A Pilot Study of Ibrutinib and R-da-EPOCH for Front Line Treatment of AIDS-Related Lymphomas
Phase: PHASE1
Conditions: AIDS-Related Lymphoma, Ann Arbor Stage II Diffuse Large B-Cell Lymphoma, Ann Arbor Stage III Diffuse Large B-Cell Lymphoma, Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma
Sponsor: National Cancer Institute (NCI)

 
AMC #101 (Version 9.0) 20DEC2024 
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NCI Version Date 20DEC2024 
SUMMARY OF CHANGES 
A Pilot Study of Ibrutinib and R-da-EPOCH for Front Line Treatment of AIDS-Related 
Lymphomas 
Version 9.0 
 
NCI Protocol #: AMC-101 
Local Protocol #: AMC-101 
 
NCI Version Date: 20DEC2024 
Protocol Date: 20DEC2024 
 
I. 
Scientific and Substantive Changes 
# 
Section 
Description of Changes 
1. 
Table 6-A 
The CAEPR risk profile for Ibrutinib (PCI-32765) Version 2.8, dated 
November 4, 2024 was added.   
2. 
Table 6-C 
Expedited Reporting Requirements for Adverse Events dated August 30, 
2024 was added. 
 
II. 
Administrative and Editorial Changes 
# 
Section 
Description of Changes 
3.  
Global 
Protocol version was updated to 9.0 and date was updated to 20DEC2024. 
4.  
Protocol 
Roster 
Sylvia Silver was removed as the AMC Biorepository Director. 
 

 
AMC #101 (Version 9.0) 20DEC2024 
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NCI Version Date 20DEC2024 
 
AIDS MALIGNANCY CONSORTIUM 
 
AMC PROTOCOL #101 
A Pilot Study of Ibrutinib and R-da-EPOCH for Front Line 
Treatment of AIDS-Related Lymphomas 
A Trial of the AIDS Malignancy Consortium (AMC) 
 
Sponsored by: 
CTEP, Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Office of HIV and AIDS Malignancy (OHAM) 
 
NCT Registration Number: 
NCT03220022 
 
NCI Supplied Agent 
Ibrutinib (NSC 748645; NCI IND#) 
 
Pharmaceutical Support 
Pharmacyclics LLC 
 
Commercially Available 
Agents:  
Rituximab (NSC 687451) 
Etoposide (NSC 141540) 
Prednisone (NSC 10023) 
Doxorubicin hydrochloride (NSC 123127) 
Vincristine sulfate (NSC 67574) 
Cyclophosphamide (NSC 26271) 
 
Protocol Chair: 
Ida Wong-Sefidan, MD 
 
Protocol Co-Chair: 
Erin Reid, MD 
Version 9.0,  20DEC2024 
NCI Version Date  20DEC2024 

 
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AMC PROTOCOL SIGNATURE PAGE 
I, ____________________, Principal Investigator at site ________, agree to conduct and follow 
this protocol: AMC Protocol # 101 – A Pilot Study of Ibrutinib and R-da-EPOCH for Front 
Line Treatment of AIDS-Related Lymphomas (Version 9.0, 20DEC2024), as written 
according to AMC, NCI, and FDA guidelines. I understand that no deviations from the protocol 
eligibility criteria or waivers for protocol deviations will be permitted. 
 
 
_________________________________  ______________________ 
Signature 
Date (DDMMMYYYY) 

 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................................ i 
I. 
Scientific and Substantive Changes ......................................................................... i 
II. 
Administrative and Editorial Changes ..................................................................... i 
AMC PROTOCOL SIGNATURE PAGE ......................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................... 3 
PROTOCOL ROSTER ....................................................................................................................... 6 
PROTOCOL SYNOPSIS .................................................................................................................... 7 
PROTOCOL SCHEMA .................................................................................................................... 10 
LIST OF TABLES ............................................................................................................................. 14 
LIST OF ABBREVIATIONS ........................................................................................................... 15 
1.0 
OBJECTIVES ........................................................................................................................ 17 
1.1 
Primary Objectives.................................................................................................17 
1.2 
Secondary Objectives.............................................................................................17 
2.0 
BACKGROUND .................................................................................................................... 18 
2.1 
Study Disease .........................................................................................................18 
2.2 
Study Agents ..........................................................................................................20 
2.3 
Study Design and Rationale ...................................................................................22 
2.4 
Correlative Studies .................................................................................................25 
3.0 
PARTICIPANT SELECTION ............................................................................................. 42 
3.1 
Eligibility Criteria ..................................................................................................42 
3.2 
Exclusion Criteria ..................................................................................................45 
3.3 
Number of Participants to be Enrolled...................................................................47 
3.4 
Participant Enrollment Procedures ........................................................................48 
4.0 
TREATMENT PLAN ........................................................................................................... 49 
4.1 
Agent Administration.............................................................................................49 
4.2 
Definition of Dose-Limiting Toxicity ....................................................................50 
4.3 
General Concomitant Medication and Supportive Care Guidelines ......................51 
4.4 
Duration of Therapy and Criteria for Removal from Treatment ...........................55 
4.5 
Duration of Follow Up ...........................................................................................56 
5.0 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 57 
5.1 
Dose Modifications for Ibrutinib and R-EPOCH ..................................................57 

 
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6.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 63 
6.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for 
Ibrutinib..................................................................................................................63 
6.2 
Classification of AEs by Severity and Relationship to Study Drug 
Administration .......................................................................................................73 
6.3 
Expedited Adverse Event Reporting ......................................................................74 
6.4 
Routine Adverse Event Reporting .........................................................................75 
6.5 
Secondary Malignancy...........................................................................................76 
6.6 
Second Malignancy ................................................................................................77 
7.0 
PHARMACEUTICAL INFORMATION ........................................................................... 78 
7.1 
Ibrutinib (NSC #748645) .......................................................................................78 
7.2 
Commercial Agents (EPOCH) ...............................................................................80 
8.0 
CLINICAL AND LABORATORY EVALUATIONS ....................................................... 83 
8.1 
Screening/Baseline Evaluations .............................................................................83 
8.2 
Evaluations During Treatment ...............................................................................85 
8.3 
Evaluation of Response..........................................................................................87 
8.4 
End of Treatment Evaluations ...............................................................................87 
8.5 
Early Discontinuation Evaluations ........................................................................88 
8.6 
Follow-up Evaluations ...........................................................................................89 
9.0 
EVALUATION OF RESPONSE ......................................................................................... 91 
9.1 
Response Assessment ............................................................................................91 
9.2 
Definition of Response ..........................................................................................92 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................. 96 
10.1 
Study Design/Endpoints.........................................................................................96 
10.2 
Sample Size/Accrual Rate ......................................................................................96 
10.3 
Stratification Factors ..............................................................................................97 
10.4 
Analysis of Primary Endpoint ................................................................................97 
10.5 
Analysis of Secondary Endpoints ..........................................................................97 
11.0 
ROLE OF DATA MANAGEMENT .................................................................................... 99 
11.1 
CRF Instructions ....................................................................................................99 
11.2 
Data Quality ...........................................................................................................99 
11.3 
Data Monitoring .....................................................................................................99 
11.4 
Collaborative Agreements Language .....................................................................99 

 
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12.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................ 100 
12.1 
IRB Approval and Informed Consent ..................................................................100 
12.2 
Changes to the Protocol .......................................................................................100 
12.3 
Women and Minorities ........................................................................................101 
13.0 
REFERENCES .................................................................................................................... 102 
APPENDIX I: SCHEDULE OF EVALUATIONS ....................................................................... 108 
APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT ........................................... 114 
APPENDIX III: PERFORMANCE STATUS SCALES .............................................................. 116 
APPENDIX IV: INFORMATION ON POSSIBLE DRUG INTERACTIONS ......................... 117 
APPENDIX V: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS .................................................... 119 
APPENDIX VI: ACSR INFORMED CONSENT ......................................................................... 122 
APPENDIX VII: AMC DATA AND SAFETY MONITORING PLAN ..................................... 127 
APPENDIX VIII: PARTICIPANT DRUG DIARY ..................................................................... 132 
APPENDIX IX: CENTRAL PATHOLOGY REVIEW ............................................................... 137 
APPENDIX X: EBV COPY NUMBER SPECIMEN PREPARATION & SHIPPING 
INSTRUCTIONS ................................................................................................................. 140 
APPENDIX XI: PHARMACOKINETICS (PLASMA LEVELS OF DOXORUBICIN, 
VINCRISTINE, AND ETOPOSIDE) ................................................................................ 144 
APPENDIX XII: ASSESSMENT OF CIRCULATING LEVELS OF PRO-INFLAMMATORY 
CYTOKINES ....................................................................................................................... 146 
APPENDIX XIII: PK PLASMA COLLECTION FOR IBRUTINIB ......................................... 148 
APPENDIX XIV: BTK/ITK OCCUPANCY SPECIMEN PREPARATION & SHIPPING 
INSTRUCTIONS ................................................................................................................. 150 
APPENDIX XV: DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP3A4 
ISOENZYMES .................................................................................................................... 152 
APPENDIX XVI: ANN ARBOR STAGING CRITERIA ............................................................ 154 
APPENDIX XVII: DOSE ADJUSTMENTS FOR IBRUTINIB AND/OR EPOCH ................. 155 
APPENDIX XVIII: LETTER TO THE PHYSICIAN ................................................................. 163 
APPENDIX XIV: CIRCULATING TUMOR DNA (CTDNA) .................................................... 166 

 
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PROTOCOL ROSTER 
AMC Protocol # 101 
A Pilot Study of Ibrutinib and R-da-EPOCH for Front Line Treatment of AIDS-Related 
Lymphomas 
 
Protocol Chair: 
Ida Wong-Sefidan, MD 
University of California, San Diego 
VA San Diego Health Systems 
3350 La Jolla Village Drive #111E 
San Diego, CA 92161 
Tel: (858) 552-8585, x7106 
Fax: (858) 552-7485 
Email: icwong@ucsd.edu 
Protocol Statistician: 
Grace Van Hyfte, MS 
Icahn School of Medicine at Mount Sinai 
1425 Madison Avenue, NYC, NY 10029Tel:  
Fax:  
Email: Grace.VanHyfte@mountsinai.org  
Protocol Co-Chair: 
Erin G. Reid, MD 
University of California, San Diego 
Moores UCSD Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0698 
Tel: (858) 822-6276 
Fax: (858) 822-6288 
Email: egreid@ucsd.edu 
Data Management/Operations: 
AMC Operations and Data Management Center 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: (301) 251-1161 
Fax: (240) 238-2842 
Email: amc-101@emmes.com 
AMC Hematologic Malignancy Working 
Group Chair: 
Richard Ambinder, MD, PhD 
Oncology Center 
Bunting-Blaustein Cancer Research Building 
1650 Orleans Street, Room 389 
Baltimore, MD 21231 
Tel: (410) 955-8839 
Fax: (410) 955-0960 
Email: ambinri@jhmi.edu 
AMC Network Resource Laboratory Director: 
Jeffrey Bethony 
The George Washington University  
Ross Hall, Room 523 
2300 Eye Street, NW 
Washington, DC 20037 
Tel: (202) 590-8342 
Fax: (202) 994-5056 
Email: jbethony@gwu.edu  

 
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PROTOCOL SYNOPSIS 
Title: 
A pilot study of ibrutinib and R-da-EPOCH for front line 
treatment of AIDS-related lymphomas (ARL) 
Phase of Study: 
Pilot study with a dose-finding and a dose-expansion cohort  
Participating Institutions: 
This protocol will be open to all AMC domestic member sites. 
Accrual Target: 
Forty (40) participants with adequate tissue for cell-of-origin 
(COO) analysis with a minimum of 15 participants with non-
germinal B-cell (GCB)-like subtype diffuse large B-cell 
lymphoma (DLBCL) subtype by immunohistochemistry (IHC) 
as confirmed by central pathology. To compensate for the 
possible misclassification of COO, this study will accrue a 
minimum of 22 participants of non-GCB DLBCL subtype by 
IHC, as determined by local pathology. To ensure target accrual, 
14 participants will be allowed on study as replacement 
participants should the participant not have adequate tissue for 
COO analysis. 
In order to guarantee the minimum participant requirement of 
non-GCB ARL, if after enrollment of 20 and 30 participants on 
trial, there are <50% non-GCB subtypes (as determined by the 
local pathology), non-GCB will be the preferentially enrolled to 
meet the minimum number of participants required in the trial.  
Population: 
Participants with histologically documented CD20 positive or 
negative AIDS-related diffuse large B-cell lymphoma (DLBCL). 
Participants must have stage II-IV disease, measurable disease by 
imaging, and ECOG Performance Status score of 0-2. 
Participants may be untreated or have received a maximum of 
one cycle of treatment with R-da-EPOCH or R-CHOP. 
Participants with CD4 ≥ 100 will be enrolled in the dose-finding 
portion of the study; participants with any CD4 counts, including 
<100, will be allowed in the dose-expansion cohort after safety is 
confirmed in dose-finding portion of the study. Participants with 
asymptomatic leptomeningeal disease by lymphoma may be 
enrolled in the dose-expansion cohort, at the physician’s 
discretion. Participants must not be on medications with 
moderate or strong CYP3A4 inhibition, including antiretroviral 
(ARV) regimens; if on a moderate or strong CYP3A4 inhibitor 
regimen prior to study enrollment, participants must be switched 
to a qualifying regimen with the last dose of the moderate and/or 
strong CYP3A4 inhibitor taken at least one week before 
administration of protocol therapy due to effects on ibrutinib. 

 
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Treatment: 
Ibrutinib will be evaluated in a 3+3 dose de-escalation design in 
the dose-finding portion of the study. Ibrutinib will be given in 
combination with R-da-EPOCH in CD20 positive disease, and 
da-EPOCH will be given in CD20 negative disease. In this 
portion of the study, ibrutinib will begin at dose level 1 (560 mg 
PO), and de-escalate to dose -1 (420 mg PO) and -2 (280 mg PO) 
if excessive toxicity is seen at dose levels 1 and -1, respectively. 
Once the recommended maximum tolerated dose (MTD) or 
recommended phase II dose (RP2D) of ibrutinib in combination 
with R-da-EPOCH is determined, additional participants will be 
enrolled into the dose-expansion portion of the study. 
In the dose-expansion stage of the study, participants will be 
treated at the MTD of ibrutinib, with intra-participant dose 
escalation and de-escalation of ibrutinib, in addition to dose-
adjustment of R-EPOCH. Dose adjustment for R-EPOCH and/or 
ibrutinib will be based on laboratory measurements of the 
previous cycle ANC or platelet nadir, whichever is lower. 
Duration: 
Participants will be treated for a maximum of 6 cycles (21-day 
cycle length) of chemotherapy. Participants with complete 
response (CR) after Cycle 4 will receive two additional cycles of 
chemotherapy. Participants who achieve a partial response (PR) 
after Cycle 4 may continue on protocol therapy or be removed 
from the study at the discretion of a CTEP-registered AMC 
investigator). Participants will be followed for 5 years after 
completion of treatment (defined as day 21 of the final treatment 
cycle), with follow-up visits every 3 months for years 1-2 post-
treatment, and then every 6 months for 3-5 years post-treatment. 
Anticipated Trial 
Duration 
34 months 
Primary Objectives: 
To assess the safety and tolerability of ibrutinib and R-da-
EPOCH in participants with ARL. This will define the RP2D of 
ibrutinib in combination with R-da-EPOCH in participants with 
ARL. 

 
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Secondary Objectives: 
(includes all participants 
unless specified) 
• To evaluate the CR rates of ARL to ibrutinib and R-da-
EPOCH. 
• To measure the 1-year and 2-year overall and progression-free 
survival (OS, PFS) of participants with ARL treated with 
combination 
ibrutinib 
and 
R-da-EPOCH, 
including 
preliminary comparison of non-GCB with historical controls 
treated with R-da-EPOCH.  
• To categorize and compare the cell-of-origin by GEP gene 
expression-based classification (GCB, activated B-cell-like, 
unclassifiable) to IHC classification (GCB, non-GCB), 
estimate the discordant classification, and correlate each 
biological classification (IHC and GEP) with treatment 
response rates and survival. 
• To calculate the percentage of participants who receive two or 
more cycles of R-da-EPOCH, and are able to continue on a 
minimum dose level of cyclophosphamide of -1 and above 
after dose adjustments for hematologic toxicities. 
• To determine the average number of days per cycle 
participants are able to stay on planned dose of ibrutinib at the 
RP2D. 
• To assess the effect of ibrutinib and R-da-EPOCH on levels 
of circulating tumor DNA. 
• To assess the effect and degree of ibrutinib and R-da-EPOCH 
on T-cell receptor signaling via ITK inhibition. 
• To assess the effect of ibrutinib and R-da-EPOCH on B-cell 
receptor signaling pathway including BTK activity in ARL. 
• To evaluate the soluble cytokine response to ibrutinib and R-
da-EPOCH. 
• To characterize the pharmacokinetics of doxorubicin, 
etoposide, and vincristine in the presence of ibrutinib, and 
vice versa, and assess the clinical relevance of any drug-drug 
interaction and correlate with pharmacodynamics outcomes. 

 
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PROTOCOL SCHEMA 
 
 
 
 
 
 
 
 
 
 
  
 
Screening and Enrollment  
Maximum 1 Cycle R-CHOP/R-EPOCH/limited therapy or Treatment Naïve AIDS-related 
Lymphomas 
(Submission of tissue block or slides for mandatory central pathology and correlative integral 
studies) 
Early discontinuation 
evaluations 
PD 
4 Total Cycles of 
Chemotherapy 
PET/CT scan +/- Diagnostic CT scans 
Surveillance/Follow-Up Evaluations for up to 5 years after 
treatment discontinuation 
6 Total Cycles of 
Chemotherapy 
Early discontinuation 
evaluations 
CR or PR (at investigator’s discretion) 
via CT chest/ab/pelvis; PET/CT 
optional 
SD or PR (at investigator discretion) 
via CT chest/ab/pelvis; PET/CT 
optional 
Pathology Confirmation 
(see Pathology Workflow Diagram) 

 
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Pathology Workflow Diagram 

 
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LIST OF TABLES 
Table 2-A: Calibrator assessment, vincristine sulfate .................................................................... 35 
Table 2-B: QC assessment, vincristine sulfate................................................................................. 35 
Table 2-C: Calibrator assessment, etoposide .................................................................................. 37 
Table 2-D: QC assessment, etoposide ............................................................................................... 37 
Table 2-E: Calibrator assessment, doxorubicin and doxorubicinol .............................................. 38 
Table 2-F: QC assessment, doxorubicin and doxorubicinol .......................................................... 38 
Table 4-A: Ibrutinib Dose Levels and Schedule .............................................................................. 49 
Table 4-B: Ibrutinib dose escalation and schema ........................................................................... 50 
Table 4-C: Dose limiting toxicities .................................................................................................... 51 
Table 5-A: Ibrutinib dose levels and schedule................................................................................. 57 
Table 5-B: EPOCH dose adjustment levels for baseline CD4 count ≥ 200 ................................... 57 
Table 5-C: EPOCH dose adjustment levels for baseline CD4 count < 200 .................................. 58 
Table 5-D: Neurological toxicities .................................................................................................... 60 
Table 5-E: Renal toxicities ................................................................................................................ 60 
Table 5-F: Hepatic toxicities ............................................................................................................. 60 
Table 6-A: Ibrutinib CAEPR and SPEER ...................................................................................... 64 
Table 6-B: Adverse events and potential risks for rituximab ........................................................ 71 
Table 6-C: FDA expedited reporting requirements ........................................................................ 75 
Table 9-A: Definition of response for PET/CT ............................................................................... 92 
Table 9-B: Criteria for response for CT .......................................................................................... 94 
Table 12-A: Accrual targets ............................................................................................................ 101 
 
 

 
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LIST OF ABBREVIATIONS 
ABC .................................................................................. activated B-cell (as determined by GEP) 
ACSR ................................................................................... AIDS and Cancer Specimen Resource 
AE ................................................................................................................................ adverse event 
AIDS .................................................................................. Acquired Immunodeficiency Syndrome 
ALT ............................................................................................................ alanine aminotransferase 
AMC ................................................................................................ AIDS Malignancy Consortium 
ANC .......................................................................................................... absolute neutrophil count 
ART.................................................................................................................. antiretroviral therapy 
ARL.......................................................................................................... AIDS-related lymphomas 
ARV .............................................................................................................................. antiretroviral 
AST ............................................................................................................... aspartate transaminase 
BCR............................................................................................................................ B-cell receptor 
BTK............................................................................................................. Bruton's tyrosine kinase 
cART ............................................................................................... combined antiretroviral therapy 
CBC................................................................................................................. complete blood count 
CDC ............................................................................. Centers for Disease Control and Prevention 
CDUS .................................................................................................. Clinical Data Update System 
CFR ...................................................................................................... Code of Federal Regulations 
COO ............................................................................................................................. cell-of-origin 
CR ........................................................................................................................ complete response 
CRF ......................................................................................................................... case report form 
CT ................................................................................................................. computed tomography 
CTA............................................................................................................... clinical trial agreement 
CTCAE ..............................................Common Terminology Criteria for Adverse Event reporting 
CTEP ....................................................................................... Cancer Therapy Evaluation Program 
CTEP-AERS ..................................................................... CTEP Adverse Event Reporting System 
CTMS ......................................................................................... Clinical Trials Monitoring Service 
DARF ......................................................... investigational agent [drug] accountability record form 
DHHS ............................................................................ Department of Health and Human Services 
DLBCL ............................................................................................ diffuse large B-Cell lymphoma 
DLT ................................................................................................................. dose-limiting toxicity 
DMC ...................................................................................................... data monitoring committee 
EBER-ISH........................................... Epstein-Barr encoding region (EBER) in situ hybridization 
EBV...................................................................................................................... Epstein-Barr virus 
ECOG PS ................................. Eastern Cooperative Oncology Group Performance Status [Score] 
FDA.................................................................................................. Food and Drug Administration 
GCB ........................................................................ germinal center B-cell (as determined by IHC) 
GCSF..................................................................................... granulocyte colony-stimulating factor 
GEP……………………………………………………………………...gene expression profiling 
HAART ...................................................................................... highly active antiretroviral therapy 
HHV-8.............................................................................................................. human herpesvirus 8 
HIV ................................................................................................. human immunodeficiency virus 
IDB ......................................................................................................... Investigational drug branch 
IHC ................................................................................................................ immunohistochemistry 
IRB ........................................................................................................... institutional review board 

 
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IND .......................................................................................investigational new drug [application] 
ITK ................................................................................................................ inducible T-cell kinase 
kg......................................................................................................................................... kilogram 
KSHV .................................................................................. Kaposi sarcoma-associated herpesvirus 
LLN ................................................................................................................. lower limit of normal 
MTD ........................................................................................................... maximum tolerated dose 
mg ...................................................................................................................................... milligram 
NCI ............................................................................................................ National Cancer Institute 
NCT.............................................................................................National Clinical Trials [Registry] 
NIH…………………………………………………………… .......... National Institutes of Health 
NHL………………………………………………………………… ....... non-Hodgkin lymphoma 
pBTK................................................................................. phosphorylated Bruton’s tyrosine kinase 
PEL ....................................................................................................... primary effusion lymphoma 
PI ..................................................................................................................... principal investigator 
PI .......................................................................................................................... protease inhibitors 
PIO ........................................................................................................ Protocol Information Office 
PD .......................................................................................................................progressive disease 
PO ...................................................................................................................... per oral [by mouth] 
PR ............................................................................................................................. partial response 
RP2D ..................................................................................................... recommended Phase II dose 
RNA .....................................................................................................................ribose nucleic acid 
SAE ................................................................................................................. serious adverse event 
SD ................................................................................................................................ stable disease 
ULN ................................................................................................................ upper limit of normal 

 
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1.0 
OBJECTIVES 
1.1 
Primary Objectives 
To assess the safety and tolerability of ibrutinib and R-da-EPOCH in participants with 
ARL. This will define the recommended phase II dose (RP2D) of ibrutinib in combination 
with R-da-EPOCH in participants with ARL. 
1.2 
Secondary Objectives 
1.2.1 To evaluate the complete response (CR) rates of ARL to ibrutinib and R-da-
EPOCH. 
1.2.2 To measure the 1-year and 2-year overall and progression-free survival of 
participants with ARL treated with combination ibrutinib and R-da-EPOCH, 
including preliminary comparison of non-GCB with historical controls treated with 
R-da-EPOCH. 
1.2.3 To categorize and compare the cell-of-origin by GEP gene expression-based 
classification (GCB, activated B-cell-like, unclassifiable) to IHC classification 
(GCB, non-GCB), estimate the discordant classification, and correlate each 
biological classification (IHC and GEP) with treatment response rates and survival. 
1.2.4 To calculate the percentage of participants who receive two or more cycles of R-da-
EPOCH, and are able to continue on a minimum dose level of cyclophosphamide 
of -1 and above after dose adjustments for hematologic toxicities. 
1.2.5 To determine the average number of days per cycle participants are able to stay on 
planned dose of ibrutinib at the RP2D. 
1.2.6 To assess the effect of ibrutinib and R-da-EPOCH on levels of circulating tumor 
DNA. 
1.2.7 To assess the effect and degree of ibrutinib and R-da-EPOCH on T-cell receptor 
signaling via ITK inhibition. 
1.2.8 To assess the effect of ibrutinib and R-da-EPOCH on B-cell receptor signaling 
pathway including BTK activity in ARL. 
1.2.9 To evaluate the soluble cytokine response to ibrutinib and R-da-EPOCH. 
1.2.10 To characterize the pharmacokinetics of doxorubicin, etoposide, and vincristine in 
the presence of ibrutinib, and vice versa, and assess the clinical relevance of any 
drug-drug interaction and correlate with pharmacodynamics outcomes. 

 
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2.0 
BACKGROUND 
2.1 
Study Disease 
2.1.1 AIDS related lymphomas 
Lymphomas are a significant complication of HIV infection. Epidemiologically, 
patients living with HIV/AIDS have a higher incidence of non-Hodgkin lymphoma 
(NHL).1 For this reason, in 1985, the Centers for Disease Control (CDC) expanded 
the definition of AIDS to include NHL in this population.2 Since the introduction 
of combined antiretroviral therapy (cART) in the mid-1990s, AIDS-related 
lymphomas (ARL) have decreased in incidence and improved in outcome, mostly 
due to better control of HIV and improved immune function. However, despite the 
three-fold increase in survival of patients with AIDS-related lymphomas, ARL 
continues to be one of the most common malignancies in the setting of HIV/AIDS. 
Given estimates of a minimum of 11-17-fold risk compared to the general 
population, the life time risk of lymphoma may be about 10%.3 Consequently, many 
patients still die of disease refractory to standard therapy. While there are emerging 
data for treatment of non-ARL, ARL continues to be a rare disease with few clinical 
trials available, mainly due to the limited number of patients. 
2.1.2 Classifications of ARL 
The diagnostic category of ARL is heterogeneous and diverse in nature, not only 
clinically, but morphologically, genetically, and molecularly. As in HIV-negative 
NHL, a number of defined genetic abnormalities and subtypes exist in ARL. For 
instance, in HIV-negative diffuse large B-cell lymphoma (DLBCL), DLBCL can 
be classified according to its cellular origin of cell-of-origin (COO): germinal 
center B-cell (GCB)-like or non-germinal center B-cell (non-GCB)-like subtype. 
The 
germinal 
type 
typically 
expresses 
GCB-associated 
markers 
by 
immunohistochemistry (IHC), such as CD10 and BCL6. The non-GCB subtype is 
mainly CD10-negative, BCL-6 negative and MUM-1 positive, though lymphoma 
typing based on markers is a field in flux and best defined by genomic profiling. 
COO for DLBCL can also be distinguished by gene-expression profiling (GEP). 
The division of DLBCL into GCB and activated B-cell-like (ABC) subtypes based 
on GEP has proved to be important in understanding the pathogenesis of the 
disease. ARL can be divided into GCB and non-GCB variants; however, in contrast 
to immunocompetent patients, only a limited number of gene expression profiling 
studies exist of AIDS-related DLBCL and other ARL.  
It is likely that ARLs are in some ways dissimilar to non-HIV related lymphomas. 
For example, many ARL are driven by Epstein-Barr virus (EBV) and human 
herpesvirus-8 (HHV-8), or Kaposi sarcoma-associated herpesvirus (KSHV). These 
lymphoma subtypes, typically ascertained by IHC, have in some studies been 
shown to predict both lymphoma-specific and overall survival in the general 
population. In the HIV-negative population, non-GCB DLBCL has inferior 
survival compared with GCB DLBCL.4 Similarly, patients with HIV-associated 
non-GCB DLBCL have been shown to have inferior survival and increased rates of 
recurrent/refractory disease.5,6 In a Phase II study of patients with HIV-associated 
DLBCL treated with R-EPOCH, tumor subtype by IHC was the only characteristic 

 
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associated with lymphoma-specific outcome. In the setting of planned short course 
(3 cycles of chemotherapy) patients with GCB subtype had a 95% 5-year PFS, 
while those with non-GCB had only a 44%.6 In contrast, a retrospective analysis of 
several AMC clinical trials with full course R-EPOCH showed that 
subclassification of AIDS-associated DLBCLs into GCB or non-GCB type using 
IHC methods alone did not show any difference in survival.7 This difference in 
these study results may be due to treatment factors as the AMC study had a more 
heterogeneous treatment program; alternatively, it may be explained by the finding 
that AIDS-related DLBCL expresses a unique immunophenotype compared to non 
AIDS-related DLBCL. A study by Madan et al. looking at protein expression of 
germinal center and activated B-cell markers between AIDS versus non AIDS-
related DLBCL, found that non-AIDS DLBCL clustered into distinct GCB and 
ABC types, while AIDS-related DLBCL formed a single cluster with an 
intermediate germinal center ABC phenotype, suggesting a distinctive 
pathophysiology.8 Therefore, at this time, traditional categories of non-GCB and 
GCB using IHC may not be accurately classifying ARL, as in HIV-negative 
lymphomas, and more studies looking into the gene expression profile of ARLs 
may be warranted. 
2.1.3 Treatment of ARL 
The treatment of ARL has changed over the last few decades. Better control of HIV 
and the improvement of overall immune status have allowed patients to be treated 
with combination chemotherapy similar to those used in the HIV-negative 
population. Treatments for ARL include regimens such as rituximab, doxorubicin, 
cyclophosphamide, vincristine, and prednisone (R-CHOP)9 and rituximab with 
infusional etoposide, vincristine, and doxorubicin, with oral prednisone and bolus 
dose-adjusted cyclophosphamide (R-EPOCH).10 Although R-EPOCH and R-
CHOP were not compared in a randomized fashion, response and survival rates 
with R-EPOCH are improved compared with historical R-CHOP studies without 
increased toxicities.10,11 In an AMC study comparing R-EPOCH to historical data 
on R-CHOP, patients with aggressive CD20+ B-cell non-Hodgkin lymphoma 
(NHL), including DLBCL, Burkitt/Burkitt-like lymphoma, or other aggressive 
lymphomas associated with HIV infection, treated with R-EPOCH had a 73% 
complete response (CR) rate versus a ~50% CR rate with R-CHOP.10 Currently, R-
EPOCH and R-dose-adjusted (da)-EPOCH are accepted as the standard of care 
chemotherapy regimen in most cases of ARL. However, cancer research has 
entered a molecular age. Classifying tumors with respect to immunophenotype and 
genomic features is ever more essential to improving treatment. Improved therapy 
for ARL is needed and targeting inhibition in an active pathway of ARL may be 
the next approach to improving survival in this group of patients. Like in non-ARL, 
we seek to identify ways to continue to improve outcomes beyond current 
combination immunochemotherapy. 

