A Randomized Double-Blind Phase III Study of Ibrutinib During and Following Autologous Stem Cell Transplantation Versus Placebo in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma of the Activated B-Cell Subtype
Phase: PHASE3
Conditions: Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Refractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type
Sponsor: National Cancer Institute (NCI)

1 
Update #09 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
PROTOCOL UPDATE TO ALLIANCE A051301 
 
 
A RANDOMIZED DOUBLE-BLIND PHASE III STUDY OF IBRUTINIB DURING AND FOLLOWING 
AUTOLOGOUS STEM CELL TRANSPLANTATION VERSUS PLACEBO IN PATIENTS WITH 
RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA OF THE ACTIVATED B-
CELL SUBTYPE 
NCI-supplied agent(s): Ibrutinib (NSC #748645, 
); IND holder: NCI-CTEP 
Commercial agent(s): BCNU (Carmustine) (NSC# 409962), Etoposide (NSC# 141540), Ara-C (Cytarabine) (NSC# 
63878), Melphalan (NSC# 8806), Cyclophosphamide (NSC#26271) 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
X Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
X Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other:  
 
 
 
 
 
If your site utilizes the CIRB as your IRB of record for this study, no recommended level of IRB review 
is provided by the Alliance. This amendment must be implemented within 30 days after posting. Please 
refer to the CIRB amendment application and CIRB guidelines for further instructions. 
 
If your site utilizes a local IRB as your IRB of record for this study, IRB approval (or disapproval) is 
required within 90 days. Expedited IRB Approval is allowed. Please follow your local IRB guidelines. 
 
UPDATES TO THE PROTOCOL: 
Cover Page 
• 
 has been removed from the cover page. 
• 
 has replaced 
 as the Transplant Committee Chair. 
• 
 has been removed from the cover page. 
• 
 has replaced 
 as the Primary Statistician. 
 
 
 
 
 
 
 
 
 
 
NCT02443077

2 
Study Resources 
The contact information for the Alliance Biorepository at Washington University has been updated. 
 
CTSU Contact Information 
The table has been updated with the current CTSU template language. 
 
Schema Page 3 
• 
In the “Study Procedures” column, the continuation timing has been changed to “day +30 to +75.” 
• 
In footnote 3, the 21 day window has been changed to 45 days.  
 
Section 3.3 (Eligibility Criteria [Step 1]) 
In Section 3.3.4 (Prior Treatment), the following has been added to the second criterion: “Prior CART 
therapy is allowed and counts as one line of therapy.” 
 
Section 4.2 (Cancer Trials Support Unit Registration Procedures) 
This section has been updated with the current CTSU template language. 
 
Section 4.5 (Patient registration/randomization procedures) 
This section has been updated with the current CTSU template language. 
 
Section 5.0 (Study Calendar) 
• 
The two columns under “Cycles 2-13” have been combined. 
• 
The requirement for the BM biopsy prior to registration has been removed. 
• 
In footnote #, the ≤ 21 day window has been changed to ≤ 30 days. 
• 
In footnote **, the first sentence has been revised to read: “Treatment assessment on Day 1 and 
Day 15 of Cycle 2 and Day 1 of Cycles 3 through 13 can be performed outside the study/transplant 
center, provided the results are made available to the treating study investigator.” 
• 
In footnote **, the +/- 4 day window has been changed to +/- 7 days.  
• 
The former footnote *** has been removed. 
• 
In footnote 2, the ≤ 21 day window has been changed to ≤ 45 days.  
• 
Footnote 10 has been revised as follows: “Bone marrow biopsy and aspirate per institutional 
standards within 84 days (12 weeks) prior to registration. Repeat performed for response 
assessment at 3 months only if positive prior to registration or if there is a clinical concern.” 
• 
In the “Crossover Phase” study calendar, in footnote *, the +/- 4 day window has been changed to 
+/- 7 days. 
• 
In the “Crossover Phase” study calendar, in footnote 2, the ≤ 21 day window has been changed to 
≤ 28 days. 
 
Section 6.1 (Data Collection and Submission) 
This section has been updated with the current CTSU template language. 
 
Section 7.0 (Treatment Plan/Intervention) 
In the first sentence, the 21 day window has been changed to 45 days. 
 
Section 7.3 (Continuation) 
In the first sentence, “Day +60” has been changed to “Day +75.” 
 
Section 13.1 (Study Design) 
This section has been updated to reflect the revised sample size with this amendment.  
 

3 
Section 13.2 (Sample Size, Accrual Time and Study Duration) 
This section has been updated to describe the rationale for the sample size and statistical design changes 
being made with this amendment. 
 
Section 13.5 (Interim Analysis Design for Primary Endpoint) 
This section has been completely revised to reflect the updated statistical design with this amendment. 
 
Section 13.6 (Analysis Plan for Secondary Endpoints) 
This section has been completely revised to reflect the updated statistical design with this amendment.  
 
Section 13.9 (Inclusion of Women and Minorities) 
• 
The enrollment table has been updated to reflect the revised sample size. 
• 
The ethnic and racial categories have been removed from under the enrollment table to align with 
the current Alliance model protocol template. 
 
Section 14.1 (Imaging Correlative Science) 
Section 14.1.4 (Statistical Design) has been revised to reflect the updated statistical design and sample size 
for the main study. 
 
Section 14.2 (Pharmacogenetics [Alliance A051301-PP1]) 
In Section 14.2.4 (Statistical Design), the second paragraph has been revised to reflect the updated sample 
size of the main study. 
 
Section 14.3 (Biomarkers studies in Alliance A051301 [Alliance A051301-ST1]) 
• 
In Section 14.3.1 (BCR Mutational Analysis), the “Statistical Design” section has been revised to 
reflect the updated statistical design and sample size for the main study. 
• 
In Section 14.3.2 (BCL2 and MYC assessment prognostic markers), the “Statistical Design” section 
has been revised to reflect the updated statistical design and sample size for the main study. 
_____________________________________________________________________________________ 
UPDATES TO THE EARLY SAFETY MODEL CONSENT: 
No changes have been made to the Early Safety model consent.  
 
UPDATES TO THE RANDOMIZED STUDY MODEL CONSENT: 
Why is this study being done? 
The last sentence has been revised to read: “There will be about 160 people with “ABC” subtype DLBCL 
taking part in this study.” 
 
 
Replacement protocol and model consent documents have been issued. 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 

Alliance A051301 
Version Date: 03/22/2022 
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Update #09 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments:  
For data submission: 
Regulatory documentation must 
be submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
(Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), 
or CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email : 
1-888-823-5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions. 
 
Do not submit study data or 
forms to the CTSU. Do not copy 
the CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
 
 

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Version Date: 03/22/2022 
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Update #09 
A RANDOMIZED DOUBLE-BLIND PHASE III STUDY OF IBRUTINIB DURING AND FOLLOWING 
AUTOLOGOUS STEM CELL TRANSPLANTATION VERSUS PLACEBO IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA OF THE ACTIVATED B-CELL SUBTYPE 
Schema Page 1 of 3 
 
Pre-Registration Eligibility Criteria 
• Central pathology review submission (see section 3.2.1) 
Required Initial Laboratory Values  
(See also section 3.3.3) 
Eligibility Criteria (see section 3.3) 
Creatinine 
≤ 2.0 mg/dL 
• Diagnosis of DLBCL, non-GCB (see section 3.3.1) 
OR Calc. Creatinine Clearance 
by Cockcroft-Gault  
≥ 40 mL/min 
• Eligible for high-dose chemotherapy and AutoHCT (see section 
3.3.2) 
Total Bilirubin 
≤ 1.5 x ULN* 
• Adequate organ function for transplant (see section 3.3.3) 
AST/ALT 
≤ 3 x ULN 
• Progressed or refractory to prior anthracycline-containing 
chemotherapy (see section 3.3.4) 
PT/INR 
< 1.5 x ULN 
• ≤ 3 prior regimens for large cell component (see section 3.3.4) 
PTT (aPTT) 
< 1.5 x ULN 
• Chemosensitive disease (see section 3.3.4) 
*Unless isolated hyperbilirubinemia attributed to 
Gilbert’s syndrome 
• Not pregnant and not nursing (see section 3.3.5) 
• Age ≥ 18 years 
• No chronic use of strong or moderate CYP3A inhibitors or strong 
CYP3A inducers (see section 3.3.7) 
 
• Intercurrent or recent Illness (see section 3.3.8) 
 
 
• ECOG performance status ≤ 2 
 
 
 

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Update #09 
A RANDOMIZED DOUBLE-BLIND PHASE III STUDY OF IBRUTINIB DURING AND FOLLOWING 
AUTOLOGOUS STEM CELL TRANSPLANTATION VERSUS PLACEBO IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA OF THE ACTIVATED B-CELL SUBTYPE 

Alliance A051301 
Version Date: 03/22/2022 
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Update #09 
A RANDOMIZED DOUBLE-BLIND PHASE III STUDY OF IBRUTINIB DURING AND FOLLOWING 
AUTOLOGOUS STEM CELL TRANSPLANTATION VERSUS PLACEBO IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA OF THE ACTIVATED B-CELL SUBTYPE 
Schema Page 3 of 3 
 
STUDY TIMELINE 
 
Approximate Timing 
Clinical Procedures 
Study Procedures 
3-16 weeks pre AutoHCT 
Salvage chemotherapy 
Pre-registration for central review 1 
2-3 weeks pre AutoHCT 
Stem cell collection 
Registration2 (see section 4.0) 
5 weeks 
AutoHCT 
Conditioning regimen (Cycle 1)3: 
BEAMi or CBVi 
12 months 
 
Continuation (Cycles 2-13): 
Continuation to start day +30 to +75 
24 months 
 
Follow up for PFS24 (primary endpoint) 
60 months 
 
Long-term follow up 
 
1 Central review will consist of confirmation of diagnosis and determination of non-GCB. Turnaround 
time will be approximately 5 business days. 
2 Following registration, it will take 7-10 days for ibrutinib to arrive at local site. 
3 Conditioning regimen (Cycle 1) is to begin ≤ 45 days following registration. 
 

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Update #09 
TABLE OF CONTENTS 
Section 
Page 
1.0 
BACKGROUND .............................................................................................................................. 9 
1.1 
DLBCL Biology: Cell of Origin Subtypes ..................................................................................... 9 
1.2 
Ibrutinib for ABC DLBCL ........................................................................................................... 10 
1.3 
Summary of Clinical Safety ......................................................................................................... 11 
1.4 
Selection of Primary Endpoint: 24-Month PFS ............................................................................ 11 
1.5 
Registration Quality of Life (QOL) Measurements ..................................................................... 12 
2.0 
OBJECTIVES ................................................................................................................................ 12 
2.1 
Primary objective ......................................................................................................................... 12 
2.2 
Secondary objective(s) ................................................................................................................. 12 
2.3 
Correlative science objective(s) ................................................................................................... 12 
3.0 
PATIENT SELECTION ............................................................................................................... 13 
3.1 
On-Study Guidelines .................................................................................................................... 13 
3.2 
Pre-Registration Eligibility Criteria (Step 0) ................................................................................ 14 
3.3 
Eligibility Criteria (Step 1) ........................................................................................................... 14 
4.0 
PATIENT REGISTRATION ....................................................................................................... 16 
4.1 
Investigator and Research Associate Registration with CTEP ..................................................... 16 
4.2 
Cancer Trials Support Unit Registration Procedures ................................................................... 17 
4.3 
Patient Pre-Registration Requirements ......................................................................................... 19 
4.4 
Patient Registration Requirements ............................................................................................... 20 
4.5 
Patient Registration/Randomization Procedures .......................................................................... 20 
4.6 
Registration to Correlative and Companion Studies .................................................................... 21 
4.7 
Stratification and Grouping Factors ............................................................................................. 21 
4.8 
Re-Registration at the time of progression ................................................................................... 21 
5.0 
STUDY CALENDAR .................................................................................................................... 23 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 27 
6.1 
Data Collection and Submission .................................................................................................. 27 
6.2 
Specimen collection and submission ............................................................................................ 28 
6.3 
Imaging submission ...................................................................................................................... 30 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 33 
7.1 
Stem Cell Mobilization, Collection, and Infusion ........................................................................ 33 
7.2 
Conditioning Regimen (Cycle 1).................................................................................................. 34 
7.3 
Continuation (Cycles 2-13) .......................................................................................................... 35 
7.4 
Crossover at Disease Progression ................................................................................................. 36 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ............................................ 36 
8.1 
Ancillary therapy, concomitant medications, and supportive care ............................................... 36 
8.2 
Dose Modifications ...................................................................................................................... 38 
8.3 
Unblinding Procedures ................................................................................................................. 40 
8.4 
Overdose ....................................................................................................................................... 40 
9.0 
ADVERSE EVENTS ..................................................................................................................... 41 
9.1 
Routine adverse event reporting ................................................................................................... 41 
9.2 
CTCAE Routine Reporting Requirements ................................................................................... 42 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................... 42 

