib in evaluable patients with relapsed, refractory Hodgkin’s lymphoma. A participant will 
be deemed response evaluable if he/she has completed at least one cycle of therapy, has at least 
one imaging study (CT, MRI or PET) and has not missed >25% of treatment dose (14 doses) 
prior to cycle 3 day 1.  Any participant receiving at least 1 dose of ibrutinib will be considered 
evaluable for toxicity analysis. 
9.3. 
Endpoints  
9.3.1. Primary Endpoints 
• 
Overall Response Rate (ORR) 
Overall response rate (ORR) is defined as the proportion of participants having a complete (CR) 
and partial (PR) response. 
9.3.2. Secondary Endpoints 
• 
Duration of response (DOR) 
Duration of response is measured from date of documented tumor response, CR or PR, to date of 
disease progression. 
• 
Progression Free Survival (PFS) 
Progression-free survival is measured from date of study entry to date of progression or death, 
whichever occurs first. 
9.3.3. Exploratory Endpoints 
The influence of ibrutinib on T cell behavior and antitumor effect will be assessed using pre-
therapy and post therapy flow cytometry measures of Th1 and Th2 at predetermined time points 
in therapy. 
PDL1 and PDL2 copy number analysis on paraffin-embedded tissue sections will be assessed by 
FISH.  
All patients undergoing any exploratory evaluations will be assessed for correlative analysis.   
9.4.0    Statistical Analysis Plan 
9.4.1. Efficacy Analysis                                                                                                               
A one-sample binomial test will be used to assess ORR. The null hypothesis that the ORR is less 
than or equal to 30% will be rejected if 13 or more participants have an ORR. The ORR will be 


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reported as a proportion with a 95% confidence interval. DOR and PFS will be reported as 
medians with 95% confidence intervals using Kaplan-Meier methods to account for censoring.   
9.4.2. Safety Analysis 
Frequency of grade 3 or higher adverse events will be tabulated as will all grade 1 and 2 adverse 
events with frequency greater than 5%, e.g. occurring in 2 or more individuals. 
9.4.3. Biomarker Analyses  
• 
Pre/Post Th1 Th2 Changes for ORR+ and ORR- individuals 
McNemar’s test will be used to evaluate the statistical significance of pre /post therapy changes 
in Th1 and Th2 positivity separately for those who have an ORR and for those who do not.  A 
conditional logistic regression model will be used to explore whether pre-post changes in Th1 
and Th2 are predictive of ORR. 
• 
Association of PDL1 and PDL2 positivity with ORR 
The association between PDL1 and PDL2 positivity will be explored using Fisher’s exact test. A 
logistic regression model will be used to explore the association of PDL1 and PDL2 copy gain 
with ORR. 
9.5. 
Sample Size Determination 
A study of 31 evaluable participants was deemed feasible. To accomplish this with an expected 
dropout not evaluable rate of 12%, a total sample population of 35 patients will be consented. 
We specified statistical power of 85% to distinguish a null hypothesis value of 30% against an 
alternative value of 50% assuming a binomial test of one proportion with a target, one-sided type 
error of 11%. Under these assumptions the null hypothesis will be rejected if there are 13 or 
more ORRs among the 31 participants. 
9.6 
Accrual Rate, Accrual Duration and Expected Study Duration 
 
The expected accrual rate across the 4 institutions is 35 participants per year. Thus it is expected 
that the duration of accrual will be one year. An additional year is planned for evaluation of the 
primary, secondary and safety endpoints. 
10.  
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.  


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10.1.1 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: 
• 
Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the subject through the completion of final study procedures. 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
• 
Complications that occur as a result of protocol-mandated interventions (e.g. invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• 
Pre-existing condition:  A pre-existing condition (documented on the medical history CRF) 
is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period. 
• 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be 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. 