 
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2.2 
Study Agents 
2.2.1 Ibrutinib 
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an integral 
component of the B-cell receptor (BCR) and cytokine receptor pathways. 
Constitutive activation of B-cell receptor signaling is important for survival of 
malignant B-cells; BTK inhibition results in decreased malignant B-cell proliferation 
and survival. It is an oral drug approved as monotherapy in other B-cell 
lymphoproliferative diseases such as Waldenström macroglobulinemia, mantle cell 
lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma. 
2.2.2 R-EPOCH 
R-EPOCH consists of infusional rituximab, etoposide, vincristine sulfate, 
cyclophosphamide, and doxorubicin hydrochloride, with oral prednisone, in 
combination with recombinant human granulocyte colony-stimulating factor 
(GCSF). 
The components of EPOCH are at most weak inhibitors of CYP3A4 and unlikely 
to cause significant alterations to ibrutinib in the clinically relevant range utilized 
in this study.12 However, ibrutinib may inhibit ABCB1, for which doxorubicin, 
etoposide, and vincristine are all substrates. Inhibition of ABCB1 may lead to 
increased concentrations of ABCB1 substrates, which may cause increased 
myelosuppression. Myelosuppression has been observed with other ABCB1 
substrates, like paclitaxel13 and sunitinib14 in the presence of ABCB1 inhibitors or 
functional polymorphisms in ABCB1. Since drug interaction studies suggest that 
there is little chance of a clinically significant drug interaction via CYP450 between 
ibrutinib and EPOCH, a full pharmacokinetic profile to assess for the bi-directional 
pharmacokinetic interaction will not be performed in this study. 
Rituximab 
Rituximab is a chimeric mouse/human anti-CD 20 monoclonal antibody that binds 
human C1q, mediate complement-dependent cell lysis and lyse human target cells 
through antibody dependent cellular cytotoxicity. It has documented anti-tumor 
activity in CD20 positive lymphoma and FDA-approved for that indication. Please 
refer to the approved package insert for complete prescribing and toxicity 
information. 
Etoposide 
Etoposide, or VP-16, is an epipodophyllotoxin derived from the mandrake plant 
Podophyllum peltatum (P. peltatum). Etoposide is a substrate for CYP1A2, 
CYP2E1, CYP3A4/5, UGT1A1, ABCB1, ABCC1, and ABCC3 and a weak 
inhibitor of CYP2C9 and CYP3A4. It is a cell cycle phase specific agent that blocks 
topoisomerase II. It has a biphasic half-life and is eliminated by both renal clearance 
and metabolism. The major and dose-limiting toxicity of etoposide is 
myelosuppression. Constipation, diarrhea, dysphagia, aftertaste, abdominal pain, 
stomatitis, and anorexia have also been reported. Mucositis and hepatotoxicity are 
seen primarily with high doses. Transient hypotension and other anaphylactic-like 

 
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symptoms are associated with rapid infusion. Please refer to the approved package 
insert for complete prescribing and toxicity information. 
Prednisone 
Prednisone is a corticosteroid and its mechanism of action, as a cytotoxic agent is 
not clearly understood. Short-term use produces minimal side effects but prolonged 
use is associated with hypertension, hyperglycemia, myopathy, osteoporosis, 
pancreatitis, and immunosuppression. Alterations in mood and insomnia are 
common acute side effects. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
Vincristine sulfate 
Vincristine sulfate is a vinca alkaloid from the plant Cantharanthus roseus (C. 
roseus). Vincristine is a substrate for CYP3A4/5, ABCB1, ABCC1, ABCC2, 
ABCC3, and ABCC10 and a weak inhibitor of CYP3A4. It acts by binding to or 
crystallizing microtubular proteins of the mitotic spindle. It is a cell cycle phase 
specific agent and can also affect DNA-directed RNA polymerase. It has a triphasic 
half-life and primary elimination is by the liver into the bile and feces. The major 
and dose-limiting side effect of vincristine is neurotoxicity. The main manifestation 
is a mixed sensorimotor peripheral neuropathy. Reduced or loss of deep tendon 
reflexes, paresthesias, weakness, myalgias and motor disturbances may occur. 
Autonomic toxicity also occurs which may cause constipation, obstipation, 
abdominal cramps and ileus. It has mild myelosuppressive effects and is a vesicant 
causing local necrosis at the site of injection if extravasation occurs. Please refer to 
the approved package insert for complete prescribing and toxicity information. 
Cyclophosphamide 
Cyclophosphamide is an alkylating agent and is cell cycle nonspecific. It causes 
cross-linking of DNA and is the most active single agent in the treatment of non-
Hodgkin lymphoma. Cyclophosphamide is a substrate of CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. Cyclophosphamide is a weak-to-
moderate inducer of CYP2B6, CYP2C8, and CYP2C9 and weak inhibitor of 
CYP3A4 and UGT (isozyme not specified). Side effects of cyclophosphamide 
include nausea, vomiting, myelosuppression and alopecia. Sterility and testicular 
atrophy are common in men and amenorrhea is seen in women. Hemorrhagic 
cystitis is caused by metabolites of cyclophosphamide excreted through the urine. 
Bladder irritation can be reduced by adequate hydration. Please refer to the 
approved package insert for complete prescribing and toxicity information. 
Doxorubicin hydrochloride 
Doxorubicin is an anthracycline antibiotic that binds tightly with DNA, inhibits 
nucleic acid synthesis and causes DNA strand breaks. Although active throughout 
the cell cycle, cells in S phase are most sensitive. Doxorubicin is a substrate for 
aldoketoreductase, NADPH-dependent cytochrome reductase, CYP2D6, CYP3A4, 
ABCB1, ABCC1, ABCC2, ABCG2, and SLC22A16. Doxorubicin also has been 
noted to be an inducer of ABCB1, a moderate inhibitor of CYP2B6, and a weak 
inhibitor 
of 
CYP2D6 
and 
CYP3A4. 
Common 
side 
effects 
include 

 
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myelosuppression, alopecia, and stomatitis, which is dose related and may be 
severe. Drug-induced cardiomyopathy which may result in congestive heart failure 
is a cumulative dose dependent effect and risk becomes considerable at total doses 
exceeding 500 mg/m2. Doxorubicin is given intravenously and is a vesicant causing 
severe local necrosis at the site of injection if extravasation occurs. Nausea and 
vomiting are frequent. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
2.3 
Study Design and Rationale 
2.3.1 Rationale 
The activation of the B-cell receptor (BCR) signaling pathway plays a role in 
proliferation and survival in B-cell NHL. Chronic BCR signaling engages the 
adaptors CD79A and CD79B in a Syk-dependent mechanism. Downstream of 
CD79A/B, BTK is activated.15 Although data are lacking regarding BTK inhibition 
in EBV or KSHV driven lymphomas, many NHL that occur in the setting of late 
stage AIDS are virally associated (EBV, KSHV), and these viruses are known to 
modulate BCR and subsequent signaling pathways to drive persistence and 
proliferation. Additionally, EBV latent membrane protein 2A (LMP2A) may 
initiate both BTK-dependent and BTK-independent pathways.16 
Activation of the BCRB-cell receptor pathway is a new therapeutic target in B cell 
lymphoma, as BTK is an essential kinase for B cell survival.17 An inhibitor to the 
BCR signaling pathway with BTK inhibitors like ibrutinib may improve response 
rates and survival. 
Outside of AIDS-related DLBCLs, BTK inhibitors have been most promising in 
targeted inhibition of aberrant pathways in non-GCB DLBCL. Preclinical studies 
with BTK inhibitors showed inhibition of outgrowth of CD79 mutant non-GCB 
DLBCL cells.15 A Phase II trial of single-agent ibrutinib in participants with 
relapsed or refractory DLBCL demonstrated an overall response rate (ORR) of 23% 
(16/70 participants) with a much higher response in the non-GCB subtype, (12/29, 
41%) (five CR and seven PR) versus the GCB subtype, (1/20, 5%) (1PR).18 In a 
phase I trial of R-CHOP and ibrutinib, all 18 participants with DLBCL who 
received the recommended Phase II dose had an overall response. For those 
subtyped and treated at the recommended phase II dose, five (71%) of seven 
participants with the GCB subtype and two (100%) participants with the non-GCB 
subtype had a complete response.19 By contrast, for ARL, the division of oncogenic 
phenotypes of GCB and non-GCB has not been optimally determined.8 While 
enrichment of patients for non-GCB seemingly would be ideal for a study with 
BTK inhibitors, exclusion of AIDS patients with GCB DLBCL based on IHC alone 
may be premature in this population as ARL may have a distinct molecular profile 
that is not best stratified by IHC alone.8 More importantly, there are no current trials 
examining ibrutinib, a drug which has and continues to revolutionize the non-ARL 
arena, in ARL. 
Given the activity demonstrated by ibrutinib in non-HIV DLBCL, we would like to 
evaluate the safety and feasibility of ibrutinib with chemotherapy in HIV patients 
with DLBCL. We propose a multi-center pilot study which will combine the BTK-

 
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inhibitor ibrutinib with R-EPOCH chemotherapy in participants with treatment-
naïve ARL. This pilot study will consist of a dose-finding cohort, and a dose-
expansion cohort. The dose-finding portion of the study will be a dose de-escalation 
study beginning with ibrutinib 560 mg daily dose level. The minimum dose will be 
ibrutinib 280 mg daily as ibrutinib in combination with chemotherapy may require 
less than the FDA approved dose. The dose-expansion portion of the study will use 
ibrutinib at the recommended phase II dose (RP2D) in combination with 
chemotherapy. 
The main reasons for this trial are to provide feasibility data for the combination 
of ibrutinib and R-EPOCH in DLBCL, and in particular, evaluate the safety and 
feasibility this combination in persons with HIV patients, specifically non-GCB or 
ABC subtypes.  
There are several added benefits to this trial. In particular, this study builds on data 
provided by the ongoing Phase III trial using R-CHOP and ibrutinib in the front-
line setting for non-GCB DLBCL,19 which excludes HIV patients. Data from this 
trial will also allow the AMC to move forward to a larger efficacy study of ibrutinib 
and R-EPOCH in ARLs. An expanded cohort will enrich the population at the 
RP2D; accordingly, it will help gain insight into the proof-of-concept of ibrutinib 
and R-EPOCH, as well as improve the characterization and evaluation of the 
toxicity profile, interactions, tolerability, and pharmacology of ibrutinib in 
combination with R-da-EPOCH in ARL. More importantly, while we will not have 
power to distinguish non-GCB versus GCB, this trial will provide some information 
in the context of the current randomized Phase III R-CHOP and ibrutinib versus R-
CHOP;19 if the observed pattern seen in this trial fits with the Phase III outcomes, 
then it would support the use of ibrutinib in the ARL population, particularly for 
DLBCL. Finally, since assignment of COO is increasingly important with the 
emergence of novel therapies that have selective biological activity in GCB and 
non-GCB or ABC lymphomas, we will obtain a GEP on each tumor sample in 
addition to IHC for assessment of GCB and non-GCB classification. This may 
allow us to more accurately correlate ARL biology with treatment response and 
survival with ibrutinib at the end of treatment. 
2.3.2 Study design 
The proposed trial will be a multi-center pilot study studying of ibrutinib in 
combination with R-da-EPOCH. This pilot study will include a dose-finding cohort 
followed by a dose-expansion cohort at the MTD or RP2D. 
Participants must not be on medications, including antiretroviral (ARV) regimens, 
with moderate or strong CYP3A4 inhibition; if on a moderate or strong CYP3A4 
inhibitor regimen prior to study enrollment, participants must be switched to a 
qualifying regimen with the last dose of the moderate or strong CYP3A4 inhibitor 
taken at least one week before administration of protocol therapy due to effects on 
ibrutinib. Participants must have tissue (block, core or slides) available for 
submission available for mandatory central pathology review and additional 
correlative integral studies. 
The pilot study aims to determine the MTD and RP2D of ibrutinib in combination 

 
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with R-EPOCH using a 3+3 dose de-escalation design. The decision to enroll 
participants in subsequent cohorts will be made after the available safety data at a 
given dose level of ibrutinib are reviewed, each participant in the current cohort 
must have completed at least cycle 1 (or 21 days) of ibrutinib and R-da-EPOCH 
before safety data will be reviewed. MTD will be the dose at which less than 2/6 of 
participants have a dose-limiting toxicity (DLT). The protocol team reviewed the 
safety among the first 3 participants enrolled on 01MAY2018 and confirmed 
that dose level 1 was the MTD. 
R-da-EPOCH will be given on a 21-day cycle. EPOCH will be dose-adjusted based 
on nadir counts in the previous cycle (see below). Ibrutinib will be dosed daily on 
days 1-21. Participants with CD20 negative disease will receive the same treatment 
of EPOCH, but without rituximab. There will be no intra-participant dose escalation 
of ibrutinib in the dose-finding portion of the study. Given this is combination 
therapy, with the hypothesis that ibrutinib will have synergy with R-EPOCH, we 
have allowed ibrutinib de-escalation as needed for toxicity to a dose of 280 mg. 
Once the RP2D or MTD dose is determined, additional participants will be enrolled 
into the dose-expansion cohort in order to better characterize the toxicity and safety 
profile, assess the pharmacokinetics, and identify early signs of efficacy within the 
GCB and non-GCB population. In the dose-expansion portion of the study, R-da-
EPOCH will be given on a 21-day cycle. Ibrutinib and EPOCH will be dose-
adjusted based on nadir counts in the previous cycle (see below). Ibrutinib, at the 
MTD, will be dosed daily on days 1-21 of each cycle except when held for toxicities 
as specified below. 
Participants may receive treatment for a maximum of 6 cycles (21-day cycle length) 
total of chemotherapy in the dose-finding and dose-expansion cohort portion of the 
study. Participants will be allowed to enroll after one cycle of R-da-EPOCH or R-
CHOP, as noted in the eligibility criteria; this cycle will count as Cycle 1 of therapy 
on study. A restaging diagnostic CT (chest/abdomen/pelvis, with PET/CT optional) 
will be performed after Cycle 4. Participants with CR after Cycle 4 will receive two 
additional cycles of chemotherapy. Given there is a range of what qualifies as PR 
(including participants with residual PET avidity which may represent CR with 
residual “healing tissue”), participants who achieve a PR after Cycle 4 may 
continue on protocol therapy or be removed from the study at the discretion of the 
physician (local investigator). PET/CT will be performed to document remaining 
active sites of lymphomatous disease 4-8 weeks after the beginning of Cycle 6, or 
within 4-8 weeks of treatment discontinuation if treatment was stopped after Cycle 
4 and prior to Cycle 6 due to excessive toxicity. 
Forty participants with adequate tissue for COO analysis (IHC and GEP) will be 
enrolled in the dose-finding and dose-expansion cohorts. A maximum of 54 
participants will be allowed on the trial; for participants who do not have adequate 
tissue for GEP, tumor content of ≥ 60%, we will replace up to 14 participants 
(assuming 30-35% insufficient tissue for GEP) on trial. If we need to replace more 
than 14 participants, AMC and other involved parties will discuss a remediation 
plan. Therefore, the maximum number of participants is 54 participants (40 
evaluable with 14 replacements, if needed). 

 
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2.3.3 Study Design Flow 
The goal will be to obtain at least 40 participants with adequate tissue for COO 
and 15 participants with central pathology confirmed non-GCB (by IHC) subtype, 
and eventually ABC subtype (by GEP), for analysis. Given this is a multicenter trial 
and adequacy of tissue and IHC confirmation for COO will need to be reviewed 
and confirmed at the AMC Pathology Core Lab at Weill Cornell Medical College. 
In addition, given logistical and financial restraints, COO by GEP will be 
completed in batches. Therefore, IHC will be the only marker used for accrual and 
participant selection. To account for this logistical challenge inherent to a 
multicenter trial, the following method for adequacy of tissue for COO and IHC 
review will be implemented: 
• COO (non-GCB or GCB) by IHC will be required and determined at each 
individual AMC site in which the participant is being treated. To compensate 
for the possible 30% misclassification rate, we will accrue a minimum of 22 
participants with non-GCB histology via IHC as determined by the local 
pathologist.  
• Diagnostic slides with IHC staining and the remaining tissue block will be sent 
within 1 month for central pathologic confirmation of IHC and central 
pathologic confirmation of adequacy of tissue for GEP analysis. Tissue, 
specifically formalin-fixed, paraffin-embedded specimens, will preferentially 
be used for COO biomarkers, GEP and IHC, in that order of priority.  
• The AMC core laboratory will confirm COO by IHC on a case-by-case basis; 
the IHC determined at the AMC core lab will be used in the final analysis. 
Remaining tissue will be banked and batched at the AMC Biorepository for the 
GEP and other correlative studies. Given logistical and financial restraints, 
COO by GEP will be completed in batches. Note: because IHC will be used to 
determine the number of participants in each subgroup, COO by IHC will be an 
integral biomarker, while because COO by GEP will not change enrollment or 
treatment, COO by GEP will be an integrated marker. Remaining tissue will be 
used for the subsequent exploratory biomarkers and banked for additional 
studies for the future.  
• In order to ensure for the minimum participant requirement for non-GCB ARL, 
if after enrollment of 20 and 30 participants on trial, there are <50% non-GCB, 
non-GCB COO (as determined at individual AMC site) will be the 
preferentially enrolled to meet the minimum number of participants required in 
the trial (22 non-GCB participants). 
2.4 
Correlative Studies 
Integral Biomarker 
2.4.1  IHC for COO 
We hypothesize that COO by IHC and GEP will differ and help determine whether 
either or both could have identified those patients who might benefit from the 
addition of ibrutinib to their treatment regimen.  

 
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COO is traditionally defined by IHC. IHC for COO is also helpful for upfront 
analysis because it can be done rapidly in the context of a pathologic diagnosis. At 
this time, it is not known whether in HIV-positive patients there is a difference in 
BTK dependency among the DLBCL COO subtypes. In AIDS, GC DLBCL are 
more common, so COO assessment by IHC will provide rapid decision-making to 
make sure that sufficient patients with non-GC DLBCL are enrolled; IHC will be 
used to ensure a minimum number of non-GC cases (15 centrally confirmed non-
GC DLBCL). In addition, this study will give us an opportunity to obtain GEP on 
each tumor sample, in addition to IHC, for assessment of GCB and non-GCB 
classification. GCB and non-GCB subgroups have different pathologies and 
treatment outcomes. By obtaining COO with GEP, this will allow us to assess the 
concordance among of GEP to IHC, and to correlate biology with treatment 
response rates and survival. 
Ibrutinib may be an important factor in HIV-positive lymphomas. Retrospectively, 
after closure of the trial, the Lymph2Cx results on the pre-treatment biopsy will be 
compared to Hans IHC results. The Hans method for IHC classification for COO, 
which has been used as a surrogate for gene expression profiling in multiple studies, 
and is the most accepted immunohistochemical method for subclassification. This 
relies on assessing expression of CD10, BCL6 and MUM1/IRF4. Cases classified 
as GC will be those with CD10 expression in more than 30% of tumor cells and 
also those that are CD10-, BCL6+, MUM1/IRF4 -. All others will be classified as 
non-GC. While not as accurate as gene expression profiling (through microarray 
technology or RNA sequencing), it can be achieved within two days of receipt of 
the specimen, and requires standard diagnostic material. Nanostring (Lymph2CX) 
is an alternative classification method (Section 2.4.2), which has better 
concordance with gene expression data than immunohistochemistry.  
IHC for COO (i.e., staining for CD10, BCL6 and IRF4) is used routinely in Dr. 
Cesarman’s lab using standard FFPE sections. If there is a technical failure, the 
assay will be repeated. The main reason for repeated technical failure is poor 
preservation/fixation. Another source of possible failure is if the specimen received 
is not diagnostic, i.e., does not have DLBCL. If this occurs, it is unlikely that other 
methods would succeed, and a repeat biopsy will be recommended, and if not 
possible, participants would be replaced on the trial.  
IHC is a highly reproducible method. The AMC Pathology Core Lab at Weill 
Cornell Medical College is approved to perform IHC by all major compliance 
agencies, including CLIA, NY State and CAP. Reproducibility and accuracy are 
parameters assessed by these agencies. There are in-built positive and negative 
controls in the specimens, as there are positive and negative normal infiltrating cells 
within the vast majority of diagnostic DLBCL specimens. In addition, the lab 
includes positive (lymphoma) and negative control (tonsil) sections with every 
antibody run. Scoring will be done by microscopic visualization by a 
hematopathologist. 
Dr. Cesarman’s laboratory is one of the largest in the country and among the first 
to perform immunohistochemistry for the diagnosis of lymphomas, back in the 80s. 
Currently six faculty members, which are board certified hematopathologists, are 

 
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part of this group. The lead hematopathologist evaluating the slides and reporting 
the results will be Dr. Amy Chadburn, who has approximately 30 years of 
experience with IHC for lymphoma diagnosis and classification.  
The pathology laboratory at the specific site the participant is enrolled at will 
perform the IHC assays. The IHC will be reviewed and confirmed at the AMC 
Pathology Core Lab at Weill Cornell Medical College. When specific IHCs are not 
available, the IHC will be performed at the AMC Pathology Core Lab at Weill 
Cornell Medical College. If the study is done on site, slides will be sent to Weill 
Cornell for confirmation and centralized review. 
Integrated Biomarkers 
2.4.2  GEP for COO 
We hypothesize that COO by IHC and GEP will differ and help determine whether 
either or both could have identified those patients who might benefit from the 
addition of ibrutinib to their treatment regimen. 
This assay provides molecular COO subtyping of DLBCL into GCB, ABC, and 
unclassifiable subtypes, which have different biological features such as gene 
expression, mutation profiles, signal pathway activation, and prognosis. A phase II 
study of DLBCL in HIV-negative patients demonstrated improved outcome when 
ibrutinib (which targets the B cell receptor signaling pathway that is upregulated in 
the ABC subtype) was added to R-CHOP for treatment of patients with the non-
GCB subtype.19 Retrospectively, after closure of the proposed trial, the Lymph2Cx 
results on the pre-treatment biopsy will be compared to Hans IHC results.  
In a phase I/II clinical trial performed at the NCI, N=80 patients with relapsed or 
refractory DLBCL, ibrutinib produced complete or partial responses in 37% 
(14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB 
DLBCL (P = 0.0106).46 COO subtyping for this study was performed using 
Affymetrix platform and a data analysis algorithm that is no longer in research or 
clinical use. Lymph2Cx has been applied to 2 different population based patient 
cohorts of 119 and 344 patients respectively,47 however, not yet reported in clinical 
trials. As of February 2017, a retrospective analysis of 221 patients treated on the 
GELA trial, LNH2003, is under review, but not yet published. The ECOG phase II 
1412 trial and the Celgene ROBUST phase III trial, also using the Lymph2Cx 
assay, are not yet complete. 
The Lymph2Cx assay that will be used in this clinical trial is exactly comparable 
to the published studies. Concordance studies with 30 cases showed 100% 
agreement between the original result from the publication and results in the 
Molecular Diagnostics of Arizona Laboratory.47 We have standardized operating 
procedures, controls, and a completely locked algorithm. The original reports of the 
2 subtypes of DLBCL were based on gene expression profiling of snap frozen 
tissues, which was a purely research methodology. Shortly thereafter, for practical 
reasons, an IHC assay was developed called the “Hans algorithm,”48 which was 
approximately 83% accurate compared to the original gene expression method. 
Subsequently, numerous IHC and other molecular methods were developed. An 

 
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extensive meta-analysis and review concluded that the molecular methods were 
more accurate.49 Subsequently, our research consortium undertook to test several 
molecular methods resulting in development of the Lymph2Cx assay on the 
nCounter platform by Nanostring, which uses formalin-fixed paraffin embedded 
tissues.47 This assay is now going through commercial development to become an 
FDA-cleared test. “Lymph2Cx” is the original published, academic, name of the 
assay from the LLMPP research consortium. At this time, the commercial prototype 
of Lymph2Cx is under development by Nanostring and is generally referred to as 
the “Lymphoma Subtyping Test” or “LST” until such time as the product is 
officially through the FDA clearance process and formally named by the company. 
The Lymph2Cx is the only DLBCL cell-of-origin assay at such an advanced stage 
of development. Due to ease of implementation, IHC assays continue to be used in 
the clinical setting at this time. However, a recent study of 218 cases demonstrated 
that using 9 different popular IHC staining algorithms, only 4% of tumors were 
misclassified as GCB but 21% as ABC/non-GCB by all IHC methods.50 This is 
compared to the 98% concordance between different laboratories using the 
Lymph2Cx assay.47 For these reasons we chose the Lymph2Cx assay as the 
molecular method of choice. 
Archived paraffin blocks were used for the initial development and publications of 
the Lymph2Cx assay, and were up to 20 years old. To avoid potentially degraded 
tissue, the protocol first requires cutting a 10-micron thick section off the surface 
of the block before cutting the deeper tissue sections used for analysis. Fresh versus 
14-day old unstained tissue sections, at ambient temperature, were compared and 
yielded the same results on 5 samples indicating a 2-week time lag between cutting 
the samples and initiating testing is acceptable. The accuracy of the Lymph2Cx 
assay using paraffin embedded tissue biopsies and the nCounter instrument was 
first compared against the gold standard (frozen tissue, Affymetrix gene expression 
profiling) in the prior publication from our research consortium and demonstrated 
an accuracy of 98%.47 Subsequently, we evaluated the performance of the 
Lymph2Cx assay in our own laboratory and showed a perfect 30/30 (100%) 
concordance with the prior results. Reproducibility between 2 different technical 
staff members, pathologists, and instruments was 100% for 9 samples repeated 2 
weeks apart. Precision was assessed by repeating 5 cases on 3 different occasions, 
with 100% concordance. Dilutional studies demonstrated that 400ng was the 
minimal reliable input for the assay. The different substances, including all reagents 
used in the assay, were tested and demonstrated no interference. 
An important pre-analytical variable is percentage of tumor, which should be a 
minimum of 60% based on a second dilutional study demonstrating that 60% and 
50% gave reliable results, but that 40%, 30%, and 20% did not. To be conservative, 
60% was chosen to allow for slight variability in tumor content estimates and 
different cuts off of the block. To address the tumor percent, an H&E stained 
section of each case will be assessed by Dr. Rimsza, who will estimate tumor purity. 
If needed, macro-dissection of the tissue sections will be performed to increase 
tumor content. Input is 1 x 10-micron thick section for a 1cmX1cm biopsy. For 
smaller biopsies, proportionally more sections will be taken, and if more than 2 
sections are required, macrodissection will be utilized to remove excess paraffin. 

 
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Dr. Rimsza will measure the size of the tumor area and determined the number of 
needed sections at the same time that she determines the tumor content. A 
Pathology Quality Assurance form is used to document the tissue input specifics 
(size/number of needed sections and percent tumor). At this time, only formalin 
fixed biopsies (not other fixatives) have been assessed. The Pathology reports on 
the biopsies will be reviewed to determine whether formalin or another fixative was 
used. The average raw count of the housekeeping genes in the assay is used as a 
final quality control marker – samples with <20 counts for this metric are reported 
as “Poor Quality.” The materials for this study will be analyzed in the exact same 
manner as the samples in the clinical laboratory that are tested for medical care. A 
positive and negative control and up to ten samples can be included in each 12-well 
cassette. Positive controls include a mixture of oligonucleotides which hybridize 
with all probes in the assay. These were pre-mixed by the manufacturer, 
lyophilized, and reconstituted into stock solutions. The negative control is a well in 
the cassette that includes all reagents and probes, but no RNA. Scoring is not 
applicable in this assay. 
The lab performing this assay is Molecular Diagnostics – Arizona Laboratory, 
Mayo Clinic Arizona, CLIA #03D2113087; Medical Director: Dr. Lisa Rimsza; 
Performing technologist: Colleen Ramsower, MB(ASCP) and Tameson Yip, 
MB(ASCP). “MB” indicates these staff members are certified in molecular biology 
by the American Society of Clinical Pathologists. Testing for the proposed trial will 
follow the exact same procedures as are used for the samples in the clinical 
laboratory. Dr. Rimsza has extensive experience with the assay, which is actively 
testing Mayo Clinic patients for clinical use. She is the senior author on the initial 
publication, co-author on 2 additional publications, co-inventor on the assay patent, 
and is the Medical Director of a CAP-CLIA certified laboratory performing the 
assay. This is the first clinical laboratory in the country to offer the test for patient 
care. She both directs the laboratory and signs the medical results cases. 
Circulating Tumor DNA 
2.4.3  Circulating tumor DNA – cancer mutations 
NextGen Sequencing of circulating tumor DNA to identify residual tumors on the 
basis of oncogene mutations will be performed at an AMC Core Laboratory.. This 
is a feasibility study that relies on commercial assays. This is an early study for 
ctDNA and is designed to test the logistics, infrastructure, and assay performance 
for potentially CD4 lymphocyte -depleted, HIV+ samples. 
The statistical analysis will be descriptive in nature, describing the number of single 
nucleotide variations (SNV) identified at each sample collection time point and 
whether the type of mutation or frequency in blood changes over the course of 
treatment.  
Circulating tumor DNA – B cell receptor clonality 
NextGen Sequencing for BCR rearrangement using LymphoTrack technology will 
also be performed in an AMC Core Laboratory at Johns Hopkins. This study relies on 
newly developed procedures. The statistical analysis will also be descriptive in nature. 

 
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Exploratory Biomarkers 
2.4.4  BTK IHC 
It has been well documented that the primary target of ibrutinib is BTK, which is 
involved in B cell receptor signaling in lymphoma, so expression of BTK will be 
used to determine if the relevant drug target is expressed and if lack of response is 
due to lack of BTK expression. Currently, there are little data of BTK expression 
in ARL. We hypothesize that there will be more specimens lacking BTK expression 
in participants with poorer response to therapy. If this is the case, future treatment 
can be designed to use ibrutinib only participants whose ARL expresses BTK. 
In addition to BTK IHC, we will also be performing phosphorylated expression of 
BTK in pre-treatment biopsies. In some experimental systems, it has been shown 
that phosphorylated BTK (pBTK) correlates with cytotoxic sensitivity to ibrutinib, 
though it has not been clearly shown that total or phosphorylated expression of 
BTK in pre-treatment biopsies predicts response to therapy. However, this has not 
been done in the context of ARLs, where there is evidence that some lymphomas, 
such as PEL lack BTK expression and cell lines are resistant to ibrutinib.21 
Preclinical and some clinical studies have used Western blotting or flow cytometry 
to study activation of BTK pre-and post-treatment. However, in the context of this 
trial, tumor material is only in the form of formalin-fixed, paraffin embedded tissue 
sections. Therefore, IHC is the only possible method to assess expression of BTK 
and pBTK in ARL. One recent study that used this method, reporting that 
approximately 65% of DLBCLs express BTK, and showed that BTK expression 
together with high expression of MYC or BCL2 is a poor prognostic indicator (Han 
et al Anticancer Res 2021). If BTK is not expressed, our expectation is that these 
tumors would not respond to Ibrutinib, but to our knowledge this has not been 
explored in the context of a clinical trial 
Antibodies are available that have been shown to work in FFPE tissue sections for 
BTK and pBTK. Dr. Cesarman’s laboratory has extensive experience in IHC. If 
interpretation by visual examination is difficult because of a range of intensities, 
image analysis will be used for quantitative analysis, as exemplified in other 
publication from our group.22 The antibody validated for use in FFPE tissues (anti-
BTK antibody ab25971) from Abcam and Anti-BTK Antibody (phospho-Tyr551) 
from Thermo-Fisher will be used. There is potential variability with regard to 
staining intensity based of tissue fixation and processing procedures, which will be 
done at different pathology departments from the various AMC sites, however 
problems scoring as positive or negative are not expected, in the context of good 
controls (tonsil tissue will be used, and this has positive and negative cells and a 
very specific cytoplasmic expression pattern can be seen with scattered bright 
positive cells in the germinal center, and a more diffuse but positive pattern in the 
mantle zones). If quantification is difficult in specific cases, these will be excluded 
from quantitative analyses. 
Scoring will be done by microscopic visualization and interpretation by two 
hematopathologists and for quantification, slides scanning and image analysis using 
HALO. If difficulties with any given antibody, others commercially available (there 

 
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are several clones/vendors that carry BTK antibodies) will be tested. Dr. Chadburn 
and Dr. Cesarman will be interpreting the results and supervising the assay. They 
both have more than 20 years of experience with IHC of lymphoma. The laboratory 
conducting the assay is the Immunopathology Laboratory at Weill Cornell Medical 
College, which is a well-established, high volume laboratory. This laboratory is an 
AMC Central Lab. 
2.4.5  EBER-ISH 
Approximately 20% of ARL cases will be EBV positive. This method will be used 
to determine if the ARL is EBV positive. This will be important to assess if the 
presence of this virus affects response to therapy at the tumor level concurrently 
with the blood EBV levels. At this time, there is little information regarding BTK 
expression in a large series of EBV positive lymphomas, and their response to 
ibrutinib. We hypothesize that some EBV positive lymphomas will lack BTK 
expression and that in these, ibrutinib will not provide a therapeutic advantage. 
There are numerous studies showing that EBV proteins LMP1 and LMP2 can 
activate NF-kB, and this signaling may bypass the need for BCR signaling. For 
example, many EBV-positive lymphoma cell lines are resistant to dasatinib.23 
There are no clinical studies assessing sensitivity of EBV positive ARL to ibrutinib. 
EBER ISH is a well-established method for EBV detection in FFPE sections. It is 
routinely used clinically, and has well known performance characteristics. We will 
use a known EBV positive lymphoma specimen as a positive control. The majority 
of cells are EBV negative, so a negative control is available in the same section. To 
score, there will be microscopic visualization and interpretation by two 
hematopathologists. Positive cases are those in which atypical lymphoma cells are 
EBER-positive. A few positive cells within a lymph node, which do not correspond 
to the lymphoma cells, will be interpreted as negative, since these are seen in many 
lymphoid specimens from individuals carrying latent EBV. 
Dr. Chadburn and Dr. Cesarman will be interpreting the results and supervising the 
assay. They pathologists have more than 20 years of experience with IHC of 
lymphoma. The laboratory conducting the assay is the Immunopathology 
Laboratory at Weill Cornell Medical College, which is a well-established, high 
volume laboratory. This laboratory is an AMC Central Lab. 
2.4.6  Blood cytokines 
Elevated serum levels of these cytokines (IL-6, IL10, IP10/CXCL10, and 
BCA1/CXCL13) are known to be produced by T helper cells and/or activated B 
cells, and are elevated in those HIV+ persons who develop NHL.24-27 Additionally, 
some of these cytokines were seen to predict response to treatment for persons with 
AIDS-NHL in the AMC-034 study.28 Similarly, serum levels of the soluble 
receptors that will be quantified in serum (sIL2R, sCD30, sTNFR2, and sCD14) 
have been associated with the development of AIDS-NHL in recent preliminary 
studies (Hussain, Epeldegui and Martinez-Maza, unpublished results).27,29 
Therefore, defining the effect of ibrutinib treatment on the serum levels of these 
cytokines and soluble receptors is expected to be informative. We hypothesize that: 
1) pre-treatment initiation serum levels of these molecules (IL-6, IL10, CXCL10, 

 
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CXCL13, sIL2R, sCD30, sTNFR2, and sCD14) will predict response to therapy, 
and 2) that treatment will lead to decreased levels of these molecules. 
Several cohort-based studies of the molecular epidemiology of AIDS-NHL have 
shown that levels of these molecules are elevated prior to the development of these 
cancers.24-27,29-32 Additionally, studies in a murine model of AIDS-NHL, using 
SCID mice implanted with an AIDS-Burkitt lymphoma line (2F7) showed that 
tumor growth was associated with a marked increase in CXCL13 levels.33 In the 
same murine/human AIDS-NHL model, IL-6, CXCL10 and IL-10 also were seen 
to be elevated in animals bearing tumors, when compared to controls (Widney and 
Martinez-Maza, unpublished results). 
A recently published study of cytokines and immune activation biomarkers in 
AIDS-related non-Hodgkin lymphoma treated with rituximab plus infusional 
EPOCH showed that CXCL13, IL-6 and IL-10 serum levels were associated with 
response to therapy.28 
These molecules will be quantified using a multiplexed immunometric assay 
system (Luminex platform), using assay reagents that are commercially available 
from R&D Systems. These are the same assays that have been used in several recent 
published studies, in which it was seen that these molecules are detectable in the 
great majority of persons,24,34-36 and also, that most of these molecules (sCD14, sIL-
2R, sTNFR2, CXCL13, IL-6, IL-10) showed high temporal stability.36 
The assay technology was chosen for several reasons: 1) The assays to be used are 
multiplexed immunometric assays, which are technically robust and repeatable, and 
require only a small serum/plasma volume, 2) The assays will be obtained from a 
highly-respected manufacturer (R&D Systems) and are commercially-available, so 
any investigator can utilize these same assays in future studies, enhancing the 
reproducibility of this work, and 3) These assays and molecules have been proven 
to be temporally stable over time in healthy populations,36 and to be markedly-
upregulated in persons who have AIDS-related lymphoma.24-27 These markers have 
been studies in many studies by us in the past, and have always been readily 
detectable in frozen serum/plasma.24-27,34 Additionally, we know from unpublished 
pilot studies that several of these molecules are stable and do not degrade rapidly 
(biochemical stability) when blood is collected under standard conditions, and is 
processed within a reasonable amount of time (Martinez-Maza, unpublished 
observations). 
The technical performance characteristics of the assays to be used have been 
reported previously, in a publication aimed at defining these parameters, as well as 
temporal stability (how much these markers vary over an extended period of time 
in healthy persons).36 The major sources of variability are driven by poor blood 
collection techniques and processing. Therefore, given that blood will be collected 
and processed using a standard protocol, these sources of variation should be 
minimized in this study. Positive and negative laboratory controls will be added to 
all assay plates. Positive controls will be archival human serum known to have 
elevated levels of these cytokines, as well as lower, but detectable levels, from prior 
work. Negative controls will include assay wells to which no human serum was 

 
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added. Results will be presented in picograms per milliliter – no scoring system 
will be used. 
These studies will be done at the AMC Biomarkers Core Lab at UCLA (Martinez-
Maza, PI). The laboratory that will do these assays has extensive published 
experience assessing cytokines and other immune activation biomarkers using the 
proposed immunometric assay technology.24-45 
2.4.7  Chemotherapy pharmacokinetics 
There is a potential for a drug interaction between ibrutinib and the components of 
EPOCH. Ibrutinib is primarily metabolized by CYP3A4 with additional 
contribution by CYP2D6.51 Ibrutinib is a sensitive substrate whose exposure is 
altered when administered with CYP3A4 inhibitors (~24-29-fold increase in 
exposure) and inducers (~10-13 fold decrease in exposure).51 In order to minimize 
variability in ibrutinib exposure, we have opted to only enroll participants on non-
CYP3A4-interacting antiretroviral regimens rather than creating separate cohorts 
for the CYP3A4-inducers and inhibitors. Ibrutinib has a low propensity to inhibit 
CYP450s in vivo but has a potential to inhibit ABCB1, for which doxorubicin, 
etoposide, and vincristine are all substrates. Inhibition of ABCB1 may lead to 
increased concentrations of ABCB1 substrates which may cause myelosuppression. 
R-EPOCH consists of infusional rituximab, etoposide, prednisone, vincristine, 
cyclophosphamide, and doxorubicin in combination with recombinant human 
granulocyte colony-stimulating factor (GCSF). The components of EPOCH are, at 
most, weak inhibitors of CYP3A4 and unlikely to cause significant alterations to 
ibrutinib in the clinically relevant range utilized in this study.12 Since ibrutinib 
exposure is highly variable but proportional to dose over the dose range proposed 
in this study (% CV for AUC is ~75%), we will assess ibrutinib PK to correlate 
with other pharmacodynamics endpoints (laboratory, toxicity, and efficacy). Given 
that we do not anticipate a clinically significant drug-drug interaction via the 
CYP3A4 pathway, we will propose trough level monitoring to provide  
an assessment of exposure for ibrutinib as was performed by the company  
in 
their 
NDA 
to 
the 
FDA. 
Ibrutinib 
trough 
levels 
collected 
at  
Days 1, 8, 15, and 22 of Cycle 1 were utilized successfully for exposure-response 
analyses 
(section 
2.2.4 
of 
the 
FDA 
Clinical 
Pharmacology 
review; 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000ClinP
harmR.pdf). We plan to incorporate the expansion to a full PK profile for ibrutinib 
if toxicities are frequent and severe with the combination. We will propose a limited 
sampling schema for doxorubicin, etoposide, and vincristine to assess whether 
ABCB1 inhibition by ibrutinib is clinically significant. We will obtain PKs only on 
participants at the MTD. 
We hypothesize that no pharmacokinetic-based drug-drug interaction will occur 
between ibrutinib and R-EPOCH since the trial is only enrolling non-CYP3A4 
modulating antiretrovirals. However, we hypothesize that ibrutinib will inhibit 
ABCB1, which will not alter the systemic pharmacokinetics of doxorubicin, 
etoposide, and vincristine but may cause increased myelosuppression.  
In AMC-061, a lower sunitinib dose resulted in equivalent drug exposure but 

 
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increased neutropenia in the ritonavir-containing ARV cohort compared to other 
regimens.14 Sunitinib is a CYP3A4 and ABCB1 substrate52 while ritonavir is a 
potent inhibitor of both CYP3A4 and ABCB1.53 
The resulting data will be able to be compared with existing data. Since the drug 
combination being explored in this clinical trial is different, one cannot predict if 
the same effect will be observed. 
Liquid chromatography with tandem mass spectrometry is the gold-standard for 
drug quantitation. The Analytical Pharmacology Core Lab already has developed 
and validated separate analytical methods for doxorubicin, etoposide, and 
vincristine. For etoposide and vincristine, plasma containing EDTA is the matrix 
that has been validated in the Analytical Pharmacology Core Lab. For doxorubicin, 
heparinized plasma is the matrix that has been validated in the AMC Pharmacology 
Core Lab at Johns Hopkins University. 
2.4.7.1 Bioanalytical method for determining vincristine sulfate 
This is for an integrated assay aimed at assessing drug exposure in 
participants on the clinical trial. The bioanalytical method for determining 
vincristine in human plasma with the anticoagulant dipotassium 
ethylenediaminetetraacetic acid (K2EDTA), was developed utilizing liquid 
chromatography coupled with tandem mass spectrometry (LC-MS/MS) in 
the Analytical Pharmacology Core Laboratory the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins, under the direction of 
Michelle A. Rudek, PharmD, PhD. The analytical method was validated as 
recommended by the FDA Guidance for Industry: Bioanalytical Method 
Validation, May 2001 (http://www.fda.gov.cder/-guidance/index.htm). 
Plasma samples (1000 μL) were prepared for analysis by liquid-liquid 
extraction with 2 mL of extraction solution (2 ng/mL of internal standard in 
100% MeOH). The mixture was vortex-mixed for 30 seconds then 
centrifuged (913 x g, 10 min). A 1.5 mL aliquot of the supernatant was 
collected and transferred into a borosilicate glass tube, and then 4 mL of n-
Butyl chloride was added into it. The mixture was vortex-mixed for 10 
seconds then centrifuged (1430 x g, 10 min). A 3.0 mL aliquot of the 
supernatant was collected and transferred into a borosilicate glass tube. The 
mixture was evaporated under a gentle nitrogen flow at 40°C until 
completely dry. To the residue, 100 μL of MeOH/water (40:60, v/v) was 
pipetted into each tube. The tubes were then vortex-mixed for 30 seconds, 
and then the final sample solution was transferred into autosampler vials. A 
20 μL aliquot of the final sample solution was loaded onto a Waters Atlantis 
C18 HPLC column (100 mm x 2.1 mm i.d., 3 μm) and separated by isocratic 
elution using a pre-mixed mobile phase composed of 0.1% (v/v) formic acid 
in 2 mM of ammonium acetate in water: 100% MeOH (57:43, v/v), 
delivered at 0.25 mL/min. A triple quadrupole mass spectrometer with a 
positive electrospray ionization interface was operated in the selected-ion 
monitoring mode to detect the m/z 413.3→362.4 and m/z 397.3→376.2, 
transitions for vincristine and internal standard, respectively. 