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Update #09 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Ibrutinib (NSC # 748645, 
) ......................................................................................................................................... 46 
10.0 
DRUG INFORMATION ............................................................................................................... 50 
10.1 General Considerations: ............................................................................................................... 50 
10.2 Ibrutinib (NSC #748645, 
)...................................................................................... 50 
10.3 BCNU (Carmustine, NSC# 409962) ............................................................................................ 56 
10.4 Cyclophosphamide (NSC# 26271) ............................................................................................... 57 
10.5 Etoposide (NSC# 141540) ............................................................................................................ 59 
10.6 Ara-C (Cytarabine, NSC# 63878) ................................................................................................ 60 
10.7 Melphalan (NSC# 8806) .............................................................................................................. 62 
10.8 G-CSF (filgrastim, NSC# 614629) ............................................................................................... 63 
10.9 PEG-G-CSF (pegfilgrastim, NSC# 725961) ................................................................................ 64 
10.10 Mesna (NSC# 113891) ................................................................................................................. 64 
11.0 
MEASUREMENT OF EFFECT .................................................................................................. 65 
11.1 Schedule of Evaluations: .............................................................................................................. 65 
11.2 Measurement of Treatment/Intervention Effect ........................................................................... 65 
11.3 Definitions of analysis variables .................................................................................................. 68 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 69 
12.1 Duration of Treatment .................................................................................................................. 69 
12.2 Definitions and Follow-up Requirements .................................................................................... 69 
12.3 Extraordinary Medical Circumstances ......................................................................................... 70 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 70 
13.1 Study Design ................................................................................................................................ 70 
13.2 Sample Size, Accrual Time and Study Duration .......................................................................... 70 
13.3 Statement for Primary Endpoint ................................................................................................... 71 
13.4 Statement for Secondary Endpoint ............................................................................................... 71 
13.5 Interim Analysis Design for Primary Endpoint ............................................................................ 72 
13.6 Analysis Plan for Secondary Endpoints ....................................................................................... 72 
13.7 Early Safety Monitoring ............................................................................................................... 73 
13.8 Protocol-Specific Monitoring Plan ............................................................................................... 73 
13.9 Inclusion of Women and Minorities ............................................................................................. 74 
13.10 Clinical Data Update System (CDUS) ......................................................................................... 74 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 74 
14.1 Imaging Correlative Science ........................................................................................................ 74 
14.2 Pharmacogenetics (Alliance A051301-PP1) ................................................................................ 76 
14.3 Biomarkers studies in Alliance A051301 (Alliance A051301-ST1) ............................................ 78 
15.0 
REFERENCES .............................................................................................................................. 82 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ................................. 87 
APPENDIX II 
CYP3A INDUCERS AND INHIBITORS ................................................................ 88 
APPENDIX III 
ALLIANCE A051301 MEDICATION CALENDARS............................................ 90 
APPENDIX IV 
COLLABORATIVE AGREEMENT PROVISIONS .............................................. 93 
APPENDIX V 
CHILD-PUGH SCORE ............................................................................................. 95 
 
 

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Update #09 
1.0 
BACKGROUND 
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma worldwide. Even though 
rituximab/anthracycline-containing chemotherapy (e.g. R-CHOP) can cure a significant proportion 
of patients with this disease in the modern era, approximately 40% are either refractory to front-line 
treatment or relapse following therapy [1-3]. Gene expression profiling has identified two distinct 
subtypes of DLBCL with a differential response to front-line chemotherapy [4, 5]. The two main 
subtypes originally identified, germinal center B-cell-like (GCB) and activated B-cell-like (ABC)1 
have dramatically different 5-year survival rates of 60% versus 35% after CHOP respectively. At the 
time of relapse, regardless of disease subtype, the standard of care involves salvage chemotherapy 
followed by autologous hematopoietic cell transplantation (AutoHCT) in chemosensitive patients.[6] 
With this approach, 24-month progression-free survival (PFS) following transplantation in the 
rituximab era approaches 48% and 24-month overall survival (OS) 65%.[7-9] Disease progression or 
relapse following AutoHCT is the major cause of mortality in this patient population. The majority 
of relapses (~70%) occur in the first 12 months following AutoHCT [9]. The current study was thus 
designed to improve survival outcomes in this patient population by incorporating biologically 
targeted therapy in the treatment program. 
Patients with relapsed DLBCL in the rituximab era have poor outcomes with conventional standard 
approaches to AutoHCT. Additionally, patients with the ABC subtype of DLBCL as defined by either 
mRNA or protein methods have proven inferior outcomes in the front-line setting with standard 
chemotherapy approaches and differential response to salvage therapies in the relapsed/refractory 
setting. Ibrutinib is a selective inhibitor of BTK, a critical component of the chronic active BCR 
signaling pathway, which plays a central role in the pathogenesis of ABC DLBCL. Our hypothesis is 
that the addition of ibrutinib, which as a single agent is clinically active in the relapsed/refractory 
setting of ABC DLBCL, will augment transplant effectiveness and target residual low-burden disease 
thus leading to an improvement in 24-month PFS and OS in this patient population. This is a 
randomized placebo-controlled phase III study that will evaluate ibrutinib therapy during and 
following AutoHCT in this high-risk patient population. This approach is novel in selectively 
targeting the ABC subtype of disease using a biologically relevant small molecule inhibitor in 
combination with high-dose therapy. In this regard, this approach can make a major contribution to 
the treatment of patients with relapsed DLBCL. 
1For the purpose of this discussion, the terms non-GCB and ABC will be used interchangeably. 
1.1 
DLBCL Biology: Cell of Origin Subtypes 
The Lymphoma/Leukemia Molecular Profiling Project at the NCI (LLMPP) has used molecular 
profiling to subdivide diffuse large B-cell lymphoma into distinct subtypes with a differential 
response to front-line chemotherapy [4, 5]. The two main subtypes originally identified, 
germinal center B-cell-like (GCB) and activated B-cell-like (ABC) have dramatically different 
5-year survival rates of 60% versus 35% respectively. A multivariate predictive model of overall 
survival was created from 27 genes chosen from different functional groups differentially 
expressed in the two subtypes [5]. This gene expression- based outcome predictor was able to 
stratify patients into risk groups with strikingly distinct overall survival rates. One half of the 
patients could be placed in a favorable risk group (GCB) with a 71% 5-year survival rate. One 
quarter of the patients were in a poor risk group with only a 15% 5-year survival rate and the 
remaining quarter of patients had a 36% 5-year survival rate [10]. These results have been 
extended to the protein level by immunohistochemistry, with several classifier algorithms since 
developed that retain predictive ability, even though they exhibit variable cross-correlation. [11-
13] Moreover, this biological separation, as captured by GEP or IHC profiling, has been 
validated in the rituximab era [11, 14] and in the setting of first-line stem cell transplantation 
[15]. Recent studies suggest that there may be an effect modification by chemotherapy regimen 
utilized in the first [16, 17] and the second line [18] setting. 

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Update #09 
The accumulating evidence regarding differential outcomes by biologic subtypes and the 
development of efficient methodology to assign individual patients to these are making their 
characterization in clinical trials and practice imperative. In the front-line setting, a completed 
intergroup study (C50303) is attempting to prospectively evaluate outcomes by molecular 
subtype and by chemotherapy regimen utilized. In the relapsed setting, BioCORAL identified 
differential activity of salvage regimens by disease subtype with R-DHAP performing better 
than R-ICE in the GCB but not the non-GCB or ABC cohorts. The future standard of care will 
undoubtedly incorporate assignment of DLBCL patients to molecular subtypes at diagnosis and 
salvage. 
This is the first cooperative group study specifically targeted to the ABC subtype of DLBCL. 
We will register patients for the study who have been deemed to have non-GCB DLBCL as 
defined by IHC-based criteria (Hans algorithm). A secondary, correlative analysis will examine 
the subset of patients with ABC-DLBCL as determined by previously identified gene expression 
classifiers [14, 19] on paraffin-embedded tissue. 
The BCR signaling pathway that is chronically active in ABC DLBCL has several members 
with well-recognized recurrent mutations. These include CD79, mutated in 20% of cases, and 
CARD11, mutated in ~10% [20]. Moreover, MYD88, an adaptor protein that mediates toll and 
interleukin (IL)-1 receptor signaling, is mutated in ~30% of cases of ABC DLBCL [21]. The 
presence of these mutations may affect response to ibrutinib therapy, as CD79 acts upstream of 
BTK, CARD11 is further downstream, and MYD88 interfaces with components of this pathway. 
In the phase II study reported recently, 5/7 patients with CD79 mutations and 4/5 patients with 
both CD79 and MYD88 mutations responded to ibrutinib, while none of the ABC patients with 
CARD11 mutations responded to the drug [22]. We hypothesize that these mutations will be 
significantly associated with outcomes in our study and we will collect archival tissue to assess 
for their presence. This trial will be the first to selectively target a molecular subtype of 
relapsed/refractory DLBCL and can potentially identify additional patient subgroups that are 
more likely to derive benefit from AutoHCT and ibrutinib independently. In this regard, it can 
make a major contribution to the treatment of patients with relapsed DLBCL and serve as a 
model for future trials. 
1.2 
Ibrutinib for ABC DLBCL 
The B-Cell receptor (BCR) signaling pathway plays a prominent role in the pathobiology of 
ABC-subtype DLBCL [23]. Chronic active BCR signaling engages CARD11 to activate NF-
kB, a key regulator of cell survival in this disease [24]. CARD11 is itself mutated in ~10% of 
ABC DLBCLs [24]. Bruton’s tyrosine kinase (BTK) is upstream of CARD11 in the BCR 
signaling pathway [20]. A mutation in BTK leads to absence of B-cells in the developing 
organism, as established by the existence of the human genetic immunodeficiency disease X-
linked agammaglobulinemia (XLA), and the mouse genetic immunodeficiency disease X-linked 
immunodeficiency [25]. Further upstream of BTK is CD79, which is mutated in more than 20% 
of ABC DLBCL tumors [23]. 
Ibrutinib is a first-in-class selective inhibitor of BTK with in vitro activity in ABC lymphoma 
cell lines [26] and clinical activity in ABC patients. In the phase I study involving 47 patients 
with lymphoid malignancies, ibrutinib was very well tolerated with minimal myelosuppression 
or liver function abnormalities and only isolated instances of grade 3 diarrhea and fatigue that 
were not clearly dose related. Notably, the incidence of grade 3 or 4 hematologic toxicity was 
only 8% in this heavily pretreated patient population. Despite the fact that most of the patients 
enrolled were refractory to prior therapy, a remarkable 51% overall response rate was observed 
with 3 of 8 (38%) patients with relapsed/refractory DLBCL responding [27, 28]. A relapsed, 
refractory DLBCL-specific phase II study of ibrutinib was recently reported [22]. This study 
enrolled 70 patients with a median of 3 (range 1-7) prior regimens, 23% of whom had relapsed 

Alliance A051301 
Version Date: 03/22/2022 
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Update #09 
after autologous transplant. There was no excess hematological or other unexpected toxicity 
identified. In 25 reported cases with ABC subtype DLBCL, the response rate was 40% (8% CR, 
32% PR) versus 5% in the patients with GCB. Progression-free survival was a median of 5.5 
months in the ABC subgroup. This agent is active in relapsed and refractory ABC DLBCL as 
monotherapy. It is also tolerable and orally bioavailable on a once daily schedule, making it 
ideal for use during and following AutoHCT. We hypothesize that using ibrutinib in the setting 
of minimal disease burden will abrogate relapse and improve clinical outcomes. 
1.3 
Summary of Clinical Safety 
Integrated safety data from a total of 1,523 subjects with B-cell malignancies treated with 
ibrutinib monotherapy in 17 studies that have completed primary analysis or final analysis 
included in the CSR as of the 31 July 2017 cutoff date for the current IB update in B-cell 
malignancies are summarized below.   
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N = 1,523): 
Most frequently reported 
TEAEs >10% a 
Most frequently reported Grade 
3 or 4 TEAEs >2% a  
Most frequently reported 
Serious TEAEs >1% b  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Pyrexia 
Cough 
Anemia 
Febrile neutropenia 
Pyrexia 
Hypertension   
Sepsis 
Anemia  
Diarrhea  
Cellulitis 
Upper respiratory tract infection 
 Neutropenia  
Atrial fibrillation 
Fatigue 
Pleural effusion 
Dyspnoea 
Oedema peripheral 
Neutrophil count decreased 
Urinary tract infection 
Thrombocytopenia    
Febrile Neutropenia 
Lung infection 
Muscle spasms 
Hyponatraemia 
Abdominal pain 
Constipation 
Hypokalaemia 
Acute kidney injury 
Arthralgia 
 
Anemia 
Vomiting 
 
Respiratory failure 
Decrease appetite 
 
 
Dyspnoea 
 
 
Headache 
 
 
Pneumonia 
 
 
Rash 
 
 
Hypertension 
 
 
Abdominal pain 
 
 
Back pain 
 
 
Contusion 
 
 
Dizziness 
 
 
a Source is Table 5 of IB (v11), b Source is Table 6 of IB (v11) 
For more detailed information, refer to the current version of the Investigator’s Brochure. 
1.4 
Selection of Primary Endpoint: 24-Month PFS 
Since DLBCL is ultimately a curable disease, even in the relapsed/refractory setting, we 
designed this trial with a dichotomous primary endpoint that best captures the curative potential 

Alliance A051301 
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Update #09 
of the proposed therapy. This assessment will occur 12 months following completion of ibrutinib 
or placebo therapy. Data from randomized studies in DLBCL suggest that the majority of the 
relapse events following AutoHCT occur in the first 24 months [7-9, 18]. Specifically in patients 
with relapsed DLBCL of the non-GCB subtype, Thieblemont et al suggest that over 80% of the 
relapses have occurred by 24 months [18]. Furthermore, a large population-based study has 
shown that 24-month event-free survival (defined similarly to our definition of PFS in this trial) 
is very strongly associated with OS and is a robust endpoint for disease-related outcomes in 
DLBCL [29]. 
1.5 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study. Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 NCCTG and 
Mayo Clinic Cancer Center oncology clinical trials, the second involving 43 clinical trials. 
Routine inclusion of these measures should be considered similar to that of including 
performance status, either as stratification or prognostic covariates [30, 31]. 
2.0 
OBJECTIVES 
2.1 
Primary objective 
To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS) 
compared to placebo in patients with non-GCB DLBCL as determined by IHC. 
2.2 
Secondary objective(s) 
2.2.1 To evaluate the ability of ibrutinib to improve overall survival (OS) compared to placebo.  
2.2.2 To evaluate the ability of ibrutinib to improve progression free survival (PFS) compared to 
placebo. 
2.2.3 To evaluate the ability of ibrutinib to improve post-transplant response rates compared to 
placebo. 
2.2.4 To evaluate time to hematopoietic recovery in the two arms. 
2.2.5 To evaluate the safety and tolerability of ibrutinib compared to placebo. 
2.2.6 To evaluate the incidence of secondary malignancies in the two arms. 
2.2.7 To evaluate immune reconstitution in the two arms. 
2.3 
Correlative science objective(s) 
2.3.1 To assess whether pre-AutoHCT positive FDG-PET is associated with inferior 24-month 
PFS as well as PFS and OS.  
2.3.2 To assess whether pre-AutoHCT FDG-PET results are differentially associated with 24-
month PFS, PFS and OS in the ibrutinib versus placebo arms. 
2.3.3 To evaluate the application of the Lugano criteria and change in quantitative measurements 
between pre-AutoHCT and post AutoHCT (e.g. delta SUV, %SUV decline and %MTV 
decline, and other available applicable quantitative measurements) to assess the association 
between changes in these variables and outcomes, such as PFS and OS. 