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• 
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
• 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be considered 
an AE.  Subjects with treatment-related lymphocytosis should remain on study treatment and 
continue with all study-related procedures. 
10.1.2 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: 
• 
Results in death (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening.  Life-threatening is defined as an AE in which the subject was at risk of 
death at the time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe.  If either the Investigator or the IND Sponsor believes 
that an AE meets the definition of life-threatening, it will be considered life-threatening. 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be immediately life-threatening 
or require hospitalization, but may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject or subject may require intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such events are 
intensive treatment in an emergency department or at home for allergic bronchospasm, 
blood dyscrasias, or convulsion that does not result in hospitalization; or development of 
drug dependency or drug abuse. 
10.1.3 Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v m 4.03) will be used for grading the severity (intensity) of nonhematologic AEs.  The 
CTCAE v 4.03 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 v m4.03, the 
following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities 


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• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
10.1.4 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: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration 
of the investigational product; or, a causal relationship is 
considered biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that 
a relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures.  Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
10.2 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 


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anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation. 
10.3 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
10.3.1 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. 
If an adverse event is identified by the physician or staff during a non-evaluation time point the 
AE should also be recorded and reported in the manner by which all other AEs are processed.  
10.3.2 Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be captured from ingestion of study drug until 30 
days following the last dose of study drug.  
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. All adverse events, regardless of seriousness, 
severity, or presumed relationship to study drug, must be recorded using medical terminology in 
the source document. All records will need to capture the details of the duration and the severity 
of each episode, the action taken with respect to the study drug, investigator’s evaluation of its 
relationship to the study drug, and the event outcome. Whenever possible, diagnoses should be 
given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, 
sore throat, and head congestion should be reported as "upper respiratory infection").  
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  
If a death occurs within 30 days after the last dose of study drug, the death must be reported as a 
serious adverse event.  


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10.3.3 Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 90 days 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.   
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 90 days after the last dose of study drug must be reported. Any occurrence of pregnancy must 
be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. All 
pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. Pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old and this must be reported to Pharmacyclics 
Drug Safety, or designee, per SAE reporting timelines. Any congenital anomaly/birth defect 
noted in the infant must be reported as a serious adverse event. 
10.3.4 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. 
10.3.6 Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to KCI Drug 
Safety per the SAE reporting timelines.   
10.3.6.1  Major Hemorrhage 
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 


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*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or 
higher AE per CTCAE v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 10.3.6 above. 
10.3.7 Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be reported on 
FDA Medwatch (Form 3500A). 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up MEDWATCH.  A final 
report to document resolution of the SAE is required.  The Pharmacyclics protocol number 
Ibrutinib PCI-32765 should be included on SAE reports to Pharmacyclics.  A copy of the fax 
transmission confirmation of the SAE report to Pharmacyclics should be attached to the SAE and 
retained with the patient records. The principal Investigator is required to notify his/her 
Institutional Review Board (IRB) of a serious adverse event according to institutional policy.   
SAEs and AESIs must be reported within 24 hours of awareness of the event.  Each site is 
responsible for reporting these events to both Pharmacyclics and KCI via email or fax: 
Pharmacyclics: 
AEintakeCT@pcyc.com 
Fax: 408-215-3500 
Karmanos: 
houdec@karmanos.org 
Fax: 313-576-8368 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 


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• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to                                 
study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts) 
10.4 
Reporting to Regulatory Agencies: 
Serious adverse events that are unlisted/unexpected, at least possibly associated to the study 
drug, and that have not previously been reported in the Investigators brochure, or reference 
safety information document will be forwarded to FDA by the IND holder (Karmanos) 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. 
11 STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS   
12  
DATA AND SAFETY MONITORING 
 
1. 
Scheduled investigator meetings will be held monthly or more frequently depending on 
the activity of the protocol.  These meetings will include the protocol investigators and 
research staff involved with the conduct of the protocol. 
2. 
During these meetings the investigators will discuss: 
 