 
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Summary information taken from the assay validation performed by the 
Analytical Pharmacology Core Laboratory at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins is detailed below. 
Carryover was effectively eliminated by washing the autosampler injection 
needle with a solution of MeOH/water (60:40, v/v) between injections. 
There was no cross interference between the analytes and internal standard. 
Peaks that interfered with the detection of the vincristine or the internal 
standard were not evident in extracted ion chromatograms of plasma from 
multiple anonymous normal human donors. Calibration curves were 
quadratic at concentrations ranging from the 0.2 ng/mL lower limit of 
quantitation to 50 ng/mL. The validation studies demonstrated acceptable 
within-day and between-day accuracy and precision. See details from 
Calibrator and QC assessment tables below. Samples with concentrations 
exceeding the upper limit of quantitation can be diluted up to 10-fold using 
drug-free human plasma while maintaining precision and accuracy. Based 
on the validation performed by Damen et. al., vincristine was stable in 
plasma for at least three freeze/thaw cycles at -20°C and -70°C. 
Furthermore, vincristine was stable up to 23 days in the final extract at 
nominally 2-8°C. Vincristine was stable in plasma up to 7 months at -20°C 
and -70°C. Stock solution of vincristine was stable up to 10 months when 
stored at -20°C. 
Table 2-A: Calibrator assessment, vincristine sulfate 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day 
Precision 
Vincristine 
92.53 –110.83% 
1.58 – 13.52% 
*** – 2.59% 
***If Model Mean Square < Error Mean Square (Between-Run Precision 
with “No additional variation result of performing assay in different 
runs.”) 
Table 2-B: QC assessment, vincristine sulfate 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day 
Precision 
Vincristine 
93.17 – 
107.13% 
2.72 – 6.98% 
*** – 7.84% 
***If Model Mean Square < Error Mean Square (Between-Run Precision 
with “No additional variation result of performing assay in different 
runs.”) 
2.4.7.2 Bioanalytical method for determining etoposide and its metabolite,  
3’-O-desmethyl etoposide 
This is for an integrated assay aimed at assessing drug exposure in 
participants on the clinical trial. The bioanalytical method for determining 
etoposide and its metabolite, 3’-O-desmethyl etoposide, in human plasma 

 
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with the anticoagulant dipotassium ethylenediaminetetraacetic acid 
(K2EDTA), was developed utilizing liquid chromatography coupled with 
tandem mass spectrometry (LC-MS/MS) in the Analytical Pharmacology 
Core Laboratory the Sidney Kimmel Comprehensive Cancer Center at 
Johns Hopkins, under the direction of Michelle A. Rudek, Pharm.D., Ph.D. 
The analytical method was validated as recommended by the FDA 
Guidance for Industry: Bioanalytical Method Validation, May 2001 
(http://www.fda.gov.cder/-guidance/index.htm). 
Plasma samples (100 μL) are prepared for analysis by liquid-liquid 
extraction with a solution of 50 mM of L-Ascorbic Acid in water (40 μL), 
then 1 mL of extraction solution with (0.1 μg/mL of internal standard in 
100% ethyl acetate). The mixture was vortex-mixed for 30 seconds, and 
then centrifuged (1430 x g, 10 min). A 950 μL aliquot of the supernatant 
was collected and transferred into a borosilicate glass tube. The mixture was 
evaporated under a gentle nitrogen flow at 35°C until completely dry. To 
the residue, 100 μL of acetonitrile/water (50:50, v/v) was pipetted into each 
tube. The tubes were vortex-mixed for 30 seconds, and then the final sample 
solution was transferred into autosampler vials. A 10 μL aliquot of the final 
sample solution was loaded onto a Waters Atlantis C18 HPLC column (100 
mm x 2.1 mm i.d., 3 μm) and separated by isocratic elution using a binary 
mobile phase composed of 0.1% (v/v) formic acid in 100% of acetonitrile 
(A1) and 0.1% (v/v) formic acid in water (B1) (45% A1: 55% B1, v/v) 
delivered at 0.3 mL/min. A triple quadrupole mass spectrometer with a 
positive electrospray ionization interface was operated in the selected-ion 
monitoring mode to detect the m/z 589.6→228.9 and m/z 575.3→228.8, 
and m/z 657.2→383.0, transitions for etoposide, 3’-O-desmethyl etoposide 
and internal standard, respectively. 
Summary information taken from the assay validation performed by the 
Analytical Pharmacology Core Laboratory at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins is detailed below. 
Carryover was effectively eliminated by washing the autosampler injection 
needle with a solution of acetonitrile/water (50:50, v/v) between injections. 
There was no cross interference between the analytes and internal standard. 
Peaks that interfered with the detection of the etoposide, 3’-O-desmethyl 
etoposide or the internal standard were not evident in extracted ion 
chromatograms of plasma from multiple anonymous normal human donors. 
Calibration curves were linear at concentrations ranging from the 5 ng/mL 
lower limit of quantitation to 5,000 ng/mL. The validation studies 
demonstrated acceptable within-day and between-day accuracy and 
precision. See details from Calibrator and QC assessment tables below. 
Samples with concentrations exceeding the upper limit of quantitation can 
be diluted up to 10-fold using drug-free human plasma while maintaining 
precision and accuracy. Long-term stability for etoposide and 3’-O-
desmethyl etoposide in stock upon storage at -20°C was demonstrated for 
up to 80 days. Long-term stability for etoposide and 3’-O-desmethyl 
etoposide in human plasma upon storage at -70°C is ongoing. 

 
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Table 2-C: Calibrator assessment, etoposide 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day 
Precision 
Etoposide 
91.47 –110.43% 
1.67– 9.33% 
*** – 1.81% 
3’-O-desmethyl 
etoposide 
95.82 – 105.87% 
4.48 – 10.72% 
*** for all 
***If Model Mean Square < Error Mean Square (Between-Run Precision 
with "No additional variation result of performing assay in different 
runs.") 
Table 2-D: QC assessment, etoposide 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day 
Precision 
Etoposide 
98.43 – 114.83% 
2.81– 7.40% 
*** – 9.96% 
3’-O-desmethyl 
etoposide 
99.95 – 102.84% 
4.03 – 8.20% 
*** – 9.49% 
***If Model Mean Square < Error Mean Square (Between-Run Precision 
with "No additional variation result of performing assay in different 
runs.") 
2.4.7.3 Bioanalytical method for determining doxorubicin and its metabolite, 
doxorubicinol 
This is for an integrated assay aimed at assessing drug exposure in 
participants on the clinical trial. The bioanalytical method for determining 
doxorubicin and doxorubicinol in human plasma with the anticoagulant 
heparin was developed utilizing liquid chromatography coupled with 
tandem mass spectrometry (LC-MS/MS) in the Analytical Pharmacology 
Core Laboratory the Sidney Kimmel Comprehensive Cancer Center at 
Johns Hopkins, under the direction of Michelle A. Rudek, Pharm.D., Ph.D. 
The analytical method was validated as recommended by the FDA 
Guidance for Industry: Bioanalytical Method Validation, May 2001 
(http://www.fda.gov.cder/-guidance/index.htm). 
Plasma samples (100 μL) were prepared for analysis by liquid-liquid 
extraction with 4 mL of extraction solution (60 nM of internal standard in a 
solution of 2-Propanol: CHCl3 (20:80, v/v)). The mixture was shaken at 
high speed for 10 min, and then centrifuged (1430 x g, 10 min). The top 
layer was discarded, and the bottom layer was transferred into a borosilicate 
glass tube. The mixture was evaporated under a gentle nitrogen flow at 40°C 
until completely dry. To the residue, 100 μL of acetontrile/water (50:50, 
v/v) was added into each tube. The tubes were then vortex-mixed and 
sonicate for 5 min, and then the final sample solution was transferred into 
autosampler vials. A 5 μL aliquot of the final sample solution was loaded 
onto a Waters Atlantis RP18 HPLC column (150 mm x 2.1 mm i.d., 3.5 μm) 
and separated by isocratic elution using a binary mobile phase composed of 
0.1% (v/v) formic acid in 100% of acetonitrile (A1) and 0.1% (v/v) formic 

 
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acid in water (B1) (60% A1: 40% B1, v/v) delivered at 0.20 mL/min. A 
triple quadrupole mass spectrometer with a positive electrospray ionization 
interface was operated in the selected-ion monitoring mode to detect the 
m/z 544.3→397.1, m/z 546.3→399.2, and m/z 854.5→286.3 transitions for 
doxorubicin, doxorubicinol and internal standard, respectively. 
Summary information taken from the assay validation performed by the 
Analytical Pharmacology Core Laboratory at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins is detailed below. 
Carryover was effectively eliminated by washing the autosampler injection 
needle with a solution of acetonitrile/water (50:50, v/v) between injections. 
There was no cross interference between the analytes and internal standard. 
Peaks that interfered with the detection of the doxorubicin, doxorubicinol 
or the internal standard were not evident in extracted ion chromatograms of 
plasma from multiple anonymous normal human donors. Calibration curves 
were linear at concentrations ranging from the 10 nM lower limit of 
quantitation to 2000 nM. The validation studies demonstrated acceptable 
within-day and between-day accuracy and precision. See details from 
Calibrator and QC assessment tables below. Samples with concentrations 
exceeding the upper limit of quantitation can be diluted up to 10-fold using 
drug-free human plasma while maintaining precision and accuracy. Long-
term stability for doxorubicin and doxorubicinol in stock upon storage at -
20°C were demonstrated for up to 75 days. 
Table 2-E: Calibrator assessment, doxorubicin and doxorubicinol 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day 
Precision 
Doxorubicin 
96.73 –106.07% 
4.15 – 10.26% 
*** – 5.20% 
Doxorubicinol 
97.00 – 104.10% 
6.36 – 11.29% 
*** – 2.47% 
 
Table 2-F: QC assessment, doxorubicin and doxorubicinol 
Analyte 
Accuracy 
Within-day 
Precision 
Between-day  
Precision 
Doxorubicin 
94.79 – 106.42% 
3.98 – 5.36% 
1.73 – 7.61% 
Doxorubicinol 
94.25 – 105.46% 
3.30 – 5.88% 
1.70 – 7.23% 
***If Model Mean Square < Error Mean Square (Between-Run Precision 
with "No additional variation result of performing assay in different 
runs.") 

 
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2.4.8  EBV viral load 
A distinctive feature of aggressive HIV-NHLs is their high association with gamma 
herpesviruses such as Epstein-Barr virus (EBV). These viruses play important 
oncogenic roles and their intrinsic presence in the tumors may represent potential 
therapeutic targets.60,61 EBV-associated HIV-NHL includes the majority of 
immunoblastic DLBCL variants, primary effusion lymphoma (PEL), plasmablastic 
lymphoma (PBL), and about 30-60% of Burkitt lymphoma (BL). EBV DNA can 
be a tumor marker in these lymphomas. In post-transplant lymphoma, 
nasopharyngeal carcinoma, Hodgkin lymphoma, and nasal lymphoma there are data 
to suggest that clearance of viral DNA is associated with response to therapy.62-65 
EBV-positive DLBCL has EBV-mediated oncogenic signaling pathway activation, 
and these multiple intracellular pathways can be potential therapeutic targets in this 
disorder. Thus, EBV-associated protein, LMP1 can induce the activation of various 
downstream pathway molecules such as PI3K/Akt and NF-kB activation. The 
activation of NF-kB is one of essential factors contributing to prolonged survival 
and aggressive phenotype of DLBCL. In a more aggressive subtype of diffuse large 
B-cell lymphoma, activated B-cell like type, chronic active B-cell receptor 
signaling and MYD88 mutation are known to stimulate NF-kB transcription and 
activation. As a result, a key molecule mediating B-cell receptor signaling pathway, 
BTK can have a critical role, and BTK has been emerging as a therapeutic target in 
DLBCL. Considering the close association between B-cell receptor signaling 
pathway and PI3K/Akt pathway in DLBCL targeting BTK might be helpful for 
improving treatment outcome of EBV-positive DLBCL. We hypothesize that the 
addition of ibrutinib with R-da-EPOCH will affect the EBV viral load and 
reactivation in positive tumors. We anticipate that participants who fail to clear 
EBV viral DNA will also fail to achieve sustained CR. Descriptive statistics such 
as frequencies and percentages will be used to aid in the evaluation of EBV gene 
expression patterns (associations) in positive tumors banked at baseline. 
The PCR methods used for EBV DNA are all quite similar and involve use of a 
standard. Two standards are widely used and are comparable. One involves use of 
a Burkitt cell line (Namalwa) that is unusual in that the EBV is integrated and does 
not replicate as virus. The total amount of cell DNA thus yields an estimate of the 
total viral DNA. By targeting the large internal repeat region of the virus, the 
sensitivity of the assay is increased. Positive controls are DNA extracted from an 
EBV(+) Burkitt cell line. Negative controls are DNA from an EBV(-) cell line. 
Viral DNA is quantitated as copies/ml plasma. This PCR methodology was selected 
because this is a standard viral DNA assay. The particular method for this study has 
been used in many other cooperative group studies.64 This PCR method has also 
been validated against a commercial B95.8 DNA standard. 
Blood will be mailed at ambient temperature and separated into plasma and cells at 
the receiving lab. Variability is minimized by following a standard operating 
procedure. Technicians assaying specimens are supervised and certified before 
handling study specimens. GLP are followed. 

 
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The Ambinder laboratory at Johns Hopkins will be performing this particular 
correlative study. They have ample experience with this assay, and they have 
performed the same assay for other AMC studies. The assay has also been used in 
for the Eastern Cooperative Oncology Group (ECOG) Hodgkin studies, and the 
Children’s Oncology Group Hodgkin studies. 
2.4.9  Ibrutinib pharmacokinetics 
Potential drug interactions will be taken into account in this study. In cancer 
patients, ibrutinib exposure is variable but proportional to dose over the dose range 
proposed in this LOI (% CV for AUC is ~75%).51 Ibrutinib is primarily metabolized 
by CYP3A4 with additional contribution by CYP2D6.51 Ibrutinib has a low 
propensity to inhibit CYP450s in vivo, but may inhibit ABCB1 at clinically relevant 
concentrations.51 However, ibrutinib is a sensitive substrate whose exposure is 
altered when administered with CYP3A4 inhibitors (~24-29-fold increase in 
exposure) and inducers (~10-13 fold decrease in exposure).51 For this study, we 
have opted to only enroll participants on non-CYP450-interacting antiretroviral 
regimens to minimize variability in ibrutinib exposure. 
PK sampling studies are proposed for all participants on the study, with evaluations 
to be obtained prior to the initiation of treatment, and then pre-treatment on Cycle 
1 Day 8. If significant toxicity (defined as a DLT, see Section 4.2) is observed, an 
expanded profile, Day 8 at 0.5, 1, 2, 4, 6, 8, and 24 hours (Day 9) after ibrutinib, 
will be obtained. In discussions with Pharmacyclics, the specific assay and assay 
methods, performance, and operating characteristics information for ibrutinib PK 
is proprietary information and has not been published. Therefore, this information 
is confidential. However, in general, the pharmacokinetics of ibrutinib will be 
performed at Frontage Laboratories and managed through Pharmacyclics. 
2.4.10 BTK occupancy/ITK occupancy 
BTK occupancy will be measured in this trial to determine the pharmacodynamics 
of ibrutinib in HIV patients with ARL. However, in conjunction with BTK 
occupancy, inducible T-cell kinase (ITK) occupancy will also be performed, which 
is the more interesting aspect to this specific HIV population. 
Ibrutinib may have intriguing and provocative off targets effects, which may 
improve the control of HIV. Ibrutinib may have inhibitory effects on HIV viral 
replication and spread. In addition to inhibition of BTK, ibrutinib is known to 
inhibit ITK. ITK is a Tec family tyrosine kinase that regulates T cell receptor 
(TCR)-induced activation of PLC-1, Ca2+ mobilization and transcription factor 
activation, and actin rearrangement downstream of both TCR and chemokine 
receptors. ITK mediates T cell receptor signaling, which is highly relevant given 
productive HIV infection requires T cell activation.66 Without active ITK protein, 
HIV cannot effectively take advantage of many signaling pathways within T cells, 
which in turn reduces or blocks the spread of the virus. We therefore propose to 
concurrently assess ITK inhibition and HIV viral loads in this study for evidence 
of possible anti-HIV activity resulting from ibrutinib. If identified, this could have 
broader implications regarding therapy of HIV with ibrutinib beyond ARL. We 
hypothesize that ITK will also be inhibited with ibrutinib and further suppress HIV 

 
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viral load replication. Currently, there are no data available for in-vivo or in-vitro 
models in for BTK or ITK occupancy in this specific population. However, there 
are data using these assays in other diseases such as CLL.67,68 
Thus far, BTK and/or ITK occupancy is our only reliable PD measurement tool. 
Phosphorylation of BTK and ITK is theoretically possible, but in practice it is very 
difficult due to the logistics of blood collection and rapid isolation of cells. 
Furthermore, occupancy is the only validated assay currently available for ibrutinib. 
The method for BTK and ITK occupancy Pharmacyclics will use will be by and 
large the same as the ones used in previous studies. They have made improvements 
recently (as of 2016), but the results are comparable and the improvements simply 
improve accuracy and precision. For BTK, the positive control is DOHH2 lysates 
(treated with ibrutinib) and the negative control is Jurkat lysates (treated with 
ibrutinib). For ITK, it is the reversal of BTK. No scoring is used in this study. The 
occupancy is a calculated based upon the pre-treatment dose measurements. Each 
sample is compared to the pre-treatment level for that specific patient reducing the 
impact of assay variability on the overall results. 
Pharmacyclics® had the current form of the assay validated and it is now run, using 
our specific protocol, at Cambridge Biomedical. Samples will be sent to Cambridge 
Biomedical, who runs the assays on Pharmacyclics’ behalf. 
The proposed collection methods proposed in this study have no known impact on 
the stability of BTK or ITK occupancy. Experiments were conducted where 
ibrutinib was placed into freshly isolated human blood and the samples were either 
processed immediately or processed at 24 hours (as in this trial). The resulting 
occupancy readings were ostensibly the same and within validation parameters. 
Both occupancy assays have been validated. In discussions with Pharmacyclics, the 
specific assay and assay methods, performance, and operating characteristics 
information for BTK and ITK occupancy is proprietary information and has not 
been published. Therefore, this information is confidential. However, in general, 
the pharmacokinetics of ibrutinib will be performed and managed this through 
Pharmacyclics. 

 
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3.0 
PARTICIPANT SELECTION 
A rostered AMC physician investigator must document that each protocol participant meets 
all stated eligibility criteria. Participating sites must have documentation that each 
eligibility requirement is satisfied prior to participant enrollment. In compliance with 
CTEP policy, no exceptions to eligibility criteria will be granted under any circumstance. 
NOTE: Institutions may use this section of the protocol as an eligibility checklist for source 
documentation if it has been reviewed, signed, and dated before registration/randomization 
by the study investigator. If used as source documentation, this checklist must be printed, 
the investigator must check each item to document their assessment that the participant 
meets each eligibility criterion, and the completed checklist must be maintained in the 
participant’s chart. 
Participant ID Number: 101 - ___ ___ ___ - ___ ___ ___ ___ ___ 
Patient’s Initials (L, F, M [optional]): ___ ___ ___ 
NOTE: All questions regarding eligibility should be directed to the study chair. 
3.1 
Eligibility Criteria 
___ 
3.1.1 Participants must have histologically (via at least a core or ideally, incisional or 
excisional biopsy) documented CD20 positive or negative diffuse large B-cell 
lymphoma (DLBCL). 
___ 
3.1.2 Tissue available from the diagnostic biopsy in the form of blocks, tissue cores, or 
slides available for submission to central pathology is required for all participants 
enrolled to this study, for analysis of integral biomarkers. Formalin-fixed paraffin-
embedded tissue from diagnostic tissue is acceptable and recommended. See 
Appendix IX for full details. Submission of the institutional diagnostic slides is also 
preferred for all participants enrolled in the study. Tissue and diagnostic slides are 
required to be submitted within 1 month of enrollment. 
___ 
3.1.3 Stage II-IV disease (See Appendix XVI, Ann Arbor Staging Criteria). Participant 
will need measurable disease by CT or PET scans if enrolled in the dose-expansion 
cohort. 
___ 
3.1.4 HIV positive. Documentation of HIV-1 infection by means of any one of the 
following: 
• Documentation of HIV diagnosis in the medical record by a licensed health care 
provider; 
• Documentation of receipt of ART (at least three different medications) by a 
licensed health care provider (documentation may be a record of an ART 
prescription in the participant’s medical record, a written prescription in the 
name of the participant for ART, or pill bottles for ART with a label showing 
the participant’s name); 
• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating >1000 
RNA copies/mL; 

 
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• Any licensed HIV screening antibody and/or HIV antibody/antigen combination 
assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot 
confirmation or HIV rapid multispot antibody differentiation assay. 
NOTE: A “licensed” assay refers to a U.S. FDA-approved assay, which is required 
for all IND studies. 
___ 
3.1.5 For the dose-finding cohort participants lymphoma must be untreated.  
For the dose-expansion cohort participants may have either untreated lymphoma 
or may have received prior therapy. Please see the exclusion criteria Section 3.2.2. 
for full details of chemotherapy participants may have received off study.  
___ 
3.1.6 Ages 18 – 64.  
___ 
3.1.7 ECOG performance status < 2 (Karnofsky > 50%, see Appendix III). 
___ 
3.1.8 For the dose-finding cohort participants must have a CD4 count ≥ 100 cells/mm3  
For the dose-expansion cohort participants may have any CD4 count, including a 
CD4 count <100 cells/mm3. 
___ 
3.1.9 Participants must have organ and marrow function within the following parameters: 
• Absolute neutrophil count: ≥ 1,000/mm3, unless decreased due to bone marrow 
involvement with lymphoma. 
• Platelets: ≥ 75,000/mm3, unless decreased due to bone marrow involvement 
with lymphoma. 
• Hepatic impairment: 
o Total bilirubin: ≤ 1.5 times the institutional ULN; if potentially due to 
lymphoma, in the dose-expansion cohort, the first cycle may be given 
without ibrutinib and if transaminitis and bilirubinemia improves to meet 
parameters, participant may be enrolled. 
• AST (SGOT) / ALT (SGPT): < 2 times the institutional ULN; if potentially due 
to lymphoma, in the dose-expansion cohort, the first cycle may be given without 
ibrutinib and if transaminitis and bilirubinemia improves to meet parameters, 
participant may be enrolled. 
• Creatinine: 
o Creatinine levels below the normal institutional upper limits; or, 
o Creatinine clearance ≥ 50 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal; unless decreased due to renal involvement 
by lymphoma. 
___ 
3.1.10 Participants must not be on medications, including ARV regimens such as 
cobicistat, indinavir, or ritonavir, or agents with moderate or strong CYP3A4 
inhibition; if on a moderate or strong CYP3A4 inhibitor regimen prior to study 
enrollment, participants must be switched to a qualifying regimen with the last dose 
of the strong CYP3A4 inhibitor taken at least one week before administration of 
ibrutinib. See Appendix XV. 

 
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___ 
3.1.11 Willingness of sexually active participants to use adequate contraception. Because 
the effects of ibrutinib on the developing human fetus are unknown, tyrosine 
kinases may be teratogenic, and rituximab crosses the placenta, both men and 
women of child-bearing potential treated or enrolled on this study must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
before study entry, for the duration of study participation, 90 days after completion 
of ibrutinib, and 12 months after the last dose of rituximab, whichever comes last. 
Men who only have sex with other men do not need to use contraception 
specifically for this study (Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately). 
___ 
3.1.12 All participants will be required to be screened for Hepatitis B. All participants who 
present with acute hepatitis B or show normal transaminases and are HBsAg+ and 
IgM+ for Hepatitis core antigen will not be eligible for trial enrollment. Per IDSA 
and AASD guidelines, those participants that show no immunity, defined by the 
lack of Hepatitis B surface antibody, and show evidence of chronic infection (i.e., 
HBsAg+, HBcore+, HBsAB-) will be required to be on anti-Hepatitis B therapy, 
during the study, in order to be eligible. The exact Hepatitis B therapy will be at the 
discretion of the infection disease specialist or investigator. If infected with 
Hepatitis B, participants will be permitted to enroll in the study provided liver 
function tests meet criteria listed above, there is no evidence of cirrhosis AND 
participants will be required to be on anti-Hepatitis B therapy. 
___ 
3.1.13 All participants will be required to be screened for Hepatitis C. If Hepatitis C 
antibody positive, with or without a positive Hepatitis C RNA level, participants 
will be permitted to enroll in the study provided liver function tests meet criteria 
listed, and have no evidence of cirrhosis. Participants diagnosed with Hepatitis C 
less than 6 months from trial enrollment will be considered to have acute Hepatitis 
C, and will be excluded from study UNLESS Hepatitis C viral load is undetectable. 
___ 
3.1.14 Adequate cardiac function defined as an ejection fraction on ECHO or MUGA that 
is at or above the institutional normal limits.  
For the dose-expansion cohort, if the participant had a pre-treatment ECHO prior 
to pre-study therapy which reports adequate cardiac function defined as an ejection 
fraction on ECHO or MUGA that is at or above the institutional normal limits, a 
repeat ECHO will not need to be repeated prior to start of study treatment. 
___ 
3.1.15 Participants must be able to swallow oral pills. 
___ 
3.1.16 Ability to understand and willing to sign a written informed consent document. 

 
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3.2 
Exclusion Criteria 
Participants who do not fulfill the criteria as listed in Section 3.1 above, are ineligible. 
Additionally, the presence of any of the following conditions will exclude a participant 
from study enrollment: 
___ 
3.2.1 Participants who have had chemotherapy other than R-EPOCH, R-CHOP or limited 
therapy as outlined in Section 3.2.2, or radiotherapy other than palliative radiation 
for medical emergencies (like cord compression), within the last 4 weeks. 
___ 
3.2.2 For the dose-finding cohort prior cytotoxic chemotherapy or radiotherapy for this 
lymphoma is exclusionary. 
For the dose-expansion cohort participants may have received: 
• A maximum of one cycle of combination chemotherapy, including 
rituximab-containing regimens R-CHOP and R-EPOCH. The start of 
previous chemotherapy cycle must occur at least 21 days but no more than 
28 days prior to beginning treatment under this protocol, and such cycle will 
count towards the maximum of 6 cycles under this study (i.e., cycle off 
study will count as Cycle 1). 
OR 
• 1 prior cycle of limited therapy including cyclophosphamide and/or 
rituximab and/or glucocorticoids to improve hepatic or renal function 
impaired due to lymphoma involvement. The start of this therapy may occur 
up to 28 days prior to beginning treatment under this protocol; 
cyclophosphamide administration must have been completed at least 14 
days prior to initiation of protocol therapy. Such treatment will not count 
towards the maximum of 6 cycles under this study (i.e., participants will 
receive 6 cycles on study). 
___ 
3.2.3 For the dose-finding cohort rituximab within 12 months prior to study registration 
will be exclusionary; only exception will be if rituximab was given for indications 
other than the treatment of aggressive lymphoma. 
For the dose-expansion cohort one cycle of rituximab as part of R-CHOP or R-
EPOCH or limited therapy as outlined in Section 3.2.2 may be administered off 
study prior to enrollment; prior rituximab will also be allowed if rituximab was 
given for indications other than the treatment of aggressive lymphoma. 
___ 
3.2.4 Participants who are receiving any other investigational agents. 
___ 
3.2.5 Participants who have previously received ibrutinib for another indication. 
___ 
3.2.6 Expected survival < 2 months. 
___ 
3.2.7 Participants with a history of an opportunistic fungal infection or active fungal 
infection requiring, or at high risk of requiring, prophylactic or treatment with 
fluconazole, voriconazole or posaconazole. 

 
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___ 
3.2.8 Participants with known brain metastases from solid tumors should be excluded 
from this clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. 
___ 
3.2.9 Presence of second active tumor, other than non-melanoma skin cancer, carcinoma 
in situ of the cervix, or Kaposi’s sarcoma (KS) that requires systemic therapy. 
___ 
3.2.10 For the dose-finding cohort participants with known or suspected parenchymal 
brain, spinal cord, leptomeningeal disease prior to study enrollment will be 
excluded.  
For the dose-expansion cohort participants with known or suspected parenchymal 
brain or spinal cord disease, or symptomatic leptomeningeal disease will be 
excluded. Asymptomatic leptomeningeal disease will be allowed. 
___ 
3.2.11 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to ibrutinib or other agents used in study. 
___ 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that, in the opinion of the 
investigator, would limit compliance with study requirements. 
___ 
3.2.13 Pregnancy or breastfeeding. A pregnancy test must be performed within 7 days 
prior to ibrutinib initiation in women of childbearing potential. Pregnant women 
are excluded because ibrutinib is a tyrosine kinase inhibitor with the potential for 
teratogenic or abortifacient effects. Breastfeeding must be discontinued because of 
unknown but potential risks in the nursing infant. 
___ 
3.2.14 Unable to comply with the requirements of the protocol, or unable to provide 
adequate informed consent in the opinion of the Principal Investigator. 
___ 
3.2.15 Serious, ongoing, non-malignant disease or infection, which in the opinion of the 
investigator and/or the sponsor would compromise other protocol objectives. 
Participants with active opportunistic infections are ineligible. 
___ 
3.2.16 Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study 
entry. Splenectomy will not be considered an exclusionary major surgery. 
___ 
3.2.17 History of cutaneous or mucocutaneous reactions, or diseases in the past, due to 
any cause, severe enough to cause hospitalization or an inability to eat or drink for 
> 2 days. This exclusion relates to the long-term possibility of severe cutaneous or 
mucocutaneous reactions to rituximab that might occur at increased frequency in 
participants who have had severe skin disease or reactions in the past. 
___ 
3.2.18 Myocardial infarction (MI) within 6 months prior to study entry, New York Heart 
Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or 
electrocardiographic evidence of acute ischemic or active conduction system 
abnormalities. 
 
 

 
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3.3 
Number of Participants to be Enrolled 
3.3.1 Proposed sample size 
This study will enroll a minimum of 9 participants and a maximum of 54 
participants. 
The goal of the study is to accrue 40 participants with adequate tissue for COO 
analysis with minimum of 15 participants with non-GCB subtype DLBCL as 
confirmed by central pathology by IHC. To compensate for the possible 30% 
misclassification rate of COO, this study will accrue a minimum of 22 participants 
of non-GC DLBCL subtype by IHC, as performed by the local pathologist, to reach 
the accrual target of 15 participants with central pathology confirmed non-GC 
subtype. Assuming 30-35% insufficient tissue for GEP COO (tumor content of 
<60%), 14 participants will be allowed on study as replacement participants should 
the participant not have adequate tissue for COO analysis, for a maximum of 54 
participants on study.  
3.3.2 Accrual rate 
Approximately 1 participant per month during the dose-finding portion, and 3 
participants per month during the dose-expansion cohort. 
 
Physician Signature: ______________________________ Date: ___________________ 
(Optional unless this section is used as an eligibility checklist) 
 
 

 
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3.4 
Participant Enrollment Procedures 
Sites must have this protocol approved by their Institutional Review Boards (IRB) and be 
registered for study participation with the AMC Operations and Data Management Center 
(ODMC) before they may enroll participants. 
All enrollment and data collection will occur via AMC Advantage eClinicalSM Internet 
Data Entry System (Advantage eClinical). After the participant signs the informed consent 
form and a CTEP-registered AMC investigator has verified all eligibility criteria, the site 
will register the participant via Advantage eClinical by completing the protocol-specific 
eligibility checklist. Enrollment will occur no more than 1 week before treatment initiation 
(enrollment 1 day before or on the day of treatment is strongly encouraged). Once the 
eligibility checklist is successfully submitted, a system-generated confirmation email will 
be issued to the enrolling site. If the on-line system is inaccessible, the site must notify the 
AMC ODMC (via email at amcpm@emmes.com or via phone at 301-251-1161) for 
enrollment instructions. 
3.4.1 Enrollment 
After the screening evaluations have been obtained and the participant is 
determined to be eligible, the participating site will complete the protocol-specific 
eligibility checklist and enroll the participant into AMC-101 (on-line via Advantage 
eClinical). Enrollment should occur no more than 1 week prior to administration of 
the first dose of the protocol agent(s) (enrollment 1 day prior to or on the day of 
treatment is strongly encouraged). Once the eligibility checklist is submitted, a 
system generated confirmation email will be sent to the enroller upon successful 
completion of the participant enrollment. If the on-line system is inaccessible, the 
site should notify the AMC ODMC (via email at amcpm@emmes.com or via phone 
at 301-251-1161) for further instructions. 
Participants must be enrolled into AMC-101 prior to receiving the first dose 
of the protocol agent(s). 