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2.3.4 To assess whether the GSTT1 null polymorphism is correlated with pulmonary toxicity after 
BCNU-containing conditioning regimens as part of autologous stem cell transplantation. 
2.3.5 To assess whether other polymorphisms in the BCNU metabolism pathway or BCNU 
damage repair pathway(s) are associated with pulmonary toxicity after BCNU-containing 
conditioning regimens as part of autologous stem cell transplantation. 
2.3.6 To evaluate whether any of the proposed DNA polymorphisms are associated with other 
toxicities. 
2.3.7 To assess whether DLBCL subtype based on the Lymphoma Subtyping Test (LST) is 
associated with 24-month PFS, PFS, and OS with ibrutinib compared to placebo in patients 
treated on this protocol. 
2.3.8 To assess whether activating mutations in the BCR pathway are associated with response to 
ibrutinib and with clinical outcomes in patients treated on this protocol. 
2.3.9 To assess whether there are any phenotypic associations with IHC markers (particularly 
MYC protein expression level) and presence of these mutations. 
2.3.10 To assess whether BCL2, MYC, and Ki67 expression by IHC affect clinical outcomes in 
patients treated on this protocol. 
2.3.11 To assess whether translocations in MYC with or without BCL2 and BC6 have poor 
outcomes in patients treated on this protocol and whether ibrutinib modifies the prognosis. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements. 
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate. 
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol: 
NOTE that these guidelines are phrased in the negative; i.e., these are potential participants who 
should not be enrolled to the study. 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers 
or cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
• 
Patients who cannot swallow oral formulations of ibrutinib. 
• 
Significant non-hematologic toxicity from salvage therapy except for alopecia and fatigue. 

Alliance A051301 
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Update #09 
3.2 
Pre-Registration Eligibility Criteria (Step 0) 
3.2.1 Central pathology review submission 
Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be 
submitted for central pathology review. This review is mandatory prior to registration to 
confirm eligibility and should be initiated as soon as possible. 
3.3 
Eligibility Criteria (Step 1) 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later 
would be considered Day 28. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive 
months). 
 
3.3.1 Documentation of Disease: 
Diagnosis of WHO diffuse large B-cell lymphoma, non-GCB by central review 
confirmation.  
 
3.3.2 Eligible for high-dose therapy and AutoHCT 
Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous 
stem cell transplantation by local transplant center. 
 
3.3.3 Adequate organ function to proceed to transplant 
Patient must have adequate organ function to proceed to transplant as defined below: 
 
Cardiac: New York Heart Association Class I or less. Ordinary physical activity does not 
cause undue fatigue, palpitations, dyspnea, or angina pain. Patients 60 years or older must 
have a left ventricular ejection fraction (LVEF) at rest ≥ 40% measured by echocardiogram 
or MUGA. 
 
Pulmonary: DLCO (corrected or uncorrected for hemoglobin per institutional standards), 
FEV1, FVC ≥ 40% of predicted 
 
Hepatic: Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) unless isolated 
hyperbilirubinemia attributed to Gilbert’s syndrome. AST and ALT ≤ 3 x upper limit of 
normal (ULN). 
 
Renal: Creatinine ≤ 2.0 mg/dL OR creatinine clearance (calculated clearance permitted) ≥ 
40 mL/min by Cockcroft-Gault formula. 
 
PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN 
 
3.3.4 Prior Treatment 
 
Patient must have progressed or be refractory to prior anthracycline-containing 
chemotherapy (e.g. R-CHOP, DA-EPOCH-R, etc). 
 
No more than 3 prior regimens for large cell component (e.g. one induction and two salvage 
therapies). Monoclonal antibody alone or involved field/involved site radiotherapy do not 
count as lines of therapy. Prior CART therapy is allowed and counts as one line of therapy. 

Alliance A051301 
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Update #09 
 
Prior use of ibrutinib is allowed unless patient has had disease progression while receiving 
ibrutinib. 
___ 
Patient must have chemosensitive disease as defined by at least a partial response to salvage 
therapy at their latest assessment. 
___ 
No major surgery ≤ 7 days prior to registration and no minor surgery ≤ 3 days prior to 
registration (with the exception of intravenous access placement, e.g. Hickman or PICC). 
___ 
3.3.5 Not pregnant and not nursing, because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative serum pregnancy test 
must be obtained within 14 days prior to registration. 
Women of childbearing potential must use adequate contraception from study start to one 
month after the last dose of protocol therapy. Adequate contraception is defined as hormonal 
birth control, intrauterine device, double barrier method or total abstinence. Men must 
practice complete abstinence or agree to use an adequate contraception method from study 
start to one month after the last dose of protocol therapy. 
___ 
3.3.6 Age ≥ 18 years 
 
3.3.7 Concomitant medications 
___ 
Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A 
inducers (see Appendix II). 
___ 
Patients should not require concurrent therapeutic doses of steroids (> 20 mg of 
prednisone/day or equivalent) unless they need them for the indications listed in Appendix 
II. Steroids should be discontinued for 14 days before starting protocol treatment. 
 
3.3.8 Intercurrent or Recent Illness 
 
HIV infected patients are eligible provided they meet all other eligibility criteria, and: 
• 
There is no prior history of AIDS defining conditions other than historically low CD4+ 
T-cell count or B-cell lymphoma 
• 
In the opinion of an expert in HIV disease, prospects for long-term survival are excellent 
were it not for the diagnosis of lymphoma 
• 
Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic 
booster is not allowed 
• 
Zidovudine is not allowed 
• 
Once daily combination pills for HIV containing a pharmacologic booster such as 
cobicistat are not allowed 
• 
Patients with multi-drug resistant HIV are not eligible 
Patients cannot have: 
 
Active central nervous system or meningeal involvement by lymphoma. Patients with a 
history of CNS or meningeal involvement must be in a documented remission by CSF 
evaluation and contrast-enhanced MRI imaging for at least 91 days prior to registration. 
___ 
Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any 
bone marrow biopsy prior to initiation of therapy. 
___ 
A known bleeding diathesis. 

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Update #09 
___ 
Requirement for warfarin or similar vitamin K antagonists. These drugs are prohibited 28 
days prior to the first treatment and throughout the trial. 
___ 
History of stroke or intracranial hemorrhage ≤ 6 months before treatment. 
___ 
Currently active, clinically significant hepatic impairment (Child-Pugh class B or C 
according to the Child Pugh classification [see Appendix V]). 
___ 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ibrutinib or other agents used in study. 
___ 
Serologic status reflecting active hepatitis B or C infection. Patients that are positive for 
hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must 
have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients 
will be excluded.) 
 
3.3.9 ECOG Performance Status must be ≤ 2 
4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
IVR—MD, DO, or international equivalent; 
NPIVR—advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
AP—clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such 
as the Roster Update Management System (RUMS), OPEN, Rave; acting as a primary 
site contact, or with consenting privileges 
Associate (A)—other clinical site staff involved in the conduct of NCI-sponsored trials; and 
Associate Basic (AB)—individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
RCR requires the following registration documents: 

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Update #09 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an Active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Site Registration Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.1 Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
PO on the protocol. One way to search for a protocol is listed below. 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password 
• Click on Protocols in the upper left of the screen 
• 
Enter the protocol number in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand, the select Alliance and 
protocol number A051301. 
• Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU) 
4.2.2 Requirements for A051301 Site Registration 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 

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Update #09 
4.2.3 Checking Site Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
- Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.2.4 Submitting Regulatory Requirements 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU 
(2878), or CTSURegHelp@coccg.org in order to receive further instruction and support. 
4.2.5 Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website. The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site 
receiving an Approved site registration status and enrolling patients to the study. To 
maintain an approved site registration status the CI must re-sign the DTL at least annually 
and when a new version of the DTL is released; and to activate new task assignments 
requiring CI sign-off. Any individual at the enrolling site on a participating roster may 
initiate the site DTL. Once the DTL is submitted for CI approval, only the designated DTL 
Administrators or the CI may update the DTL. Instructions on completing the DTL are 
available in the Help Topics button in the DTL application and include a Master Task List, 
which describes DTL task assignments, CI signature, and CTEP registration requirements. 
4.3 
Patient Pre-Registration Requirements 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
• 
Central pathology review submission: For all patients pre-registered to Alliance 
A051301, real time histopathology review is required. FFPE tissue from the diagnostic or 
relapse biopsy for histopathology review is required for all patients at pre-registration.  
Pre-registration procedures: Patients who have 1) met pre-registration eligibility criteria and 
2) been consented, will be pre-registered using the OPEN registration system per section 4.5. 
Once a patient has been pre-registered, the FFPE tissue should be sent to Cleveland Clinic 
within 7 days, along with the completed “Central Pathology Results Form.” Failure to submit 
this form with the specimens will delay turnaround time for central review. The specimen will 

Alliance A051301 
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Update #09 
be centrally reviewed to confirm study eligibility. See section 6.2 for specimen collection and 
submission details. 
4.4 
Patient Registration Requirements 
• 
Confirmation of eligibility by central review: Within 5 business days of receipt of a 
suitable specimen sample at Cleveland Clinic, sites will be notified via e-mail whether or 
not the patient is eligible based on the central pathology review. If a sample is deemed 
unsuitable after central pathology review, a request for an alternative sample will be made. 
The results section of the “Central Pathology Results Form” will be completed by the 
pathologist and laboratory performing the subtyping, scanned, and sent via e-mail to the 
responsible CRA listed on the form. After receiving the results form via e-mail, the 
institution must forward the form to the Alliance Patient Registration office at 
random01@mayo.edu in order to register the patient. Once the form is forwarded to the 
Alliance Patient Registration Office and the Registration and Randomization Eligibility 
Criteria have been met, the patient can be registered using the OPEN system per section 4.5. 
The same patient ID number obtained at pre-registration from the OPEN system should be 
used to register the patient. Retain the “Central Pathology Results Form” confirming 
eligibility for your records and to upload via Rave. 
• 
FDG-PET/CT obtained during salvage therapy will be acquired at the time of study entry 
and will be centrally reviewed. Please note, this will not be a real time review to confirm 
eligibility. For more information see section 6.3 and section 14.1. 
4.5 
Patient Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar' role on either the LPO or participating organization roster. Registrars must hold a 
minimum of an AP registration type. If a DTL is required for the study, the registrar(s) must 
also be assigned the OPEN Registrar task on the DTL. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the 
treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on 
the site’s IRB approval. If a DTL is required for the study, the IVR or NPIVR must also be 
assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration. 
Please print this confirmation for your records. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 

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Update #09 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.6 
Registration to Correlative and Companion Studies 
4.6.1 Registration to substudies described in section 14.0 
There are two substudies within Alliance A051301. These correlative science studies must 
be offered to all patients enrolled on Alliance A051301 (although patients may opt to not 
participate). These substudies do not require separate IRB approval. The substudies included 
within Alliance A051301 are: 
• 
“Pharmacogenetics 
of 
high-dose 
chemotherapy 
and 
treatment 
efficacy 
in 
relapsed/refractory DLBCL,” Alliance A051301-PP1 (section 14.2) 
• 
Biomarker studies in Alliance A051301 (A051301-ST1) (section 14.3) 
If a patient answers “yes” to question #1 in the model consent, “I agree to have my blood 
specimen collected, and I agree that my specimen sample(s) and related information may be 
used for the blood study described above,” they have consented to participate in the substudy 
described in section 14.2. The patient should be registered to Alliance A051301-PP1 at the 
same time they are registered to the treatment trial (A051301). Samples should be submitted 
per section 6.2.4. 
If a patient answers “yes” to question #2 in the model consent, “I agree to have my tissue 
specimen collected, and I agree that my specimen sample(s) and related information may be 
used for the tissue study described above,” they have consented to participate in the substudy 
described in section 14.3. The patient should be registered to Alliance A051301-ST1 at the 
same time they are registered to the treatment trial (A051301). Samples should be submitted 
per section 6.2.3. 
4.7 
Stratification and Grouping Factors  
Patients will be assigned to one of the following groups at study entry: 1) Early safety assessment 
or 2) Double-blinded randomization. 
Patients will be stratified at study entry by prior use of ibrutinib, type of transplant regimen 
planned (CBV vs. BEAM), and time to relapse (≤ 12 months or > 12 months). Time to relapse 
is calculated from day 1 of initial treatment (e.g. R-CHOP) to time of clinical relapse (by exam, 
imaging or pathology). Patients who never achieve a CR to front-line therapy are considered to 
be in the ≤ 12 months group. 
4.8 
Re-Registration at the time of progression 
Progression is defined by the CT-based response criteria. Upon confirmation of progression, 
patients may elect to cross-over to treatment with ibrutinib as long as the following eligibility 
criteria are met: 
ANC ≥ 1000/μL, platelets ≥ 30,000/μL 
Serum creatinine ≤ 2.0 mg/dL OR 
Calc. creatinine clearance ≥ 40 mL/min by Cockgroft-Gault 
AST, ALT ≤ 2x ULN 
Total bilirubin ≤1.5x ULN (except for patients with Gilbert’s syndrome) 

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Update #09 
Re-registration procedures: 
OPEN may be accessed at https://open.ctsu.org, from the OPEN tab on the CTSU website at 
https://www.ctsu.org, or from the OPEN Registration tab on the Alliance website. 
To enroll a patient within OPEN, institution staff must have: 
1. 
A valid and active CTEP-IAM account. This is the same user ID and password used for 
CTSU’s website (for more information see https://www.ctsu.org/public/CTEP-
IAM_Factsheet.pdf). 
2. 
Enrollment of patients on Alliance coordinated protocols requires a “Registrar” role in the 
Alliance roster. Assignment of the “Registrar” role is managed through the Alliance 
Central Office via submission of a roster update form signed by the Principal Investigator 
of the member network. 
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information is 
provided on the CTSU members’ website OPEN tab, or within the OPEN URL. For any 
additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923, 
or 
ctsucontact@westat.com. 

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Update #09 
5.0 
STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
on this trial. 
Note: Cycle 1 ends on AutoHCT day +29, and Cycle 2 begins with a Day 1 visit between AutoHCT 
day +30 and +60. 
 