• 
Safety of protocol participants (adverse events and reporting) 
• 
Validity and integrity of the data (data completeness on case report forms and 
complete source documentation) 
• 
Enrollment rate relative to expectation of target accrual, (eligible and ineligible 
participants) 
• 
Retention of participants, adherence to the protocol and protocol deviations 
•       Protocol amendments 
 
 
 
3. 
In addition, Data and Safety Monitoring Reports (DSMR) of the research meetings will be 
completed by the Study Coordinator from each site and submitted to the Karmanos Data 
and Safety Monitoring Committee (DMSC) monthly for review.  (See Appendix 5)   The 
DSMC will review safety of study subjects and will recommend continuation or closure of 


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the study.  The DSMC will review the safety data quarterly and will recommend 
termination if they judge the rate and severity of AEs to be unacceptable. The DSMC’s 
recommendations will guide study conduct. 
 
4. 
The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring Committee 
(DSMC) is composed of medical providers, pharmacists and research staff and provides 
the primary oversight of data and safety monitoring for KCI Investigator-initiated trials.   
12.1  
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study. 
 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval. The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
12.2  
Informed Consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
 
Documentation of the informed consent process will be documented in the patient’s records. The 
original consent form must be maintained in the Investigator’s study files. 
 
12.3  
Protected Subject Health Information Authorization 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 


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applicable data privacy protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or access, accidental or 
unlawful destruction, or accidental loss or alteration must be put in place. Study personnel whose 
responsibilities require access to personal data agree to keep the identity of study subjects 
confidential. 
 
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator to allow 
direct access to his or her original medical records for study-related monitoring, audit, IEC/IRB 
review, and regulatory inspection. 
 
 
Exploratory biomarker and pharmacokinetic research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the researchers cannot make decisions 
as to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law. Privacy 
and confidentiality of data generated in the future on stored samples will be protected by the 
same standards applicable to all other clinical data. 
12.4 
Study Files and Record Retention 
Investigational Study Drug Accountability for the drug is the responsibility of the local principal 
investigator. The investigator will ensure that the drug is used only in accordance with this 
protocol and Good Clinical Practice.  Drug accountability records indicating the drug’s delivery 
date to the site (if applicable), inventory at the site (if applicable), use by each patient, and 
disposal of the drug (if applicable and if approved by KCI) will be maintained by the clinical 
site. 
 
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers. Please refer to Section 5.4.1.3 for additional details. 
 
All research study documents will be retained in accordance with E6 Good Clinical Practice: 
Consolidated Guidance as stated “Essential documents should be retained for a minimum of 2 
years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational agent. These 
documents will be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor.”  It is the responsibility of the sponsor to inform 
the investigator/institution as to when these documents no longer need to be retained.  
 
Iron Mountain (IM) storage facility provides long-term storage of research documents for 
Karmanos Cancer Institute, Clinical Trial Office.  
12.5 
Study Monitoring/Audit Requirements 
Clinical trial data will be captured in OnCore’s (Clinical Trial Management System) electronic 
data capture system.   Site personnel will be trained on the eCRF system by the Karmanos 
OnCore administrator. Trial data entered in Oncore will be verified by source documentation. 


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CRFs should be completed by within 10 business days of the availability of clinical 
documentation of a study visit.  Data clarification and queries should be completed within 7 
working days of notification.  
 
Each participating site will submit source documents to KCI’s clinical trials office.  A KCI CTO 
monitor specialist will remotely monitor essential clinical trial data. Frequency of monitoring 
will be based on accrual at a site but will occur at least once every 1 month if a patient has been 
enrolled. 
 
Monthly screening and enrollment logs are to be sent to the KCI Lead Study Coordinator.  
If deemed necessary by the primary site or sponsor an audit team may review contracted site data 
and materials in an on-site review. 
 