 
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4.0 TREATMENT PLAN 
4.1 
Agent Administration 
Protocol agents will be administered on an inpatient or outpatient basis. Reported adverse 
events and potential risks for ibrutinib and R-da-EPOCH are described in Section 6.0. 
Appropriate dose modifications for ibrutinib and R-da-EPOCH are described in Section 
5.0. No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the participant's malignancy. 
Each cycle (21 days) of treatment will include R-da-EPOCH and ibrutinib (oral, daily) (see 
Sections 4.1.1 and 4.1.2). Adherence to the target treatment date is highly encouraged; 
however, delays of up to 3 days for subsequent cycles are permitted to accommodate site 
and participant schedules. If the next cycle is delayed no ibrutinib should be administered 
during the dose delay for R-da-EPOCH. For CD20 negative lymphomas, each cycle of 
treatment will include da-EPOCH. 
NOTES: The participant will be requested to maintain a medication diary of each 
dose of medication. The medication diary will be returned to clinic staff at the end of 
each course. 
The site will be required to document study agent return by the participant in the 
source documents. Non-compliance with study agent administration should be noted 
at the time of diary collection and the participant should be instructed again 
regarding dosing instructions. 
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 participant 
should not take extra capsules on the next day to make up the missed dose. 
4.1.1 Ibrutinib 
Dosing cohorts of ibrutinib are shown Section 5.1. Given the RP2D of ibrutinib in 
combination with R-CHOP in HIV-negative participants is 560 mg, the starting 
dose level of ibrutinib in this trial will be 560 mg daily. 
In the dose-finding portion of the study, ibrutinib will begin at dose level 1 
(560 mg PO), and de-escalate to dose -1 and -2 if excessive toxicity is seen at dose 
levels 1 and -1, respectively. 
Ibrutinib will be given on days 1-21 of each cycle. Each dose level of ibrutinib will 
be assessed to determine safety, tolerability, and RP2D in participants. 
Table 4-A: Ibrutinib Dose Levels and Schedule 
Dose Levels 
Ibrutinib Dosing (daily) 
1 
560 mg 
-1 
420 mg 
-2 
280 mg 
 

 
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4.1.2 R-da-EPOCH-ibrutinib regimen (EPOCH-ibrutinib for CD20 negative disease) 
• Rituximab 375 mg/m2 IV, Day 1 (for CD20 positive lymphoma; biosimilar 
agents are permitted); 
• Etoposide 50 mg/m2/24 hours x 4 days (96 ±6 hours infusion), Days 1-4; 
• Doxorubicin 10 mg/m2/24 hours x 4 days (96 ±6 hours infusion), Days 1-4; 
• Vincristine 0.4 mg/m2/24 hours x 4 days (96 ±6 hours infusion), Days 1-4; 
• Prednisone 60 mg/m2 PO daily Days 1-5 (may be rounded to the nearest 10 mg); 
• Cyclophosphamide dose at 750 mg/m2 for baseline CD4 count ≥ 200 and 
375 mg/m2 for baseline CD4 count < 200, IV over 1 hour, Day 5; subsequent 
cycles adjusted as per Section 5.1 for dose modification instructions. 
• Ibrutinib at cohort dose orally days 1-21. 
• Pegfilgrastim 6 mg subcutaneously from one calendar day up until 48 hours 
after completion of chemotherapy; if pegfilgrastim is not available, then 
filgrastim (or biosimilar) 300 or 480 mg starting day 6 for a minimum 10 days 
and until ANC >5000 cells/mm3. 
4.1.3 Criteria for initiation of subsequent cycles 
For cycles 2 – 6, repeat R-da-EPOCH with ibrutinib regimen every 21 days 
(maximum of 6 cycles) if the following criteria are met: 
• ANC ≥ 1000/mm3 and platelets ≥ 75,000/mm3.  
• Adequately recovered from treatment associated toxicity. 
• See Appendix XVII for details of ibrutinib and EPOCH dose adjustments. 
4.2 
Definition of Dose-Limiting Toxicity 
The dose de-escalation and schema, and definitions of dose limiting toxicities (DLTs) are 
as follows: 
Table 4-B: Ibrutinib dose escalation and schema 
Number of Participants 
at Dose Level 
Number of Participants 
with Cycle 1 DLT 
Action 
3 
0 
RP2D, move on to dose-
escalation cohort 
3 
1 
Treat another 3 participants 
at the same dose 
6 
1 
RP2D, move on to dose-
escalation cohort 
3-6 
≥ 2 
RP2D exceeded, dose de-
escalate to one level down 
 

 
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Table 4-C: Dose limiting toxicities 
Dose-limiting 
toxicity 
Definition applies to cycle 1 of the dose-finding portion of the 
trial 
Hematologic  
ANC nadir < 500 cells/mm3 on ≥ 3 nonconsecutive days at least 
3 days apart (i.e., ANC <500 cells/mm3 on days 9, 12, and 15). 
Febrile neutropenia (ANC < 500/mm3) requiring critical care 
support (i.e., intubation OR pressor support). 
Platelet count < 25/mm3 resulting in a life-threatening bleed OR 
treatment delay for following cycle of > 7 days. 
Non-hematologic 
Any Grade ≥ 3 toxicity that causes a dose delay of > 1 week for the 
next planned treatment cycle despite adequate treatment/ 
supportive care. 
 
4.3 
General Concomitant Medication and Supportive Care Guidelines 
Participants MUST receive medically appropriate care and treatment for HIV infection, 
including antiretroviral medications. 
4.3.1 Concomitant medication 
4.3.1.1 
HAART therapy: Participants must not be on medications, including 
ARV regimens, with moderate or strong CYP3A4 inhibition; if on a 
moderate or strong CYP3A4 inhibitor regimen prior to study enrollment, 
participants must be switched to a qualifying regimen with the last dose 
of the moderate or strong CYP3A4 inhibitor taken at least one week 
before administration of protocol therapy due to effects on ibrutinib. 
Antiretroviral naïve participants: It is recommended that participants 
who are not on HAART at study entry begin therapy at the discretion of 
the treating provider(s). Diagnosis of HIV should not delay the initiation 
of HAART. However, given potential drug interactions, it may be 
preferred that participants complete the infusional chemotherapy before 
initiation of HAART. Participants must not be started on regimens with 
moderate or strong CYP3A4 inhibition. For further standard of care  
HIV management guidelines, please refer to the U.S. Department  
of 
Health 
and 
Human 
Services 
guidelines 
at 
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-
treatment-guidelines/0/. Supportive care and prophylaxis must be 
followed and regimen will be determined based on CD4 count. 
Only changes in antiretroviral therapy, receipt of any disallowed 
medications (e.g., medicines that inhibit CYP3A4), or any concurrent 
medications that are attributed to SAEs will be reported in the 
Concomitant Medications form in Advantage eClinical from study 
enrollment through the last day of the final cycle of treatment. 

 
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4.3.1.2 All participants who tested positive for Hepatitis B and C must initiate 
treatment and remain on treatment for the duration of the study. The exact 
therapy will be administered per the standard of care. 
4.3.2 Supportive care guidelines 
4.3.2.1 
Prevention of tumor lysis syndrome (cycle 1 only) 
It is recommended that participants with evidence of high numbers of 
circulating tumor cells (≥ 50,000/mL) or high tumor burden (bone marrow 
involvement, high lactate dehydrogenase [LDH]) receive allopurinol. 
Additional measures such as aggressive IV hydration and urinary 
alkalization will be used at the discretion of the Investigator. 
4.3.2.2 
Precautions for surgeries or procedures 
The following guidance69,70 should be applied during the peri-
operative/peri-procedure period for participants who require surgical 
interventions or procedures while on treatment and receiving ibrutinib: 
• For surgery or invasive procedures 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 procedures, and restarted at 
the discretion of the investigator when the surgical site is reasonably 
healed without serosanguineous drainage or the need for drainage tubes. 
• For procedures such as 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 
participant is on ibrutinib, it is not necessary to hold ibrutinib. For 
intrathecal CNS prophylaxis, a short hold (up to 3 days, suggested 2 
days prior and 1 day post) should be considered based on the clinical 
situation of the participant, including assessment of underlying 
lymphoma and bleeding risk. 
• For emergency procedures, ibrutinib should be healed after the 
procedure until the surgical site is reasonably held, for at least 7 days 
after the urgent surgical procedure. 
4.3.2.3 
Central nervous system (CNS) work up 
If lymphomatous CNS involvement (including parenchymal brain, spinal 
cord or leptomeningeal) is clinically suspected, or the participant is 
symptomatic from CNS involvement during screening, participants must 
complete a full diagnostic work-up for CNS involvement with imaging and 
lumbar puncture (LP), and results of these studies must be known PRIOR 
to registration. 
In the dose-finding portion of the study, no participants with known or 
suspected parenchymal brain, spinal cord, or leptomeningeal disease will be 
allowed on study.  

 
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In the dose-expansion portion of the study, no participants with known or 
suspected parenchymal brain or spinal cord disease, or symptomatic 
leptomeningeal disease will be allowed on study. However, asymptomatic 
leptomeningeal disease will be allowed in the dose-expansion cohort. For 
asymptomatic participants, if the participant’s screening CSF returns 
positive by flow cytometry or cytology AFTER registration, they may still 
remain on study but must receive treatment dose intrathecal chemotherapy 
per institutional standards (see 4.3.2.4). 
4.3.2.4 
CNS treatment for positive CSF 
See Section 4.3.2.2 for recommendations regarding hold of ibrutinib while 
on treatment. In cases in which there may be a higher risk of bleeding (i.e., 
history of difficult LP access), it may be useful to perform the LP under 
fluoroscopy. 
Placement of an Ommaya reservoir is strongly recommended for cases of 
leptomeningeal CNS lymphomatous involvement in order to maximize 
CNS distribution of intrathecally administered chemotherapy. Additionally, 
Ommaya reservoir access does not require ibrutinib to be held due to the 
lower risk of bleeding complications. Therefore, placement of an Ommaya 
reservoir in patients requiring treatment of leptomeningeal CNS lymphoma 
would minimize interruption of ibrutinib dosing. 
Although the specific regimen may vary at each center, a suggested regimen 
is listed below: 
• Cytarabine 50 mg 
• Methotrexate 12 mg 
• Hydrocortisone 50 mg 
Intrathecally administer twice a week until CSF is negative, then weekly x 
1 month and then monthly x 6 months 
4.3.2.5 
CNS prophylaxis for negative CSF 
See Section 4.3.2.2 for recommendations regarding hold of ibrutinib while 
on treatment. In cases in which there may be a higher risk of bleeding (i.e., 
history of difficult LP access), it may be useful to perform the LP under 
fluoroscopy. 
CNS prophylaxis will be required in participants who meet the following 
criteria: lymphomatous involvement of bone marrow, testes, sinuses, or 
epidural regions. One of the following regimens will be required: IT 
liposomal cytarabine (Depocyt®), IT cytarabine, or IT methotrexate. The 
specific dosing regimen will be at the discretion of the primary oncologist 
but should include 4-6 doses of therapy. 
4.3.2.6 
Growth Factor (GF) therapy with G-CSF, GM-CSF, or pegfilgrastim\ 
filgrastim (or biosimilar), beginning about 24-48 hours (1-2 days) after 
the administration of cyclophosphamide will be used in all participants 
until post nadir recovery of blood counts from each chemotherapy cycle. 

 
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4.3.2.7 
Use of erythropoietic factors, as per drug package insert, is allowed at 
the discretion of the Investigator. 
4.3.2.8 
Prophylaxis against Pneumocystis jirovecii (P. jirovecii) is required, with 
the specific regimen at the discretion of the Investigator. Recommended 
options include trimethoprim/sulfamethoxazole (80-400 mg daily or 
160-800 mg Mondays, Wednesdays, Fridays), dapsone 100 mg daily, or 
atovoquone 1500 mg with food once daily). 
4.3.2.9 
Prophylaxis against other common opportunistic infection (OI) is 
dependent upon the participant’s medical history and CD4 cell count at 
study entry, and at the discretion of the Investigator. Fluconazole, 
voriconazole, and posaconazole are at least moderate CYP3A4 
inhibitors, so may not be used for prophylaxis or treatment in 
combination with ibrutinib on this study. If fluconazole, voriconazole, or 
posaconazole is required, ibrutinib must be discontinued. Topical and/or 
antifungal agents are permitted. Prophylaxis against Mycobacterium 
avium (M. avium) is recommended if CD4 cells are < 100/mm3. 
Antiherpetic prophylaxis is recommended in participants. Investigators 
may consider famciclovir when available as it is the least 
myelosuppressive option. 
4.3.2.10 Investigators should be vigilant about detecting cases of suspected 
pulmonary and/or CNS fungal infections, specifically, aspergillosis 
which has been seen with other clinical trials with ibrutinib alone or in 
combination with chemotherapy. 
4.3.2.11 Quinolone antibacterial prophylaxis: Participants with a CD4 count of 
< 100/mm3 at baseline or whose CD4 count decreases below 100/mm3 
during therapy are required to receive quinolone prophylaxis. Begin 
quinolone prophylaxis during each cycle no later than Day 8 of 
chemotherapy and continue until documented recovery from neutropenia 
(ANC ≥ 1000/mm3). If participants are allergic or intolerant of 
quinolones an alternative antibiotic will be used. 
4.3.2.12 Transfusions: Participants will be allowed platelet and packed red blood 
cell transfusions while on treatment. Specifically, given hemostasis-related 
adverse effects of ibrutinib correlate with platelet dysfunction, platelet 
transfusions should be considered for serious bleeding regardless of the 
platelet count. 

 
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4.3.3 Reporting requirements for concomitant medications 
All medications must be reported in the site’s source documents at baseline. All 
medications will be reviewed and updated in the site’s source documents at all visits 
where indicated in the schedule of evaluations (Appendix I). Only a subset of 
medications will be reported in the Concomitant Medications CRFs after study 
entry, as listed below: 
• Anti-seizure medications 
• Prophylactic medications 
o Antiviral 
o Antifungal 
o Quinolone/Antibiotic therapy (See Section 4.3.2.10) 
o Any other medications used for prophylaxis of opportunistic infections 
• Hepatitis medications 
• Growth colony stimulation factors (GCSF) 
• Erythropoiesis Stimulating Agents (ESA) 
• Anti-retroviral medications.  
o Note: Antiretroviral therapy will be collected in the On Study Form. If the 
participant remains on the same anti-retroviral medications throughout 
study participation that have already been reported in the On Study Form, 
then do not report them in the Concomitant Medications Form. If the 
participant changes or discontinues anti-retroviral therapy for any reason, 
then update the Concomitant Medication Form with the start and stop date 
of the discontinued medication(s) and start date of the new (if applicable) 
medication(s). 
• Receipt of disallowed medications (CYP3A4 modulating) after study 
enrollment, as per Appendix XV. 
4.4 
Duration of Therapy and Criteria for Removal from Treatment 
In the absence of treatment delays due to adverse event(s), treatment may continue for 6 
cycles or until one of the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Other unacceptable adverse event(s) 
• Participant decides to withdraw from treatment or all other further study participation 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the investigator 
• Pregnancy. 

 
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Participants will be removed from study treatment when any of the above criteria applies. 
The reason for study treatment removal and the date the participant was removed must be 
documented in the Off Protocol Treatment Form in Advantage eClinical. 
4.5 
Duration of Follow Up 
Participants will be treated for a maximum of 6 cycles (21-day cycle length); treatment for 
ARL off study, as defined in Section 3.1.4, will count as Cycle 1. Participants with CR 
after Cycle 4 will receive two additional cycles of chemotherapy. Participants who achieve 
a PR after Cycle 4 may continue on protocol therapy or be removed from the study at the 
discretion of the local registered AMC investigator. 
Participants who discontinue ibrutinib (due to toxicity, participant refusal, or any other 
reasons) but continue R-da-EPOCH are considered on study until protocol chemotherapy 
is completed, and should have efficacy, toxicity, and follow-up data reported. Participants 
who discontinue all protocol therapy after having a CR or PR are followed for up to 5 years 
after treatment for recurrence and survival. Participants who discontinue protocol therapy 
due to disease progression, cross over to non-protocol therapy (if PR or stable disease at 
physician discretion), or other reasons are followed for survival only for up to 5 years after 
treatment. 
Participants will be followed for 5 years after completion of treatment, with follow-up 
visits every 3 months for years 1-2 post-treatment, and then every 6 months for 3-5 years 
post-treatment. See Section 8.6 for full details of requirements for follow up. 

 
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5.0 DOSING DELAYS/DOSE MODIFICATIONS 
5.1 
Dose Modifications for Ibrutinib and R-EPOCH 
5.1.1 Dose de-escalation, dose-finding portion 
Table 5-A: Ibrutinib dose levels and schedule 
Dose Levels 
Ibrutinib Dosing (daily) 
1 
560 mg PO, on day 1 – 21 of each cycle 
-1 
420 mg PO, on day 1 – 21 of each cycle 
-2 
280 mg PO, on day 1 – 21 of each cycle 
 
Dose adjustment for R-da-EPOCH will be based on laboratory measurements of 
the previous cycle ANC or platelet nadir, whichever is lower. Dose adjustment is 
based on measurements of twice weekly CBC only, even if additional CBCs are 
obtained. Twice weekly CBCs must be at least 3 days apart. If the participant does 
not obtain twice weekly CBC counts (i.e., only obtains one or less CBC within a 
week), it will be assumed the counts that would have been obtained are the same as 
the nadir counts, but clinical evidence of severe neutropenia/thrombocytopenia in 
absence of lab availability may be discussed by investigator with protocol chairs to 
determine subsequent cycle dosing. CBCs may be stopped after absolute neutrophil 
count or platelet recovery after the final cycle of the study therapy. 
After the initial cycle of therapy, dose adjustments for CD4 count should adhere to 
the instructions in Table 5B and Table 5C. 
Table 5-B: EPOCH dose adjustment levels for baseline CD4 count ≥ 200 
Drugs 
-4 
-3 
-2 
-1 
1 
Doxorubicin (mg/m2/day) 
Continuous on days 1-4) 
10 
10 
10 
10 
10 
Etoposide (mg/m2/day) 
Continuous on days 1-4) 
50 
50 
50 
50 
50 
Cyclophosphamide (mg/m2/day) 
Bolus on day 5) 
0 
187.5 
375 
562.5 
750 
(maximum dose) 
Vincristine (mg/m2/day) 
Continuous days 1-4 
0.4 
0.4 
0.4 
0.4 
0.4 
Prednisone (mg/m2) 
Daily, days 1-5 
60 
60 
60 
60 
60 
 
 
 

 
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Table 5-C: EPOCH dose adjustment levels for baseline CD4 count < 200 
Drugs 
-2 
-1 
1 
2 
3 
Doxorubicin (mg/m2/day) 
Continuous on days 1-4 
10 
10 
10 
10 
10 
Etoposide (mg/m2/day) 
Continuous on days 1-4 
50 
50 
50 
50 
50 
Cyclophosphamide (mg/m2/day) 
Bolus on day 5 
0 
187.5 
375 
562.5 
750 
(maximum dose) 
Vincristine (mg/m2/day) 
Continuous days 1-4 
0.4 
0.4 
0.4 
0.4 
0.4 
Prednisone (mg/m2) 
Daily, days 1-5 
60 
60 
60 
60 
60 
5.1.2 Dose adjustment for dose-expansion cohort participants 
For the dose-expansion portion of the study, there will be intra-participant dose 
escalation and de-escalation of ibrutinib, in addition to dose-adjustment of R-da-
EPOCH. Dose adjustment for R-da-EPOCH and/or ibrutinib will be based on 
laboratory measurements of the previous cycle ANC or platelet nadir, whichever is 
lower. Dose adjustment is based on measurements of twice weekly CBC only, even 
if additional CBCs are obtained. Twice weekly CBCs must be at least 3 days apart. 
If the participant does not obtain twice weekly CBC counts (i.e., only obtains one 
or less CBC within a week), it will be assumed the counts that would have been 
obtained are the same as the prior, but clinical evidence of severe 
neutropenia/thrombocytopenia in absence of lab availability may be discussed by 
investigator with protocol chairs to determine subsequent cycle dosing. CBCs may 
be stopped after absolute neutrophil count or platelet recovery after the final cycle 
of study therapy. The dose adjustment for each cycle of ibrutinib and R-da-EPOCH 
will be based on the following criteria noted below. This schema was chosen to 
preferentially decrease cyclophosphamide initially, given that the most common 
grade 3 or 4 events in R-da-EPOCH in previous AMC trials were neutropenia: up 
to 42%.10 Grade 3-4 neutropenia can also be seen with single agent ibrutinib,27,28 
but to a lesser degree. 
5.1.3 Hematologic toxicity 
Ibrutinib must be discontinued in participants who experience a DLT as defined in 
Section 4.2 during cycle 1 on dose-finding portion of the study. Dose adjustments 
for ibrutinib occur WITHIN the cycle, and dose adjustments for EPOCH occur 
PRIOR TO each cycle based on nadir counts of ANC <500 cells/mm3 and platelet 
counts <25,000 cells/mm3. Ibrutinib and/or chemotherapy drug adjustment based 
on nadir counts are as follows: 
 
 

 
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Dose Adjustment for EPOCH and Ibrutinib 
Dose adjustment chart schema: See Appendix XVII for full details. 
 
 
 
5.1.4 Non-hematologic toxicities 
5.1.4.1 
Nausea, vomiting, diarrhea 
Ibrutinib has been associated with nausea, vomiting, and diarrhea. 
Ibrutinib should be held if ≥ Grade 3 drug-related nausea, vomiting, diarrhea 
or dehydration as listed below occurs. Drug should be held until toxicity is 
Grade ≤ 1; at that time, ibrutinib may be re-started with a dose-reduction by 
140mg to a minimum of 280mg. If ≥ Grade 3 toxicity recurs at the minimum 
dose of 280mg, ibrutinib must be discontinued permanently. 
Nausea and Vomiting: Nausea and vomiting should be managed according 
to standard practice as outlined in the published American Society of 
Clinical Oncology (ASCO) guidance “Preventing and Treating Nausea and 
Vomiting Caused by Cancer Treatment.” Briefly, antiemetic agents 
including, but not limited to, 5HT-3 antagonists, aprepitant, lorazepam, 
diphenhydramine, or phenothiazines may be considered. The use of empiric 
anti-emetic coverage is strongly encouraged, as is early and aggressive 
management of nausea, decreased oral intake and/or vomiting in 
participants treated with ibrutinib.  
Diarrhea: Treat diarrhea promptly with supportive care. Encourage fluid 
intake. Loperamide anti-diarrhea therapy is permitted and should be 
recorded when used; recommendations include 4 mg at first onset of 
Twice weekly CBCs 
at least 3 days apart
ANC nadir <500/mm3 on ≥ 3 nonconsecutive days 
at least 3 days apart 
(i.e. ANC <500/mm3 on 3 CBCs over ≥7 day period) 
OR febrile neutropenia
See Table A in Appendix XVII
ANC nadir <500/mm3 on 2 nonconsecutive days 
at least 3 days apart 
(i.e. ANC <500/mm3 on 2 CBCs over <7 day period) 
AND/OR platelets <25,000/mm3
See Table B (for ANC) and
Table C (platelets) in Appendix XVII
ANC nadir <500/mm3 lasting ≤3 days 
(i.e. ANC <500/mm3 on 1 CBC) 
and platelets ≥25,000/mm3
See Table D in Appendix XVII
ANC nadir ≥500/mm3 and platelets ≥25,000/mm3
See Table E in Appendix XVII

 
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diarrhea, then 2 mg after each unformed stool. Daily dose should not exceed 
16 mg/day. Encourage participants to seek a nutritional consult. Treat 
diarrhea promptly with appropriate supportive care. 
5.1.4.2 
Neurologic toxicities 
Table 5-D: Neurological toxicities 
Toxicity 
Dose 
Moderate paresthesias (inability to button) 
Vincristine: No change 
Inability to walk on heels or obstipation 
Vincristine: 25% dose 
reduction 
Ambulation difficulties attributed to new 
neuropathy 
Omit vincristine 
5.1.4.3 
Renal toxicities 
Table 5-E: Renal toxicities 
Toxicity 
Dose 
Creatinine Clearance <50cc/min 
Etoposide: reduce 25% based on full dose 
cycle 1 or previous dose for cycles 2-6 
5.1.4.4 
Hepatic toxicities 
Table 5-F: Hepatic toxicities 
Toxicity 
Dose 
Direct bilirubin 1.2-3.0 
Doxorubicin: reduce 50% based on full dose 
cycle 1 or previous dose for cycles 2-6 
Direct bilirubin 3.1-5.0 
Doxorubicin: reduce 75% based on full dose 
cycle 1 or previous dose for cycles 2-6 
Vincristine: reduce 50% based on full dose 
initially or previous dose for cycles 2-6 
Direct bilirubin >5.0 
Omit doxorubicin and vincristine 
5.1.4.5 
Skin/mucositis 
Participants who have evidence of clinically significant skin rash or 
oral/pharyngeal mucositis attributed to ibrutinib should have ibrutinib held 
until improvement to Grade ≤1. If rash/mucositis is attributed to ibrutinib, 
ibrutinib may be re-started with a dose-reduction by 140 mg to a minimum 
of 280 mg. If ≥ Grade 3 toxicity recurs at the minimum dose of 280 mg, 
ibrutinib must be discontinued permanently. 
 
 

 
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5.1.4.6 
Aspergillosis 
Several cases of invasive aspergillosis have been reported in patients who 
received ibrutinib alone or in combination with other therapies; it is possible 
that ibrutinib contributed to these adverse events. Therefore, investigators 
should be vigilant about detecting cases of suspected pulmonary and/or 
CNS fungal infections including aspergillosis. All suspected and confirmed 
cases of fungal infections should be reported to CTEP in 24 hours 
(expedited adverse event reporting). If a case of aspergillosis is suspected 
or observed, ibrutinib should be held until the infection has clinically 
improved and/or controlled on treatment. Ibrutinib may be restarted based 
on the investigator’s discretion. Please note treatment with voriconazole and 
posaconazole may not be used in combination with ibrutinib given they are 
strong CYP3A4 inhibitors.  
5.1.4.7 
Viral infections 
The following additional serious viral infections, either new, reactivated, or 
exacerbated, have been identified in clinical studies or post marketing 
reports. The majority of participants received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. These viral 
infections included JC virus, progressive multifocal leukoencephalopathy 
(PML), cytomegalovirus, herpes simplex virus, parvovirus B19, varicella 
zoster virus, West Nile virus, and hepatitis C. In some cases, the viral 
infections occurred up to one year following discontinuation of rituximab 
and have resulted in death. 
5.1.4.8 
Cardiac toxicity 
Doxorubicin: If clinical findings suggesting congestive heart failure are 
present, doxorubicin will be discontinued and evaluation by MUGA should 
be performed.  
Rituximab: The incidence of serious cardiovascular events in the double-
blind part of the clinical trials was 1.7% and 1.3% in rituximab and placebo 
treatment groups, respectively. Three cardiovascular deaths occurred during 
the double-blind period of the rheumatoid arthritis (RA) studies, including 
all rituximab regimens (3/759=0.4%) as compared to none in the placebo 
treatment group (0/389). Since participants with RA are at increased risk for 
cardiovascular events compared with the general population, participants 
with RA should be monitored throughout the infusion and rituximab should 
be discontinued in the event of a serious or life-threatening cardiac event. 
Ibrutinib: An increased risk of atrial fibrillation (AF) compared to the 
general population has been documented. The mechanism(s) by which 
ibrutinib may promote AF are unknown. Participants treated with ibrutinib 
should be closely monitored for the development of AF, which can be 
associated with a 5-fold increased risk of ischemic stroke, a leading cause 
of morbidity and mortality, unrelated to the underlying lymphoma. 
Anticoagulation should be used in cases of AF as clinically indicated. 

 
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5.1.4.9 
 Bowel obstruction and perforation 
Abdominal pain, bowel obstruction and perforation, in some cases leading 
to death, were observed in participants receiving rituximab in combination 
with chemotherapy for DLBCL. In post-marketing reports, which include 
both participants with low-grade or follicular NHL and DLBCL, the mean 
time to onset of symptoms was 6 days (range 1-77) in participants with 
documented gastrointestinal perforation. Complaints of abdominal pain, 
especially early in the course of treatment, should prompt a thorough 
diagnostic evaluation and appropriate treatment. 
5.1.4.10 Dehydration 
Altered taste and decreased food and liquid intake are associated with 
ibrutinib administration. These toxicities can be actively managed with fluid 
management and nutritional consultation, as appropriate. To prevent 
dehydration, participants should consume at least 2 liters of fluid orally, on 
a daily basis, in particular during the days that they are being treated with 
ibrutinib. If participants are experiencing dysgeusia, popsicles or oral 
electrolyte fluid replacement may be recommended. 
5.1.4.11 Hyperuricemia 
Hyperuricemia has been observed with ibrutinib. Serum uric acid should be 
monitored, especially in participants with high tumor burden. Supportive 
care should be provided to all participants. Allopurinol and/or rasburicase 
should be administered based on the degree of hyperuricemia. 

 
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6.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 6.1) and the characteristics of an observed AE (Section 6.2) 
will determine whether the event requires expedited (via CTEP-AERS) in addition to 
routine reporting (via Advantage eClinical). 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting beginning April 
1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Version 5.0 of 
CTCAE. 
Monitoring will be performed by Emmes. 
6.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for Ibrutinib 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset of 
AEs, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. The SPEER is a list of 
events that are protocol-specific exceptions to expedited reporting to NCI via CTEP-AERS 
(except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_events_adeers 
for 
further clarification. 
NOTE: The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER. Report ONLY AEs higher than this grade expeditiously via CTEP-AERS. If this 
CAEPR is part of a combination protocol using multiple investigational agents and has an 
AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
6.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for ibrutinib 
(NSC 748645) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer  
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidel
ines.pdf for further clarification. Frequency is provided based on 2082 patients. 
Below is the CAEPR for ibrutinib. 

 
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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
Table 6-A: Ibrutinib CAEPR and SPEER 
 
Version 2.8, November 4, 20241 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2086] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Blood and lymphatic 
system disorders - Other 
(leukostasis) 
  
 
 
Leukocytosis 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Ventricular arrhythmia   
 
 
Ventricular fibrillation   
 
 
Ventricular tachycardia   
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Mucositis oral 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Edema limbs 
 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
 
 
Sudden death NOS 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders 
- Other (drug-induced 
liver Injury) 
  
 
 
Hepatobiliary disorders 
- Other (hepatotoxicity) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  

 
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Version 2.8, November 4, 20241 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2086] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Hepatitis B reactivation   
 
Infection3 
 
 Infection3 (Gr 3) 
 
 
Infections and 
infestations 
- 
Other, 
specify (hepatitis E) 
  
 
 
Infections 
and 
infestations 
- 
Other 
(bronchopulmonary and 
central nervous system 
infections)4 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
INVESTIGATIONS 
  
 
Lymphocyte 
count 
increased2 
 
  
Neutrophil 
count 
decreased 
 
 
 Neutrophil 
count 
decreased (Gr 4) 
 
Platelet count decreased 
 Platelet count decreased 
(Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
 
Hyperuricemia 
  
 
 
Tumor lysis syndrome   
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Muscle cramp 
 
  
 
Myalgia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) 
  
 
Neoplasms 
benign, 
malignant 
and 
unspecified (incl cysts 
and polyps) - Other 
(benign neoplasm of 
skin)5 
 
  
 
 
Treatment 
related 
secondary malignancy5   
NERVOUS SYSTEM DISORDERS 
  

 
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Version 2.8, November 4, 20241 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2086] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
  
 
Dizziness 
 
  
 
Headache 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
 
Pneumonitis6 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Purpura 
 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(angioedema)7 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)8 
 
 Skin and subcutaneous 
tissue disorders - Other 
(rash)8 (Gr 3) 
 
 
Stevens-Johnson 
syndrome 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
  
 
 
Hypotension 
  
 
Vascular 
disorders 
- 
Other (hemorrhage)9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Leukostasis and/or leukocytosis have been observed especially in patients with chronic 
lymphocytic leukemia (CLL) and mantle cell leukemia (MCL). 
 
3Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
4Fungal infections especially respiratory tract infections due to aspergillus and/or pneumocystis 
and central nervous system (CNS) infections due to aspergillus have been observed in clinical 
trials of ibrutinib. These reports may include incidents of presumptive fungal infections based on 
response to anti-fungal agents and/or radiographic evidence. 
 

 
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5Other malignant diseases have been observed in patients who have been treated with ibrutinib 
including solid tumors, skin cancer, and hematological malignancies. 
 
6Pneumonitis is included in the group term Interstitial Lung Disease (ILD) which also includes 
lung infiltration, bronchiolitis, pulmonary fibrosis, eosinophilc pneumonia, pulmonary toxicity, 
and alveolitis allergic. 
 
7Angioedema may be seen in association with the immune-related adverse event of anaphylaxis. 
 
8Rash may include but is not limited to the terms dermatitis, erythema, rash generalized, rash 
maculo-papular, rash pustular, rash pruritic, and urticaria. 
 
9It is possible that treatment with ibrutinib may increase the risk of hemorrhage which may occur 
anywhere in the body including CNS hemorrhage (including but not limitied to Intracranial 
hemorrhage, Intraventricular hemorrhage, and Subdural hematoma), Ecchymoses, Purpura 
(petechia), Gastrointestinal hemorrhage (including but not limited to Anal hemorrhage, Cecal 
hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal 
varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-
abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral 
hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and 
Upper gastrointestinal hemorrhage), Genitourinary tract hemorrhage (including but not limited 
to Hematuria and Vaginal hemorrhage), Respiratory tract hemorrhage (including but not limited 
to Epistaxis), and Spontaneous hemorrhage. 
 
 
Adverse events reported on Ibrutinib (PCI-32765) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Ibrutinib (PCI-32765) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (hemorrhagic diathesis); Blood and lymphatic system disorders - Other 
(lymphadenitis); Blood and lymphatic system disorders - Other (pancytopenia); Febrile 
neutropenia; Hemolysis  
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block complete; Atrioventricular 
block first degree; Cardiac disorders - Other (bundle branch block left); Cardiac disorders - Other 
(extrasystoles); Chest pain - cardiac; Heart failure; Myocardial infarction; Palpitations; 
Pericardial effusion; Pericarditis; Sinus bradycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (eye discharge); Eye 
disorders - Other (macular edema); Eye disorders - Other (ocular hyperemia); Eye disorders - 
Other (retinal hemorrhage); Eye pain; Floaters; Glaucoma; Keratitis; Periorbital edema; 
Photophobia; Vision decreased; Watering eyes  
GASTROINTESTINAL DISORDERS - Abdominal distension; Cheilitis; Colitis; Dyspepsia; 
Enterocolitis; 
Esophagitis; 
Flatulence; 
Gastritis; 
Gastroesophageal 
reflux 
disease; 
Gastrointestinal disorders - Other (gluteal intramuscular bleed); Gastrointestinal disorders - 
Other (irritable bowel syndrome); Gastrointestinal disorders - Other (tongue discoloration); Oral 

 
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dysesthesia; Oral pain; Pancreatitis; Periodontal disease; Small intestinal obstruction; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other (early 
satiety); General disorders and administration site conditions - Other (multiple organ dysfunction 
syndrome); General disorders and administration site conditions - Other (sensation of foreign 
body); General disorders and administration site conditions - Other (temperature intolerance); 
Generalized edema; Injection site reaction; Localized edema; Non-cardiac chest pain; Pain  
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory 
response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related 
reaction; Injury, poisoning and procedural complications - Other (excoriation) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT 
corrected interval prolonged; INR increased; Investigations - Other (cardiac murmur); 
Investigations - Other (increase CRP); Lymphocyte count decreased; Weight gain; Weight loss; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypoglycemia; 
Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - 
Other (cachexia); Metabolism and nutrition disorders - Other (hypoproteinemia); Metabolism 
and nutrition disorders - Other (lactose intolerance) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; 
Bone pain; Flank pain; Generalized muscle weakness; Joint effusion; Joint range of motion 
decreased; Musculoskeletal and connective tissue disorder - Other (groin pain); Musculoskeletal 
and connective tissue disorder - Other (muscle rigidity); Musculoskeletal and connective tissue 
disorder - Other (pain in jaw); Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Dysgeusia; 
Encephalopathy; Leukoencephalopathy; Memory impairment; Nervous system disorders - Other 
(mental impairment); Nervous system disorders - Other (PML); Nervous system disorders - 
Other (parosmia); Paresthesia; Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Somnolence; Stroke; Syncope   
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Insomnia; Restlessness 
RENAL AND URINARY DISORDERS - Cystitis noninfective; Renal and urinary disorders - 
Other (calculus bladder); Renal and urinary disorders - Other (polyuria); Urine discoloration; 
Urinary frequency; Urinary retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dyspareunia; Reproductive 
system and breast disorders - Other (hematospermia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Hiccups; Laryngeal inflammation; Pleural effusion; Productive cough; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (alveolitis allergic); Respiratory, thoracic 
and mediastinal disorders - Other (nasal ulcer); Sinus disorder; Sinus pain; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Nail discoloration; 
Nail loss; Photosensitivity; Pruritus; Skin atrophy; Skin hyperpigmentation; Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Flushing; Hot flashes; Thromboembolic event; Vascular disorders 

 
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- Other (peripheral coldness) 
Note: Ibrutinib (PCI-32765) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result 
in events never previously associated with either agent. 
6.1.2  Potential risks for cyclophosphamide 
Cyclophosphamide is an alkylating agent and is cell cycle nonspecific. It causes 
cross-linking of DNA and is the most active single agent in the treatment of non-
Hodgkin lymphoma. Side effects of cyclophosphamide include nausea, vomiting, 
myelosuppression and alopecia. Sterility and testicular atrophy are common in men 
and amenorrhea is seen in women. Hemorrhagic cystitis is caused by metabolites 
of cyclophosphamide excreted through the urine. Bladder irritation can be reduced 
by adequate hydration. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
6.1.3 Potential risks for doxorubicin hydrochloride 
Doxorubicin is an anthracycline antibiotic that binds tightly with DNA, inhibits 
nucleic acid synthesis and causes DNA strand breaks. Although active throughout 
the cell cycle, cells in S phase are most sensitive. Common side effects include 
myelosuppression, alopecia, and stomatitis, which is dose related and may be 
severe. Drug-induced cardiomyopathy which may result in congestive heart failure 
is a cumulative dose dependent effect and risk becomes considerable at total doses 
exceeding 500 mg/m2. Doxorubicin is given intravenously and is a vesicant causing 
severe local necrosis at the site of injection if extravasation occurs. Nausea and 
vomiting are frequent. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
6.1.4 Potential risks for vincristine sulfate 
Vincristine sulfate is a vinca alkaloid from the plant C. roseus. It acts by binding to 
or crystallizing microtubular proteins of the mitotic spindle. It is a cell cycle phase 
specific agent and can also affect DNA directed RNA polymerase. It has a triphasic 
half-life and primary elimination is by the liver into the bile and feces. The major 
and dose-limiting side effect of vincristine is neurotoxicity. The main manifestation 
is a mixed sensorimotor peripheral neuropathy. Reduced or loss of deep tendon 
reflexes, paresthesias, weakness, myalgias and motor disturbances may occur. 
Autonomic toxicity also occurs which may cause constipation, obstipation, 
abdominal cramps and ileus. It has mild myelosuppressive effects and is a vesicant 
causing local necrosis at the site of injection if extravasation occurs. Please refer to 
the approved package insert for complete prescribing and toxicity information. 
6.1.5 Potential risks for etoposide 
Etoposide, or VP-16, is an epipodophyllotoxin derived from the mandrake plant P. 
peltatum. It is a cell cycle phase specific agent that blocks topoisomerase II. It has 
a biphasic half-life and is eliminated by both renal clearance and metabolism. The 
major and dose-limiting toxicity of etoposide is myelosuppression. Constipation, 
diarrhea, dysphagia, aftertaste, abdominal pain, stomatitis, and anorexia have also 

 
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been reported. Mucositis and hepatotoxicity are seen primarily with high doses. 
Transient hypotension and other anaphylactic-like symptoms are associated with 
rapid infusion. Please refer to the approved package insert for complete prescribing 
and toxicity information. 
6.1.6 Potential risks for prednisone 
Prednisone is a corticosteroid and its mechanism of action, as a cytotoxic agent is 
not clearly understood. Short-term use produces minimal side effects but prolonged 
use is associated with hypertension, hyperglycemia, myopathy, osteoporosis, 
pancreatitis, and immunosuppression. Alterations in mood and insomnia are 
common acute side effects. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
6.1.7 Potential risks for rituximab 
The Adverse Event and Potential Risks list provides a single list of reported and/or 
potential adverse events (AE) associated with rituximab. 
 