Pre-
registration 
assessment 
Registra
tion# 
Cycle 1 
Cycles 2-13 
Clinical 
Follow 
up† 
At PD, 
withdrawal, 
or removal 
£ 
Day -6 or Day -
7 of AutoHCT 
Weekly until 
day +29* 
Day 1 and Day 15 
of Cycle 2. Day 1 
of Cycles 3 
through 13** 
Tests & Observations 
History and 
physical, Weight, 
PS 
 
X 
X 
 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Pulse, Blood 
pressure 
 
X 
 
 
 
 
 
ECG 
 
X 
 
 
 
 
 
Adverse Event 
assessment 
 
X 
X 
X 
X 
X 
X 
Patient 
medication diary 
 
 
X(1) 
 
X(1) 
 
 
Concomitant 
meds 
 
X 
 
 
X 
 
X 
Fatigue/ 
uniscale 
assessment 
 
X(2) 
 
 
 
 
 
Laboratory Studies 
CBC, Differential, 
Platelets 
 
X 
X 
X 
X 
X 
X 
Na, K, Cl, BUN, 
Serum creatinine, 
Glucose, Calcium 
 
X 
X 
X 
X 
X 
X 
AST, ALT, Alk. 
Phos., Bili, Total 
protein, Albumin 
 
X 
X 
X 
X 
X 
X 
Serum HCG 
 
X(3) 
 
 
 
 
 
PFTs 
 
X(4) 
 
 
X(4) 
 
 
PT/INR, PTT 
(aPTT) 
 
X 
 
 
 
 
 
Serum 
immunoglobulins, 
absolute B-cells, 
T-cell subsets 
 
X(5) 
 
 
X(5) 
X(5) 
 
HBsAb, HBcAb, 
HBsAg, HCAb 
 
X(6) 
 
 
 
 
 
ECHO or MUGA 
 
X(7) 
 
 
 
 
 

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Update #09 
Staging 
Central pathology 
review for 
eligibility 
X(8) 
 
 
 
 
 
 
Tumor 
measurement 
 
X 
 
 
A 
A 
X 
PET 
X(9) 
X(9) 
 
 
B 
B 
X 
CT/MRI 
chest/abd/pelvis 
 
X(9) 
 
 
C 
C 
X 
BM biopsy 
 
 
 
 
X(10) 
 
 
Correlative studies: For patients who consent to participate 
Tissue and blood 
samples 
X(12) 
X(11) 
 
 
 
 
X(12) 
# 
Labs and observations may be obtained ≤ 30 days prior to visit unless otherwise noted. 
* 
Labs to be obtained on Day +1, +8, +15, +22, and +29. If outpatient, these can be performed locally, provided the 
results are made available to the treating study health care provider within 24 hours. 
** Treatment assessment on Day 1 and Day 15 of Cycle 2 and Day 1 of Cycles 3 through 13 can be performed 
outside the study/transplant center, provided the results are made available to the treating study investigator. There 
is a +/- 7 day window for every visit. For Cycle 2 only, labs and observations completed for the Cycle 1, Day +29 
assessment can be used if obtained ≤ 7 days prior to Cycle 2, Day 1. 
† 
Clinical follow-up to be performed at the study/transplant center. For patients who complete all cycles 1-13: 
clinical follow-up is at 18 and 24 months (+/- 1 month) from registration, then every 6 months (+/-1 month) until 
5 years have elapsed from registration or until disease progression, whichever occurs first. Progression is defined 
by the CT-based response criteria. For patients who discontinue study treatment in cycles 1-13 (for reasons other 
than progression or relapse): clinical follow-up is every 3 months (+/- 14 days) until 1 year from registration 
(e.g. at months 3, 6, 9, 12); these patients will continue protocol requirements per active treatment (for example, 
PET scan at 3 months, CT/MRI scans at 6, 12 months). Following 12 months, clinical follow-up is at 18 and 24 
months (+/- 1 month) from registration, then every 6 months (+/- 1 month) until 5 years have elapsed from 
registration or until disease progression, whichever occurs first. Progression is defined by the CT-based response 
criteria.  
£ 
After disease progression or start of alternative anticancer therapy, patients will be contacted approximately every 
6 months by clinic visit or telephone to assess survival and the use of alternative anticancer therapy until death, 
withdrawal of consent, loss to follow up, study closure, or 5 years have elapsed from registration. 
1 
The Cycle 1 medication diary must begin when patient starts taking study drug on Day -6 or Day -7. For cycles 
2-13, the diary must begin the day the patient starts taking study drug in Cycle 2. Medication diaries must be 
completed per protocol and returned to the treating institution OR compliance must be documented in the medical 
record by any member of the care team (see Appendix III). 
2 
To be completed after registration and ≤ 45 days prior to treatment, see section 1.3 and Appendix I. 
3 
For women of childbearing potential (see section 3.3.3). Must be obtained within 14 days prior to registration. 
4 
Baseline PFTs with DLCO to be obtained within 84 days (12 weeks) prior to registration. Repeat PFTs with 
DLCO are strongly encouraged following AutoHCT at 3 months (+/- 1 month). 
5 
Quantitative immunoglobulin panels (IgG, IgM, IgA), absolute B-cell counts (CD19+), and T-cell subsets (CD3+, 
CD4+, CD8+) to be obtained at baseline and at 3, 6, 9, 12, 18, and 24 months (+/- 1 month) from registration. 
6 
Required for all patients prior to registration. Patients that are positive for hepatitis B core antibody, hepatitis B 
surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. 
See section 3.3.8.  
7 
For patients 60 years or older (see section 3.3.3). To be obtained within 60 days prior to registration.  
8 
Paraffin tissue block from a diagnostic biopsy (obtained at diagnosis or relapse) should be submitted for central 
pathology review for subtype determination by gene expression profiling (see sections 4.3 and 6.2.2). 
9 
The FDG-PET/CT scan obtained during salvage therapy will be acquired at study entry and submitted for central 
review (see sections 4.4 and 6.3). Repeat FDG-PET/CT is not required for eligibility. 
Baseline scans should include a whole body or limited whole body PET/CT or a PET and a diagnostic CT or MRI 
of the chest, abdomen, and pelvis documenting response to salvage therapy within 42 days of registration. The 
scans need to be submitted for subsequent central review (see section 6.3). 

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Update #09 
10 Bone marrow biopsy and aspirate performed for response assessment at 3 months only if positive prior to 
registration or if there is a clinical concern. 
11 See section 6.2.4 for patients enrolled on substudy A051301-PP1. 
12 See section 6.2.3 for patients enrolled on substudy A051301-ST1. 
A 
Tumor measurements at 3, 6, 12, 18, and 24 months from registration. 
B 
At 3 months (+/- 1 month) from registration, perform a whole body or limited whole body PET/CT or a PET with 
a diagnostic CT or MRI of the neck, chest, abdomen, pelvis. This scan is submitted for central review (see section 
6.3). Patients who are receiving post-transplant radiation can have this assessment delayed by an additional month. 
C 
At 6, 12, 18, and 24 months (+/- 1 month) from registration, perform a diagnostic CT or MRI of the neck, chest, 
abdomen, pelvis without a PET or a whole body or limited whole body PET/CT. The PET portion is not required 
by the study. These scans will be submitted for central review within 14 days of image acquisition (see section 
6.3). Following 24 months, scans are performed at the discretion of the local investigator. 
 

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Update #09 
Crossover Phase (open label ibrutinib) 
If a patient experiences disease progression and they are found to be receiving placebo, they may 
crossover to treatment with ibrutinib (see section 7.4). Progression is defined by the CT-based 
response criteria. Crossover patients will be re-registered to the study and followed per the study 
calendar below. 
 
Day 1 of each 
treatment cycle* 
At end of treatment, PD, 
withdrawal, or removal 
£ 
Tests & Observations 
 
 
History and physical, 
Weight, PS 
X 
X 
Adverse Event 
assessment 
X 
X 
Patient medication diary 
X(1) 
 
Concomitant meds 
X 
X 
Laboratory Studies 
 
 
CBC, Differential, 
Platelets 
X(2) 
X 
Na, K, Cl, BUN, Serum 
creatinine, Glucose, 
Calcium 
X(2) 
X 
AST, ALT, Alk. Phos., 
Bili, Total protein, 
Albumin 
X(2) 
X 
Staging 
 
 
Tumor measurement 
A 
X 
CT/MRI chest/abd/pelvis 
B 
X 
* Treatment assessment can be performed locally, provided the results are made available to the treating 
study healthcare provider within 24 hours. There is a +/- 7 day window for every visit. 
£ Progression is defined by the CT-based response criteria. After patients complete 12 cycles of ibrutinib or 
discontinue crossover treatment for any reason, patients will be contacted approximately every 6 months 
by clinic visit or telephone to assess survival and the use of alternative anticancer therapy until death, 
withdrawal of consent, loss to follow up, study closure, or 5 years have elapsed from original study 
registration. 
1 The medication diary must begin the day the patient starts taking ibrutinib in the crossover phase. 
Medication diaries must be completed per protocol and returned to the treating institution OR compliance 
must be documented in the medical record by any member of the care team (see Appendix III). 
2 Labs completed prior to crossover may be used for the Cycle 1 Day 1 tests if obtained ≤ 28 days prior to 
start of treatment. 
A Tumor measurement will be performed every 3 months (+/- 1 month) during active therapy and at the 
discretion of the investigator thereafter. Tumor measurement on Day 1 of Cycle 1 is considered to be the 
tumor size at disease progression on placebo. 
B Every 3 months during active therapy (+/- 1 month), perform a diagnostic CT or MRI of the chest, 
abdomen, pelvis without a PET or a whole body or limited whole body PET/CT. The PET portion is not 
required by the study. These scans do not need to be submitted for central review. Thereafter, scans are 
performed at the discretion of the investigator. 

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Update #09 
6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 Data submission schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The Data Submission Schedule is also available on the CTSU 
site within the study-specific Case Report Forms folder.  
6.1.2 Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in the 
email or log in to iMedidata via the CTSU members’ website  under Data Management > 
Rave Home and click to accept the invitation in the Tasks pane located in the upper right 
corner of the iMedidata screen. Site staff will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed. Trainings will be in the 
form of electronic learnings (eLearnings) and can be accessed by clicking on the eLearning 
link in the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning will 
appear under the study name in the Studies pane located in the center of the iMedidata 
screen; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link under 
the study name.  
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional information on 

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Update #09 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-
5923 or by email at ctsucontact@westat.com.  
6.1.3 Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status, and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent forms, 
forms with current status, and timeliness reports. Review the DQP modules on a regular 
basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link 
on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
6.1.4 Supporting documentation 
This study requires supporting documentation for diagnosis and salvage response. At the 
time of disease progression, on study and off study visit, additional documentation is 
required. Supporting documentation will include pathology and radiology reports. These 
must be submitted at the following time points: 
• 
Diagnostic biopsy report (initial diagnosis or relapse) submitted prior to registration. 
• 
Radiology report from before and after last salvage assessment submitted prior to 
registration. 
• 
Subsequent radiology reports and images will be submitted on study at 3, 6, and 12 
months, and at 18 and 24 months of follow up. Radiology reports and images will also 
be submitted at the time of disease progression prior to crossover and for the off study 
assessment. 
• 
Bone marrow biopsy report submitted prior to registration. Subsequent bone marrow 
biopsy report (if available) submitted at 3 months. 
• 
Lab reports from Cycle 2 Day 1 assessment. 
Additionally, the “Central Pathology Results Form” confirming eligibility must be uploaded 
via Rave on the Screening form. 
6.2 
Specimen collection and submission 
The Alliance A051301 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing, and shipping. The manual can be found on the BioMS and CTSU 
websites. Questions regarding the CSM should be addressed to the contacts specified in the 
manual. 
For all patients pre-registered to Alliance A051301: Real time histopathology review will be 
conducted using the paraffin tissue from a diagnostic biopsy (original diagnosis or relapse). The 
submission of these samples for central histopathology review is required for all patients 

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Update #09 
at pre-registration. Samples for central review should be submitted as soon as possible and 
within 7 days after pre-registration. See the table below and the CSM for specimen 
submission requirements. 
For patients registered to substudies A051301-PP1 and A051301-ST1: All participating 
institutions must ask patients for their consent to participate in the correlative substudies, 
although patient participation is optional. Biomarker and pharmacogenetic studies will be 
performed. Rationale and methods for the scientific components of these studies are described 
in section 14.0. For patients who consent to participate, tissue and blood will be collected at the 
time points in the table below for these studies. Please also see the study CSM for more 
instructions regarding specimen collection and submission. 
 
Pre-registration 
Registration 
At Disease 
Progression or 
Relapse 
Mandatory for all patients pre-registered to A051301: 
Original diagnostic 
stained slides OR 6 
unstained slides (4-6 
micron thickness) from 
archival paraffin 
diagnostic biopsy tissue1 
X 
 
 
For patients registered to A051301-PP1, submit the following*: 
Whole Blood2 
(EDTA/lavender top) 
 
1 x 10 mL 
 
For patients registered to A051301-ST1, submit the following**: 
Paraffin block/block 
alternative 
X3 
 
X4,5 
1 
Required for real-time central review to confirm eligibility. Biopsy can be acquired at the time 
of initial diagnosis or relapse. Submit original diagnostic stained slides: at least one H&E stained 
slide and stained slides for CD10, BCL6 and MUM1 used by the enrolling site for COO 
determination (including positive control stains) OR submit 6 unstained FFPE tissue sections 
(4-6 μm thickness) mounted onto positively charged slides. Slides should be freshly cut and 
packaged in a manner so that they do not break during shipment. If less than 6 slides are 
available, submit as many as possible.  
2 
Whole blood to be used for pharmacogenomics analyses described in section 14.2. This blood 
specimen should be collected prior to the initiation of protocol treatment. However, blood 
specimen collection may take place at a later time point while the patient is on study. 
3 
Submission of a block is highly encouraged. Absent the block, please see CSM for block 
alternative options. 
4 
Within 2 months of progression. Absent the block, please see CSM for block alternative options. 
5 
For patients randomized to the placebo arm who cross over to treatment with open-label 
ibrutinib, tissue should be submitted at both progression prior to crossover and progression 
following crossover. 
* 
Collect and submit only from patients who answer “yes” to model consent question #1. 
** Collect and submit only from patients who answer “yes” to model consent question #2. 