12.6 
Investigator Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on GCP, and applicable regulatory and country-
specific requirements. Good Clinical Practice is an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that involve the participation 
of human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki and that the clinical study data are credible. 
12.7 
Protocol Amendments 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol 
must be sent to Pharmacyclics for review and approval prior to submission to the IRB.  Written 
verification of IRB approval will be obtained before any amendment is implemented. 
12.8 
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. 
12.9 
Study Discontinuation 
Per the IST Contract, the Investigator reserves the right to terminate the study at any time.  
Should this be necessary, the Investigator will arrange discontinuation procedures in partnership 
with Pharmacyclics.  In terminating the study, the Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests.  Pharmacyclics may terminate 


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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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13. REFERENCES 
1. Advances in the treatment of relapsed or refractory Hodgkin's   lymphoma.  Ramchandren R. 
Oncologist. 2012;17(3):367-76.  
2. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory 
Hodgkin's lymphoma.Younes A, et al. J Clin Oncol. 2012 Jun 20;30(18):2183-9.  
3. Burger J., Buggy J., Emerging drug profiles: Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-
32765). Leukemia & Lymphoma 2013 Aug 28. 
4.Puri KD, Di Paolo JA, Gold MR. B-Cell Receptor Signaling Inhibitors for Treatment of Autoimmune 
Inflammatory Diseases and B-Cell Malignancies International Reviews of Immunology, 32:397–427, 
2013 
5. Muller B et al. Role of Bruton’s tyrosine kinase in innate and adaptive immunity Recent Res. Devel. 
Experimental Med., 1(2004): ISBN: 81-7895-121-5 
6. Brunner C., et al. Bruton’s Tyrosine Kinase is involved in innate and adaptive immunity Histol 
Histopathol (2005) 20: 945-955 
7. Kuppers R. New insights in the biology of Hodgkin’s Lymphoma.  Hematology Am Soc Hematol Educ 
Program. 2012;2012:328-34.  
8. Younes A. et al. A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer. 
2003 Jul 15;98(2):310-4. 
9. Wang et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell LymphomaN Engl J 
Med. 2013 Aug 8;369(6):507-16. doi: 10.1056/NEJMoa1306220. 
10. Steidl et al. Molecular Pathogenesis of Hodgkin’s Lymphoma: Increasing Evidence of the Importance 
of the Microenvironment JCO 2011 
11. Ansell et al.  PD-1 Blocade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma NEJM. 
Dec 6 2014 
12. Dubovsky et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-Selective 
pressure in T lymphocytes Blood October 2013 
13. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin 
Oncol.2007;25(5):579-586. 
14. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response 
assessment oflymphoma: consensus of the Imaging Subcommittee of International Harmonization Project 
in Lymphoma.J Clin Oncol. 2007;25(5):571-578. 
15. Advani RH, Buggy JJ, Sharman  JP, et al . Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has 
significant activity in patients with relapsed/refractory B-cell malignancies . J Clin Oncol 2013;31:88-94. 
16. Wang ML, RuleS, Martin P, et al. targeting BTK with ibrutinib in relapsed or refractory Mantle-cell 
lymphoma. New Engl J of Med 2013;369:507-16 
Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation.  Crit Rev 
Immunol 2003;23:165–197.   
Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19+CD5+ cells into peripheral blood 
following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. 
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Chang BY, Francesco M, Steggerda S, et al. Ibrutinib Inhibits Malignant Cell Adhesion and Migration 
and Reduces Tumor Burden in Lymph Node and Bone Marrow in a Murine Model of Mantle Cell 
Dissemination and Progression. 2013b AACR: Abstract 923.  
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117:6287-96. 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem 2007;2:58-61. 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B cell development and function: a 
genetic perspective. Immunol Rev 2000;175:120-127. 
Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: The dark side of B-cell differentiation.  
Nat Rev Immunol 2002;2:920–932.   
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood 
cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187-205.  
Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. 
Blood 2011;118: 4313-4320. 
 