 

 
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Table 6-B: Adverse events and potential risks for rituximab 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, more than 20 and up to 100 may have: 
• Nausea 
• Chills, fever 
• Reaction during or following infusion of the drug 
• Infection, especially when white blood cell count is low 
• Anemia which may require blood transfusions 
• Numbness and tingling of the arms and legs 
• Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab, from 4 to 20 may have: 
• Bruising, bleeding 
• Abnormal heartbeat 
• Heart attack or heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness 
• Sores in eye 
• A tear or a hole in the bowels that may require surgery 
• Diarrhea, vomiting 
• Pain 
• Swelling of the body 
• Hepatitis, or liver damage which may cause yellow eyes and skin 
• Dizziness, headache 
• Kidney damage which may require dialysis 
• Cough 
• Scarring of the lungs 
• Stuffy nose 
• Blockage of internal organs which may cause shortness of breath, wheezing, vomiting 
• Increased sweating 
• Itching, rash, blisters on the skin 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body 
• Low blood pressure which may cause feeling faint 
 

 
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RARE, AND SERIOUS 
In 100 people receiving Rituximab, 3 or fewer may have: 
• Damage to the brain caused by a virus which may result in tiredness, weakness, changes in 
thinking, and disability. This is called progressive multifocal leukoencephalopathy (PML). 
• Heart stops beating 
Also reported on rituximab trials but with the relationship to rituximab still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow 
hypocellular; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - 
Other (cyanosis); Left ventricular systolic dysfunction; Sinus bradycardia; 
Ventricular fibrillation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); 
Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; 
Gastrointestinal obstruction3; Gastrointestinal perforation4; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Flu like symptoms; Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other 
(Opportunistic infection associated with >=Grade 2 Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS 
- 
Alkaline 
phosphatase 
increased; 
Aspartate 
aminotransferase increased; Blood bilirubin increased; Cardiac troponin I 
increased; Cardiac troponin T increased; Creatinine increased; Investigations - 
Other (hyperphosphatemia); Investigations - Other (LDH increased); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; 
Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hyperuricemia; 
Hypoglycemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthritis 
 
 

 
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NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial 
Neuropathy NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Pyramidal tract syndrome; Reversible posterior leukoencephalopathy syndrome; 
Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Epistaxis; Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; 
Respiratory, thoracic and mediastinal disorders - Other (bronchiolitis obliterans) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and 
subcutaneous tissue disorders - Other (paraneoplastic pemphigus) 
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis 
Note:  Rituximab in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either 
agent. 
6.2 
Classification of AEs by Severity and Relationship to Study Drug Administration 
6.2.1 Adverse Event: Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a 
medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). 
6.2.2 Life-threatening Adverse Event: Any AE that places the participant or participant, 
in view of the Investigator, at immediate risk of death from the reaction. 
6.2.3 Serious Adverse Event (SAE): Any AE occurring at any dose that results in any of 
the following outcomes: Death, a life-threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. 
6.2.4 Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for pharmacokinetic 
sampling, but do report an admission for a myocardial infarction.  
6.2.5 Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an AE that has an attribution of possibly, probably 
or definitely related to investigational treatment. To minimize confusion the NCI 
would recommend that the term toxicity NOT be utilized for AE reporting 
purposes. The CTCAE continues to use the term ‘toxicity’ because of familiarity. 
6.2.6 Unexpected Adverse Event: Any AE that is not listed in available sources including 
the package insert, the Investigator’s Brochure, or the protocol. 
6.2.7 CTEP Adverse Event Reporting System (CTEP-AERS): An electronic system for 
expedited submission of AE reports. 

 
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6.2.8 Attribution: The determination of whether an AE is related to a medical treatment 
or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent. 
Possible – The AE may be related to the investigational agent. 
Unlikely – The AE is doubtfully related to the investigational agent. 
Unrelated – The AE is clearly NOT related to the investigational agent. 
6.3 
Expedited Adverse Event Reporting 
6.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov). The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP 
home page 
(http://ctep.cancer.gov). These requirements are briefly outlined in the table below 
(Section 6.3.3). 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only 
when Internet connectivity is disrupted. Once Internet connectivity is restored, a 
24-hour notification phoned in must be entered electronically into CTEP-AERS by 
the original submitter at the site. 
6.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician. CTEP-AERS provides a copy feature 
for other e-mail recipients. 
6.3.3 Expedited reporting guidelines 
Use the NCI protocol number and the protocol-specific participant ID assigned 
during trial registration on all reports. 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided. 
Death due to progressive disease should be reported as Grade 5 “General 
disorders and administration site conditions - Disease Progression.” Evidence 
that the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
 

 
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Table 6-C: FDA expedited reporting requirements 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY SAEs, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An AE is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening AE 
3) An AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SAEs that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Grade 1-2 Timeframes 
Grade 3-5 Timeframes 
24-Hour notification, 10 calendar days 
24-Hour notification, 5 calendar days 
NOTE:   Protocol-specific exceptions to expedited reporting of SAEs are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timeframes are defined as: 
o “24-Hour notification, 5 Calendar Days” - The SAE must initially be reported via CTEP-
AERS within 24 hours of learning of the SAE, followed by a complete expedited report 
within 5 calendar days of the initial 24-hour report. 
o “24-Hour notification, 10 Calendar Days” - The SAE must initially be reported via CTEP-
AERS within 24 hours of learning of the SAE, followed by a complete expedited report 
within 10 calendar days of the initial 24-hour report. 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-Hour notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 3-5 SAEs 
• 
Within 10 calendar days for Grade 1-2 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the 
SAE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, 
after the agent/intervention was last administered.  Footnote “1” above applies after this reporting 
period. 
 
Effective Date: August 30, 2024 
6.4 
Routine Adverse Event Reporting 
All adverse events must be reported in routine study data submissions. AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
6.4.1 Additional protocol-specific routine adverse event reporting exclusions 
All AEs, including clinically significant abnormal findings on laboratory 

 
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evaluations, regardless of severity, will be followed until satisfactory resolution. 
AEs will be reported up to 30 days following the last dose of R+daEPOCH or 
ibrutinib, whichever was administered last. 
For this study, AEs will include clinically significant events reported by the 
participant, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation that the investigator feels was related to study 
drug. A new illness, symptom, sign or clinically significant laboratory abnormality 
or worsening of a pre-existing condition or abnormality is considered an AE. All 
AEs must be recorded on the AE case report form. 
In assessing laboratory results, an abnormal laboratory value will be considered 
clinically significant if it is characterized by one or more of the following criteria: 
1. Is judged by the investigator to have a causal relationship to the investigational 
agent 
2. Requires clinical intervention or monitoring, such as: close observation, more 
frequent 
follow-up 
assessments, 
further 
diagnostic 
intervention, 
treatment/therapeutic intervention, or protocol therapy dose modification 
3. Is associated with clinical signs or symptoms, which may suggest a disease 
and/or organ toxicity, or may represent a new condition or worsening of a 
baseline condition 
4. Is associated with a serious adverse event, or is otherwise judged by the 
Investigator to be of significant clinical impact 
Results proved erroneous result by repeat testing, if performed, will not be 
considered clinically significant laboratory abnormalities. 
In general, a laboratory abnormality that is not clinically significant will be 
consistent with CTCAE grade 1 (mild) or 2 (moderate) severity, as categorized by 
the relevant severity description in the Investigations System Organ Class (SOC) 
or Metabolism and Nutrition Disorders SOC. Investigators may not designate 
laboratory abnormalities that are consistent with grade 3 or greater severity as not 
clinically significant. 
All laboratory values deemed clinically significant will be subsequently reported as 
AEs unless the result is a sign of a clinical diagnosis that is reported as an AE. 
6.4.2  Timeline for routine adverse event reporting 
All adverse events will be assessed by the investigator in the study source from the 
first dose of protocol therapy through the treatment discontinuation visit, or until 
resolution, whichever is later. After this evaluation, assessment and reporting of 
AEs will only be required for all grade 5 AEs and any SAE that the investigator 
considers related to AMC-101 protocol therapy. 
6.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 

 
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CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
6.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
adverse event reporting.  

 
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7.0 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 6.1. 
If required, commercial agents may be replaced with a suitable alternative formulation with 
approval from the protocol chairs. 
7.1 
Ibrutinib (NSC #748645) 
Chemical Name: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
1-yl]-1-piperidinyl]-2-propen-1-one 
Other Names: Ibrutinib  
Classification: Selective, irreversible, small molecule inhibitor of Bruton’s tyrosine kinase 
(Btk). 
CAS Registry Number: 936563-96-1 
M.W.: 440.5 g/mole 
Mode of Action: Ibrutinib binds covalently to a cysteine residue in the BTK active site, 
leading to potent and irreversible inhibition of BTK enzymatic activity of B-cell receptors 
(BCR). B-cell maturation is mediated by BCR signal transduction and BTK is an essential 
part of the signaling pathway. 
Description: White to off-white crystalline solid 
How Supplied: Ibrutinib is supplied by Pharmacyclics, Inc., and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI. Ibrutinib is supplied as hard 
gelatin capsules containing micronized Ibrutinib and the following excipients: 
microcrystalline cellulose; croscarmellose sodium; sodium lauryl sulfate; may contain 
magnesium stearate. Capsules are manufactured as 140 mg in a size 0, gray, hard gelatin 
capsule. Capsules are packaged in high-density polyethylene (HDPE) bottles with an 
induction seal and a child resistant screw top cap. Each bottle may contain either 120 
capsules or 92 capsules. Ibrutinib capsules are to be dispensed in their original containers. 
Storage: Ibrutinib Hard Gelatin Capsules should be stored at 15-25°C. 
Stability: Shelf life surveillance of the intact bottles is ongoing. 
Route of Administration: Ibrutinib 560 mg (4 x 140-mg capsules, or other dose level as 
assigned per Section 4.1) 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 participant 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 XV). 
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 participant should not take 
extra capsules to make up the missed dose. 

 
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Potential Interactions: Ibrutinib is primarily metabolized by CYP3A4. Any strong 
inhibitor or inducer of CYP3A4 (e.g., itraconazole, ketoconazole, clarithromycin, and 
rifampin) should be administered with caution and only after consultation with the Medical 
Monitor. Grapefruit and Seville orange juices should be avoided.  
Availability: Ibrutinib is an investigational agent supplied by Pharmacyclics and 
distributed by the Pharmaceutical Management Branch, CTEP, DCTD, NCI. 
Ibrutinib is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix II). 
7.1.1 Drug orders, transfers, and returns 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution. Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated. PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained). The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational 
agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 
(Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data 
Form (IDF), and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
In general, sites may order initial agent supplies when a participant is being 
screened for enrollment onto the study. 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
7.1.2 Agent inventory records 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing, and final disposition of all 
agents received from the PMB using the Oral NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation, and ordering investigator on this protocol. 
7.1.3 Useful links and contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 

 
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• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
The current versions of the IBs for the agents will be accessible to site 
investigators and research staff through the PMB OAOP application. Access to 
OAOP requires the establishment of a CTEP IAM account and the maintenance 
of an “active” account status and a “current” password. Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
7.2 
Commercial Agents (EPOCH) 
7.2.1 Rituximab 
Product description: Rituximab is a chimeric mouse/human anti-CD 20 
monoclonal antibody that binds human C1q, mediate complement-dependent cell 
lysis and lyse human target cells through antibody dependent cellular cytotoxicity. 
It has documented anti-tumor activity in CD20 positive lymphoma and FDA-
approved for that indication. FDA-licensed biosimilars are permitted for use on this 
protocol. Please refer to the approved package insert for complete prescribing and 
toxicity information. 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 
Route of administration: 375 mg/m2 IV, Day 1 (for CD20 positive lymphoma). 
Agent ordering: Agent will be sourced by participating centers as commercially 
available. 
7.2.2 Etoposide 
Product description: Etoposide, or VP-16, is an epipodophyllotoxin derived from 
the mandrake plant P. peltatum. Etoposide is a substrate for CYP1A2, CYP2E1, 
CYP3A4/5, UGT1A1, ABCB1, ABCC1, and ABCC3 and a weak inhibitor of 
CYP2C9 and CYP3A4. It is a cell cycle phase specific agent that blocks 
topoisomerase II. It has a biphasic half-life and is eliminated by both renal clearance 
and metabolism. The major and dose-limiting toxicity of etoposide is 
myelosuppression. Constipation, diarrhea, dysphagia, aftertaste, abdominal pain, 
stomatitis, and anorexia have also been reported. Mucositis and hepatotoxicity are 

 
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seen primarily with high doses. Transient hypotension and other anaphylactic-like 
symptoms are associated with rapid infusion. Please refer to the approved package 
insert for complete prescribing and toxicity information. 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 
Route of administration: Etoposide 50 mg/m2/24 hours x 4 days (~96-hour 
infusion), Days 1-4. 
Agent ordering: Agent will be sourced by participating centers as commercially 
available. 
7.2.3 Doxorubicin hydrochloride 
Product description: Doxorubicin is an anthracycline antibiotic that binds tightly 
with DNA, inhibits nucleic acid synthesis and causes DNA strand breaks. Although 
active throughout the cell cycle, cells in S phase are most sensitive. Common side 
effects include myelosuppression, alopecia, and stomatitis, which is dose related 
and may be severe. Drug-induced cardiomyopathy, which may result in congestive 
heart failure, is a cumulative dose-dependent effect and risk becomes considerable 
at total doses exceeding 500 mg/m2. Doxorubicin is given intravenously and is a 
vesicant causing severe local necrosis at the site of injection if extravasation occurs. 
Nausea and vomiting are frequent. Please refer to the approved package insert for 
complete prescribing and toxicity information. 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 
Route of administration: 10 mg/m2/24 hours x 4 days (~96-hour infusion), Days 1-4. 
Agent Ordering: Agent will be sourced by participating centers as commercially 
available. 
7.2.4 Vincristine sulfate 
Product description: Vincristine sulfate is a vinca alkaloid from the plant C. 
roseus. Vincristine is a substrate for CYP3A4/5, ABCB1, ABCC1, ABCC2, 
ABCC3, and ABCC10 and a weak inhibitor of CYP3A4. It acts by binding to or 
crystallizing microtubular proteins of the mitotic spindle. It is a cell cycle phase 
specific agent and can also affect DNA-directed RNA polymerase. It has a triphasic 
half-life and primary elimination is by the liver into the bile and feces. The major 
and dose-limiting side effect of vincristine is neurotoxicity. The main manifestation 
is a mixed sensorimotor peripheral neuropathy. Reduced or loss of deep tendon 
reflexes, paresthesias, weakness, myalgias and motor disturbances may occur. 
Autonomic toxicity also occurs which may cause constipation, obstipation, 
abdominal cramps and ileus. It has mild myelosuppressive effects and is a vesicant 
causing local necrosis at the site of injection if extravasation occurs. Please refer to 
the approved package insert for complete prescribing and toxicity information 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 

 
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Route of administration: 0.4 mg/m2/24 hours x4 days (~96-hour infusion), Days 1-4. 
Agent ordering: Agent will be sourced by participating centers as commercially 
available. 
7.2.5 Prednisone 
Product description: Prednisone is a corticosteroid and its mechanism of action, 
as a cytotoxic agent is not clearly understood. Short-term use produces minimal 
side effects but prolonged use is associated with hypertension, hyperglycemia, 
myopathy, osteoporosis, pancreatitis, and immunosuppression. Alterations in mood 
and insomnia are common acute side effects. Please refer to the approved package 
insert for complete prescribing and toxicity information. 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 
Route of administration: 60 mg/m2 PO daily Days 1-5 (may be rounded to the 
nearest 10 mg). 
Agent ordering: Agent will be sourced by participating centers as commercially 
available. 
7.2.6 Cyclophosphamide 
Product description: Cyclophosphamide is an alkylating agent and is cell cycle 
nonspecific. It causes cross-linking of DNA and is the most active single agent in 
the treatment of non-Hodgkin lymphoma. Cyclophosphamide is a substrate  
of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. 
Cyclophosphamide is a weak-to-moderate inducer of CYP2B6, CYP2C8, and 
CYP2C9 and weak inhibitor of CYP3A4 and UGT (isozyme not specified). Side 
effects of cyclophosphamide include nausea, vomiting, myelosuppression and 
alopecia. Sterility and testicular atrophy are common in men and amenorrhea  
is seen in women. Hemorrhagic cystitis is caused by metabolites of 
cyclophosphamide excreted through the urine. Bladder irritation can be reduced by 
adequate hydration. Please refer to the approved package insert for complete 
prescribing and toxicity information. 
Solution preparation: Investigators may refer the reader to the package insert for 
standard preparation instructions, appropriate storage, and stability information. 
Route of administration: Cyclophosphamide cycle 1 dose at 750 mg/m2 for CD4 
count ≥ 200 and 375 mg/m2 for CD4 count < 200, IV over 1 hour, Day 5; subsequent 
cycles adjusted as per Section 4.1. 
Agent ordering: Agent will be sourced by participating centers as commercially 
available. 

 
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8.0 
CLINICAL AND LABORATORY EVALUATIONS 
Schedules shown in the Study Calendar below are provided in Appendix I. 
8.1 
Screening/Baseline Evaluations 
Unless otherwise specified, the following evaluations must be performed within 28 days 
prior to participant registration. For participants who are enrolled after receiving one cycle 
of chemotherapy off study, baseline assessments that were performed within the protocol 
timelines prior to the initiation of chemotherapy off study will be accepted at study 
enrollment. All laboratory tests to document eligibility must be performed prior to 
enrollment. Any other tests or evaluations for protocol requirements at baseline that were 
not performed prior to the initiation of chemotherapy (off study) must be collected prior 
to initiation of treatment under protocol.  
NOTE: Research specimens that will be shipped to other institutions should not be 
collected before enrollment in Advantage eClinical, so that shipment through GT is 
possible upon collection. 
8.1.1 Medical history; CDC HIV risk categories, and history of current and past anti-
retroviral regimens, if available; and history of any prior AIDS-defining conditions. 
Date of initial lymphoma diagnosis is required, with a copy of the pathology report 
in the medical record. Presence of systemic “B” symptoms should be noted, as well 
as other symptoms of NHL. Current concomitant medication list, including all anti-
retroviral, anti-viral, antibiotics, over the counter medications or dietary 
supplements, and opportunistic prophylaxis should be obtained. 
8.1.2 Participants must not be on medications, including ARV regimens, with moderate 
or strong CYP3A4 inhibition; if on a moderate or strong CYP3A4 inhibitor regimen 
prior to study enrollment, participants must be switched to a qualifying regimen 
with the last dose of the moderate and/or strong CYP3A4 inhibitor taken at least 
one week before administration of ibrutinib. 
8.1.3 Physical examination, including performance status (see Appendix III, 
Performance Status Scales), vital signs (weight, height, body surface area (BSA)), 
neurological examination, and if possible, two-dimensional measurement of all 
palpable, peripheral lymph nodes and measurement of other sites of disease present. 
8.1.4 CT scan chest/abdomen/pelvis (+/- neck if involved) with contrast of diagnostic 
quality; if possible, measurement of sites of disease present. If PET/CT is feasible, 
a baseline PET/CT scan. If a PET/CT is not feasible, this will not be a protocol 
violation. MRI brain and/or spine as clinically indicated. 
8.1.5 Electrocardiogram (EKG). 
8.1.6 Laboratory tests, including: 
• CBC with differential and platelet count (within 2 weeks prior to participant 
registration). 
• Serum chemistries: magnesium, glucose, electrolytes (sodium, potassium, CO2, 
chloride), blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase (ALP), LDH, total protein, albumin, AST and ALT, and uric acid 
(within 2 weeks prior to participant registration). 

 
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• Serum pregnancy test for women of childbearing potential (within 7 days prior 
to first cycle of chemotherapy). 
• Confirmation of HIV, as defined in Section 3.1.4. 
• HIV-1 RNA viral load. 
• CD4 and CD8 cell count. 
• Quantitative serum immunoglobulin levels (IgG, IgA, IgM). 
• Assessment for Hepatitis C antibody, Hepatitis B surface antibody, Hepatitis B 
core antibody, Hepatitis B surface antigen (HBsAg). A baseline Hepatitis B or 
C viral load should be obtained on all participants who are Hepatitis B core 
antibody positive, Hepatitis B antigen positive, and/or Hepatitis C positive 
respectively. 
8.1.7 Bone marrow biopsy or aspirate for histology and determination of percent bone 
marrow involvement is required within 6 weeks prior to participant registration 
only if PET/CT not performed and there was no prior documentation of bone 
marrow involvement by lymphoma. Based on the Lugano criteria, PET/CT scan 
indicating bone or marrow involvement is sufficient to designate advanced-stage 
disease, and a bone marrow biopsy is not required. If a bone marrow is necessary, 
unilateral bone marrow biopsy/aspirate is allowed, with an aggregate core length of 
2 cm, either from one site or bilateral sites. If feasible, a portion of the bone marrow 
biopsy and aspirate will be sent for cytogenetic analysis. If bone marrow 
involvement by lymphoma has already been documented after bone marrow biopsy 
performed more than 6 weeks prior to registration the biopsy does not have to be 
repeated. Unilateral bone marrow biopsy/aspirate is allowed, with an aggregate 
core length of 2 cm, either from one site or bilateral sites. If feasible, a portion of 
the bone marrow biopsy and aspirate will be sent for cytogenetic analysis. 
8.1.8 Determination of LVEF by MUGA scan or echocardiogram. 
8.1.9 Lumbar puncture (LP) for dose-finding cohort: routine studies with cytology and 
flow cytometry.  
8.1.10 LP for Dose-Expansion Cohort: Routine CSF studies including cytology and flow 
cytometry. Asymptomatic leptomeningeal disease will be allowed in the dose-
expansion cohort. 
8.1.11 Diagnostic slides and tissue block of biopsy submitted within 1 month of 
enrollment in Advantage eClinical to the AMC Pathology Core Lab at Weill 
Cornell Medical Center and reviewed for adequacy for COO. Adequacy for COO 
is defined as adequate tissue for IHC determination of COO as well as tumor 
content of at least 60% for GEP analysis for COO. 
8.1.12 Optional donation to the AIDS and Cancer Specimen Resource (ACSR). (See 
Appendix VI for ACSR Informed Consent Form and Appendix V for ACSR 
Specimen Preparation and Shipping Instructions). 

 
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8.1.13 Correlative studies 
Note: For participants who are enrolled after receiving one cycle of chemotherapy 
off study, the following baseline studies must be collected after enrollment and 
prior to initiation of treatment under protocol. Subsequent studies will be collected 
at the specified times counting the off-study cycle as Cycle 1. 
See Appendix X and Appendix XIV for full details on collection and shipping. 
8.1.13.1 Blood samples for circulating tumor DNA 
8.1.13.2 EBV viral load 
8.1.13.3 Blood cytokines 
8.1.14 Drug diaries provided to participant (Appendix VIII) 
8.1.15 Letter to Physician provided to participant (Appendix XVIII) 
8.2 
Evaluations During Treatment 
Evaluations are to occur in both Phases unless otherwise specified. For participants 
enrolled after receiving prior treatment, the off-study chemotherapy cycle treatment counts 
as Cycle 1 for the purpose of obtaining the following studies (except for correlative studies) 
and re-staging. Participants who discontinue ibrutinib (due to toxicity, participant refusal, or 
other reasons) but continue R-da-EPOCH are considered on study until protocol 
chemotherapy is completed, and should have efficacy, toxicity, and follow-up data reported. 
8.2.1 Day 1 or within 3 days (day -3, -2 or -1) prior to each cycle of chemotherapy a 
physical examination, including weight/height/BSA, vitals, and performance status 
will be performed. Disease measurable by physical examination will be recorded 
in two dimensions, if possible. 
8.2.2 Medical history, including concomitant medication changes and any signs and 
symptoms (Day 1 or within 3 days prior). Evaluate AEs and record those required 
in Advantage eClinical. 
8.2.3 CBC with differential and platelet count 
• CBC with differential will be repeated prior to beginning each cycle (Day 1 or 
within 3 days prior). 
• For severely immune compromised participants (CD4 < 100 cell/mm3) it is 
advisable that a CBC with differential be obtained on or about day 15 of each 
cycle in order to determine length of prophylactic antibiotic treatment. 
• CBC and differential will be obtained on or about Days 9, 12 and 15 (± 3 days) 
after each cycle of chemotherapy in order to determine toxicity and 
cyclophosphamide dose adjustments. If by the second CBC, the nadir has been 
reached and the ANC is recovering, no further CBCs are necessary (i.e., 2 CBCs 
will suffice). 
8.2.4 Serum chemistries to include magnesium, glucose, electrolytes, BUN, creatinine, 
total bilirubin, ALP, LDH, total protein, albumin, AST and ALT will be repeated 
on Day 1 (- 3 days) of each cycle with results obtained no more than 72 hours prior 

 
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to dosing. Rituximab may proceed in anticipation of chemotherapy while these 
results are pending provided there is no prior history of renal insufficiency or 
hepatotoxicity, and no evidence of jaundice on physical exam. Electrolytes and 
creatinine must be monitored while on ibrutinib and participants’ potassium and 
magnesium should be corrected prior or during administration of ibrutinib. 
8.2.5 CD4 and CD8 cell count within 7 days before the end of Cycle 2 (prior to the start 
of Cycle 3 or day 1 of Cycle 3). 
8.2.6 Quantitative immunoglobulins (IgG, IgA, IgM) within 7 days before the end of 
Cycle 2 (prior to the start of Cycle 3). 
8.2.7 HIV viral load will be done at the local institution within 7 days before the end of 
Cycle 2 (prior to the start of Cycle 3). 
8.2.8 HBV and/or HCV viral load in participants who were HBV surface antigen 
positive, HBV core antibody positive, or HCV antibody positive with undetectable 
viral particles or viral load at baseline within 7 days before the end of cycles 2 and 
4 (prior to the start of cycles 3 and 5) and within 4-8 weeks after Day 1 of cycle 6. 
8.2.9 If Grade 3 or 4 hematologic toxicity occurs at any time, blood sampling for follow-
up evaluation should be performed as clinically indicated until the abnormality 
resolves. 
8.2.10 Collect participant Drug Diary and provide a new one (prior to Cycles 2-6); 
Appendix VIII. 
8.2.11 Correlative Studies 
See appendices and MOP for full details for specimen collection times, processing 
and shipping. 
8.2.11.1 Pharmacokinetics for ibrutinib: only during cycle 1: See table “Ibrutinib 
Levels” in Appendix I for timing of collection and Appendix XIII for 
shipping information. 
8.2.11.2 Pharmacokinetics for doxorubicin, vincristine and etoposide: only during 
cycle 1. 
8.2.11.3 ITK and BTK occupancy: only during cycle 1, Monday-Thursday. If this 
is not planned for Monday-Thursday, the BTK/ITK occupancy will not 
be drawn. This will not be a protocol deviation. 
8.2.11.4 Cytokines: after cycle 2 (between the last dose of ibrutinib in cycle 2 and 
before the next dose of EPOCH in cycle 3). 
8.2.11.5 Circulating tumor DNA studies will be drawn at the end of cycle 2 and 
the end of cycle 4 after ibrutinib treatment is complete and before the 
next dose of EPOCH is infused.  
 

 
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8.3 
Evaluation of Response 
For those participants enrolled after prior treatment, the off-study chemotherapy cycle 
DOES COUNT towards re-staging. After Cycle 4 (between days 10-21) and 4-8 weeks 
after the beginning of Cycle 6, the following evaluations must be performed: 
8.3.1 After Cycle 4 (between days 10-21), the following evaluations must be performed: 
• Diagnostic CT scans of chest, abdomen, and pelvis +/- neck, if involved. If 
possible, measurement of sites of disease present. 
• Participants with CR after Cycle 4 will receive two additional cycles of 
chemotherapy and complete a total of six cycles of chemotherapy. Participants 
who achieve a PR only after Cycle 4 may continue on protocol therapy or they 
may be removed from the study at the discretion of the physician (local 
Principal Investigator). Participants with stable disease after 4 cycles (i.e., who 
did not achieve at least a PR) or progressive disease at any time will be removed 
from protocol therapy and the examination and tests listed in Section 8.5 will 
be performed. These participants will be followed for survival only. 
8.3.2 After Cycle 6 (4-8 weeks after the beginning of Cycle 6), or within 4-8 weeks of 
treatment discontinuation if treatment was stopped after cycle 4 and prior to cycle 
6 due to excessive toxicity, the following evaluations must be performed: 
• PET/CT scan. 
• If diagnostic CT scans were performed at baseline and were abnormal before 
treatment, diagnostic CT scans should be repeated, including assessment of 
extranodal sites, at the end of therapy. If possible, measurement of sites of 
disease present. However, if the participant’s insurance or third party will not 
cover the costs for these tests, omission of this exam will not be considered a 
protocol violation. 
8.3.3 Participants with lymphomatous bone marrow involvement are required to have a 
repeat bone marrow exam only if all other evidence of disease has resolved (CR) 
and participant is unable to receive PET/CT scan restaging. 
8.3.4 Repeat of any other test that demonstrated lymphomatous involvement at the 
baseline evaluation. 
8.4 
End of Treatment Evaluations 
Evaluations should be performed 4-8 weeks after the beginning of Cycle 6. The following 
evaluations must be performed: 
8.4.1 See Section 8.3 for response evaluations via imaging and marrow involvement. 
8.4.2 History, physical examination, performance status will be performed. Disease 
measurable by physical examination will be recorded in two dimensions, if 
possible. 
8.4.3 Adverse event evaluation. 
8.4.4 CBC with differential and platelet count. 

 
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8.4.5 Serum chemistries to include magnesium, glucose, electrolytes, BUN, creatinine, 
total bilirubin, ALP, LDH, total protein, albumin, AST, and ALT. 
8.4.6 CD4 and CD8 cell count. 
8.4.7 Quantitative 
immunoglobulins 
(IgG, 
IgA, 
IgM). 
Once 
quantitative 
immunoglobulins are within normal limits, they no longer need to be collected. 
8.4.8 HIV viral load at the local institution will be done 4-8 weeks. 
8.4.9 HBV and/or HCV viral load in participants who were HBV core antibody positive 
or HCV antibody positive with undetectable viral load. 
8.4.10 PET/CT scan to document remaining active sites of lymphomatous disease within 
4-8 weeks after the beginning (day 1) of Cycle 6. If diagnostic CT scans were 
performed at baseline and were abnormal before treatment, diagnostic CT scans 
should be repeated, including assessment of extranodal sites, at the end of therapy. 
If possible, measurement of sites of disease present. However, if the participant’s 
insurance or third party will not cover the costs for these tests, omission of this 
exam will not be considered a protocol violation. 
8.4.11 Correlative Studies 
See appendices for full details for specimen collection times, processing and shipping. 
8.4.11.1 Blood samples for circulating tumor DNA 
8.4.11.2 EBV viral load 
8.4.11.3 Cytokines 
8.4.12 Collect participant Drug Diary  
8.5 
Early Discontinuation Evaluations 
Participants discontinuing therapy early (i.e., PD or stable disease, excessive toxicity, 
administrative reasons, participant non-compliance, etc.) will have a complete physical 
examination including performance status and blood drawn for the following studies within 
1 month after treatment discontinuation, unless otherwise noted. Participants will be 
followed for survival only for up to 5 years after the last date of treatment. 
8.5.1 CBC with differential and platelet count. 
8.5.2 Serum chemistries to include magnesium, glucose, electrolytes, BUN, creatinine, 
total bilirubin, ALP, LDH, total protein, albumin, AST, and ALT. 
8.5.3 HIV viral load (do not repeat if done within 1 month from removal from treatment). 
8.5.4 CD4 and CD8 cell count (do not repeat if done within 1 month from removal from 
treatment). 
8.5.5 Quantitative immunoglobulins (do not repeat if done within 1 month from removal 
from treatment). 
8.5.6 HBV and/or HCV viral load in participants who were HBV surface antigen 
positive, HBV core antibody positive, or HCV antibody positive with undetectable 
viral load within 2 months after the completion of chemotherapy. 

 
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8.5.7 Follow-up of all ongoing, related AEs until resolved or determined to be permanent. 
8.5.8 PET/CT scan is recommended to document remaining active sites of 
lymphomatous disease within 4-8 weeks of treatment discontinuation if treatment 
was stopped after cycle 4 and prior to cycle 6 due to excessive toxicity (do not 
repeat if it was already done after cycle 4, and if no further treatment was given 
after cycle 4). If diagnostic CT scans were performed at baseline and were abnormal 
before treatment, diagnostic CT scans should be repeated, including assessment of 
extranodal sites, at the end of therapy. If possible, measurement of sites of disease 
present. However, if the participant’s insurance or third party will not cover the 
costs for these tests, omission of this exam will not be considered a protocol 
violation. 
8.5.10 Correlative Studies 
See appendices for full details for specimen collection times, processing and 
shipping. 
8.5.10.1 Blood samples for circulating tumor DNA 
8.5.10.2 EBV viral load 
8.5.10.3 Cytokines. 
8.6 
Follow-up Evaluations 
The studies listed below will be repeated post-therapy every 3 months (-2 weeks to +4 
weeks for the first 3-month visit, then +/- 4 weeks for subsequent 3 month visits) counting 
from day 21 of the final cycle of chemotherapy for 2 years unless otherwise specified. 
Routine labs and imaging will be detailed below. All study participants should be followed 
for up to 5 years after treatment discontinuation or until death if occurring before 5 years 
of treatment discontinuation. During the third through the fifth years, only progression and 
survival should be reported every 6 months counting from day 21 of the final cycle of 
chemotherapy (+/- 4 weeks). Participants who discontinue ibrutinib (due to toxicity, 
participant refusal, or other reasons) but continue R-da-EPOCH are considered on study 
until protocol R-da-EPOCH is completed, and should have efficacy, toxicity, and follow-
up data reported. Participants who discontinue all protocol therapy after having a CR or 
PR should be followed up for 2 years after treatment, as outlined below. During the third 
through the fifth years, only progression and survival should be reported every 6 months 
counting from day 21 of the final cycle of chemotherapy (+/- 4 weeks). For participants 
who cross over to non-protocol therapy (if PR or stable disease at physician discretion), or 
discontinue therapy other reasons (Section 4.4) are followed for survival for up to 2 years 
after treatment discontinuation as outlined below. During the third through the fifth years, 
only progression and survival should be reported every 6 months counting from day 21 of 
the final cycle of chemotherapy (+/- 4 weeks). No additional studies except follow up for 
survival are required after disease progression or study discontinuation for other reasons 
(Section 4.4). In those instances in which a third-party payer denies payment for some or 
all of these laboratory analyses, absence of these test results will not be considered a 
protocol violation. 