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Update #09 
6.3 
Imaging submission 
Images will be transmitted electronically from each participating site to the Imaging and 
Radiation Oncology Core Imaging Radiology Core (IROC) QA center at Ohio State University 
(IROC Ohio). The images will be reviewed by the Alliance Neuroradiology Core Review Group.  
Images from the following time points must be submitted for central review: 
• Pre-treatment assessment (prior to last line of salvage therapy) 
• Baseline (following last line of salvage therapy) 
• 3 months 
• 6 months 
• 12 months 
• At 18 and 24 months of follow-up 
• At time of disease progression prior to crossover (real-time review) 
• Off-study assessment 
Images will be collected digitally for central review (not necessarily in real time). Real-time 
central review of images is required upon local determination of disease progression prior to 
crossover. Real-time central review of these scans will be performed as described in section 
6.3.2. 
6.3.1 Imaging submission instructions 
Complete data sets in digital DICOM format, along with Alliance Adjunctive Data Form (if 
applicable) and Alliance Image Measurement Form (if applicable), must be submitted to 
IROC Ohio within 14 days of image acquisition. 
BMP files, JPG files, or hard copies (films) are not acceptable. The raw data of the entire 
study should be saved until the scan is accepted by IROC. De-identify the patient data using 
institutional procedures to remove patient name and medical record number while 
preserving the Alliance patient ID number and protocol number. The de-identified digital 
images may be temporarily burned to a CD or transferred to a PC based system. 
Data should be transferred electronically (recommended) to IROC as follows: 
Electronically 
1) TRIAD based data transfer 
TRIAD is the American College of Radiology’s (ACR) image exchange application. 
TRIAD provides sites participating in clinical trials a secure method to transmit DICOM 
RT and other objects. TRIAD anonymizes and validates the images as they are 
transferred. 
TRIAD Access Requirements: 
• 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account, and be 
registered as an AP, NPIVR or IVR. Please refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account and 
complete registration in RCR. 
• 
To submit images, the site physics user must be on the site’s affiliated rosters and 
be assigned the 'TRIAD site user' role on the CTSU roster. Users should contact 
the site’s CTSU Administrator or Data Administrator to request assignment of the 
TRIAD site user role. RAs are able to submit standard of care imaging through the 
same method. 

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Update #09 
6.3.2 Real-time central imaging review 
A real-time imaging central review will be performed at the time of disease progression 
prior to crossover. 
Participating site needs to notify IROC Ohio of local radiology assessment at the time of 
site determination of PD, and all imaging studies will be centrally reviewed to evaluate for 
efficacy on a per time point basis and to confirm the presence of PD.  
Complete the “Alliance A051301 Central Review Form – Progression” and submit to IROC 
Ohio along with the electronic submission of the images. For Alliance members, the form 
may be found on the A051301 study page on the Alliance website under the “Supplemental 
Materials” tab. For non-Alliance institutions, the form can be found under the “LPO 
Documents” tab on the CTSU A051301 study page (www.ctsu.org). 
IROC Ohio will contact the A051301 central review panel within 24 hours (except 
weekends and holidays) of images being received for scheduling a real-time remote 
review. IROC notifies both the participating site and Alliance of the central review results 
within 24 hours after receiving the results from the central review panel. The overall 
turn-around time between imaging data receipt and central review results notification is 
within 24-72 hours after the imaging data receipt (except weekends and holidays). 
Central review results will be reported back to the site PI for further evaluation and 
determination of patient status.  
The final treatment decision is determined by the central review. If progressive disease is 
the final determination by the central review adjudication of the results, blinded treatment 
will be discontinued and the patient will be unblinded. If patient is found to be on placebo, 
they may elect to crossover to open-label ibrutinib. 

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Update #09 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. 
*Cycle 1: Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs). Only unexpected AEs relative to stem cell 
transplant will be reported. 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
*Cycles 2-13: Combinations of CTCAE Grade & Attribution Required for Routine AE 
Data Submission on Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
a 
a 
a, b 
a, b 
a, b 
Probable 
a 
a 
a, b 
a, b 
a, b 
Definite 
a 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their Institutional 
Review Board if a patient has a reportable serious adverse event. The descriptions and grading 
scales found in the 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. A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. All reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) accessed via 
https://eapps-ctep.nci.nih.gov/ctepaers/. 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI. 

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Update #09 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events 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 notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE 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. 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Alliance A051301 uses a drug under a CTEP IND. The reporting requirements for investigational 
agents under a CTEP IND should be followed for all agents (any arm) in this trial. 
• 
Hematosuppression ≤ grade 3-4 resulting in hospitalization do not require CTEP-AERS; however 
these events should still be reported as routine adverse events via CDUS. All other grade 3 or 4 
adverse events that precipitate hospitalization or prolong an existing hospitalization must be 
reported via CTEP-AERS. 
• 
All suspected and confirmed cases of fungal infections should be reported to CTEP within 24 
hours. 
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 
tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 
5.0, the new malignancies (both second and secondary) may be reported as one of the following: 
(1) Leukemia secondary to oncology chemotherapy, (2) Myelodysplastic syndrome, (3) 
Treatment-related secondary malignancy, or (4) Neoplasms benign, malignant and unspecified-
other. Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. 
 
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. CTEP requires 

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Update #09 
all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE 
to be reported via CTEP-AERS. Three options are available to describe the event: 
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) 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. 
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 reporting via CDUS unless otherwise specified. 
• 
Treatment expected adverse events include those listed in section 9.4, section 10.0, and in the 
package inserts of the commercially available agents. 
• 
CTEP-AERS reports should be submitted electronically. 
• 
Pregnancy: Although not an adverse event in and of itself, pregnancy as well as its outcome 
must be documented via CTEP-AERS. In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI Guidelines 
for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP.  
In CTCAE v5.0, pregnancy loss is defined as “Death in utero,” and any pregnancy loss should 
be reported expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC as currently CTEP-AERS recognizes this 
event as a patient death.  
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, 
the Pregnancy Information Form should be completed and submitted at the time the pregnancy 
is known and within 30 days of becoming aware of the outcome, along with any additional 
medical information (form is available on the CTEP website at http://ctep.cancer.gov/). The 
potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS report. 
9.3.2 Adverse Events of Special Interest 
Specific adverse events or groups of adverse events will be followed as part of standard 
safety monitoring activities at the National Cancer Institute-Division of Cancer Treatment 
and Diagnosis. These events will be reported to the sponsor via CTEP-AERS within 24 
hours of awareness following the procedures described for SAEs and require enhanced data 
collection. All events of Special Interest will be submitted within 24 hours of awareness 
even if they do not meet serious criteria. These events are: 
Major Hemorrhage 
Major hemorrhage is defined as any of the following 
• Any treatment-emergent hemorrhagic AEs of Grade 3 or higher* 

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Update #09 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac disorders - 
Other (bundle branch block left); Cardiac disorders - Other (extrasystoles); Chest pain - cardiac; Myocardial infarction; 
Palpitations; Pericardial effusion; Pericarditis; Sinus bradycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
EYE DISORDERS - 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 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) 
INFECTIONS AND INFESTATIONS - Conjunctivitis 
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 (hypoproteinaemia); 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; 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 - 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. 
 

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10.0 DRUG INFORMATION 
10.1 
General Considerations: 
The use of individual institution guidelines in the preparation, administration, and timing of the 
chemotherapeutic agents BCNU (carmustine), etoposide, cytarabine, cyclophosphamide, and 
melphalan is allowed. 
10.2 
Ibrutinib (NSC #748645, 
) 
Availability 
Ibrutinib (NSC 748645) and matching placebo will be provided free of charge by Pharmacyclics, 
Inc. and distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National 
Cancer Institute (NCI). 
Ibrutinib (NSC 748645) 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 
140mg in a size 0, gray, hard gelatin capsule. The placebo capsules are identical in size and 
shape, but do not contain ibrutinib. Capsules are packaged in high-density polyethylene 
(HDPE) bottles with an induction seal and a child resistant screw top cap. Each bottle 
contains 120 capsules. Ibrutinib and matching placebo capsules are to be dispensed in their 
original containers. 
Each blinded or open-label, patient-specific bottle will be labeled with: 
• The protocol number (i.e., A051301) 
• The bottle number (i.e., “Bottle 1 of 2”, “Bottle 2 of 2”, etc.) 
• The number of tablets (i.e,”120 capsules”) 
• The patient ID number (e.g., "999999") 
• The patient initials (i.e., Last initial, First initial, Middle initial [e.g., “L, FM”]) 
• The agent identification (i.e., “Ibrutinib 140 mg” or “Ibrutinib 140 mg or Placebo”) 
• A blank line for the pharmacist to enter the patient’s name 
• Administration instructions (i.e., “Take __ capsules daily.”) 
• Storage instructions (i.e., “Store at Controlled Room Temperature between 15° and 
25°C.”) 
• Emergency contact instructions 
• A Julian date 
Julian Dating 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the last 
two digits of the calendar year (e.g., 2014 = 14, 2015 = 15) and a day count (e.g., January 1 = 
001, December 31 = 365). For example, a bottle labeled and shipped on January 1, 2014 would 
have a Julian date of ‘14001’ and a bottle labeled and shipped on December 31, 2014 would 
have a Julian date of ‘14365’. The Julian date will be used by PMB for recalls. When a lot 
expires, PMB will determine the last date the expired lot was shipped and will recall all bottles 
(i.e., both veliparib and Placebo) shipped on or before that date thus eliminating any chance of 
breaking the blind. The Julian Date – Order number (e.g., 14352-0003) from the patient-specific 
label must be used as the Lot number on the NCI DARF. 
Questions about drug orders, transfers, returns, or accountability should be addressed to the 
PMB by calling (240) 276-6575 Monday through Friday between 8:30am and 4:30pm Eastern 
Time. You may also contact the PMB via e-mail at PMBAfterHours@mail.nih.gov. 

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Initial Supply/Starter Supplies 
Agent Orders: 
SAFETY RUN-IN (OPEN-LABEL) 
No open-label starter supplies will be available for this study. Open-label, patient specific 
clinical supplies will be sent to the registering investigator at the time of registration to the safety 
run-in and should arrive within approximately 7 to 10 days. This registration will be performed 
by the Alliance Statistical Center. Once a patient has been registered, the Alliance Statistical 
Center will electronically transmit a clinical drug request for that patient to the PMB. This 
request will be entered and transmitted by the Alliance Statistical Center the day the patient is 
registered and will be processed by the PMB the next business day and shipped the following 
business day. Shipments within the United States will be sent by FedEx Ground and shipments 
to Canada (if participating) will be sent by FedEx (generally one to two day delivery.  Shipments 
to United States sites can be expedited (i.e., receipt on Thursday in example above) by the 
provision of an express courier account name and number to the Alliance Statistical Center at 
the time the patient is registered.  
The initial request will be for 3 bottles of ibrutinib 140 mg [this supply will cover the 
Conditioning Regimen plus the first 2 cycles of treatment]. Approximately 2 weeks after cycle 
3 begins (2 weeks before needed), sites may reorder an additional 2 bottles [a 2 cycle (8 week) 
supply at a dose of 4 capsules given once daily] of ibrutinib 140 mg using the PMB Online 
Agent 
Order 
Processing 
(OAOP) 
application 
(https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) 
and the maintenance of an “active” account status and a “current” password. The assigned 
patient ID number (e.g., "999999") and the patient initials (e.g., "L,FM") must be entered in the 
"Patient or Special Code" field. A separate order is required for each patient ID number (e.g., 
"999999") being ordered. All drug orders will be shipped directly to the physician responsible 
for treating the patient. 
BLINDED PHASE 
No blinded starter supplies will be available for this study. Blinded, patient specific clinical 
supplies will be sent to the registering investigator at the time of randomization and should arrive 
within approximately 7 to 10 days. This randomization will be performed by the Alliance 
Statistical Center. The assigned Alliance patient ID number must be recorded by the registering 
institution for proper bottle dispersion. Once a patient has been registered, the Alliance 
Statistical Center will electronically transmit a clinical drug request for that patient to the PMB. 
This request will be entered and transmitted by the Alliance Statistical Center the day the patient 
is registered and will be processed by the PMB the next business day and shipped the following 
business day. Shipments within the United States will be sent by FedEx Ground (up to 5 business 
days for delivery) and shipments to Canada (if participating) will be sent by FedEx (generally 
one to two day delivery). Shipments to United States sites can be expedited by the provision of 
an express courier account name and number to the Alliance Statistical Center at the time the 
patient is randomized. Please note that additional processing time is required for QA/QC checks 
on patient-specific/blinded orders and next day delivery is not available. 
The initial request will be for 3 bottles of ibrutinib 140 mg or placebo [this supply will cover the 
Conditioning Regimen plus the first 2 cycles of treatment]. Approximately 2 weeks after cycle 
3 begins (2 weeks before needed), sites may reorder an additional 2 bottles [a 2 cycle (8 week) 
supply at a dose of 4 capsules given once daily] of ibrutinib 140 mg or placebo using the PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application 
(https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). (See Safety Run-In section for information on 