 


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14 APPENDICES 


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Appendix 1.  Schedule of Assessments  
Study Visits 
Screening 
Phase 
Treatment Phase (1 cycle = 28 days) 
Suspected 
PD 
Complete 
Remission 
End-of-
Treatment 
Pre-PD 
FU 
Cycle 1 
 
Cycle 2 
Cycles 
3 –7 
Cycles 8–
14 
Cycles 
15 –
Term 
 
D1 
(baseline) 
D2 
 
 
D15 
 
D1 D15 
D1 
 
D1 
D1 
Any time 
 
Within 30 D 
after treatment 
d/c 
q 12 
weeks. 
Study Visit Windows 
-28 days 
 
± 3 days beginning  cycle 2 day 1 
Any time 
 
+ 3 days 
± 7 days 
Procedures 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 x 
 
x 
x 
xj 
x 
 
x 
 
Confirm eligibility k 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 
xf 
 
 
 
 
 
 
 
 
 
xf 
 
 
 
Concomitant medications 
x 
x 
 
x 
 x 
x 
x 
x 
xj 
 
 
x 
 
Adverse events a 
 
x 
 
x 
 x 
x 
x 
x 
xj 
 
 
x 
 
Study drug compliance review  
 
x 
 
 
 x 
 
x 
x 
xj 
 
 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam, vital signs, 
weight, ECOG 
x 
x 
 
x 
 x 
x 
x 
x 
xj 
x 
 
x 
x 
Disease assessment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        PET/CT scang 
x 
 
 
 
 
 
 
xg 
xg 
xg 
x 
x 
x 
 
CT/MRI scani 
xi 
 
 
 
 
 
 
xi 
xi 
xi 
xi 
xi 
 
xi 
Bone marrow 
biopsy/aspirate r 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Disease-related 
symptomss 
x 
x 
 
 
 x 
 
x 
x 
xj 
x 
 
x 
x 
Overall response 
assessment 
 
 
 
 
 
 
 
xg,i 
xi,g 
Xi 
x 
 
 
x 
Hematology b 
x 
x 
 
x 
 x 
x 
x 
x 
xj 
 
 
x 
x 
Serum chemistry c 
x 
x 
 
x 
 x 
x 
x 
x 
xj 
 
 
x 
x 
Serum Pregnancy Test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance 
(Cockcroft-Gault) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker serum samples 
 
xe 
xe 
xe 
 xe 
 
 
 
 
xe 
 
 
 
Hepatitis serologies d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG x 
x 
 
  
 
 
If clinically indicated (e.g., subjects with palpitations, lightheadedness) 
 
 
 
 
 
  
Any new anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Ibrutinib 560mg  daily x 28 
days dispensed  p  
 
x 
 
 
 x 
 
x 
x 
xj 
 
 
 
 
 
 
 
 
 


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D = day; Term = treatment termination; d/c = discontinuation; PD = progressive disease; FU = follow-up;  
 
a AEs are reported from the time the patient ingests study drug 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. 
 
b Hematology includes: complete white blood count with differential, hemoglobin, hematocrit, platelet count. 
 
c Serum chemistry includes sodium, potassium, calcium, albumin, glucose, creatinine, AST, ALT, alkaline phosphatase, LDH, total bilirubin, and Uric Acid. 
 
d Hepatitis B serologies include Hepatitis B  IGG antibody, antigen and core antibody . If core antibody is positive the patient will need negative PCR to be eligible for study.   
 Hepatitis C serologies include Hepatitis C IGG antibody.   
 
e    Serial serum samples  pre and post therapy will be assessed for Th1 ( (IFN-g ) and Th2 cytokines ( IL-10, IL-4 and IL-13) at 4 distinct time points (pre-dose cycle 1 day one,  
cycle 1 day 2 , cycle 1 day 15) , cycle 2 day 1 and at the time of progressive disease. All samples must be PRE-DOSE on date of draw.  Utilize provided kits labeled per 
directions.  Refer to Lab manual 
 
f Fresh tumor biopsy is highly recommended. The biopsy should be a lymph node excision whenever possible.  If lymph node excision is not possible then core needle biopsies 
(minimum of 4 cores) are required. If fresh tumor tissue is unobtainable, a formalin-fixed paraffin embedded (FFPE) tumor block must be sent to the laboratory for correlative 
analysis. 
 