 
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Data to be collected and reported years 1-2 (every 3 months ±4 weeks) 
8.6.1 History, physical examination, vital signs, performance status, review of adverse 
events will be performed. Disease measurable by physical examination will be 
recorded in two dimensions, if possible. 
8.6.2 CBC with differential and platelet count. 
8.6.3 Serum renal and liver functions tests to include BUN, creatinine, total bilirubin, 
ALP, AST, and ALT. 
8.6.4 CD4 and CD8 cell count will be done 4-8 weeks, and at 6 and 12 months after the 
completion of chemotherapy. 
8.6.5 Quantitative immunoglobulins (IgG, IgA, IgM) will be done 4-8 weeks, and at 6 
and 12 months after the completion of chemotherapy. Once quantitative 
immunoglobulins are within normal limits, they no longer need to be collected. 
8.6.6 HIV viral load at the local institution will be done 4-8 weeks, and at 6 and 12 
months after the completion of chemotherapy. 
8.6.7 HBV and/or HCV viral load in participants who were HBV core antibody positive 
or HCV antibody positive, respectively, with undetectable viral load will be 
measured 4-8 weeks post Day 1 of cycle 6. 
8.6.8 PET/CT scan 4-8 weeks after the beginning (day 1) of Cycle 6 or the final cycle of 
protocol therapy, and then CT scans every 6 months (+/- 6 weeks) for 2 years. 
8.6.9 Correlative studies 
See appendices for full details for specimen collection times, processing and 
shipping. 
8.6.9.1 
Cytokines: 6 and 12 months after completion of treatment. 
Data to be collected years 3-5 (every 6 months ±6 weeks) 
8.6.10 Progression (as per participant or medical provider report) 
8.6.11 Vital status 

 
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9.0 
EVALUATION OF RESPONSE 
All participants will be evaluated for clinical response by physical examination following 
each chemotherapy cycle and by imaging studies at the conclusion of the fourth and sixth 
cycles of chemotherapy and every 6 months thereafter for 2 years. For participants enrolled 
after prior treatment, the off-study chemotherapy cycle counts towards the 6 cycles 
requirement; in those participants, only 5 cycles of chemotherapy under protocol are 
required. 
For those participants enrolled after prior treatment, the off-study chemotherapy cycle 
counts towards re-staging. 
After Cycle 4 (between days 10-21), the following evaluation(s) must be performed: 
• CT chest/abdomen/pelvis +/- neck if involved. 
• PET/CT scan to document active sites of lymphomatous disease. However, if the 
participant’s insurance or third party will not cover the costs for these tests, omission 
of this exam will not be considered a protocol violation.  
Four to eight weeks after the beginning of Cycle 6 (or 4-8 weeks after treatment 
discontinuation if treatment was stopped after cycle 4 and prior to cycle 6 due to excessive 
toxicity), the following evaluation must be performed: 
• PET/CT scan. 
• If diagnostic CT scans were performed at baseline and were abnormal before treatment, 
diagnostic CT scans should be repeated at the end of therapy, including assessment of 
extranodal sites. However, if the participant’s insurance or third party will not cover 
the costs for these tests, omission of this exam will not be considered a protocol 
violation. 
9.1 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (i.e., bone 
marrow) criteria. 
Radiologic response will be based on the Lugano Classification.71 A bone marrow aspirate 
and biopsy should only be performed after completion of therapy to confirm a CR if they 
were initially positive and participant is unable to receive PET/CT scan restaging, or if it 
is clinically indicated by new abnormalities in the peripheral blood counts or blood smear. 
 
 

 
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9.2 
Definition of Response 
9.2.1 Revised Criteria for Response Assessment per Lugano classifications for PET/CT 
response71 
Table 9-A: Definition of response for PET/CT 
Response 
Site(s) 
PET/CT-Response 
Complete 
Response (CR) 
Lymph nodes and 
extralymphatic sites 
Complete metabolic response with Score 1, 2, or 3* 
with or without a residual mass on 5PS† 
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake. 
 
Nonmeasurable lesion 
Not applicable 
Organ enlargement 
Not applicable 
New lesions 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow (see 
PET/CT response in extralymphatic sites above for 
exceptions to uptake in the marrow) 
Partial 
Response (PR) 
Lymph nodes and 
extralymphatic sites 
Partial metabolic response with Score 4 or 5† with 
reduced uptake compared with baseline 
and residual mass(es) of any size 
Nonmeasurable lesion 
Not applicable 
Organ enlargement 
Not applicable 
New lesions 
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 

 
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Response 
Site(s) 
PET/CT-Response 
No response or 
stable disease 
(SD) 
Target nodes/nodal 
masses, extranodal 
lesions 
No metabolic response with Score 4 or 5 with no 
significant change in FDG uptake from baseline at 
interim or end of treatment 
Nonmeasurable lesion 
Not applicable 
Organ enlargement 
Not applicable 
New lesions 
None 
Bone marrow 
No change from baseline 
Progressive 
disease (PD) 
Individual target 
nodes/nodal masses 
Progressive metabolic disease with Score 4 or 5 with 
an increase in intensity of uptake from baseline 
and/or 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
Nonmeasurable lesion 
None 
Organ enlargement 
Not applicable 
New lesions 
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 
Bone marrow 
New or recurrent FDG-avid foci 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal 
lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of 
the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with 
marrow activation as a result of chemotherapy or myeloid growth factors). 
 
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be 
related to lymphoma. 
 
 
 

 
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9.2.2 Revised Criteria for Response Assessment for CT response71 
Table 9-B: Criteria for response for CT 
Response 
Site(s) 
CT-Response 
Complete 
Response (CR) 
Lymph nodes and 
extralymphatic sites 
Complete radiologic response (all of the following) 
Target nodes/nodal masses must regress to 1.5 cm in 
longest diameter 
No extralymphatic sites of disease 
No new lesions 
 
Nonmeasurable lesion 
Absent 
Organ enlargement 
Regressed to normal 
New lesions 
None 
Bone marrow 
Bone marrow with 
normal morphology; if 
indeterminate, IHC negative 
Partial 
Response (PR) 
Lymph nodes and 
extralymphatic sites 
Partial remission (all of the following) 
50% decrease in SPD of up to 6 target measurable 
nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 
5 mm 5 mm as the default value 
When no longer visible, 0 0 mm 
For a node 5 mm 5 mm, but smaller than normal, use 
actual measurement for calculation 
Nonmeasurable lesion 
Absent/normal, regressed, but no increase 
Organ enlargement 
Spleen must have regressed by 50% in length 
beyond normal 
New lesions 
None 
Bone marrow 
N/A 
No response or 
stable disease 
(SD) 
Target nodes/nodal 
masses, extranodal 
lesions 
50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal sites; no 
criteria for progressive disease are met 
Nonmeasurable lesion 
No increase consistent with progression 
Organ enlargement 
No increase consistent with progression 
New lesions 
None 
Bone marrow 
N/A 

 
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Response 
Site(s) 
CT-Response 
Progressive 
disease (PD) 
Individual target 
nodes/nodal masses 
 
Extranodal lesions 
Progressive disease requires at least 1 of the 
following 
 
Perpendicular diameters: 
An individual node/lesion must be abnormal with: 
longest diameter 1.5 cm and  
Increase by 50% from perpendicular diameters nadir 
and  
An increase in longest diameter or shortest diameter 
from nadir 0.5 cm for lesions 2 cm 1.0 cm for lesions 
2 cm 
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 
Nonmeasurable lesion 
New 
or 
clear 
progression 
of 
preexisting 
nonmeasured lesions 
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 ≥ 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 
Bone marrow 
New or recurrent involvement 
 
9.2.3 Recurrent disease is defined as the appearance of tumor following documentation 
of a complete remission. 
9.2.4 Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response.  
9.2.5 Time to progression is defined as time from initiation of chemotherapy to 
documentation of first progression. 
9.2.6 Response duration is defined as the time from first documentation of response to 
documentation of first progression. 
 
 

 
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10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Endpoints 
The primary aim is to determine the MTD and RP2D of ibrutinib in combination with R-
da-EPOCH using a 3+3 dose de-escalation design. There will be no formal statistical 
testing for the dose-finding portion of the study. 
Once the RP2D or MTD dose is determined, additional 36 participants will be enrolled into 
the dose-expansion cohort. 
Secondary endpoints for safety, response, survival, COO and other biomarkers are being 
obtained to better characterize the toxicity and safety profile, assess the pharmacokinetics, 
and identify early signs of efficacy within the GCB and non-GCB population. 
10.2 
Sample Size/Accrual Rate 
10.2.1 Sample size 
The minimum sample size for this study is 9. The maximum sample size for the 
dose de-escalation dose-finding portion of the study will be 18 participants. The 
maximum number of participants on this study, including the dose-finding and 
dose-expansion portions, is 54. 
10.2.2 Accrual rate 
The accrual rate will be 1 participant per month during dose-finding and 3 per 
month during the dose-expansion phase. 
In order to ensure for the minimum participant requirement for non-GCB ARL, if 
after enrollment of 20 and 30 participants on trial, there are <50% non-GCB, 
non-GCB COO (as determined at individual AMC site) will be preferentially 
enrolled to meet the minimum number of participants required in the trial (22 non-
GCB participants by local pathology). 
10.2.3 Replacement of inevaluable participants 
For a participant who does not have adequate tissue for GEP, we will replace up to 
14 participants (assuming 30-35% insufficient tissue for GEP) on trial. If we need 
to replace more than 14 participants, AMC and other involved parties will discuss 
a remediation plan. Therefore, the maximum number of participants is 
54 participants (40 evaluable with 14 replacements, if needed). 
For a participant who does not complete cycle 1, the participant can be replaced if, 
based on a review of the available safety for that dose level, the principal 
investigator agrees that the events leading to participant withdrawal are unlikely to 
constitute a safety risk for further participant enrollment and dose escalation. This 
means that as long as participant safety is not compromised, a participant who 
withdraws from the study for administrative reasons prior to experiencing DLT 
during cycle 1 of therapy can be replaced by another participant to complete the 
number of participants evaluable per dose level required by the protocol. Similarly, 
as long as participant safety is not compromised, if an eligibility criterion or 
protocol violation occurs that substantially impairs evaluation of DLT during 
cycle 1, another participant can enter the cohort to complete the number of 

 
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participants evaluable per dose level required by the protocol. Any replacement 
participant will be enrolled into the same dosing cohort as that for the participant 
who withdrew. Participants withdrawn because of ibrutinib-related DLT may not 
be replaced. 
10.3 
Stratification Factors 
There will be no stratification of participants in this study. 
10.4 
Analysis of Primary Endpoint 
Safety analyses in general will be descriptive and will be reported in tabular format with 
the appropriate summary statistics (count and percentage). In the dose-finding portion, the 
number of DLTs identified among the DLT-evaluable subjects will be listed and 
summarized by dose level. The safety variables will be listed and summarized for (1) 
subjects in the dose-finding portion, (2) subjects in the dose expansion cohort (DEC), and 
(3) all subjects in the study. 
10.5 
Analysis of Secondary Endpoints 
Secondary aims (includes the dose-finding and dose-expansion cohort): 
The dose-finding portion of the study is a dose de-escalation study of ibrutinib, and 
therefore, a small group of participants may potentially receive ibrutinib at a higher dose 
than the dose-expansion cohort. However, given this dose of ibrutinib may likely be 
efficacious, all participants in the pilot study will be analyzed for the secondary aims. 
However, the secondary aims will be analyzed and examined by dose level of ibrutinib. 
Toxicity data will be presented by type and severity for each dose cohort. Incidence of 
toxicity related dose reductions and treatment discontinuations will be summarized for each 
dose group. 
The complete response rates and their corresponding 95% confidence intervals will be 
calculated for participants with ARL treated with combination ibrutinib and R-da-EPOCH.  
The Kaplan Meier method will be used to estimate the 1- and 2-year PFS and OS of 
participants with ARL treated with combination ibrutinib and R-da-EPOCH, as well as, 
their corresponding 95% confidence intervals. This pilot study will not be powered to 
detect changes survival from addition of ibrutinib to R-da-EPOCH. 
The participant’s lymphoma COO will be determined by GEP (GCB, ABC, unclassifiable) 
and IHC (GCB, non-GCB). The concordances and discordances between classifications 
will be estimated with binomial proportions and their 95% corresponding confidence 
intervals. The response rates and survival as categorized by GEP or IHC will be compared, 
to see which analysis of COO best correlates with treatment response. Chi-square tests will 
be used to test the associations between 1) GEP (GCB, ABC, unclassifiable) with response 
rates and 2) IHC (GCB, non-GCB) with responses rate. The Kaplan Meier method will be 
used to calculate estimates of OS and PFS within GEP (GCB, ABC, unclassifiable) and 
within IHC (GCB, non-GCB), as well as their 95% confidence intervals. The log-rank test 
will be used to test differences with respect to OS and PFS within GEP and within IHC.  

 
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The percentage of participants who receive two or more cycles of R-da-EPOCH, and are 
able to continue on a minimum dose level of cyclophosphamide of -1 and above after dose 
adjustments for hematologic toxicities will be calculated. 
The average number of days per cycle participants are able to stay on planned dose of 
ibrutinib will be calculated. 
Descriptive statistics will be used to evaluate the changes in levels of HIV-1 viral reservoirs 
and EBV viral loads from baseline (before initiation of treatment), compared with 
treatment completion. If there are sufficient data, the binomial test of proportions will be 
used to test if the long term viral reservoir is either undetectable or below baseline in at 
least half of the participants. 
To assess the effect of ibrutinib and R-da-EPOCH on HIV latency reservoirs and correlate 
with degree of ITK inhibition, Pearson or Spearman correlation coefficients will be used, 
as appropriate. 
Descriptive statistics will be used to assess the effect of ibrutinib and R-da-EPOCH on B-
cell receptor signaling pathway including BTK activity. 
Descriptive statistics will be used to evaluate the effect of ibrutinib and R-da-EPOCH on 
T-cell receptor signaling via ITK activity. 
Descriptive statistics will be used to assess the soluble cytokine response to ibrutinib and 
R-da-EPOCH. 
For ibrutinib, doxorubicin, etoposide, and vincristine: relevant individual PK parameters 
will be estimated using non-compartmental or compartmental PK methods with the 
software WinNonlin. The PK variables will be tabulated and descriptive statistics (e.g., 
geometric means and coefficients of variation) and compared across dose levels (if 
applicable) using nonparametric statistical testing techniques. The PK variables will be 
tabulated and descriptive statistics (e.g., geometric means and coefficients of variation). 
Pharmacokinetic parameters (i.e., Css, Cl, and AUC) will be correlated with 
pharmacodynamics effects using nonparametric statistical testing techniques. Significance 
for comparisons will be at the p<0.05 level. 
 
 

 
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11.0 
ROLE OF DATA MANAGEMENT 
11.1 
CRF Instructions 
Access to the internet data entry system for this study, Advantage eClinical, and 
instructions for recording of study data on CRFs will be provided by the AMC ODMC at 
www.AIDSCancer.org. Participating institutions are responsible for submitting data and/or 
data forms via Advantage eClinical in accordance with the AMC Data Entry Guide and 
specific form instructions, within the timelines specified by the AMC’s Standards of 
Procedure for Site Performance Measures. 
11.2 
Data Quality 
It is the responsibility of the AMC ODMC to assure the quality of data for the study (See 
Appendix VII, AMC Data and Safety Monitoring Plan). This role extends from protocol 
development to generation of the final study database. 
11.3 
Data Monitoring 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS 
data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 
31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can 
be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review. 
11.4 
Collaborative Agreements Language 
The Collaborative Research Agreement is presented in Appendix II. 
 
 

 
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12.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
IRB Approval and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 
56) and/or Department of Health and Human Services (DHHS) regulations for the 
Protection of Human Subjects regulations (45 CFR Part 46) must be followed. IRB 
approval of the protocol and the informed consent form must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol and informed consent, before participant 
enrollment. The IRB must also approve any significant changes to the protocol and 
documentation of this approval must be sent to the AMC ODMC. The IRB must review 
the research project at least once every 365 days during the duration of the project. 
Continuing approval of the project must also be given in writing and provided to the AMC 
ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are participant to inspection during or after completion of the study. AEs 
must be reported to the IRB according to local procedures. The IRB should receive 
notification of completion of the study and final report within 3 months of study completion 
and termination. The Investigator will maintain an accurate and complete record of all 
submissions made to the IRB, including a list of all reports and documents submitted. 
Written informed consent will be obtained from the participant. The nature and significance 
of the risks associated with the study must be explained to the participant. The informed 
consent will describe the purpose of the study, the procedures to be followed, the risks and 
benefits of participation, all risks of the investigational agent(s) and/or study participation 
as listed in the model informed consent form, and all other elements of informed consent 
as required by regulation. A copy of the consent form will be given to the participant to 
keep. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
12.2 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. All amendments require 
approval by the IRB/IEC of the treating institution. A copy of the written approval of the 
IRB/IEC must be sent to the ODMC. 
 
 

 
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12.3 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium 
(AMC). As part of their contractual obligations, each participating site within the AMC 
and the AMC as a whole is required to assure that the participation of women and minority 
participants reflects the percentage representation of these populations in their geographic 
region and, for the AMC, the United States as a whole. As such, it is expected that the 
representation of participants on this trial will reflect the constitution of the respective 
populations. 
Table 12-A: Accrual targets 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or African American 
9 
14 
1 
4 
28 
White 
4 
8 
1 
3 
16 
More Than One Race 
1 
3 
2 
1 
7 
Total 
14 
28 
4 
8 
54 
 
 

 
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APPENDIX I: SCHEDULE OF EVALUATIONS 
The schedule of evaluations below applies to all participants on study. Baseline evaluations are to be conducted within 4 weeks prior to 
start of protocol therapy unless otherwise specified. Scans and x-rays must be done 4 weeks prior to the start of therapy. In the event 
that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next 
cycle of therapy. Labs, medical history, adverse event reporting, and physical exam (including vital signs, performance status, exam and 
weight) done prior to each cycle of treatment may be done on days -3, -2, -1, or 1 of each cycle. 
 
Screening/B
aseline 
Prior to 
Each 
Cycle 
Day 814 
Days 9, 
12, 15 
End of 
Cycle 2 
End of 
Cycle 4 
End of Treatment 
Evaluations (4-8 Weeks 
Post Day 1 of Cycle 6) 
Follow Up 
Evaluations 
Early 
Discontinuation 
Evaluations 
CTEP IND Agent ibrutinib 
 
X 
 
 
 
 
 
 
 
Participant Drug Diary (provide for new 
cycle, collect/review for prior cycle) 
 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Switch to non-moderate or strong 
CYP3A4 modulating antiretroviral 
(ARV) and medication regimen 
X10 
 
 
 
 
 
 
 
 
Medical history 
X 
X2 
 
 
 
 
X 
X8 
X 
Physical exam (including node exam and 
measurement)/Height/Weight/BSA 
X 
X2 
 
 
 
 
X 
X8 
X 
Vital signs 
X 
X2 
 
 
 
 
 
 
 
Performance status 
X 
X2 
 
 
 
 
X 
X8 
X 
CBC w/differential, platelets 
X15 
X2 
 
X1 
 
 
X 
X8 
X 
Serum chemistry 
X15 
X2 
 
 
 
 
X 
X8, 21 
X 
Serum magnesium 
X2 
X2 
 
 
 
 
X 
 
X 
Serum pregnancy test 
X20 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X2 
 
 
 
 
X 
X 
X17 
Radiologic evaluation via CT 
chest/abdomen/pelvis +/- neck 
X 
 
 
 
 
X4 
X4 
X18 
 
Radiologic evaluation via PET/CT  
X12 
 
 
 
 
 
X4 
 
X 
Tumor measurement 
X 
 
 
 
 
X4 
X4 
 
X 
MRI brain and spine (if clinically 
indicated) 
X 
 
 
 
 
 
 
 
 

 
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Screening/B
aseline 
Prior to 
Each 
Cycle 
Day 814 
Days 9, 
12, 15 
End of 
Cycle 2 
End of 
Cycle 4 
End of Treatment 
Evaluations (4-8 Weeks 
Post Day 1 of Cycle 6) 
Follow Up 
Evaluations 
Early 
Discontinuation 
Evaluations 
B-HCG within 7 days prior to cycle 1 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C serologies 
X 
 
 
 
X7 
X7 
X7 
X7 
X7 
Confirmation of HIV 
X 
 
 
 
 
 
 
 
 
T cell subsets (CD4, CD8) 
X 
 
 
 
X5 
 
X5 
X5 
X 
HIV-1 RNA viral load 
X 
 
 
 
X5 
 
X5 
X5 
X 
Quant Immunoglobulins 
X 
 
 
 
X5 
 
X5 
X5 
X 
LVEF (MUGA or ECHO) 
X 
 
 
 
 
 
 
 
 
Bone marrow biopsy and/or aspirate 
required if PET/CT is not performed 
X3 
 
 
 
 
 
X6 
 
 
Lumbar puncture21 
X15 
 
 
 
 
 
 
 
 
Tissue (block, core, or slides) from at 
least a core, and ideally an incisional or 
excisional biopsy (FFPE tissue 
acceptable) AND IHC slides for central 
pathology review (Appendix IX) 
X 
 
 
 
 
 
 
 
 
Pharmacokinetics (chemotherapy) 
 
X12 
 
 
 
 
 
 
 
Pharmacokinetics (ibrutinib, pre-dose) 
 
X12 
X12 
 
 
 
 
 
 
Cytokines 
X 
 
 
 
X9 
 
X9 
X9 
X9 
EBV viral load 
X 
 
 
 
 
 
X 
 
X 
BTK/ITK  
 
X12, 18 
 
 
 
 
 
 
 
ctDNA 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ACSR Donation (optional) 
X13 
 
 
 
 
 
 
 
 
 O Only if the participant has a normal hemoglobin or asymptomatic anemia, as determined by the investigator 
 O Optional 
NOTE: For participants enrolled after prior treatment, the off-study chemotherapy cycle counts towards the 6 cycles requirement. In these participants, only 5 
cycles of chemotherapy under protocol are required. For these participants, baseline assessments that were performed within the protocol timelines prior to the 
initiation of chemotherapy off study as per Section 8.1 will be accepted at study enrollment as the pretreatment baseline values. All laboratory tests to document 
eligibility must be performed prior to enrollment. Any other tests or evaluations for protocol requirements at baseline that were not performed prior to the initiation 
of chemotherapy (off study) must be collected after enrollment and prior to initiation of treatment under protocol. The off-study chemotherapy cycle should be 
counted in the current number of cycles for the purpose of identifying the studies required in Section 8.2 (except pharmacokinetics), and re-staging. 

 
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1. 
Blood counts: CBC with differential will be obtained prior to beginning each cycle (Day -3, -2, -1 or Day 1). CBC with differential will be obtained on or 
about days 9, 12, and 15 (± 3 days) or more frequently if clinically indicated. If by the second CBC, the nadir has been reached and the ANC is recovering, no 
further CBCs are necessary (i.e., 2 CBCs will suffice). If the participant does not obtain two lab counts on 2 nonconsecutive days at least 3 days apart within 
a week but ANC nadir on any cycle < 500/mm3, then we will assume the counts that would have been obtained are the same as the single nadir counts; however, 
clinical evidence of severe neutropenia/thrombocytopenia in absence of lab availability may be discussed by investigator with protocol chairs to determine 
subsequent cycle dosing. CBCs may be stopped after absolute neutrophil count or platelet recovery after the final cycle of study therapy. For severely immune 
compromised participants (CD4 < 100 cell/mm3) it is advisable that a CBC with differential be obtained on or about day 15 of each cycle in order to determine 
length of prophylactic antibiotic treatment. 
2.  To be performed within 3 days prior to the start of each cycle of chemotherapy. Rituximab may proceed while these results are pending provided there is no 
prior history of renal insufficiency or hepatotoxicity, and no evidence of jaundice on physical exam. 
3  
Bone marrow biopsy or aspirate for histology and determination of percent bone marrow involvement is required within 6 weeks prior to participant registration 
only if PET/CT not performed and there was no prior documentation of bone marrow involvement by lymphoma. Based on the Lugano criteria, PET/CT scan 
indicating bone or marrow involvement is sufficient to designate advanced-stage disease, and a bone marrow biopsy is not required. If a bone marrow is 
necessary, unilateral bone marrow biopsy/aspirate is allowed, with an aggregate core length of 2 cm, either from one site or bilateral sites. If feasible, a portion 
of the bone marrow biopsy and aspirate will be sent for cytogenetic analysis. 
4.  Repeat imaging study and tumor measurement/evaluation at indicated times. Participants who achieve a CR after 4 cycles of treatment on all arms will receive 
2 additional chemotherapy cycles to complete a total of 6 cycles. Participants with PR at the end of cycle 4 may continue on the protocol and complete a total 
of 6 cycles of chemotherapy or be removed from study at the discretion of the investigator. Participants who achieve a CR or PR at cycle 4 should have repeat 
imaging studies performed between 4-8 weeks after Day 1 of cycle 6 or the final cycle of chemotherapy in order to confirm response. PET/CT scan is 
recommended within 4-8 weeks of treatment discontinuation if treatment was stopped after cycle 4 and prior to cycle 6 due to excessive toxicity (do not repeat 
if it was already done after cycle 4, and if no further treatment was given after cycle 4). Diagnostic CT scans should be repeated, including assessment of 
extranodal sites, at the end of therapy. If possible, measurement of sites of disease present. However, if CT scans are not feasible, this will not be a protocol 
violation. 
5.  CD4, CD8 cell count, HIV viral load, quantitative immunoglobulins within 7 days prior to the end of cycle 2 (prior to start of cycle 3 OR day 1 of Cycle 3), 
and 4-8weeks, 6 and 12 months (+/- 4 weeks) after the completion of chemotherapy. 
6.  Participants with lymphomatous bone marrow involvement are required to have a repeat bone marrow exam only if all other evidence of disease has resolved 
(CR) and participant is unable to receive PET/CT scan restaging. 
7.  HBV and/or HCV viral load in participants who were HBV antigen or core antibody positive, or HCV antibody positive with undetectable viral particles or 
viral load at baseline, at the end of cycles 2; 4; and 4-8 weeks post Day 1 of cycle 6. If discontinuing treatment early, tests will be performed within 2 months 
following completion of chemotherapy. 
8.  Indicated study should be repeated post-therapy (after the completion of chemotherapy) every 3 months (-2 weeks to +4 weeks for the first 3-month visit, and 
+/- 4 weeks for the subsequent 3 month visits) for 2 years. These studies are required at these intervals until disease progression or death (whichever occurs 
first). Participants with stable disease after 4 cycles (i.e., who did not achieve at least a PR) or who have disease progression and are alive will be removed 
from protocol therapy and the examinations and tests listed in Section 8.5 performed.. During the third through the fifth years, only progression and survival 
should be reported every 6 months counting from day 21 of the final cycle of chemotherapy (+/- 4 weeks). 
9.  Cytokines will be obtained at baselines, after cycle 2; and 1, 6, 12 months after completion of therapy. 

 
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10. If on a strong or moderate CYP3A4 modulating medication(s), including ARV regimen, participant must be switched to an alternative non-strong or moderate 
CYP3A4 modulating ARV and medication regimens at least 1 week or 7 days before administration of protocol therapy due to effects on ibrutinib. 
11.  PET/CT, if feasible. If PET/CT is not feasible, this will not be a protocol violation.  
12.  Cycle 1 only. See tables “Overview of Biomarkers and Correlative Studies” and “Ibrutinib Levels” below for full details of timing of blood draws 
13.  Optional 
14.  Within 2 weeks 
15.  Lumbar puncture (LP) for Dose-Finding Cohort: Routine CSF studies including cytology and flow cytometry. No patients with known or suspected 
parenchymal brain, spinal cord disease, or leptomeningeal disease will be allowed on study.  
LP for Dose-Expansion Cohort: Routine CSF studies including cytology and flow cytometry. In the dose-expansion portion of the study, no patients with 
known or suspected parenchymal brain or spinal cord disease, or suspected/symptomatic leptomeningeal disease will be allowed on study. Asymptomatic 
leptomeningeal disease will be allowed in the dose-expansion cohort. 
16.  Continue evaluation until the adverse event(s) is resolved or until determined to be permanent. 
17.  CT scans every 6 months (+/- 6 weeks) for 2 years. Frequency or length of follow up imaging otherwise as clinically indicated.  
18.  BTK/ITK occupancy pre-ibrutinib and 4-hours post-ibrutinib may ONLY be drawn on Monday-Thursday. If Cycle 1 is started on Friday-Sunday, this 
exploratory lab is deferred; this will not be a protocol deviation. 
19.  Within 7 days of cycle 1 
20. During the first two years of follow up, only serum renal and liver functions tests including BUN, creatinine, total bilirubin, ALKP, AST, and ALT are required. 
21. If a lumbar puncture with or without intrathecal chemotherapy is planned on study, consider the timing of the lumbar puncture relative to anticipated neutrophil 
and platelet nadirs. For a lumbar puncture, a short hold (up to 3 days, suggested 2 days prior and 1 day post) should be considered based on the clinical situation 
of the subject, including assessment of underlying lymphoma and bleeding risk. In cases in which there may be a higher risk of bleeding (i.e., history of difficult 
LP access), it may be useful to perform the LP under fluoroscopy. Ommaya reservoir access will not require ibrutinib to be held due to low risk of bleeding 
complications. CNS prophylaxis will be required in participants who meet the following criteria: lymphomatous involvement of bone marrow, testes, sinuses, 
or epidural regions. 
 
 

 
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Overview of Biomarkers and Correlative Studies 
Sample 
Collection 
Baseline/ 
Pretreatment 
Cycle 1 
Subsequent 
Cycles 
Treatment 
Discontinuation 
Handling and 
Shipping 
EBV viral load  
Whole blood 
(separate PBMC 
and plasma) 
X 
 
 
4 weeks after 
completion of 
therapy 
Appendix X 
BTK 
Whole blood 
(separate PBMC) 
X 
Post-treatment 4 hours after 
first dose of ibrutinib in Cycle 
1 only, Mon-Thurs ONLY 
 
 
Appendix XIV 
ITK 
Whole blood 
(separate PBMC) 
X 
Post-treatment 4 hours after 
first dose of ibrutinib in Cycle 
1 only, Mon-Thurs ONLY 
 
 
Appendix XIV 
Ibrutinib 
pharmacokinetics  
Plasma (heparin) 
 
See “Ibrutinib Levels” table 
below for timing 
 
 
Appendix XIII 
Etoposide and 
vincristine 
pharmacokinetics 
Plasma (EDTA) 
 
Collect between 24-48, and 
72-96 hours after the start of 
the infusion on Cycle 1 only 
 
 
Appendix IX 
Doxorubicin 
pharmacokinetics 
Plasma (heparin) 
 
Collect between 24-48, and 
72-96 hours after the start of 
the infusion on Cycle 1 only 
 
 
Appendix IX 
Cytokines 
Whole blood 
(separate plasma) 
X 
 
After cycle 2 
1, 6, 12 months 
after completion 
of therapy 
Appendix XII 
Circulating Tumor 
DNA 
Whole Blood 
X 
 
After Cycle 2, 
and 4 
Within 4 weeks 
of treatment 
discontinuation 
Appendix XIV 
 

 
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Ibrutinib Levels 
Sample 
Collection 
Cycle 1  
Handling and Shipping 
Pre-Dose 
Pre-Dose Day 8 
Ibrutinib Peripheral Blood 
Plasma (Heparin) 
X 
X 
See Appendix XIII 
 
 
Ibrutinib Levels (if significant toxicities are seen in the first week) 
If a DLT (as defined by Section 4.2) is observed, an expanded PK profile will be obtained on Day 8, 0.5, 1, 2, 4, 6, 8, 
and 24 hr (Day 9) after ibrutinib is administered. 
Sample 
Collection 
Cycle 1 Day 8* 
Handling 
and Shipping 
Pre-Dose 
0.5 hour 
post-dose 
1 hour 
post-dose 
2 hour 
post-dose 
4 hour 
post-dose 
6 hour 
post-dose 
8 hour 
post-dose 
24 hour  
post-dose  
(Day 9) 
Ibrutinib 
Peripheral 
Blood 
Plasma 
(Heparin) 
 
X 
X 
X 
X 
X 
X 
X 
See Appendix XIII 
*Each time point for the Day 8 expanded PK profile should be taken within a ± 10 minute window.

 
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APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT 
The agent, ibrutinib (hereinafter referred to as “Agent(s)”), supplied by CTEP, DCTD, NCI used 
in this protocol is provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) 
between Pharmacyclics, Inc. (hereinafter referred to as Collaborator(s)) and the NCI Division  
of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in  
addition 
to 
the 
provisions 
in 
the 
Intellectual 
Property 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the permission of the NCI. 
If a copy of this protocol is requested by a participant or participant’s family member participating 
on the study, the individual should sign a confidentiality agreement. A suitable model agreement 
can be downloaded from: http://ctep.cancer.gov. 
For a clinical protocol where there is an investigational Agent used in combination with (an)other 
investigational Agent(s), each the participant of different collaborative agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data.): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health Information 
set forth in 45 C.F.R. Part 164. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 

 
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Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this 
clinical trial. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media 
presentation should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
Fax: 301-402-1584 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 

 
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APPENDIX III: PERFORMANCE STATUS SCALES 
Karnofsky Performance Scale 
ECOG Performance Status Scale 
Percent 
Description 
Grade 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
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). 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 
 
 

 
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APPENDIX IV: INFORMATION ON POSSIBLE DRUG INTERACTIONS 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
[Note to investigators: This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment. A convenient wallet-sized information card is also included for 
the patient to clip out and retain at all times.] 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent ibrutinib. This clinical trial is sponsored by the National Cancer Institute. 
This form is addressed to the patient but includes important information for others who care for 
this patient. 
Ibrutinib interacts with many drugs that are processed by your liver. Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is also 
very important to tell them if you stop taking any regular medicine, or if you start taking a new 
medicine while you take part in this study. When you talk about your medicine with your study 
doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These are 
the things that you and they need to know: 
Ibrutinib interacts with a certain specific enzyme in your liver. 
• This enzyme is called CYP3A4. This enzyme breaks down ibrutinib, gradually reducing the 
level of the active drug in your system. 
• Other medicines may affect the activity of the enzyme. Ibrutinib must be used very carefully 
with these medicines, or you may need to switch to alternate medications. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the effectiveness 
of the drug, while substances that decrease the enzyme’s activity (“inhibitors”) could result 
in high levels of the active drug, increasing the chance of harmful side effects. This includes 
some drugs including antifungal medications. 
o Some HIV therapies include medications which are CYP3A4 inducers (e.g., efavirenz or 
etravirine) or inhibitors (e.g., ritonavir or cobicistat). This study will carefully evaluate the 
safety and tolerability of ibrutinib in patients taking these specific medications. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. Your prescribers should look at this web site 
https://crediblemeds.org/healthcare-providers/ or consult a medical reference to see if any 
medicine they want to prescribe is on a list of drugs to avoid. 
• In vitro studies indicated that ibrutinib is not a substrate of P-gp (p-glycoprotein) or BCRP 
(breast cancer resistance protein) transporters but is an in vitro inhibitor of P-gp and BCRP. 
Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1) but 
may inhibit BCRP. Ibrutinib may have an effect on P-gp or BCRP substrates in the GI tract 
due to higher local concentrations after an oral dose. Co-administration of oral narrow 

 
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therapeutic index P-gp or BCRP substrates (e.g., digoxin, methotrexate) with ibrutinib may 
increase their blood concentration. 
• Before you begin the study, your study doctor will work with your regular prescriber to switch 
any other medicines that are considered “moderate or strong inhibitors or inducers of 
CYP3A4." It is vitally important that you provide your study doctor with a complete list of 
your medications. Please be very careful! Over-the-counter drugs have a brand name on the 
label—it’s usually big and catches your eye. They also have a generic name—it’s usually small 
and located above or below the brand name, and printed in the ingredient list. Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse interaction.  
• Be careful: 
o If you take acetaminophen (Tylenol) regularly: You should not take more than 3 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age. Read labels 
carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit, or if you drink Seville orange juice or eat 
Seville oranges: Avoid these until the study is over. 
o If you take herbal medicine regularly: You should not take St. John’s wort while you are 
taking ibrutinib. 
Other medicines can be a problem with your study drugs. 
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement. 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is 
_____________________________________ 
and he or she can be contacted at  
_____________________________________ 
Ibrutinib interacts with a specific liver enzyme called CYP3A4/5, and 
must be used very carefully with other medicines that interact with this 
enzyme. 
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
strong inducers or inhibitors of CYP3A4/5. 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a list 
of drugs to avoid, or contact your study doctor. 
 