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drug orders and access to OAOP). All drug orders will be shipped directly to the physician 
responsible for treating the patient. 
UNBLINDED CROSSOVER PHASE (OPEN-LABEL)  
NOTE: Patients will not be able to obtain unblinded supplies until the patient has been unblinded 
(at progression) by following the unblinding procedures in section 8.3 AND a clinical drug 
request has been transmitted to the PMB. The patient ID number will NOT change for the cross-
over portion of the study.  
No open-label starter supplies will be available for this study. Open-label, patient specific 
clinical supplies will be sent to the registering investigator at the time of re-registration and 
should arrive within approximately 7 to 10 days. This re-registration will be performed by the 
Alliance Statistical Center. Once a patient has been re-registered, the Alliance Statistical Center 
will electronically transmit a clinical drug request for that patient to the PMB. This request will 
be entered and transmitted by the Alliance Statistical Center the day the patient is re-registered 
and will be processed by the PMB the next business day and shipped the following business day. 
Shipments within the United States will be sent by FedEx Ground and shipments to Canada (if 
participating) will be sent by FedEx (generally one to two day delivery. Shipments to United 
States sites can be expedited (i.e., receipt on Thursday in example above) by the provision of an 
express courier account name and number to the Alliance Statistical Center at the time the patient 
is re-registered.  
The initial request will be for 2 bottles of ibrutinib 140 mg [a 2 cycle (8 week) supply at a dose 
of 4 capsules given once daily]. Approximately 2 weeks after cycle 3 begins (2 weeks before 
needed), sites may reorder an additional 2 bottles [a 2 cycle (8 week) supply at a dose of 4 
capsules given once daily] of ibrutinib 140 mg using the PMB Online Agent Order Processing 
(OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).    (See Safety 
Run-In section for information on drug orders and access to OAOP).  The patient may receive 
up to 12 cycles of open-label ibrutinib therapy. All drug orders will be shipped directly to the 
physician responsible for treating the patient. 
Drug Transfers 
Tablets MAY NOT be transferred from one patient to another patient or from one protocol to 
another protocol. All other transfers (e.g., a patient moves from one participating clinical site to 
another participating clinical site, the principal investigator at a given clinical site changes) must 
be approved in advance by the PMB. To obtain an approval for transfer, investigators should 
complete and submit to the PMB (fax number 240-276-7893) a Transfer Investigational Agent 
Form available on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575. The patient ID number (e.g., "99999"') and the patient initials (e.g., "L, FM") should 
be entered in the "Received on NCI Protocol No." and the "Transferred to NCI Protocol No." 
fields in addition to the protocol number (i.e., "A051301"). 
Drug Returns 
When it is necessary to return undispensed study drug (e.g., sealed or partial bottles remaining 
when a patient permanently discontinues protocol treatment, expired bottles recalled by the 
PMB), investigators should return the study drug to the PMB using the NCI Return Drug List 
available on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-
6575. The patient ID number (e.g., "99999") and the patient initials (e.g., "L, FM") should be 
entered in the "Lot Number" field. 
Drug Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, disposition, and return of all drugs received from the PMB using the NCI 

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Investigational Agent Accountability Record available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. A separate NCI Investigational 
Agent Accountability Record must be maintained for each patient ID number (e.g., "99999") 
and each Phase (Blinded and Unblinded Crossover) on this protocol. NOTE: The Julian Date – 
Order number combination found in the upper right-hand portion of the patient-specific label 
must be used as the Lot Number. This number will be used in the event of a stock recovery or 
recall of the investigational agent. 
Investigator Brochure Availability 
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, a “current” password 
and active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
IB Coordinator:  IBCoordinator@mail.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) 
Storage and Stability 
Ibrutinib Hard Gelatin Capsules should be stored at 15 – 25°C. Shelf life surveillance of the 
intact bottles is ongoing. 
Administration 
Ibrutinib is to be taken orally, with 8 ounces (approximately 240 mL) of water. The capsules are 
to be swallowed intact and patients should not attempt to open capsules or dissolve them in 
water. Doses are to be taken at about the same time each day. If a dose is missed, it should be 
made up as soon as possible on the same day, with a return to the normal schedule the following 
day. Extra doses should not be taken to make up for missed doses. 
Subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib/placebo should follow the administration guidelines below: 
• 
For any surgery or invasive procedure requiring sutures or staples for closure, 
ibrutinib/placebo should be held at least 7 days prior to the intervention (except for 
emergency procedures) and should be held at least 7 days after the procedure, and restarted 
at the discretion of the investigator when the surgical site is reasonably healed without 
serosanguineous drainage or the need for drainage tubes. 

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• 
For minor procedures (such as a central line placement, skin or needle biopsy, lumbar 
puncture [other than shunt reservoir access], thoracentesis, or paracentesis), 
ibrutinib/placebo should be held for at least 3 days prior to the procedure and should not 
be restarted for at least 3 days after the procedure.  For bone marrow biopsies that are 
performed while the subject is on ibrutinib/placebo, it is not necessary to hold 
ibrutinib/placebo for these procedures. 
Drug Interactions 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A4 or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Refer 
to section 8.1 if a strong or moderate CYP3A inhibitor must be used. Avoid concomitant use of 
strong CYP3A inducers. Consider alternative agents with less CYP3A induction. 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, 
please refer to the current version of the IB. See Appendix II for more information. 
Mesna 
Mesna possesses a sulfhydryl group that can react with ibrutinib. Avoid mesna dosing 6 hours 
before and after ibrutinib/placebo dosing due to potential interaction with ibrutinib. 
Adverse Events 
For a comprehensive adverse events and potential risks lists (CAEPR), please see section 9.4. 
Bleeding-related Events 
There have been reports of hemorrhagic events in patients treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria. 
Initially, subjects were excluded from participation in specific ibrutinib Phase 2 and 3 studies if 
they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists 
should not be administered concomitantly with ibrutinib unless specified in the protocol. 
Supplements such as fish oil and vitamin E preparations should be avoided. In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were 
observed. Use of ibrutinib in patients requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. See Section 8.1 for guidance on concomitant 
use of anticoagulants, antiplatelet therapy and/or supplements. Ibrutinib should be held at least 
3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding. 
Patients with congenital bleeding diathesis have not been studied. 
Atrial fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation. Periodically monitor subjects clinically for atrial fibrillation. Subjects who develop 
arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset of dyspnea should be 
evaluated clinically, and if indicated, have an ECG performed. For atrial fibrillation which 
persists, consider the risks and benefits of ibrutinib treatment and follow the protocol dose 
modification guidelines (see Section 8.2). 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
Diarrhea  

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Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged, follow the protocol dose 
modifications (see section 8.2). 
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib. Some of these infections have been associated with hospitalization and 
death. Consider prophylaxis according to standard of care in subjects who are at increased risk 
for opportunistic infections (see Section 8.1). Although causality has not been established, cases 
of progressive multifocal leukoencephalopathy (PML) and hepatitis B reactivation have 
occurred in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms 
(fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy should be 
instituted as indicated. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for overall survival. 
If observed, enter data in the corresponding eCRF. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 
of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 
ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines as needed (see Section 
8.2). 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
Hypertension 

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Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
Nursing Guidelines 
There are numerous drug to drug interactions. Record all of patient’s medications including 
OTC, and herbal use. Avoid concomitant use with agents as listed in Appendix II. 
Patients should be instructed to avoid eating grapefruit (including juice) and Seville oranges 
while on ibrutinib. 
Peripheral edema is common. Instruct patients to report this to the study team. 
Gastrointestinal side effects are common (diarrhea, nausea, constipation, abdominal pain, 
vomiting, etc). Treat symptomatically and monitor for effectiveness of intervention. 
Monitor CBC w/diff. Instruct patients in energy conserving lifestyle (anemia) and to report any 
unusual bruising or bleeding and/or signs or symptoms of infection to study team. 
Arthralgias, myalgias, and muscle spasm can be seen. Treat symptomatically and monitor for 
effectiveness. 
Monitor renal function/uric acid levels, especially in patients who may be experiencing 
dehydration. 
Respiratory symptoms may include, cough, SOB, and URI. Instruct patients to report these 
symptoms to the study team. 
Rarely patients can experience secondary skin cancers. Instruct patients to report any new skin 
lesions to the study team. 
Rash can be seen. Instruct patient to report to study team. 
10.3 
BCNU (Carmustine, NSC# 409962) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Carmustine is supplied as a lyophilized powder containing no preservatives. Please refer to the 
FDA-approved package insert for complete prescribing information. 
Storage and Stability 
Unopened vials are stable under refrigeration until the labeled expiration date on the 
commercially available product. BCNU has a low melting point requiring refrigeration at all 
times prior to reconstitution. Do not use if an oil film is present at the bottom of vial. 
Preparation 
Due to its water insolubility, it is to be reconstituted with the diluent provided (3 mL of absolute 
ethanol) and then with either 27 mL or 17 mL of sterile water for injection to provide a resulting 
concentration of 3.3 mg/mL or 5 mg/mL, respectively. After reconstitution, carmustine should 
be further diluted with 500 mL 5% Dextrose or normal saline and will be stable for 8 hours at 
room temperature.  It is recommended to use PVC-free bags and tubing. 
Administration 
Carmustine should be given over 2 hours or per institutional guidelines.  

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Pharmacokinetics 
Carmustine is rapidly metabolized in the liver and is rapidly degraded to active metabolites. 
Sixty to 70% is excreted in the urine in 96 hours and 10% as respiratory CO2. Because of the 
high lipid solubility, it crosses the blood-brain barrier readily. 
Adverse Events 
The most frequent and most serious toxicity of BCNU is delayed myelosuppression. Pulmonary 
infiltrates and/or fibrosis, dry cough and difficulty breathing have been reported. Cases of fatal 
pulmonary toxicity with BCNU have been reported. Nausea and vomiting are very common. A 
reversible hepatic toxicity is demonstrated by elevated SGOT, alkaline phosphatase and 
bilirubin.  
Renal abnormalities consisting of progressive azotemia, decrease in kidney size and renal failure 
have been reported. 
Thrombophlebitis and local ulceration occur if extravasation occurs. Venous pain and flushing 
during injection and a brownish discoloration of skin on contact have also occurred. 
Rapid infusion may produce intensive flushing. Neuroretinitis has been reported. The 
occurrence of acute leukemia and bone marrow dysplasia have been reported in patients 
following long-term nitrosourea therapy. The occurrence of acute leukemia has been reported 
rarely in patients treated with anthracycline/alkylator combination chemotherapy. 
Nursing Guidelines 
Nausea and vomiting appears within 2 hours of dosing, usually lasting 4-6 hours and can be dose 
limiting. Premedicate with antiemetics and assess for response. 
Drug is an irritant – avoid skin contact. Irritation at the injection site or along the vein is common. 
May need to apply an ice pack above the injection site and decrease the infusion rate. 
Administer slowly to avoid severe local reaction, dizziness, and hypotension. 
Monitor hepatic, renal function tests. 
Monitor CBC. Due to delayed and cumulative myelosuppression (4-6 weeks), monitor CBC for 
at least 6 weeks after a dose. 
Rapid IV infusion may cause intense flushing of the skin and suffusion of the conjunctiva within 
2 hours, lasting approximately 4 hours. Neuroretinitis has been seen. 
Instruct patient to avoid the use of cimetidine as this may increase the severity of 
myelosuppression. 
Monitor phenytoin levels closely, as carmustine may decrease phenytoin levels. 
Pulmonary toxicity (interstitial fibrosis) is noted at higher dose levels and may present as late as 
3 years after dosing. Instruct patient to report and cough, SOB, dyspnea, or chest pain to the 
health care team immediately. 
10.4 
Cyclophosphamide (NSC# 26271) 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Commercially available as a powder for reconstitution in 100 mg, 200 mg, 500 mg, 1 gram, and 
2 gram vials. Please refer to the FDA-approved package insert for cyclophosphamide for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 

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Storage and Stability 
Intact vials should be stored at room temperature. Reconstituted and diluted solutions are stable 
for 24 hours at room temperature and 6 days if refrigerated. 
Preparation 
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 5, 10, 25, 50, or 100 mL 
of sterile water for injection or normal saline to give a final concentration of 20 mg/mL. 
Vigorous shaking and/or gentle warming may be necessary for non–lyophilized preparations. 
Bacteriostatic water for injection (paraben preserved only) may be used; benzyl alcohol 
derivatives may NOT be used. 
Administration 
The total dose of cyclophosphamide will be administered by IV. Supportive hydration should 
also be given per institutional guidelines. MESNA should be administered with 
cyclophosphamide as per institutional guidelines.  
Drug Interactions 
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in the liver and 
may potentially interact with any drug affecting the same isoenzyme. Inhibitors of 3A4 (e.g., 
itraconazole) could theoretically inhibit activation and inducers of 3A4 (e.g., phenytoin) could 
theoretically enhance activation of cyclophosphamide to active alkylating species. For the most 
part, such interactions have not yet been documented clinically. 
Mesna possesses a sulfhydryl group that can react with ibrutinib. Avoid mesna dosing 6 hours 
before and after ibrutinib/placebo dosing due to potential interaction with ibrutinib. 
Pharmacokinetics 
Cyclophosphamide is metabolized hepatically via CYP3A4 to its active metabolite and acreolin 
(responsible for hemorrhagic cystitis). Strong CYP3A4 inhibitors or inducers should be avoided 
during administration of cyclophosphamide. 
Adverse Events 
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, during, and 
after treatment and have adequate renal function). Syndrome of inappropriate antidiuretic 
hormone (SIADH), fatigue, alopecia, anorexia, nausea, vomiting, hyperuricemia, azospermia, 
amenorrhea, cardiotoxicity (myocardial necrosis) has been seen with transplant-type doses. 
Nursing Guidelines 
Myelosuppression is common. Monitor CBC including platelets. Instruct patient on 
signs/symptoms of infection and to inform health care team of any unusual bruising, or signs of 
bleeding. 
Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following treatment and to void 
frequently, not greater than every three hours to facilitate keeping the bladder clear of drug. 
Instruct patient to report any urinary urgency, frequency, dysuria, or hematuria. Administer 
mesna with high dose cytoxan to prevent hemorrhagic cystitis. It may be necessary to catheterize 
and provide constant bladder irrigation. 
Advise patient of possible strong metallic taste associated with Cytoxan and suggest hard candy 
with a strong flavor (cinnamon, peppermint) to alleviate it. 
Administer antiemetics as necessary to minimize nausea and vomiting, which usually occurs 6-
8 hours after administration. 
Report and record any complaint of lightheadedness, facial “heat sensation,” diaphoresis during 
administration. 