g PET/CT performed during screening, cycle 3 D1 (window of + or – 7 days) then at maximal tumor reduction on consecutive CT scans w/ contrast or at CR. 
 
h Coagulation panel includes PT, aPTT and INR 
 
i CT performed with contrast during screening, cycle 3 day 1 (+/- 7 day window)  then  every 12 weeks (+/-  7 days window) until cycle 15.  Thereafter CT with contrast 
performed every 24 weeks (+/- 7 days) 
 
j Every odd cycle (Cycles  15, 17, 19, 21, 23, 25) 
 
k  It is required that patients continue to meet eligibility on Day 1 of cycle 1 prior to dosing with the exception of the coagulation panel.   If the subject met eligibility criteria for 
the coagulation panel during screening, it does not need to be repeated to re-confirm eligibility on C1D1.  
 
p Day 1 and 15 of C1 and  C2 will be administered at the investigational site. Subsequently, day 1 of each cycle are taken on site until cycle 15. Beyond cycle 15 drug 
dispensation and clinic visits occur only on odd numbered cycles. 
 
  r   Bone marrow biopsy and/or aspirate is optional per investigator’s decision at screening however if positive must be performed at CR 
 
s Disease-related symptoms include weight loss, fatigue, fever, night sweats, pruitis abdominal pain/discomfort due to splenomegaly including early satiety, and anorexia. 
 
x  ECG’s Must be performed at screening. ECG may be repeated at the investigator’s discretion (e.g., palpitations,    lightheadedness or new onset dyspnea). 
 
 


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Appendix 2.  ECOG Status Scores and Formulas 
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.  Accessed January 4, 2008. 
 
 
 
 
 
Cockcroft-Gault Equation 
(140-Age) * Mass (in kg)] \ [72 * Serum creatinine (in mg/dL)]  
*If the patient is female, multiply the above by 0.85 


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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.  Response Criteria 
 
Revised response criteria for lymphoma 
Response criteria 
PET-CT-based response  
CT-based response  
Complete remission (CR) 
 
 
 
Lymph nodes and extralymphatic sites 
Score 1, 2, or 3* with or without a residual 
mass on 5-PS** 
Target nodes/nodal masses must regress 
to ≤1.5 cm in LDi 
     
No extralymphatic sites of disease 
Non-measured lesion 
Not applicable 
Absent  
Organ enlargement 
Not applicable 
Regress to normal  
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if indeterminate, 
IHC negative 
Partial remission (PR) 
 
 
 
Lymph nodes and extralymphatic sites 
Score 4 or 5** with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
≥50% decrease in SPD of up to 6 target 
measureable nodes and extranodal sites 
 
 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% in 
length beyond normal  
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy, or an interval scan 
Not applicable 
No response or stable disease (SD) 
 
 
 
Target nodes/nodal masses, extranodal 
lesions 
No response: score 4 or 5 with no 
significant change in FDG uptake from 
baseline, at interim or end of treatment 
Stable disease: <50% decrease from 
baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; 
no criteria for PD are met  
Non-measured lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 


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Progressive disease (PD) 
 
 
Individual target nodes/nodal masses, 
extranodal lesions 
Score 4, 5 with an increase in intensity 
of uptake from baseline and/or new 
FDG-avid foci consistent with 
lymphoma at interim or end of 
treatment assessment 
 
 
 
An individual node must be abnormal with: 
 
 
• LDi >1.5 cm  
 
 
• Increase by ≥50% from PPD nadir 
 
 
An increase in LDi or SDi from nadir 
 
 
• 0.5 cm for lesions ≤2 cm 
 
 
• 1.0 cm for lesions >2 cm  
 
 
 