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
ibrutinib. This clinical trial is sponsored by the NCI. Ibrutinib 
interacts with drugs that are processed by your liver. Because of this, it 
is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement.  

 
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APPENDIX V: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. The use 
of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These shippers may 
be ordered at the SAF-T-PAK website: www.saftpak.com. The following instructions below are 
for use with the recommended STP-210 shipper. If using another federally approved diagnostic 
shipper, please follow instructions provided for that specific shipper. 
NOTE: Specimens MUST BE SHIPPED Mondays through Thursdays as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS OR SUNDAYS in 
the ACSR. 
A. SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
BLOOD SPECIMENS 
Draw two 8.5 cc (mL) yellow top [acid citrate dextrose (ACD)] tubes from study 
participant. With a black, water resistant, sharpie pen, label each specimen with the 
following information: 
• AMC Protocol # 101 
• AMC Participant ID# 
• Date and time of collection 
• Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue 
• Specimen purpose: Donation 
Specimen shipment 
• Seal the tops of the two 8.5 cc (mL) yellow tops with parafilm. 
• Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
• Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
• Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal”. 
• Place poly-bag containing tubes into the white TYVEK bag and seal. 
• Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the 
cardboard shipper with clear packing/shipping tape. 
• Please refer to the Manual of Procedures and AMC Operations website’s 
(www.AIDSCancer.org) Shipping tab for more information and the FedEx account 
details.  

 
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Blood specimens should be shipped by overnight express at room temperature to: 
Sylvia Silver, DA 
AMC Biorepository 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: 202-994-2945 
Fax: 202-994-5056 
Email: ssilver@gwu.edu 
• Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or make 
a paper label with ‘UN#3373” and affix it to the shipper. 
• Make certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in mL and affix to 
the shipper. 
• Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
• RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
• Place the box in the FedEx pickup area at your site or call to request a package pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON FRIDAY, 
SATURDAY OR SUNDAY 
Preparation of plasma and mononuclear cells 
Refer to the ACSR’s SOP on Separation of Plasma and Mononuclear Cells on the AMC 
Operations web site for instructions on preparing plasma and PBMC aliquots. It is 
preferable that separation occurs as soon as possible. If necessary, whole blood in ACD 
(yellow top tubes) can be held at room temperature for no more than 24 hours. 
Freeze the cell suspension in 0.5 mL aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires the 
use of packaging acceptable for dry ice and Class 9 label with weight of dry ice written 
on package. 

 
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PREPARATION OF TISSUE SAMPLES 
Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice 
immediately. The specimens may stay on dry ice until being transferred to a -80ºC freezer. 
Tissue specimens for donation may be batched for shipping after storage in -80ºC freezer.  
*NOTE: Specimens can only be accepted Monday through Thursday. Therefore, 
specimens can only be shipped Sunday-Thursday for delivery the next day. Shipping 
frozen tissue requires the use of packaging acceptable for dry ice and Class 9 label with 
weight of dry ice written on package. 
TISSUE specimens should be shipped by overnight express to: 
Sylvia Silver, DA 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 
C. RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC Advantage 
eClinical system. The GlobalTraceSM shipment manifest must accompany all specimen 
shipments. 
 
 

 
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APPENDIX VI: ACSR INFORMED CONSENT 
Study Title for Study Participants: 
Collecting Blood and Tissue Sample Donations for 
Research for HIV/AIDS-Related Cancers 
Official Study Title: 
Biospecimen Collection and Donation to the AIDS  
and Cancer Specimen Resource (ACSR) 
What is the usual approach to donate blood and/or tissue to the ACSR? 
You are being asked to donate blood and/or tissue for future research. You are being asked to 
donate your blood and/or tissue samples to the ACSR because you have HIV infection and are 
being considered for participation in an AIDS Malignancy Consortium (AMC) clinical trial. The 
AMC works with the ACSR to collect donated samples from persons with HIV infection for 
research studies. People who do not take part in an AMC clinical trial can also donate samples to 
the ACSR. 
What are my other choices if I do not take part in this study? 
It is your choice to donate or not donate your blood and/or tissue samples. You may still take part 
in the AMC clinical study if you choose not to donate blood or biopsy samples to the ACSR.  
You may also choose to donate: 
• Blood but not tissue, or 
• Tissue but not blood. 
What is the AIDS and Cancer Specimen Resource (ACSR)? 
The ACSR is a biorepository (biobank) that collects human biological specimens (samples) from 
persons who have HIV or cancers related to HIV/AIDS. The ACSR stores the samples and some 
of the donor’s medical information for use by researchers in future research studies. The National 
Cancer Institute (NCI) has set up the ACSR to assist researchers locate samples needed for their 
studies. 
The ACSR has an independent research panel that approves researchers’ requests to use the 
ACSR’s stored samples for research studies. The ACSR only gives samples and medical 
information to researchers after their projects have been approved. Researchers may use the 
samples to study cancers and other diseases associated with HIV disease. This information may 
help us learn more about the causes of HIV-related diseases and cancers and to develop better 
ways to screen, diagnose, and treat them. 
Why is this study being done? 
The purpose of this study is to collect samples for the ACSR for future research studies. 
Researchers may study samples from the ACSR in combination with hundreds or thousands of 
other samples to explore how biologic or genetic factors may be related to HIV-related diseases 
and cancer. The information might help doctors in the future to identify who will or will not benefit 
from treatment. The samples may be used to learn more about how HIV-related diseases and 
cancers develop. The samples may also lead to new tests or discoveries. Finally, researchers may 
use the samples to study the genetic material from your cancer tissue and compare it to the material 
from your normal tissue (blood) to try to find the differences that exist. These studies could make 
it possible to identify many of the changes that are associated with diseases such as cancers. It may 

 
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also help us tailor treatments to a patient's unique genetic make-up and/or to the genetic markers 
of the tumors. 
What extra tests and procedures will I have if I take part in this study? 
1) If you agree to donate blood, the medical team will draw about 2 tablespoons of blood to 
give to the ACSR. This takes about 10 minutes. 
2) If you agree to donate tissue, your leftover tissue biopsy material will be donated to and 
stored by the ACSR. 
3) Some of your clinical information will be released to the ACSR and entered into their 
database. The information given to the ACSR will not include your name or any information 
that could personally identify you. 
We will only give the ACSR tissue that is left over after making decisions about your treatment or 
diagnosis. The study doctor will not take any extra biopsies just for the ACSR. 
We cannot tell you right now what future research these samples would be used for. Instead, we 
are asking that you give approval to give your samples for future testing without contacting you 
again. The results of whatever research is done on your samples will not be told to you or your 
doctor. The results of the tests will not be placed in your study records. 
How long will ACSR keep my samples? 
Your blood and/or tissue sample will be stored until it is used for research. The samples may be 
stored indefinitely. 
What possible risks can I expect from taking part in this study? 
• Blood Draw: The risks of drawing blood include temporary discomfort from the needle stick, 
bruising, and, rarely, infection. 
• Confidentiality: The ACSR will receive study samples with code numbers. There will be no 
personal identifiers on the samples. Then the samples will be re-labeled with a barcode and 
stored for future testing. While the ACSR and researchers who study ACSR samples will have 
no information that could identify you, there is a risk that someone could use information from 
genetic studies to trace your samples back to you. The researchers believe the chance that 
someone will identify you is very small, but the risk may change in the future as people come 
up with new ways of tracing information. In some cases, this information could be used to 
make it harder for you to get or keep a job. There are laws against misuse of genetic 
information, but they may not give full protection. The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
Let your study doctor know of any questions you have about these possible risks. You can ask the 
study doctor questions about side effects at any time. 
What possible benefits can I expect from taking part in this study? 
This study is unlikely to help you. This study may help us learn things that may help people in the 
future. 
The information may help to identify those who are at increased risk and those who may benefit 
from targeted treatment and screening. In turn, these studies could help find ways to prevent or 
improve treatments for HIV-related diseases and AIDS-related cancers. 

 
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Can I stop taking part in this study? 
Yes, you may withdraw your samples from the ACSR at any time. You may contact your AMC 
study coordinator if you would like to withdraw your samples. The coordinator can ask in writing 
that your sample be removed from research use and that any identifiable sample and information 
still in their possession be destroyed. However, if any research has already been done using some 
of your samples, the data will be kept and analyzed as part of those studies. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
What are the costs of taking part in this study? 
There will be no cost to you for donating your samples to the ACSR. You will not be paid for 
taking part in this study. 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor. The AMC will not offer to pay for medical treatment for injury. Your 
insurance company may not be willing to pay for study-related injury. If you have no insurance, 
you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to seek payment 
for injury even though you are in a study. 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, the researchers will do 
their best to make sure that any information that is released will not identify you. Some of your 
health information, and/or information about your specimen, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of these 
organizations are: 
• The AIDS Malignancy Consortium (AMC) 
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Office for Human Research Protections and the National Cancer Institute in the U.S. 

 
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To protect your privacy, the AMC does not keep identifying information that links study 
participants to specific samples. As a result, the AMC and ACSR will not be able to link the results 
from studies that use your samples back to you. Thus, information, including genetic information, 
that researchers may obtain in studies that use your samples may not be directly linked to you and 
will not be placed in your medical record. However, some clinical and basic information obtained 
confidentially from the AMC will be attached with these data. It is possible that findings may one 
day help, for example, people of the same race or sex as you. It also is possible that genetic factors 
might come to be associated with people who have HIV and cancer through these kinds of studies. 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at 1-800-4-CANCER (1-800-422-6237). 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of study 
doctor[s]) at __________________ (insert telephone number). 
Please circle your answer to show whether or not you would like to take part in each option: 
1) I agree to donate my blood to the ACSR for future research that may be used to learn about, 
prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
NO 
2) I agree to donate my blood to the ACSR for future research that may include genetic testing to 
learn about, prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
NO 
3) I agree to donate some of my tissue biopsy material that is not required for my treatment or 
diagnosis to the ACSR for future research that may be used to learn about, prevent, diagnose, 
or treat HIV-related diseases and cancer. 
YES 
NO 
4) I agree to donate some of my tissue biopsy material to the ACSR for future research that may 
include genetic testing to learn about, prevent, diagnose, or treat HIV-related diseases and 
cancer. 
YES 
NO 

 
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My Signature Agreeing to Take Part in the Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my 
questions have been answered. I will be given a signed copy of this form. I agree to take part in 
the optional study.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
Signature of person(s) conducting the informed consent discussion________________________ 
 
Date of signature_____________________________________ 
 
 

 
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APPENDIX VII: AMC DATA AND SAFETY MONITORING PLAN 
(Version 8.0  16JULY2020) 
 
Introduction 
The AIDS Malignancy Consortium (AMC) Data and Safety Monitoring Plan (DSMP) outlines the 
measures employed by the group to monitor the safety of participants and ensure the data validity 
and integrity for all clinical trials it conducts. This includes methods to: 1) monitor the progress of 
trials and the safety of participants; 2) comply with regulatory requirements for adverse event (AE) 
reporting; 3) processes for trial termination or temporary suspension and major modifications; and 
4) plans for ensuring data accuracy and protocol compliance. As the AMC conducts protocols of 
varying research phase, region of conduct, IND sponsor (AMC investigator, CTEP, or industry-
sponsored) and clinical data entry system use, this plan addresses broad processes applying to the 
range of trial designs and requirements. Refer to the individual AMC protocol to identify the 
applicable study characteristics for the relevant requirements described in this plan. 
Monitoring the Progress of Trials and the Safety of Participants 
Routine and expedited AE reporting 
All AMC protocols that collect safety data adhere to the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm), as applicable to the clinical 
protocol. AEs are to be recorded in the source documents, assessed by a clinical investigator for 
the AE reporting criteria, and promptly reported in the clinical data entry system as required by 
each protocol. For AMC trials conducted under a CTEP IND and AMC trials conducted within the 
U.S., all AEs that meet the NCI’s expedited reporting requirements are reported to the NCI via the 
CTEP Adverse Event Reporting System (CTEP-AERS) web application, either directly or through 
integration with Medidata Rave where this system is employed for AMC protocols. Use of this 
system ensures notification to the protocol chair and Investigational Drug Branch (IDB) at CTEP, 
as required for trials conducted under a CTEP IND, and a uniform expedited reporting and safety 
review process for AMC domestic trials. The system may also be programmed to include sponsor 
notification as required for trials with industry support. Alternate process for expedited AE 
reporting to the AMC protocol chairs and AMC Operations and Data Management Center 
(ODMC) within the clinical data entry system (AdvantageEDC or Advantage eClinical only) may 
be defined in the protocol for select trials (international studies and The ANCHOR Study). 
All serious adverse events (SAEs) received by the AMC ODMC will be reviewed by the AMC 
medical monitor at the AMC ODMC for consideration of individual participant safety, safe trial 
conduct, data reporting quality for AE term selection, and appropriate application of the regulatory 
criteria for seriousness, expectedness, and relatedness to the investigational therapy. If alternate 
procedures are followed for SAE review, the process for adequate medical monitoring will be 
defined in the AMC protocol and the Transfer of Regulatory Obligations (TORO) with the sponsor. 
AMC medical monitor review includes review of the CTEP-AERS report before CTEP submission 
for IDB review (if applicable), or review of the SAE report in the data entry system for trials not 
using CTEP-AERS for expedited reporting. The IND sponsor or its designee will issue the 
determination as to whether the AE requires IND safety reporting to FDA as a serious and 
unexpected suspected adverse drug reaction (SUSAR). For protocols not conducted under an IND, 

 
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in the event of disagreement between the reporting physician and the AMC medical monitor 
regarding the relationship of the AE to the investigational agent(s) (i.e., determination of whether 
the attribution is unrelated or unlikely, or possible, probable, or definite), the AMC medical 
monitor will provide the final determination of the relationship. IND safety reporting to FDA is 
performed by CTEP for trials conducted under a CTEP IND; IND safety reporting is performed 
by the sponsor or sponsor’s designee (AMC ODMC or other party defined in the study agreement 
or TORO) for IND studies sponsored by AMC investigators or industry sponsors. 
Expedited reporting to the Institutional Review Board (IRB) 
For trials subject to local IRB review, the site principal investigator is responsible for ensuring that 
expedited AE reports for its trial participants and any unanticipated problems that affect the local 
institution only are submitted to the local IRB of the reporting institution, per the local IRB’s 
requirements for such reporting. For studies reviewed by the NCI CIRB, the protocol chair will 
render a determination as to whether a SAE or other problem constitutes a trial-wide unanticipated 
problem that requires reporting to the NCI CIRB; reporting will occur per the NCI CIRB’s 
standards of procedure.  
To comply with investigator notification requirements for IND studies under 21 CFR 312.32 and 
312.55, IND safety reports from all trials the AMC conducts and reports from external sponsors 
investigating the same agents are made available to all investigators upon receipt from the sponsor 
or its designee, either via the password-protected section of the AMC Operations web site (AMC 
trials subject to local IRB review only) or the CTSU website (trials subject to CIRB review/CTEP 
IND agents). The site clinical investigator responsible for the applicable AMC protocol(s) is 
responsible for reviewing any IND safety reports received and documenting submission to the IRB 
of record (if required by local policy) within the timeline defined by the Clinical Trials Monitoring 
Branch (CTMB) audit guidelines. 
Procedures for monitoring trial progress and pharmacovigilance 
For trials using AdvantageEDC or Advantage eClinical for clinical data entry, the AMC ODMC 
provides on demand tabular listings of all reported AEs and SAEs on a participant level to the 
protocol chair and co-chair(s) for review via the password-protected section of the AMC 
Operations web site, www.AIDScancer.org. For trials using OPEN and Medidata Rave for clinical 
data collection, data listing will be made available using that system. Summary reports of AEs by 
frequency and relationship to the investigational agent(s) are provided to all AMC investigators 
and their staff It is the responsibility of each site to provide trial-specific AE listings to their 
respective IRB, if required by its policies. For blinded studies, the AE and SAE listings are 
reviewed and tabulated without treatment assignment. 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site. The progress of each AMC trial is reviewed regularly by the protocol chair and 
also by the appropriate Scientific Working Group (SWG) during scheduled conference calls 
(monthly SWG calls and as required, protocol-specific monitoring conference calls). Summary 
accrual, summary AE, and individual SAE reports are provided to SWG leadership and protocol 
chairs to monitor participant safety during these monthly calls. 
The AMC medical monitor reviews listings of all reported AEs on a quarterly basis for assuring 
compliance with the protocol requirements for AE reporting and the identification of any safety 
concerns (individual AE or increased frequency/severity of expected AEs) for the agents under 

 
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investigation. Findings from these reviews are communicated to the protocol chairs and all AMC 
investigators, and posted to the AMC Operations web site. 
Data and Safety Monitoring Board Review (DSMB) review 
The AMC has formed an independent Data and Safety Monitoring Board (DSMB) for AMC trials 
and for the ANCHOR Study. As required by NCI policy, the AMC requires DSMB review for all 
phase III randomized trials. All other clinical trials that the AMC initiates will be reviewed by the 
AMC ODMC and AMC Statistical Center during protocol development to issue a recommendation 
as to whether the study requires DSMB oversight, which will require the approval of the AMC 
Executive Committee. This determination will be based on the phase of the study, experimental 
design, risk posed by the investigational approach, extent of data available on the safety of an 
investigational agent, risk posed by the natural course of the health condition under research, and 
the categories of vulnerable populations involved. The involvement of a DSMB in reviewing an 
AMC protocol will be identified in each clinical protocol as approved CTEP and, as applicable, 
the NCI CIRB. 
Regarding the composition of the AMC DSMB, voting members usually include physicians, 
statisticians, an ethicist, and a patient advocate. All voting members have no other affiliation to 
the AMC, and are appointed by the AMC Executive Committee with the approval of the OHAM 
Director. Nonvoting members are the AMC group statistician, the protocol statistician, an AMC 
ODMC staff member, two representatives (normally a clinician or statistician) from CTEP, and 
the grant program directors from the NCI Office of HIV and AIDS Malignancy (OHAM). 
The DSMB reviews all applicable AMC studies in accordance with the National Cancer Institute’s 
Policy for Data and Safety Monitoring. Confidential reports of all trials under review are prepared 
by the AMC group statistician with support from the AMC ODMC. A written report containing 
the current status of each trial monitored, and when appropriate, any toxicity and outcome data, 
are sent to DSMB members by the AMC ODMC within the timelines specified by the DSMB 
charter. This report addresses specific toxicity issues and any other concerns about the conduct of 
the trial, as defined by the protocol plan for DSMB review. The report may contain information 
for the DSMB to render determinations for participant safety, early trial termination, results 
reporting, or continuing accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB chair to 
the AMC group chair and AMC ODMC. The DSMB report contains recommendations on whether 
to close each study reviewed, whether to report the results, and whether to continue accrual or 
follow-up. A primary recommendation (e.g., continue with no change; recommended or required 
modification; stop) must be included in the document. The group chair or designee is then 
responsible for notifying the protocol chair and relevant SWG chair before the recommendations 
of the DSMB are carried out. In the unlikely event that the protocol chair does not concur with the 
DSMB, then the OHAM program directors and the NCI division director or designee must be 
informed of the reason for the disagreement. The protocol chair, relevant SWG chair, group chair, 
DSMB chair, and NCI division director or designee will be responsible for reaching a mutually 
acceptable decision about the study. CTEP approval of a protocol amendment will be required 
prior to any implementation of a change to the study. 
Following a DSMB meeting, the DSMB’s recommendations are provided to all AMC investigators 
and staff. It is each site principal investigator’s responsibility for conveying this information to its 
local IRB as relevant for its protocol participation. For trials reviewed by the NCI CIRB, the AMC 

 
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ODMC will support notification to the CIRB as required per its procedures. 
Cohort trial reviews not subject to DSMB review 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the protocol chair, AMC medical monitor, and protocol statistician determine 
whether these criteria have been met based on a review of all safety data for the protocol-defined 
evaluation period. If applicable for phase II trials, stopping the trial for toxicity or efficacy, or 
suspending enrollment pending observation of responses in a multi-stage phase II trial, is based on 
meeting criteria stated in the protocol, and the protocol chair, AMC medical monitor, and protocol 
statistician determine whether these criteria have been met. 
Plans for Assuring Compliance with Requirements Regarding AE Reporting 
The protocol chair, AMC group chair, and the AMC ODMC share responsibility in assuring that 
participating investigators comply with applicable regulatory and protocol requirements for AE 
reporting. The AMC site principal investigator certifies compliance with NCI and FDA 
requirements for trial conduct by signing the site subaward agreement for the grant and the AMC 
Adherence Statement for site membership; clinical investigators also certify compliance in 
completing the protocol signature page for each protocol active at the site, and Form FDA-1572 
for CTEP investigator registration, and also for AMC IND studies sponsored by AMC 
investigators or industry sponsors. Protocol compliance with AE identification, assessment and 
reporting requirements is assessed by the AMC ODMC using several methods: 1) programmed 
system checks and messages to instruct the site to complete routine and/or expedited reporting 
when certain criteria are reported in the clinical data entry system; 2) programmed data reports 
provided to the protocol chairs that identify reports requiring expedited AE reporting; 3) remote 
review of data entry or data reports to ensure compliance with protocol and NCI AE reporting 
requirements; 4) AMC medical monitor review described in the section above; and, 5) routine site 
audits by reviewing the site’s source documentation. 
The clinical data entry systems used for AMC studies include the Oncology Patient Enrollment 
Network, OPEN for enrollment, and Medidata Rave for clinical data entry for enrolled 
participants; trials activated before September 1, 2020 or that involve only AMC international sites 
may be reported in AdvantageEDC/Advantage eClinical, a web-based data entry and enrollment 
system. These data entry systems are programmed to notify the site investigator, protocol chair, 
AMC medical monitor, and AMC ODMC via email in the event that a site reports an AE that 
meets expedited reporting criteria to NCI and/or FDA. Additional reporting conditions may be 
programmed depending on the sponsor reporting requirements of a given protocol (e.g., adverse 
events of special interest [AESI]). If the site does not follow with an expedited report, the AMC 
ODMC contacts sites to request compliance with reporting requirements. Additionally, the 
protocol chair, AMC ODMC, and the AMC medical monitor review reported AEs on a routine 
basis to identify AEs reported by sites that require expedited reporting. The protocol chair, AMC 
SWG chairs, AMC group chair, and IND sponsors have general oversight for assuring that routine 
and expedited adverse reporting requirements are met by the responsible parties. 
For studies monitored by CTEP using the Data Mapping Utility (DMU), cumulative protocol- and 
patient-specific data will be submitted weekly to CTEP electronically via the DMU. For trials 
monitored by the NCI’s Clinical Data Update System (CDUS), AE information is transmitted 
electronically to NCI on a quarterly basis. For trials monitored by NCI’s Clinical Trials Monitoring 
Service (CTMS), AE information is transmitted electronically to NCI every two weeks. 

 
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Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible 
for the Grant 
In the event that temporary or permanent suspension of a trial, or major modification to the 
protocol is under consideration, the protocol chair will convene the AMC ODMC, AMC Statistical 
Center, and SWG chair by conference call to discuss the options. Suspension actions will also be 
reviewed by the AMC Executive Committee for program oversight and direct communication of 
the action with the OHAM program directors. For phase III trials, closure decisions are typically 
rendered by the AMC DSMB; if the trial in question is under AMC DSMB oversight but rendered 
by the AMC investigators, the AMC DSMB will be notified of the suspension and the reason. For 
phase I and II trials, the protocol chair also has the option of asking the DSMB to review the study. 
The AMC ODMC will inform the CTEP Protocol Information Office (PIO), with copy to OHAM 
Directors, when studies are temporarily or permanently closed. In the event of major trial 
modification, CTEP must approve all protocol amendments prior to distributing to the AMC sites. 
Plans for Assuring Data Accuracy and Protocol Compliance 
All study data for AMC clinical trials are entered directly by AMC clinical site staff into the 
applicable clinical data entry system for the trial. During data entry, the system performs validation 
checks on many fields and performs consistency checks between select fields. Range checks are 
placed on each field to eliminate entry of out-of-range values. Edit check programs are run on the 
database on a set schedule to identify and resolve inconsistencies between forms or data collected 
at different points in time. Submitted data entry forms are reviewed for compliance with the 
protocol and data entry instructions according to the AMC ODMC’s standards for data quality 
processes. AMC ODMC staff routinely interacts with site staff to resolve any data submission 
problems. 
In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate 
compliance with regulatory issues, and to review data for specific cases by checking source 
documents. These reports are sent to the site principal investigator and to the NCI. In the event 
that major violations are identified, sites are asked to provide a written corrective and preventative 
action plan to correct deficiencies. If needed, a repeat site audit is conducted. In the event that a 
site does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee 
has the option to implement remedial action(s) for the site. Possible actions include, but are not 
limited to, suspending enrollment of new patients to AMC trials until deficiencies are corrected; 
recommending a decrease in funding to the site; and requiring specific training for site 
investigators or staff members. 

 
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APPENDIX VIII: PARTICIPANT DRUG DIARY 
YOU MUST KEEP THIS DIARY AND BRING IT TO EVERY APPOINTMENT. 
Participant ID #: _______________ 
Cycle #____ 
Taken once each day in the morning. One cycle (round) is 21 days. 
 
Day of 
Cycle 
Date 
Ibrutinib Taken 
Time 
Ibrutinib Taken 
# of Capsules 
Taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
INSTRUCTIONS TO THE PARTICIPANT: 
1. Please record in the chart below the date and time each Ibrutinib dose was taken. Be sure to record the dose when you take it, and avoid writing entries 
for several days at once. In the “Comments” section write any problems you are having with the medicines, indicate why if you missed a dose, or if 
you only took part of the medicine, or you threw up within 2 hours of taking the pills. 
2. You should take Ibrutinib in the morning, with an 8-ounce glass of water. Do not open, break, or chew the capsule. If your dose needs more than one 
capsule of Ibrutinib, take the capsules at the same time. 
3. If you miss an Ibrutinib dose for any reason, take it as soon as you remember on the same day. On the next day, take your next ibrutinib dose at your 
regular time. Do not take extra doses of ibrutinib on the same day to make up for a missed dose. 
4. YOU MUST KEEP THIS DIARY. PLEASE BRING IT TO EVERY STUDY APPOINTMENT. Please bring your pill bottle including any unused 
capsules with you. 

 
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Day of 
Cycle 
Date 
Ibrutinib Taken 
Time 
Ibrutinib Taken 
# of Capsules 
Taken 
Comments 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
Physician’s office will complete this section: 
1. Date patient started protocol treatment________________________________________ 
2. Date patient was removed from study_________________________________________ 
3. Patient’s planned total daily dose____________________________________________ 
4. Total number of capsules taken this cycle______________________________________ 
5. Total number of capsules returned _____________________________________________ 
6. Physician/Nurse/Data Manager’s Signature ____________________________  
Date ________________  
 
 
 
 
 
 

 
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Participant ID #: _______________ 
Cycle #____ 
Taken once each day in the morning, for days 1-5 of each cycle. 
Instructions to the Participant: Please fill out this diary for oral prednisone given as part of the EPOCH chemotherapeutic mixture. If receiving 
EPOCH as an outpatient, please fill in the full diary on all days prednisone is taken. If receiving EPOCH as an inpatient, your dose will be documented 
in your hospital record in which you need only check “In Hospital” box on the chart below. 
YOU MUST KEEP THIS DIARY.  PLEASE BRING IT TO EVERY STUDY APPOINTMENT.  Please bring unused capsules with you. 
Day of 
Cycle 
Date 
Prednisone Taken 
Time 
Prednisone Taken 
Dose Taken 
At home or in hospital 
Comments 
1 
 
 
 
At Home 
 In Hospital 
 
2 
 
 
 
At Home 
 In Hospital 
 
3 
 
 
 
At Home 
 In Hospital 
 
4 
 
 
 
At Home 
 In Hospital 
 
5 
 
 
 
At Home 
 In Hospital 
 
Physician’s office will complete this section: 
1. Date patient started protocol treatment________________________________________ 
2. Date patient was removed from study_________________________________________ 
3. Patient’s planned total daily dose____________________________________________ 
4. Total number of tablets taken this cycle______________________________________ 
5. Total number of tablets returned _____________________________________________ 
6. Physician/Nurse/Data Manager’s Signature ____________________________ 
Date ________________  

 
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Filgrastim/Pegfilgrastim 
Participant ID #: _______________ 
Cycle #____ 
Please check the box below for the medication you were given, and if filgrastim circle (doses bolded below) the correct dose.  
  Pegfilgrastim (Neulasta) – 6 mg taken once, 24-48 hours after chemotherapy, subcutaneously. 
  Filgrastim (Neupogen, G-CSF or biosimilar) - 300 mcg or 480 mcg starting day 6 for a minimum 10 days (please speak to your 
physician about when to discontinue use), subcutaneously 
Were you trained on the self-administration of the medication subcutaneously? Yes or No (please circle one) 
Day of 
Cycle 
Date 
Peg/filgrastim 
Administered 
Time 
Peg/filgrastim 
Administered 
Dose 
Administered 
Comments 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 

 
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Day of 
Cycle 
Date 
Peg/filgrastim 
Administered 
Time 
Peg/filgrastim 
Administered 
Dose 
Administered 
Comments 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
Physician’s office will complete this section: 
1. Date patient started supportive treatment________________________________________ 
2. Date patient ended supportive treatment________________________________________ 
3. Patient’s planned daily dose_________________________________________________ 
4. Physician/Nurse/Data Manager’s Signature ____________________________ 
Date ________________  
 

 
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APPENDIX IX: CENTRAL PATHOLOGY REVIEW 
Handling of Tissues: 
Tissues should be submitted to the following address: 
Julio Cordero 
Research Coordinator  
Laboratory of Hematopathology  
Department of Pathology and Laboratory Medicine  
Weill Cornell Medical College/The New York Presbyterian Hospital  
Starr-702  
525 East 68th Street  
New York, New York, 10065  
Phone: (212) 746-6357  
Fax: (212) 746- 8173  
Email: juc9045@med.cornell.edu 
 
Sample 
collection 
and 
processing 
for 
mandatory 
histopathology 
review 
by 
immunohistochemistry (IHC) and gene expression profiling (GEP) 
Diagnosis confirmation and quality assessment are mandatory for all patients pre-registered to this 
study. Submission of the institutional diagnostic slides is preferred for all participants enrolled in 
the study. Submission of tissue from the diagnostic biopsy in the form of paraffin blocks, tissue 
cores, or slides (see below) is required for all patients enrolled to this study. Incisional or excisional 
biopsy is strongly preferred over a core needle biopsy. Diagnosis by fine needle aspirate (FNA) 
only is NOT acceptable for enrollment. 
Pathology reports must also be included. 
REQUIRED SPECIMEN SUBMISSION 
Option A (Highly encouraged): Tissue block (formalin fixed, paraffin embedded). If 
requested, the block can be returned to the originating pathology lab.  
Option B: Tissue sections. We require submission of one H&E stained slide and 17 tissue 
sections (or 18 if H&E is not available). These should be 4-5 μm in thickness and mounted 
onto positively charged slides. If slides of a different section thickness (4-10 μm) are the only 
available option, then submit the unstained slides and note the thickness on a submission form so 
that the appropriate number of slides can be processed (NOTE: The H&E must be standard 
thickness). 
Quality assessment and IHC for COO will not be performed until it is clear that there is 
enough tissue for GEP. 
Tissue will be distributed as follows: 
i. 
The central pathology lab will confirm diagnosis, assess the COO using IHC and the Hans 
algorithm, estimate the % tumor cells to provide for GEP, and mark areas of involvement 
by lymphoma in the H&E slide.  
ii. The marked H&E slide will be sent with 2-8 blank tissue sections (see table below) for 
GEP. 

 
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iii. The remaining slides will be used for complete central pathology review (see below). 
Tissue Requirements for GEP Assay  
Tumor Surface Area  
Number of Slides (5 μm thickness)* 
Minimum Number of Slides  
Recommended Input  
2 mm2 
4 
8 or more as available  
3 mm2 
3 
8  
4-7 mm2 
2 
5-7  
8-15 mm2 
1 
3-4  
≥ 16 mm2 
1 
2  
* Slide mounted tissue sections with 4-10 μm thickness also are acceptable. The minimum number 
of slides should be adjusted to obtain a total tissue volume of 0.04 mm3  
Specimen Accessioning: Upon receipt, each specimen from AMC will be logged into GlobalTrace 
and receive an Immunopathology Laboratory accession number which will be sequential with the 
other specimens received for various clinical trials, and will be entered into Copath. This will avoid 
delays in processing. Specimens belonging to AMC will be so stated under “Clinical Information”, 
and therefore can be easily identified and tracked. A report will be issued within one week that 
includes review of H&E-stained section, diagnosis and immunohistochemistry for COO. A verbal 
preliminary diagnosis of the H&E, or if IHC stains are provided, can be given in two days if 
requested. This will be followed by additional reports describing the results of additional 
immunohistochemistry, in situ hybridization (EBER) and molecular analysis (if requested or 
considered informative for final diagnosis). All the reports will be sent by FAX to the Operations 
Center as well as to the submitting physician, and hard copies to both will follow.  
Pathology Review: Specimens received will undergo histopathologic diagnosis and classification, 
immunostaining and molecular analysis. Specifically, cases will be processed as follows:  
1. Histopathology- Process tissue, pathologist review of H&E and classification.  
2.  Immunohistochemistry for lymphoid, proliferation and COO, including as needed: CD20, 
CD3, BCL-6, CD10, MUM1, Ki67. Additional markers will be considered, if the COO is not 
clear using these markers. 
3.  In situ hybridization for EBER will be done. In addition, when indicated for accurate 
classification, FISH for BCL6, BCL3, and/or MYC will be performed. 
Tumor block/tissue slides for GEP: Given the tissue for GEP will be done in batches, the tissue 
block/slides will be kept at central pathology until GEP is completed. The tissue slides will be 
shipped in batches of 10 to Dr. Lisa Rimsza.  
 

 
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Record of Specimens: This study will track specimens via GlobalTrace, a component of the AMC 
Advantage eClinical system. The GlobalTrace shipment manifest must accompany all specimen 
shipments. 

 
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APPENDIX X: EBV COPY NUMBER SPECIMEN PREPARATION & SHIPPING 
INSTRUCTIONS 
Virus Quantitation (EBV and KSHV) 
To ship blood for viral quantitation, place two 8.5 mL yellow top (ACD) tubes into a diagnostic 
shipper approved for a volume of at least 30 cc. The use of the SAF-T-PAK STP 210 diagnostic 
cardboard shipper is recommended Each sample tube should be labeled using a Sharpie pen with 
the following information: 
• Protocol #: AMC-101 
• 9-digit Participant # 
• Date and time of collection 
• Specimen type: Whole Blood 
• Specimen purpose: EBV, KSHV 
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.  
Specimen Shipment 
Specimens are accepted MONDAY through THURSDAY. All specimens should be shipped 
OVERNIGHT to the AMC Biorepository at GWU. 
Sylvia Silver, DA 
George Washington University Medical Center  
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 
• It is the responsibility of the Primary Investigator to ensure that all staff personnel who will be 
handling, packaging, and/or shipping clinical specimens act in conformance with International 
Air Transport Association (IATA) regulations (IATA Packing Instruction 650) relating to the 
handling and shipping of hazardous goods. (IATA Packing Instruction 650 is located on the 
AMC web site.) 
• Use a federally approved shipper for biological substance shipment (Category B). Label the 
shipper with the "Infectious substance" diamond shaped label. On one side, in black marker 
write “Biological Substance, Category B, UN 3373”, your name or name of responsible person, 
date of collection and phone number of the person responsible for the package. Package and 
label the shipment in accordance with the instructions provided for that specific shipper. 
• A Shipper’s Declaration for Dangerous Goods is not required. However, for all dry ice 
shipments, the following information must be shown in sequence on the airway bill in the 
“Nature and Quality of Goods” box: Dry Ice, 9, UN1845, number of boxes being shipped, net 
weight of dry ice per box. 
Please Note: The shipper will be mailed back to the AMC site. The STP-210 SAF-T-PAK shipper 
is a complete kit (bubble wrap, absorbent paper, labels, etc.) for specimen shipment. To reuse the 
shipper, you will need new labels, wrap, etc.  