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Use of an ice cap may be helpful in preventing or limiting alopecia. 
Corticosteroids, phenothiazine, imipramine, vitamin A succinylcholine, digoxin, thiazide 
diuretics, warfarin and allopurinol may inhibit Cytoxan metabolism and modify its’ effect.  They 
may also increase bone marrow suppression. 
Advise female patients of possible menstrual changes or amenorrhea. 
Patients on anticoagulant therapy should have INR levels carefully monitored as cytoxan 
increases their effect. 
Monitor electrolytes and for signs/symptoms of SIADH and tumor lysis syndrome. 
Monitor digoxin levels closely as cytoxan may decrease these levels. 
Cytoxan may potentiate doxorubicin-induced cardiomyopathy. Instruct patient to report any 
chest pain. 
10.5 
Etoposide (NSC# 141540) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Etoposide is commercially available as a solution for injection in 5 mL, 7.5 mL, 25 mL, and 50 
mL vials containing 20 mg/mL. Please refer to the FDA-approved package insert for etoposide 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
Storage and Stability 
Intact vials of etoposide for injection should be stored at room temperature and protected from 
light.  
Preparation 
Etoposide will be admixed in 0.9% sodium chloride for IV infusion and concentrations should 
be followed as per institution guidelines. It is recommended that concentrations should be < 0.4 
mg/mL but if higher concentrations are necessary then stability will be limited to 8 hours at 
room temperature. For BEAM, etoposide may be prepared undiluted in PVC-free bag for 
administration with normal saline hydration that is given concurrently in the same lumen. 
Administration 
For BEAM, etoposide should be given over 1-2 hours diluted in normal saline. For CBV, 
etoposide may be given undiluted over 4 hours with normal saline hydration given concurrently. 
Drug Interactions 
Etoposide is metabolized hepatically via CYP3A4 and 3A5. Strong CYP3A4 inhibitors or 
inducers should be avoided during administration of etoposide. 
Pharmacokinetics 
Etoposide is metabolized hepatically via CYP3A4 and 3A5 
Adverse Events 
Myelosuppression, predominantly neutropenia and thrombocytopenia, is the most common 
toxicity associated with etoposide. Nausea and vomiting range from mild to severe in severity, 
depending on the dose. Etoposide is moderately highly emetogenic. Mucositis is also common 
and hypotension may be seen with rapid infusions. Alopecia is likely. 

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Nursing Guidelines 
Monitor CBC. Neutropenia may be severe. Instruct patients to report any sign/symptoms of 
infection to the health care team. 
Rare myocardial infarctions have been reported in patients who have received prior mediastinal 
XRT. Instruct patient to report any chest pain, or racing of the pulse to the health care team 
immediately. 
Advise patient of possible mild, reversible alopecia. 
A rapid infusion may cause hypotension and/or allergic reaction; administer medication over 
30-60 minutes and monitor VS during administration. 
Drug is a radiosensitizer and irritant. Assess IV patency before and throughout infusion. Patients 
who have receive prior radiation may experience radiation recall. Assess skin in these areas and 
monitor closely. Instruct patient to report any rash or skin changes to the health care team 
immediately. 
Anaphylaxis is rare but has been observed. Symptoms may include hypotension, bronchospasm, 
fever, or chills. Have the anaphylaxis tray available. 
Nausea and vomiting are usually mild. However the incidence is increased with oral 
administration. Premedicate with antiemetics as ordered and monitor for their effectiveness. 
Instruct patient in importance of maintaining adequate hydration to avoid hyperuricemia. 
Monitor liver function tests. 
Etoposide solution is oil based and settles to bottom of bag or drip chamber. Be sure to agitate 
bag to avoid reaction to concentrated solution. Reaction would include flushing, shortness of 
breath, back pain, and anxiety. 
Advise patient that facial flushing is common and may occur even after administration. 
Monitor INR closely in patients on warfarin therapy, as etoposide may increase PT time. 
May increase the toxicity of methotrexate or cyclosporine (cytotoxicity) when given 
concurrently. 
10.6 
Ara-C (Cytarabine, NSC# 63878) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Commercially available as a sterile powder for reconstitution in vials of 100 mg, 500 mg, 1000 
mg, and 2000 mg or a preservative free 20 mg/mL solution in 5 mL, 25 mL and 50 mL vials, or 
a 100 mg/mL solution in 20 mL vials. Please refer to the package insert for additional 
information. 
Storage and Stability 
Intact vials should be stored at room temperature 15-30°C (59 to 86°F). Solutions reconstituted 
with bacteriostatic diluents for infusion are stable for 8 days at room temperature. 
Preparation 
Cytarabine powder is reconstituted with sterile water for injection or 0.9% sodium chloride for 
injection. Solutions reconstituted with bacteriostatic should not be used for IV administration of 
high dose cytarabine (> 1 gm/m2), as are used in this study. Solutions for parenteral 

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administration should be reconstituted to a concentration of 100 mg/mL. Reconstituted solutions 
are further diluted in D5W or 0.9% sodium chloride for IV infusion. 
Administration 
Cytarabine will be administrated intravenously over 1-2 hours or per institutional guidelines. 
Adverse Events 
The most common adverse reactions reported with cytarabine (“usual dosage” e.g., ≤ 200 
mg/m2/day) 
include 
hematologic, 
gastrointestinal, 
dermatologic, 
and 
hepatic. 
Myelosuppression includes neutropenia, thrombocytopenia and anemia. Cytarabine is 
considered highly emetogenic. In addition to nausea and vomiting, diarrhea and mucositis are 
reported in > 10% of patients receiving cytarabine. Alopecia is common. Rash, including hand-
foot syndrome, is reported also. Mild jaundice, and elevated transaminase levels also are 
reported in > 10% of patients. Fever (noninfectious) is also reported among the most common 
adverse reactions associated with cytarabine. 
Less commonly, a “cytarabine syndrome” or “Ara-C syndrome” has been reported. The 
syndrome may be characterized by fever, myalgia, bone pain, rash, malaise, and chest pain. 
Nursing Guidelines 
Can be a potent myelosuppressive agent. Monitor CBC closely. Anemia, leukopenia, and 
thrombocytopenia are expected. Nadir within 5-7 days with recovery expected in 2-3 weeks. 
Hematological toxicity is more intense if Ara-C is given as a continuous IV infusion versus an 
IV bolus. 
Nausea and vomiting is dose-related, common, and often preventable with antiemetic drugs. 
Administer as ordered and assess for their effectiveness. 
Instruct patient of possibility of metallic taste. The use of sugarless hard candies may lessen this 
effect. 
Stomatitis is possible. May try dabbing Vit.E oil to lesions. Instruct patient not to swallow. 
May cause pancreatitis or peritonitis. Instruct patient to report any severe or worsening 
abdominal pain immediately. 
Monitor LFT’s-elevations of LFT’s may occur. 
Cerebellar toxicity can occur in 16-40% of patients with more severe symptoms at higher doses. 
Monitor for these toxicities with each dose of Ara-C. Signs and symptoms of cerebellar toxicity 
can include: lethargy with progressive confusion, ataxia, nystagmus, slurred speech. Report any 
of these or other neurological changes to the MD immediately. 
Instruct patient to report any shortness of breath or difficulty breathing as this may be a sign of 
a rare but life threatening pulmonary complication. 
Monitor for signs of conjunctivitis and/or keratitis. This is usually prevented with prophylactic 
glucocorticoid eye drops. 
Assess for skin rash. This may present itself as a erythema without exfoliation, or a generalized 
rash. Report to MD. 
Monitor for “Ara-C” syndrome. This is characterized by bone and muscle pain, chest pain, fever, 
general weakness, reddened eyes, and skin rash. Report these to the MD, as patient may need to 
be treated with corticosteroids. 

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10.7 
Melphalan (NSC# 8806) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Melphalan for IV use is commercially available in 50 mg vials. The product is a lypholized 
powder with 20 mg povidone per vial. Also provided is 10 mL of special diluent for use in 
reconstituting the product. The special diluent has 0.2 g sodium citrate, 6 mL propylene glycol, 
0.5 mL 95% ethanol, and sterile water. Please refer to the FDA-approved package insert for 
complete prescribing information. 
Storage and Stability 
Intact vials should be stored at room temperature (15°-30°C) and protected from light. 
Reconstituted solutions are chemically and physically stable for at least 90 minutes at room 
temperature. Solutions further diluted in 0.9% sodium chloride to a concentration of 0.1 mg/mL 
to 0.45 mg/mL are stable for at least 60 minutes. Solutions diluted to 1 mg/mL are reported to 
be physically stable for at least 4 hours at room temperature-chemical stability of this dilution is 
not known. Because of the relative instability of melphalan solutions, it is recommended that 
administration of the diluted solution be completed within 60 minutes of reconstitution. 
Reconstituted solutions should not be refrigerated. 
Preparation 
Melphalan should be prepared immediately before intended use. Each vial is reconstituted with 
10 mL of the special diluent to yield a concentration of 5 mg/mL. The reconstituted solution 
may be diluted with 0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL. 
Alternatively, when the required concentration necessitates an unacceptable volume of fluid, the 
reconstituted solution may be administered undiluted or per institutional guidelines. 
Administration 
Melphalan should be given over 20-30 minutes and infusion must be completed within 60 
minutes of preparation. 
Adverse Events 
The major toxicity of melphalan is bone marrow suppression, usually lasting four to eight weeks. 
Other toxicities include nausea, vomiting, diarrhea, and mucositis. Less common toxicities 
include pulmonary fibrosis, interstitial pneumonitis, vasculitis, alopecia, hemolytic anemia, and 
allergic reactions. 
Nursing Guidelines 
Hematologic toxicity is a major and dose-limiting adverse effect and is principally manifested 
by leukopenia and thrombocytopenia. Myelosuppression usually occurs 2-3 weeks after therapy 
and may persist for 6 weeks or more. Monitor CBC frequently. Instruct patient to report any 
signs/symptoms of infection, unusual bruising or bleeding to the health care team. 
Assess for nausea and vomiting and treat symptomatically. Severe nausea and vomiting has been 
reported with high dose treatment. Premedicate with antiemetics before high dose IV treatment. 
Occasional diarrhea and stomatitis has been reported also. Treat symptomatically. Encourage 
good oral care. 
Assess for pulmonary toxicity. Instruct patient to report any unusual cough, chest pain, or 
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Anaphylaxis is possible with IV administration. Have anaphylaxis tray and necessary emergency 
equipment nearby when administering IV. Monitor for signs symptoms of hypersensitivity 
reaction, which include, rash, diaphoresis, difficulty breathing, and hypotension. 
Drug is an irritant. Avoid extravasation. Establish IV patency before and throughout 
administration. 
Monitor renal function tests. Increased nephrotoxicity of cyclosporine can be increased by 
melphalan. 
10.8 
G-CSF (filgrastim, NSC# 614629) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
Commercial filgrastim is available in 1 mL and 1.6 mL vials containing 300 mcg and 480 mcg 
filgrastim, and in prefilled syringes containing 300 mcg/0.5 mL or 480mcg/0.8 mL. Please refer 
to the FDA-approved package insert for filgrastim for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
Storage and Stability 
Intact vials and prefilled syringes should be stored in the refrigerator at 2-8° Centigrade (36-46° 
Fahrenheit). Do not freeze. 
Administration 
Filgrastim will be administered as a subcutaneous injection. Doses should be rounded (to the 
vial size) per institutional guidelines. 
Adverse Events 
The most common side effect associated with filgrastim is medullary bone pain. Bone pain is 
usually reported as mild or moderate and, if necessary, may be treated with non-opioid or opioid 
analgesics.  
Nursing Guidelines 
Patients may need instruction in subcutaneous drug administration. Advise patient to take drug 
at the same time each day. 
WBC and ANC must be monitored and communicated to medical doctor and to patient. 
Patients may need to deal with financial concerns due to expense of this drug. 
Keep drug refrigerated. It will be stable for ten months or more when refrigerated. There is 
significant loss of activity if the drug is stored above or below 2-8°C (35.6°F-46.4°F). Vials 
should not be shaken. 
Assess for mild-moderate transient bone pain and advise patient in comfort measures. 
Acetaminophen is the recommended analgesic for mild bone pain. May be beneficial to give at 
the time of injection. 
Patients may experience rash. 
Patients can experience “flu-like” symptoms– headache, fever, nausea, vomiting. Treat 
symptomatically and assess for effectiveness. 

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10.9 
PEG-G-CSF (pegfilgrastim, NSC# 725961) 
Procurement 
Institutional pharmacy shall obtain supplies from normal commercial supply chain or 
wholesaler. 
Formulation 
6mg/0.6ml syringe. 
Storage and Stability 
Syringes should be kept refrigerated and stable for 48 hours at room temperature. 
Administration 
Injections should be given under the skin (subcutaneously). 
Adverse Events  
The most common side effect associated with pegfilgrastim is medullary bone pain. Bone pain 
is usually reported as mild or moderate and, if necessary, may be treated with non-opioid or 
opioid analgesics. 
Nursing Guidelines 
Do not administer pegfilgrastim in the period between 14 days before and 24 hours after 
administration of cytotoxic chemotherapy. 
Warn patients of bone pain, arthralgia and myalgia. Treat symptomatically and monitor for 
effectiveness. 
Instruct patients to report any peripheral edema to study team. 
Headache may be seen. Treat symptomatically and monitor for effectiveness. 
While rare, instruct patient to report any rash or skin changes. 
10.10 Mesna (NSC# 113891) 
Procurement 
Mesna should be obtained from commercial supplier. Please refer to the product’s commercial 
package insert for complete information. 
Storage and Stability 
Intact vials are stored at room temperature. Diluted solutions are physically and chemically 
stable for 24 hours under refrigeration. 
Preparation 
Mesna is available as an injectable solution. Mesna may be further diluted in 5% dextrose, 5% 
and 0.45% sodium chloride, normal saline, or lactated Ringer’s solution to a final concentration 
of 1 to 20 mg/mL. 
Administration 
Mesna is often given as an intravenous injection over 5 minutes or longer. Mesna has also been 
given orally and as a continuous intravenous infusion. 
Adverse Events 
At the doses used for uroprotection, mesna is virtually non-toxic. However, the following 
adverse effects may be attributable to mesna: 
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, altered taste 
Dermatologic: Rash, uticaria 

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Other: Lethargy, headache, joint or limb pain, hypotension, fatigue 
Nursing Guidelines 
Doses of mesna should always be given on time. Oral mesna can be very nauseating. Provide 
antiemetics when oral mesna is sent home with patient. Oral mesna should be mixed with juice, 
water, milk, or carbonated beverage for administration. Instruct patient that all doses must be 
taken in their entirety and on time. If this is not possible due to nausea, patient must return to 
the clinic or the ER to have the missed dose and all subsequent doses administered by IV. 
Instruct patient to report any rash. 
Patients may experience some arthralgia/back pain. Treat symptomatically. 
11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the revised international working 
group guidelines (Lugano classification) [33]. 
11.1 
Schedule of Evaluations: 
A whole body or limited whole body PET/CT scan or a PET and CT of neck, chest, abdomen 
and pelvis will be performed at 3 months (+/- 1 month) for initial response assessment. This can 
be delayed by up to an additional month for patients undergoing post-transplant radiotherapy. 
Following this, either a PET/CT or a diagnostic CT of the neck, chest, abdomen, and pelvis will 
be repeated at 6, 12, 18, and 24 months (+/- 1 month). Additional scans are to be performed at 
the discretion of the treating physician at the time of suspected disease progression or off study 
evaluation. 
Supporting documentation should be submitted, per section 6.1.1. 
11.2 
Measurement of Treatment/Intervention Effect 
11.2.1 Target Lesions & Target Lymph Nodes 
• 
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 
(eg, 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. 
11.2.2 Metabolic Response at 3 month (or Cycle3) Assessment 
Response will be evaluated by the PET-CT based response criteria column in Section 11.2.5. 
Patients will also be evaluated for progressive disease (PD) by the CT-based criteria column 
in Section 11.2.5. Baseline refers to imaging used to document response to salvage therapy 
that was completed within 42 days of registration. 