 
 
 
 
New or clear progression of pre-existing 
non-measured lesions 
 
 
 
 
 
 
 
 
Bone marrow 
 
 
 
 
 
 
 
New FDG-avid foci consistent with 
lymphoma rather than another etiology, 
e.g. infection, inflammation. If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
 
 
 
 
 
 
New or recurrent FDG avid foci 
 
In the setting of splenomegaly, the splenic length 
must increase by >50% of the extent of its prior 
increase beyond baseline (e.g., a 15 cm spleen 
must increase to >16 cm). If no prior 
splenomegaly, must increase by at least 2 cm 
from baseline 
 
 
New or recurrent splenomegaly 
New lesions 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any axis if less 
than 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
 
 
 
New or recurrent involvement 
 
 
 
 
 
 
 


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Deauville Criteria for PET Score 
1 no uptake 
2* uptake <mediastinum 
3* uptake >mediastinum but <liver 
4 Uptake moderately increased compared to the liver at any site. 
5 Uptake markedly increased compared to the liver at any site or/and 
new sites of disease. 
 
* If mediastinal blood pool activity is equal or greater than liver then the uptake within the lesion 
should be compared with liver (lesion uptake less than liver=score 2; lesion uptake equal to 
liver=score 3). 
 
Source: Report on the Second International Workshop on interim positron emission tomography in lymphoma held 
in Menton, France, 8-9 April 2010. Meignan M, Gallamini A, Haioun C, Polliack A. Leuk Lymphoma 51; 
2010:2171-80.(33) Cheson et al. JClin Oncol 32 2014 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5 
Barbara Ann Karmanos Cancer Institute 
Data and Safety Monitoring (DSM) Report 
 
PROTOCOL #: 
 
 
REPORT DATE: 
     
                                                                                       
PROTOCOL TITLE 
  
 
ATTENDANCE 
  
  
 
  
  
 
  
 
 
  
 
 
PROTOCOL ACTIVITY SINCE LAST REPORT 
Accrual Goal: 
Eligible: 
 
Total number of AE’s to date:  
Accrual to Date: 
 Ineligible 
(provide reason):  
Accrual Since  
Last Monthly  
Report: 
 
SPECIFICALLY FOR PHASE I TRIAL &/OR DOSE ESCALATING TRIALS: 
DOSE LEVEL 
ACCRUAL 
  1 
  
  2 
 
  3 
 
RECORD ALL GRADE 3, 4, AND 5 AE’S AND GROUP BY CTCAE CATEGORIES.  RECORD THE DATE OF 
THE OCCURRENCE, ATTRIBUTION AND IF REPORTABLE TO THE IRB.   SHADE THE ROWS OF THE 
AE’S THAT HAVE OCCURRED FOR THIS REPORT.  ATTACH THE IRB REPORT FORM FOR THE 
REPORTABLE EVENTS THAT OCCURRED ON THIS REPORT. 
Pt. ID# 
Category and  type of adverse reaction 
 
Date of 
Occurrence 
Grade1 
Attribution2 
Reportable to IRB (Y/N) 
Yes with date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Grade: 1-Mild, 2-Moderate, 3- Severe, 4-Life-threatening, or 5- Death. 
2. Attribution: 1-unrelated, 2 - unlikely, 3 - possibly, 4 - probably, or 5 - definitely   
 
 
 
 
 


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OFF TREATMENT  Provide reason [progression, death, toxicity, completed therapy, etc.]. 
  
 
PROTOCOL DEVIATIONS  Accidental or unintentional change from the protocol. 
  
 
PROTOCOL AMENDMENTS  Include date submitted and approved by the IRB.  
  
 
OTHER COMMENTS 
 
 
Investigator Signature/Date:  
 
Study Coordinator Signature/Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6 
See attached diary 
 
 


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Appendix 7.  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 
 
Source:  
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.