 
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Instructions below for bloods collected on Friday-Sunday: 
In the event that blood samples are drawn on Friday, the samples must be processed into plasma 
and peripheral blood mononuclear cells (PBMC) immediately to maintain their viability for 
analysis, frozen over the weekend, and shipped to the lab on Monday. Preparation of Plasma and 
Peripheral Blood Mononuclear Cells (PBMCs) 
It is preferable that separation occur as soon as possible. If necessary, whole blood in ACD 
(yellow top tubes) can be held at room temperature for no more than 24 hours. 
Materials 
• Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
• 15 mL conical centrifuge tubes (sterile) 
• PBS (sterile) 
• 1, 5 mL and 10 mL serologic pipettes (sterile) 
• 1.5 mL NUNC tubes 
• Alcohol-saturated, control rate freezer container 
• DMSO freezing media 
• 50% Cryoprotective Medium, Cambrex (catalog no.:12-132A) 
• 50% Heat Inactivated Fetal Bovine Serum 
 
 

 
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Plasma Separation and Freezing Procedures 
1. The 8.5 mL tubes of whole blood in acid citrate dextrose should be rotated gently two or 
three times before being centrifuged. Do not transfer before centrifugation. 
2. Separate the cells by centrifugation at 500 g for 10 minutes. 
3. Remove 0.5 mL aliquots of plasma and put into separate 1.5 mL NUNC tubes and transfer 
to liquid nitrogen storage. 
PBMC Separation and Freezing Procedures 
1. The cells and plasma remaining from the previous step are transferred into a 15 mL conical 
tube or 50 mL centrifuge tube depending on volume. 
2. Sterile PBS should be added to the suspended whole blood cells in an equal volume and 
pipetted up and down to mix (1:1). 
3. The whole blood-PBS mixture should be carefully overlaid onto 4-5 mL of room 
temperature LSM or Ficoll-Hypaque solution in a sterile 15 mL conical centrifuge tube. A 
sharp interface should exist between the LSM and the whole blood mixture. (If the layer 
of LSM gets mixed with the blood-PBS, the tube should be gently rotated to mix the blood, 
PBS, and LSM, and transfer to a 50 mL sterile conical tube. An equal volume of PBS is 
added, and the cells are separated at 600 g for 15 minutes. After removal of LSM-PBS 
supernatant, return to Step 2). 
4. Centrifuge the 15 mL conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will band at 
plasma/LSM interface. 
5. The fluffy white layer just below the plasma layer should be aspirated off and transferred 
to an appropriately labeled 15 mL sterile conical centrifuge tube. Be careful to remove only 
the interface and a minimum amount of the LSM or Ficoll-Hypaque. 
6. Add three volumes of PBS to the cell suspension and or enough to fill conical and mix by 
pipetting up and down. 
7. Centrifuge at 500 g for 10 minutes. 
8. Aspirate off and discard supernatant, taking care not to disturb pellet. 
9. Resuspend in 12 mL of PBS. Take 10 µl of suspension for cell counting (dilute accordingly 
whether using a hemocytometer or automated cell counter). Centrifuge again for 10 
minutes at 500g to wash cells. 
10. Using a 1 mL pipette, the *DMSO freezing mixture should be added dropwise to the cell 
pellet suspension. Gently finger-tap between drops to resuspend cells. If the cell pellet is 
small, only 0.5 mL of freezing media is added (and only one aliquot of cells is frozen). If 
the cell pellet is large, up to 2 mL of freezing media can be added in a drop wise fashion. 
(Cell densities of 1 - 10 million PBMC/ml are best for cryopreservation. If a 
hemocytometer is available, the optimal concentration is 5 x 106 PBMC/ml). 
*Important: Do not put the DMSO containing media on the cell button all at once. 
11. Freeze the cell suspension in 0.5 mL aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 

 
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Billing 
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details. It is only to be used for billing 
shipment of specimens to the lab where the sample is processed and/or stored. 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC Advantage 
eClinicalSM system. The GlobalTraceSM shipment manifest must accompany all specimen 
shipments.  
Technical Questions 
Sylvia Silver, DA 
George Washington University Medical Center  
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 

 
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APPENDIX XI: PHARMACOKINETICS (PLASMA LEVELS OF DOXORUBICIN, 
VINCRISTINE, AND ETOPOSIDE) 
All pharmacokinetic blood samples should be processed into plasma and aliquoted (equal volume 
into multiple tubes (NUNC cryotubes 1.8 mL with feet and inside threading [product #377267] 
are preferred). Plasma should be stored at -80o C or lower until shipped in batch. 
1.  Two tubes will be collected at each of the following time points: between 24-48, and 72-96 
hours after the start of the infusion. For doxorubicin, collect ~6 cc of blood in green-top 
vacutainer tubes containing sodium heparin. For etoposide and vincristine, collect one ~10 
cc of blood in lavender-top vacutainer tubes containing EDTA, for both drugs together. 
Ensure that the actual time of blood collection and the nominal time of blood collection (e.g., 
24-48 time point) are documented with each specimen collected and in the data fields 
associated with the specimen in GlobalTraceSM. 
2.  Specimens should be processed within 30 minutes and in no more than one hour following 
collection. Centrifuge blood sample at 2500 RPMs for 10 minutes to obtain plasma. 
3.  The number of aliquots will differ for each tube type. For the green top tube, transfer ~1.5 mL 
aliquots of plasma into multiple labeled 2 mL cryovials (~2-3 tubes anticipated per blood 
draw). For the purple top tube, transfer ~1.5 mL aliquots of plasma into multiple labeled 2 mL 
cryovials (~3-5 tubes anticipated per blood draw). Do not discard any plasma but place in 
another cryovial. Ensure that the green-top aliquots are labeled as doxorubicin and the purple-
tops as etoposide or vincristine. 
4.  Label each tube with the following information: 
• AMC Protocol # AMC-101 
• 9-digit AMC Participant ID# 
• Date and time of blood collection 
• Specimen type - “Plasma” 
• Specimen purpose: “Doxorubicin PK” (for the green-top tube) or “Etoposide or Vincristine 
PK” (for the purple-top tube) and collection time (i.e., 24-48, and 72-96 hours) 
5.  Freeze the NUNC cryogenic tubes immediately and maintain frozen at -80o C. 
If there were samples not obtained at the required time points, please inform the Analytical 
Pharmacology Core (APC) Laboratory prior to shipping. 
Shipment 
Samples will be kept at the study site and periodically during the study shipped to the APC 
Laboratory. Unless otherwise stated, samples will be shipped to the APC Laboratory under the 
direction of Michelle A. Rudek, Pharm.D., Ph.D. Specimens should be stored through the duration 
of the PK study (through 72-96 hr sample) and shipped as a batch by participant (more than one 
participant/shipment is acceptable if the site has >1 participant on-study). A participant's samples 
should be shipped to the APC lab within 1 month of the last sample's collection date. (i.e., if the 
72-96 hr sample is collected on 1/1/2018, all of that participant's samples should be at the APC lab 
by 2/1/2018). If a second set of participant samples can be batched by waiting up to 2 weeks (i.e., 
1.5 months), this deviation is allowed.  

 
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Please ship 2 aliquots (for both green top and purple top) to the APC laboratory. Once 
receipt is confirmed, the third/back-up aliquot may be shipped. 
Overnight shipments should occur on Monday through Wednesday (Tuesday is the preferred 
day) except when the following day is a holiday. A fax or call should be place to the Analytical 
Pharmacology Core Laboratory prior to shipment providing the shipment tracking information. 
Samples should be shipped on dry ice to: 
Analytical Pharmacology Core Laboratory* 
Attn: AMC101 Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
Technical Questions 
Michelle Rudek (mrudek2@jhmi.edu) for questions for questions regarding the PK. Linping Xu 
(lxu11@jhmi.edu) or India Hinton (ihinton1@jhmi.edu) for questions regarding processing or 
shipments.  
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.  
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC Advantage 
eClinicalSM system. The GlobalTraceSM shipment manifest must accompany all specimen 
shipments. 

 
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APPENDIX XII: ASSESSMENT OF CIRCULATING LEVELS OF PRO-
INFLAMMATORY CYTOKINES 
SHIPPING INSTRUCTIONS AND SAMPLE PROCESSING 
A. 
General 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS or SUNDAYS 
in the AMC BIOREPOSITORY. 
Should the site collect specimens on Friday through Saturday, samples should be processed 
for plasma according to the AMC Biorepository’s SOP on Separation of Plasma and 
Mononuclear Cells, available on the AMC Operations web site. At least four 0.5 mL 
aliquots of serum are required. Aliquots should be frozen at specimens at -80°C and 
shipped on dry ice to the AMC Biorepository the following week. 
B. 
Specimen preparation, packaging, and shipment 
Draw two 6 cc (mL) red top [no additive] tubes from study participant. Seal the tops of the 
tubes with parafilm. Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
Tape around the bubble wrap so that the roll stays together and the tubes cannot fall out or 
break. Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal.” Place poly-bag containing tubes into the white TYVEK 
bag and seal. Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal 
the cardboard shipper with clear packing/shipping tape. 
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked “FED-
EX PRIORITY OVERNIGHT.” Mark “OTHER” in the airbill under “Packaging.” Under 
airbill section “Special Handling,” indicate “YES-SHIPPERS DECLARATION NOT 
REQUIRED.” Place “From/To” information onto areas provided on the shipper. 
Blood specimens should be shipped by overnight express at room temperature to: 
Sylvia Silver, DA 
George Washington University Medical Center  
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 

 
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Specimen Labeling 
Each sample tube should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-101 
• 9-digit Participant ID # 
• Visit # 
• Date and time of specimen collection 
• Specimen Type: “Serum” 
• Purpose: “Cytokine Assays” 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp. Make certain that 
the net volume of the specimen being shipped is written in the space provided on the shipper or 
make a separate label with the volume in mL and affix to the shipper. Affix airbill to shipper so 
that the ‘UN’ and ‘VOLUME’ labels are visible. RETAIN THE TOP COPY OF THE AIRWAY 
BILL FOR YOUR RECORDS. Place the box in the FedEx pickup area at your site or call to 
request a package pickup. 
Billing 
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.  
Contact for site questions (9AM-5PM Pacific Time) 
Lab Manager: Larry Magpantay (lmagpantay@mednet.ucla.edu) 
Lab phone: 310-206-6846 
Marta Epeldegui office phone: 310-206-6846 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
The AMC Biorepository will separate serum, aliquot the serum into as many 0.5 mL aliquots until 
the sample is used as per AMC Biorepository SOPs, and store at -80°C. Specimens should be sent 
in batch at the end of the study to UCLA’s Martinez-Maza laboratory per SOP. 

 
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APPENDIX XIII: PK PLASMA COLLECTION FOR IBRUTINIB 
Collect the ibrutinib PK blood samples according to the time points described in the protocol (see 
“Ibrutinib Levels” table in Appendix I). 
USE 1 x 2-mL GREEN TOP SODIUM HEPARIN TUBE FOR EACH PK COLLECTION. 
1. Allow tube to fill COMPLETELY, as far as the vacuum will allow. 
2. Mix the tube immediately upon completion to avoid clotting by inverting gently 5 times. 
DO NOT SHAKE. 
3. Place the blood samples on melting ice until centrifugation 
4. Place the sample in a refrigerated centrifuge (0-4°C). 
NOTE: Use a refrigerated centrifuge bucket in cases where a refrigerated centrifuge is not 
available. Maintain cold temperature during the plasma preparation process. 
5. Centrifuge tube within 60 minutes of collection at 4°C for 15 minutes at 2500 rpm. 
6. Transfer plasma with pipette equally into two 2-mL cryovials (approximately 0.5 mL of 
plasma in each tube). 
7. Enter the Subject ID number on the sample labels. 
8. Store plasma samples in a freezer at -70°C or below, within approximately 60 minutes of 
blood collection. 
9. Ship samples FROZEN in batches (after collection from each subject is completed) to 
Central Labs. 
NOTE: Every effort should be made to collect the full 2 mL blood sample at each time point. 
In the event that less than 1 mL of blood is collected, the sample will be processed as 
described above except that the plasma will not be divided into two tubes. This single plasma 
sample should be frozen, stored and shipped with the primary set of samples. 
 
PK Sample Shipping Instructions 
PK SPECIMENS to be batch shipped (FROZEN) from each subject. Please include: 
• One primary set of samples for each subject 
• One back-up set of samples for each subject (in a separate shipment unless only single 
plasma sample available) 
Samples should be shipped on dry ice Monday through Thursday only. 

 
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As much as possible, a complete set of primary samples (all time points) for a subject should be 
batched and shipped together in the same shipment, to the Biorepository at George Washington 
University. 
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.  
The address is:  
Sylvia Silver, DA 
George Washington University Medical Center  
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 
Instructions for the Biorepository only. 
Samples will be shipped in batches annually, after confirmation from the AMC ODMC. 
Ship the back-up set after the confirmation of receipt of the primary set by Frontage Labs. 
Do NOT ship back-up aliquots of plasma in the same shipment as the primary samples from the 
same subject. 
To avoid sample mix-ups or misidentification, place the samples in the shipment by subject 
number and sample time using zip-lock bags or segmented cartons. There should be adequate 
amount of dry ice included in the shipment to last for three days of shipping. Please ship the 
samples to the following address: 
Notify Frontage Laboratories at least 1 day prior to the arrival of the sample, providing shipping 
details 
and 
tracking 
numbers 
for 
the 
shipment. 
E-mail 
Joseph 
Falcone 
at 
samplemanagement@frontagelab.com. The e-mail must specify the study number, the number of 
pharmacokinetic samples, the time of shipment pick-up and include an electronic sample 
inventory. This is in addition to entering samples in GT. 
Prior to shipment, prepare a sample shipment list (or Inventory list) containing the details of each 
sample / label identification included in the shipment. All of the sample details on this list must 
correspond with the details included on the individual sample labels, as each sample label will be 
checked against the list by Frontage sample coordination personnel. Any discrepancies between 
information on the sample tubes and information on the e-rosters will be verified and noted in the 
e-rosters prior to shipping. All sample correspondence must contain the Study Number, Study 
Drug, and Site references (including emergency contact details and responsible shipment 
coordinator). 

 
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APPENDIX XIV: BTK/ITK OCCUPANCY SPECIMEN PREPARATION & SHIPPING 
INSTRUCTIONS 
A. 
General 
This lab may only be drawn and sent OVERNIGHT EXPRESS Monday-Thursday. If 
this blood is planned for Friday-Sunday, then the patient’s blood for this particular 
study will be deferred.  
Each sample tube should be labeled using a Sharpie pen with the following information: 
• Protocol #: AMC-101 
• 9-digit Participant # 
• Date and time of collection 
• Specimen type: Whole Blood 
• Specimen purpose: BTK/ITK occupancy 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS or SUNDAYS 
in the AMC BIOREPOSITORY. 
Should the site collect specimens on Friday through Sunday, samples will be discarded. 
B. 
Specimen preparation, packaging, and shipment 
Draw two 6 cc (mL) yellow top Acid Citrate Dextrose (ACD) tubes from study participant. 
Seal the tops of the tubes with parafilm. Place the two sealed tubes into bubble wrap 
(provided in STP-210 kit). Tape around the bubble wrap so that the roll stays together and 
the tubes cannot fall out or break. Place absorbent material sheet around the bubble wrapped 
tubes and slip into a biohazard poly-bag and “self-seal.” Place poly-bag containing tubes into 
the white TYVEK bag and seal. Place the TYVEK bag into the STP-210 diagnostic 
cardboard shipper. Seal the cardboard shipper with clear packing/shipping tape. 
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked “FED-
EX PRIORITY OVERNIGHT.” Mark “OTHER” in the airbill under “Packaging.” Under 
airbill section “Special Handling,” indicate “YES-SHIPPERS DECLARATION NOT 
REQUIRED.” Place “From/To” information onto areas provided on the shipper. 
Please refer to the Manual of Procedures and AMC Operations website’s 
(www.AIDSCancer.org) Shipping tab for more information and the FedEx account details.  
 

 
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Blood specimens should be shipped by overnight express at room temperature to: 
Sylvia Silver, DA 
George Washington University Medical Center  
Ross Hall, Room 118 
2300 Eye St, NW 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 

 
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APPENDIX XV: DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP3A4 
ISOENZYMES 
Some inhibitors and inducers of CYP3A enzymes are listed below. Because lists of such agents 
are frequently changing, the study team should check a frequently-updated medical reference for 
a list of drugs to avoid or minimize use of. The general categorization into strong, moderate, and 
weak inhibitors according to the website is displayed below. Refer to Section 4.3 on instructions 
for concomitant use of CYP3A inhibitors and inducers with ibrutinib. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
COBICISTAT 
Efavirenz 
INDINAVIR 
Etravirine 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Amprenavir 
St. John’s Wort 
Aprepitant 
Troglitazone 
Atazanivir 
Erythromycin 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 

 
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Inhibitors of CYP3A 
Inducers of CYP3A 
NOT azithromycin 
 
Chloramphenicol 
 
Ciprofloxacin 
 
Boceprevir 
 
Ciprofloxacin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Dronedarone 
 
Fosamprenavir 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
Posaconazole 
 
star fruit 
 
Telaprevir 
 
Troleandomycin 
 
Voriconazole 
 
Source: 
https://crediblemeds.org/healthcare-providers/. Please refer to a constantly-updated 
resource for the most recent list of agents. 

 
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APPENDIX XVI: ANN ARBOR STAGING CRITERIA 
STAGE DESCRIPTION 
STAGE I 
Involvement of a single lymph node region (I) or of a single extralymphatic organ 
or site (IE). 
STAGE II 
Involvement of two or more lymph node regions on the same side of the diaphragm 
(II), or localized involvement of extralymphatic organ or site and of one or more 
lymph node region on the same side of the diaphragm (IIE). 
STAGE III 
Involvement of lymph node regions on both sides of the diaphragm (III), which 
may also be accompanied by localized involvement of extralymphatic organ or site 
(IIIE) or by involvement of the spleen (IIIS), or both (IIISE). 
STAGE IV 
Diffuse or disseminated involvement of one or more extralymphatic organs or 
tissues with or without associated lymph node enlargement. 
A 
Absence of systemic symptoms 
B 
Presence of one or more general symptoms: (1) unexplained weight loss of more than 10% 
of the body weight in the 6 months before admission; (2) unexplained fever with 
temperatures above 38C; (3) night sweats. 
______________________________________________________________________________ 
Notes: 
1. The lymphatic structures are defined as the lymph nodes (N), spleen (S), thymus, Waldeyer’s 
ring, appendix and Peyer’s patches. 
2. The reasons for classifying the patient as stage IV is defined further by defining sites by 
symbols: 
H - Liver 
L - Lung 
M - Marrow 
O - Bone 
P - Pleura 
D - Skin 
3. 
Liver involvement is always considered Stage IV disease, as is bone marrow involvement 
away from a site of an involved lymph node. 
 
 

 
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APPENDIX XVII: DOSE ADJUSTMENTS FOR IBRUTINIB AND/OR EPOCH 
Dose adjustments for ibrutinib occur WITHIN the cycle, and dose adjustments for EPOCH occur 
PRIOR TO each cycle based on nadir counts of ANC <500/mm3 and platelet counts <25,000/mm3. 
Please note for tables A-E, for those who had one cycle of CHOP/EPOCH +/- Rituximab prior to 
enrollment in the dose-expansion cohort, the first cycle on study will be “Cycle 2.” 
Reminder: Ensure the participant received pegfilgrastim or filgrastim (or biosimilar) as directed. 
If the participant is on filgrastim, continue filgrastim (or biosimilar) for a minimum of 10 days and 
until ANC >5000/mm3. 
 
 
 
 
Twice weekly CBCs 
at least 3 days apart
ANC nadir <500/mm3 on ≥ 3 nonconsecutive days 
at least 3 days apart 
(i.e., ANC <500/mm3 on 3 CBCs over ≥7 day period) 
OR febrile neutropenia
See Table A in Appendix XVII
ANC nadir <500/mm3 on 2 nonconsecutive days 
at least 3 days apart 
(i.e., ANC <500/mm3 on 2 CBCs over <7 day period) 
AND/OR platelets <25,000/mm3
See Table B (for ANC) and
Table C (platelets) in Appendix XVII
ANC nadir <500/mm3 lasting ≤3 days 
(i.e., ANC <500/mm3 on 1 CBC) 
and platelets ≥25,000/mm3
See Table D in Appendix XVII
ANC nadir ≥500/mm3 and platelets ≥25,000/mm3
See Table E in Appendix XVII

 
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Table A 
 
 
 
Event 
Cycle of 
Event 
Action (Ibrutinib) 
Action (EPOCH) 
ANC nadir < 
500/mm3 on ≥ 3 
nonconsecutive 
days at least 3 days 
apart (i.e., ANC 
<500/mm3 on 3 
CBCs over ≥ 7-day 
period) OR febrile 
neutropenia 
1 – 6 
 
For the dose-expansion cohort, if this 
is the first cycle on study (after Cycle 
1 off study), start ibrutinib at the 
MTD dose reduced by 140mg 
Hold ibrutinib until ANC recovers 
≥1000, then resume daily ibrutinib at 
dose reduced by 140 mg for current 
and next cycle 
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 

 
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Table B 
 
Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
ANC nadir < 
500/mm3 on 2 
nonconsecutive 
days at least 3 
days apart (i.e., 
ANC <500/mm3 
on 2 CBCs over 
<7-day period) 
 
1 
Hold 
ibrutinib 
until 
ANC 
recovers ≥ 1000, then resume 
daily ibrutinib at the same dose 
for current and next cycle. 
After restart of ibrutinib, if ANC 
again drops <500 within the 
same cycle or ANC is <1000 at 
day 1 of the next cycle, hold 
ibrutinib until ANC recovers ≥ 
1000, then resume daily ibrutinib 
at dose reduced by 140 mg 
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 
2 – 6 
when patient has 
NOT yet had a 
dose reduction in 
either 
cyclophosphamide 
OR ibrutinib 
For the dose-expansion cohort, if 
this is the first cycle on study 
(after Cycle 1 off study), start 
ibrutinib at the MTD 
 
Hold 
ibrutinib 
until 
ANC 
recovers ≥1000, then resume 
daily ibrutinib at the same dose 
for current and next cycle 
After restart of ibrutinib, if ANC 
again drops <500 within the 
same cycle or ANC is <1000 at 
day 1 of the next cycle, hold 
ibrutinib until ANC recovers ≥ 
1000, then resume daily ibrutinib 
at dose reduced by 140 mg  
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
cyclophosphamide 
but NOT ibrutinib 
Hold 
ibrutinib 
until 
ANC 
recovers ≥ 1000, then resume 
daily ibrutinib at dose reduced by 
140 mg for current and next cycle 
Same dose level 
of EPOCH as 
previous cycle 

 
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Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
BOTH 
cyclophosphamide 
AND ibrutinib 
Hold 
ibrutinib 
until 
ANC 
recovers ≥1000, then resume 
daily ibrutinib at dose reduced by 
140 mg for current and next 
cycle. If the event recurs after a 
minimum ibrutinib dose of 280 
mg, 
discontinue 
ibrutinib 
permanently 
Same dose level 
of EPOCH as 
previous cycle 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
cyclophosphamide 
AND ibrutinib has 
been permanently 
discontinued 
N/A 
Dose-adjust 
cyclophosphamide 
one level down 
(by 187.5 mg/m2) 
 
 
 

 
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Table C 
Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
Platelets < 
25,000/mm3  
1 
Hold 
ibrutinib 
until 
platelets 
≥50,000/mm3, then resume daily 
ibrutinib at the same dose for current 
and next cycle. 
After restart of ibrutinib, if platelets 
again drop <25,000/mm3 within the 
same cycle, hold ibrutinib until 
platelets recover ≥50,000/mm3, then 
resume daily ibrutinib at dose 
reduced by 140 mg. Similarly, after 
restart of ibrutinib, if platelets are 
<75,000/mm3 at day 1 of the next 
cycle, then decrease daily ibrutinib 
by 140 mg. 
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 
2 – 6 
when patient has 
NOT yet had a 
dose reduction in 
either 
cyclophosphamide 
OR ibrutinib 
 
For the dose-expansion cohort, if 
this is the first cycle on study (after 
Cycle 1 off study), start ibrutinib at 
the MTD 
Hold 
ibrutinib 
until 
platelets 
>50,000/mm3, then resume daily 
ibrutinib at the same dose for current 
and next cycle 
After restart of ibrutinib, if platelets 
again drop <25,000/mm3 within the 
same cycle, hold ibrutinib until 
platelets recover ≥50,000/mm3, then 
resume daily ibrutinib at dose 
reduced by 140 mg. Similarly, after 
restart of ibrutinib, if platelets are 
<75,000/mm3 at day 1 of the next 
cycle, then decrease daily ibrutinib 
by 140 mg. 
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
cyclophosphamide 
but NOT ibrutinib 
Hold 
ibrutinib 
until 
platelets 
≥50,000/mm3, then resume daily 
ibrutinib at dose reduced by 140 mg 
for current and next cycle 
Same dose level 
of EPOCH as 
previous cycle 

 
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Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
BOTH 
cyclophosphamide 
AND ibrutinib 
Hold 
ibrutinib 
until 
platelets 
≥50,000/mm3, then resume daily 
ibrutinib at dose reduced by 140 mg 
for current and next cycle. If the 
event recurs after a minimum 
ibrutinib 
dose 
of 
280 
mg, 
discontinue ibrutinib permanently 
Same dose level 
of EPOCH as 
previous cycle 
2 – 6 
when patient has 
previously 
required a dose 
reduction in 
cyclophosphamide 
AND ibrutinib has 
been permanently 
discontinued 
N/A 
Reduce 
cyclophosphamide 
by 187.5 mg/m2 
for the next cycle 
 
 

 
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Table D 
Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
ANC nadir < 
500/mm3 lasting 
≤3 days (i.e., 
ANC <500/mm3 
on 1 CBC), and 
platelet nadir 
≥25,000/mm3  
1 – 6 
 
For the dose-expansion cohort, if 
this is the first cycle on study (after 
Cycle 1 off study), start ibrutinib at 
the MTD 
Hold ibrutinib until ANC ≥ 1000, 
then resume daily ibrutinib at the 
same dose for current and next 
cycle 
After restart of ibrutinib, if ANC 
again drops <500 within the same 
cycle or ANC is <1000 by day 1 of 
the next cycle, hold ibrutinib until 
ANC recovers ≥ 1000, then resume 
daily ibrutinib at dose reduced by 
140 mg  
Same dose level 
of EPOCH as 
previous cycle. 
 

 
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Table E 
Event 
Cycle of Event 
Action (Ibrutinib) 
Action (EPOCH) 
ANC nadir ≥ 
500/mm3 and 
platelets ≥ 
25,000/mm3  
1 
 
Continue the same dose of ibrutinib 
for the current and next cycle 
 
Increase 
cyclophosphamide 
by 187.5 mg/m2 
the next cycle up 
to maximum dose 
of 750 mg/m2 
2 – 6 
 
For the dose-expansion cohort, if 
this is the first cycle on study (after 
Cycle 1 off study), start ibrutinib at 
the MTD 
IF 
the 
current 
cycle 
cyclophosphamide is 750 mg/m2, 
THEN ibrutinib may be increased 
by 140 mg to a maximum dose of 
560 mg. Otherwise, continue the 
same dose of ibrutinib for the 
current and next cycle 
Increase 
cyclophosphamide 
by 187.5 mg/m2 
the next cycle up 
to maximum dose 
of 750 mg/m2 
 
* Management of missing labs: If the participant does not obtain two lab counts on 2 
nonconsecutive days at least 3 days apart within a week but ANC nadir on any cycle <500/mm3, 
then we will assume the counts that would have been obtained are the same as the single nadir 
counts; however, clinical evidence of severe neutropenia/thrombocytopenia in absence of lab 
availability may be discussed by investigator with protocol chairs to determine subsequent cycle 
dosing. 
** For the participants in the dose-expansion cohort who come in after cycle 1 OFF study, the first 
cycle on study will be counted as cycle 2. The same cycle 1 dose-adjustment rules will be applied 
for participants who received EPOCH and have documented twice weekly labs documenting a true 
nadir. If the participant received R-CHOP or there are insufficient records of nadir, the participant 
will start at dose level +1 of cyclophosphamide based on CD4 count and ibrutinib at the MTD 
dosing. 
*** Note: these dose reductions do not apply to participants with baseline cytopenias attributable 
to bone marrow involvement with lymphoma, or to the period of time participants are receiving 
EPOCH infusions. Reductions on these participants will be discussed with the PI or protocol chair 
on an individual basis. 
 
 

 
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APPENDIX XVIII: LETTER TO THE PHYSICIAN 
 
Model letter to be provided to the treating HIV physician of the participant. 
 
(Date) 
 
RE: 
AIDS Malignancy Consortium (AMC) Protocol-101 and Avoidance of Exclusionary 
Medications 
Dear Dr. (Provider Name), 
We are reaching out to you as your patient, (Patient Name), is receiving therapy at Institution 
Name for diffuse large B-cell lymphoma (DLBCL). (Patient Name) has enrolled in a clinical trial, 
AMC-101, for the upfront treatment of DLBCL. The therapy involves an oral drug named 
ibrutinib, in combination with more traditional therapy EPOCH (etoposide, prednisone, 
vincristine, cyclophosphamide, and doxorubicin). 
We are writing this letter because potential harmful interactions have been identified with 
medications which are moderate and strong inhibitors of cytochrome 3A4 (CYP 3A4). 
Specifically, CYP 3A4 is responsible for ibrutinib metabolism. Therefore, to avoid excess toxicity 
of ibrutinib, we are avoiding these particular drug-drug interactions.  
Patients need to be changed to a non- strong or moderate CYP 3A4 inhibitor HAART regimen at 
least one week prior to starting therapy for DLBCL. HAART drugs used frequently, such as both 
ritonavir (Norvir, also in Kaletra) and cobicistat (Tybost, also in Stribild), are included in the list 
of strong CYP 3A4 inhibitors. In addition, we are excluding the use of all moderate and strong 
CYP3A4 inhibitors one week prior to starting therapy for DLBCL and during therapy. For ease of 
review, we are including a table on page 2 with all restricted medications. 
We are asking for your assistance with this protocol requirement for your patient’s HAART 
regimen and other prohibited medication. 
Your patient enrolled on this study on (Enrollment Date). Please notify us in advance of any 
planned medication change. If you would like to discuss the trial, please feel free to call me at 
(Phone Number). Information on this clinical trial is also available online at 
https://clinicaltrials.gov/ct2/show/NCT01771107. 
Thank you in advance, 
 
 
Printed Name 
Title 
Site Name 
Phone 
Pager 
 
 

 
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Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
COBICISTAT 
Efavirenz 
INDINAVIR 
Etravirine 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Amprenavir 
St. John’s Wort 
Aprepitant 
Troglitazone 
Atazanivir 
 
Erythromycin 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 
NOT azithromycin 
 
Chloramphenicol 
 
Ciprofloxacin 
 
Boceprevir 
 

 
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Inhibitors of CYP3A 
Inducers of CYP3A 
Ciprofloxacin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Dronedarone 
 
Fosamprenavir 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
Posaconazole 
 
star fruit 
 
Telaprevir 
 
Troleandomycin 
 
Voriconazole 
 
Source: 
https://crediblemeds.org/healthcare-providers/. Please refer to a constantly-updated 
resource for the most recent list of agents. 
 
 

 
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APPENDIX XIV: CIRCULATING TUMOR DNA (CTDNA) 
Background 
Testing for circulating tumor DNA can include both NextGen sequencing for BCR rearrangement 
and NextGen sequencing to identify residual tumors on the basis of oncogene mutations. These 
are feasibility studies, possibly using commercial assays. 
Collection of Specimen(s) 
Collect three 10 mL Streck Cell-Free DNA BCT® tubes at baseline, after cycle 2, after cycle 4, 
and at the end of treatment. It is critical to mix tubes thoroughly by inverting the tube 8-10 times 
end-over-end immediately after collection. One inversion is a complete turn of the wrist, 180 
degrees and back. 
Handling of Specimens(s) 
To ship blood for circulating tumor DNA, place the three 10 ml Streck Cell-Free DNA BCT® tubes 
into a canister of a STP-100 SAF-T-PAK shipper (VWR# 11217-163), wrapping each tube in 
bubble wrap and using the absorbent paper at the bottom of the canister. Each sample tube should 
be labeled using a Sharpie pen with the following information: 
1. Protocol #: AMC-101 
2. 11-digit Participant # 
3. Date and time of collection 
4. Specimen type: Whole Blood 
5. Specimen purpose: circulating tumor DNA (ctDNA) 
Place the lid on the canister and place it inside of the ambient SAF-T-PAK shipper indicating on 
packaging “AMC Study - Call AMC Biorepository (202)-994-3422 for pick-up. Seal the 
ambient shipper with cellophane shipping tape. 
Shipping of Specimen(s) 
Specimens are accepted MONDAY through THURSDAY. All specimens should be shipped 
overnight to: 
Sylvia Silver, DA  
George Washington Medical Center  
Ross Hall, Room 118  
2300 Eye Street, NW  
Washington, DC 20037  
Tel: (202) 994-3422 
Fax: (202) 994-5056 
1. It is the responsibility of the Primary Investigator to ensure that all staff personnel who will be 
handling, packaging, and/or shipping clinical specimens act in conformance with International 
Air Transport Association (IATA) regulations (IATA Packing Instruction 650) relating to the 
handling and shipping of hazardous goods. (IATA Packing Instruction 650 is located on the 
AMC web site.) 

 
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2. Use a federally approved shipper for biological substance shipment (Category B). Label the 
shipper with the "Infectious substance" diamond shaped label. On one side, in black marker 
write “Biological Substance, Category B, UN 3373”, your name or name of responsible person, 
date of collection and phone number of the person responsible for the package. Package and 
label the shipment in accordance with the instructions provided for that specific shipper. 
3. A Shipper’s Declaration for Dangerous Goods is not required. However, for all dry ice 
shipments, the following information must be shown in sequence on the airway bill in the 
“Nature and Quality of Goods” box: Dry Ice, 9, UN1845, number of boxes being shipped, net 
weight of dry ice per box. 
Please Note: The shipper will be mailed back to the AMC site. The STP-100 SAF-T-PAK 
shipper (VWR Cat # 11217-163) is a complete kit (bubble wrap, absorbent paper, labels, etc.) 
for specimen shipment. To reuse the shipper, you will need new labels, wrap, etc. There is a 
refurbishment kit with extra bubble wrap and absorbent material (STP102) (VWR Cat # 11217-
166) sufficient for 15 mailings. 
Instructions below for bloods collected on Friday-Sunday: 
In the event that blood samples are drawn on a Friday, the Streck Cell-Free DNA BCT® tubes 
must be kept at ambient temperature and shipped the following MONDAY to the AMC 
Biorepository. 
Billing 
Please refer to the Manual of Procedures and AMC Operations website’s (www.AIDSCancer.org) 
shipping tab for more information and the FedEx account details. It is only to be used for billing 
shipment of specimens to the lab where the sample is processed and/or stored. 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC Advantage 
eClinicalSM system. The GlobalTraceSM shipment manifest must accompany all specimen 
shipments.  
Technical Questions 
Contact Jeffrey Bethony, PhD or Sylvia Silver, DA  
Tel: (202) 590-8342 
Fax: (202) 994-5056 
Email: jbethony@gwu.edu or ssilver@gwu.edu 
George Washington Medical Center  
Ross Hall, Room 118  
2300 Eye Street, NW  
Washington, DC 20037  
Monday-Friday (8:00 AM-5:00 PM Eastern Time) 
Site(s) performing correlative study: Dirk Dittmer lab/Richard Ambinder lab