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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
12.1.1 Patients who do not progress, relapse or experience unacceptable toxicity will continue on 
therapy for a total of 12 cycles in the continuation phase (Cycles 2-13). After treatment is 
completed, patients will be followed per the study calendar in section 5.0.  
12.1.2 Disease Progression or Relapse: Progression is defined as PD by the CT-based response 
criteria in Section 11.2.5. Remove from protocol therapy any patient with disease 
progression or relapse (PD) by CT-based response criteria. If a patient has progressive 
metabolic disease (PMD) on the Cycle 3 response assessment but does not meet criteria for 
PD by CT-based response criteria, they should continue treatment per protocol. Document 
details, including tumor measurements, on data forms. 
At the time of disease progression, patients’ treatment assignment will be unblinded. See 
section 8.3 for unblinding instructions. Patients receiving placebo will be offered therapy 
with ibrutinib. 
After disease progression or start of alternative anticancer therapy, patients will be contacted 
approximately every 6 months by clinic visit or telephone, to assess survival and the use of 
alternative anticancer therapy until death, withdrawal of consent, loss to follow up, study 
closure, or 60 months have elapsed from registration, whichever occurs first. 
12.1.3 Discontinuation of study agent: If the patient discontinues ibrutinib in cycle 1 or 
continuation cycles 2-13 for reasons other than progression or relapse and they have not 
withdrawn study consent, they will continue protocol follow up requirements per study 
calendar in section 5.0 as per active treatment. For example, imaging scans will be 
performed at 3, 6, 12, 18, and 24 months, and clinical follow-up at 3, 6, 9, 12, 18, and 24 
months from registration, then every 6 months for up to 60 months from registration.  
Once they progress or start alternative lymphoma therapy, they will be followed 
approximately every 6 months by clinic visit or telephone to assess survival and the use of 
alternative anticancer therapy until death, withdrawal of consent, loss to follow up, study 
closure, or 60 months have elapsed from registration. 
12.2 
Definitions and Follow-up Requirements 
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient were to continue protocol treatment. 
Notification of the local IRB may be necessary per local IRB policies. 
Definition of clinical follow-up: The follow-up period where the study participant is no longer 
receiving treatment, but is still following the study calendar for tests, exams, and correlative 
endpoints (e.g., specimen collection, quality of life, disease assessments as required by the 
study). 
Definition of survival only follow-up: The follow-up period where the study participant is 
monitored for long-term endpoints, is no longer receiving study treatment, and is not required 
to follow the study calendar for tests, exams, and correlative endpoints (e.g. specimen collection, 
quality of life, disease assessments as required by the study). In this follow-up period, there is a 
schedule in which case report forms should be submitted, but the physician visits are based on 
the standard of care.  

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12.2.1 Follow-up for Ineligible Patients 
Study participants who are registered to the trial but deemed ineligible must complete 
follow-up requirements as specified below:  
Baseline, on-study, endpoint (e.g., relapse or progression), off treatment, and survival data 
submission required. 
12.2.2 Follow-up for Patients Never Receiving Protocol Intervention 
Study participants who are registered to the trial but who never go on to receive study 
intervention must still complete follow-up requirements as specified below: 
Baseline, on-study, and off treatment data submission required. 
12.3 
Extraordinary Medical Circumstances 
If, at any time, the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• Document the reason(s) for discontinuation of therapy on data forms. 
• Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
A total of 160 patients (80 per arm) will be randomized between ibrutinib arm and placebo arm 
with equal probability stratified at study entry by prior use of ibrutinib (yes vs. no), type of 
transplant regimen planned (CBV vs. BEAM), and time to relapse (≤ or > 12 months). This 
study will recruit 166 patients, including a cohort of 6 patients to investigate the safety of 
ibrutinib as described in section 13.7 below. 
13.2 
Sample Size, Accrual Time and Study Duration 
Relapsed DLBCL is the second largest indication for AutoHCT after multiple myeloma. The 
original projections were based on a CIBMTR query of member institutions for the 4-year period 
of 2009 – 2012, whereby 635 DLBCL patients per year underwent an AutoHCT among the top 
40 U.S. sites and 770 patients per year among the top 60 U.S. sites [Tim Fenske personal 
communication]. Assuming broad cooperative group and BMT-CTN participation and that 30-
50% of these patients would be assigned to the ABC subtype, we expected that 231 – 385 
patients would be potentially eligible every year and as many as 96 could have been enrolled. 
However, the screening logistics employed initially (including the subtype assignment tool) 
resulted in only ~13% of screened patients proceeding to registration. We made major 
modification at a later version that have now resulted in ~52% of patients registering. In that 
same period, alternative treatment strategies (CART cells, novel antibody-drug conjugates) have 
been approved that further limited the number of transplants being performed nationally and the 
number of patients enrolled on study. We expect the current accrual numbers to hold at these 
lower levels.  
Accounting for about 5% of attrition due to dropouts or ineligibilities, this study will randomize 
a total of 160 patients between the two arms (80 patients per arm). From Gisselbrecht et al [7] 
and Vose et al [9], we expect a median PFS of the placebo arm to be about 24 months. We would 
consider the experimental agent clinically meaningful if its 24-month PFS is 67% or higher 
(odds ratio=2). Assuming that 152 (=0.95x160) patients have at least 2 year of follow-up, the 
asymptotic test comparing the Kaplan-Meier estimators at 2 years with 1-sided alpha=10% will 
have 74% of power. This design includes one interim analysis for futility after 40 randomized 

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patients reach the 2-year PFS end point. This study will take about 90 months (66 months for 
patient accrual based on a projected accrual of 2.5 patients per month and 24 months for 
additional follow-up). 
Changes as of Update #06 
As of September 17, 2018, this study has pre-registered 254 patients and has registered 32 
patients (n=6 for early safety monitoring and n=26 of 296 patients required for the randomized 
portion of the study). The large degree of attrition is primarily due to inadequate tissue for 
running the LST assay, failed central review of histology, ineligibility based on LST results even 
among patients who are non-GCB by IHC, and patient/investigator decision to not proceed with 
registration due to delays in testing.  These issues are being addressed by site education of tissue 
requirements and change in eligibility based non-GCB determination by central review (Hans 
algorithm). It is expected that this modification will allow for timelier randomization, decreasing 
attrition currently related to the extended period of time between pre-registration and 
registration, and decreasing tissue requirements necessary for running and interpreting the LST 
assay.  
The 26 patients already randomized with confirmed ABC subtype by LST will be included as 
part of the 296 total patients required in the randomized portion of the study. Based on current 
available data, it is anticipated that, approximately 160 patients per year will be pre-registered 
going forward, with up to 96 patients (60%) lost prior to registration due to insufficient tissue 
(10%), failure to confirm a DLBCL diagnosis upon central path review (10%), failure to confirm 
non-GCB subtype upon central path review (25%), and patient/investigator decision (15%). It 
is therefore estimated that a total of 64 patients will be registered per year. At this rate, it is 
anticipated that it will take approximately 4 years to accrue the remaining 270 patients required. 
Accounting for 24 months of follow-up after the completion of accrual, the primary analysis is 
anticipated approximately 6 years after the implementation of Update #06. 
Changes as of Update #09 
As of November 16, 2021, this study has registered 89 patients (n=6 for early safety monitoring 
and n=83 patients required for the randomized portion of the study). Due to concerns over lower-
than-expected accrual rate and to ensure that the study is completed in a timely manner, the total 
sample size for the randomized portion of the trial has been reduced from 296 patients (148 per 
arm) to 160 (80 per arm). Assuming a 5% attrition due to dropout or ineligibilities, we expect 
152 patients (76 per arm) will be evaluable for the primary endpoint. This sample size provides 
74% power at a 1-sided Type I error of 0.10 to detect an improvement in 24-month PFS 
probability with ibrutinib compared to placebo, assuming a 24-month PFS of 67% in the 
ibrutinib arm versus 50% in the placebo arm. This design includes one interim analysis for 
futility when 40 (26%) of randomized patients have reached the 2-year PFS endpoint. This 
interim analysis will occur in March 2022. 
13.3 
Statement for Primary Endpoint 
The primary clinical endpoint of this phase III trial is 24-month progression-free survival (PFS), 
as measured by the Kaplan-Meier estimator. PFS is defined as the time between registration and 
disease progression or death due to any cause, whichever comes first. Progression is defined as 
PD by the CT-based response criteria. 
13.4 
Statement for Secondary Endpoint 
Secondary endpoints include overall survival (OS), progression free survival (PFS), response 
rate assessment following AutoHCT (at 3 months), time to hematopoietic recovery, safety and 
tolerability of ibrutinib therapy, incidence of secondary malignancies, and immune 
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For the patients who receive the experimental therapy after progression from the control therapy, 
response rate and PFS will be estimated. The baseline for PFS in these analyses will be the time 
of progression from the first (randomized) treatment. 
13.5 
Interim Analysis Design for Primary Endpoint 
The primary analysis is to compare the 24-month PFS probability between the two arms using 
the chi-squared test for 2-sample binomial proportions. If there are any cases with PFS censored 
before 2 years, then we will compare the Kaplan-Meier estimates of the two arms at 2 years. 
Interim Analysis: Interim analyses will be conducted when 40 randomized patients have at least 
2 years of follow-up. Based on the design setting and the accrual status on November 16 2021, 
the interim analysis for futility will occur in March 2022. At the interim analysis, the trial will 
be terminated for futility if the observed difference (experimental vs. control) in PFS between 
the two arms is < 0 (i.e., the stopping boundary is Z = 0). Otherwise, the trial will continue to 
the final analysis. 
Final Analysis: The final analysis will be conducted when all patients have reached the 2-year 
follow-up. At the final analysis, if Z > 1.282 (equivalently, p-value < 0.1) it will be concluded 
that ibrutinib is associated with an improved 24-month PFS. Below is the operating 
characteristics of this design based on a simulation of 10,000 trials. 
24-month PFS (%) 
Prob stopping early for futility 
(Z < 0) 
Final analysis conclusion 
Power 
Control 
Treatment 
Efficacy (Z > 1.282) 
Futility 
50% 
50% 
43.3% 
10.2% 
46.6% 
10.2% 
60% 
22.0% 
46.6% 
31.5% 
46.6% 
67% 
10.6% 
76.9% 
12.5% 
76.9% 
Using logistic regression, multivariable analyses will be conducted to adjust for the stratification 
factors and other clinical predictors. If there are patients whose PFS time are censored before 2 
years, then the logistic regression will be modified using the method of Jung [34] to include all 
patients in the analysis. We will also conduct a multivariable analysis using the Cox regression 
model using the raw PFS data. 
13.6 
Analysis Plan for Secondary Endpoints 
Secondary endpoints are analyzed only at the final analysis.  
Hierarchical Testing for Secondary Endpoint: If the primary comparison of 24-month PFS is 
significant at the overall one-sided significance level of 0.10, then the PFS hazard rates between 
the two arms will be compared using the log-rank test at a .10 one-sided significance level. If 
the log-rank test for PFS is significant at the 0.10 significance level, then we will compare the 
OS between the two arms using the log-rank test at a 1-sided significance level of 0.05. The 
marginal power for the OS comparison is provided below. 
Both the primary and secondary analyses will be conducted using the intent-to-treat principle. 
In terms of OS, Vose et al. described a 2-yr OS of 66% for R-BEAM, which corresponds to an 
annual hazard rate of 0.207 under an exponential OS model. Thus with 160 patients (152 
evaluable patients), the log-rank test with a one-sided significance level of 5% has 
approximately 82% of power to detect a hazard ratio (experimental vs. control) of 0.53 assuming 
a monthly accrual rate of 2.5 patients and all patients are followed for survival for up to 5 years. 
Under the design setting and the assumption of exponential distributions for PFS and patients 
followed for up to 5 years, we would have a power of 91% at the one-sided type I error of 10% 
if we used the log-rank test (instead of chi-squared test) to compare PFS between the two arms. 

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For each arm, the distributions of OS, PFS, and time to neutrophil and platelet engraftment will 
be estimated using the Kaplan-Meier method. OS, PFS, and time to neutrophil and platelet 
engraftment will be compared between the two arms using the log-rank test and Cox regression 
method adjusting for the known predictors. The metabolic response proportion following 
AutoHCT will be compared between the two arms using chi-squared test. 
Treatment-related mortality, incidence of secondary malignancies and hematologic toxicity of 
ibrutinib therapy will be summarized using contingency tables. 
13.7 
Early Safety Monitoring 
Ibrutinib has been shown to augment chemotherapy-induced cytotoxicity in ABC-like DLBCL 
cells [20, 35]. Ibrutinib has a low toxicity profile, and it has been safely combined in completed 
and currently ongoing studies with alkylator-based treatment regimens for patients with 
lymphoproliferative disorders. Thus, we expect its combination with preparative regimen 
chemotherapy to be effective and well tolerated. To ensure safety during the engraftment phase, 
we will hold ibrutinib following completion of the preparative regimen. Additionally, we will 
treat a cohort of 6 patients per open-label safety run-in (all getting ibrutinib in Cycles 1-13). 
These patients will not be randomized and will be excluded in the statistical analysis to compare 
the two arms. We require that at least 2 patients out of the 6 receive therapy with BEAMi and 2 
patients with CBVi. We will consider amendment of the study if the number of patients who 
experience grade 3/4 unexpected toxicities is greater than or equal to 2 among the 6 patients. 
The expected rate of grade 3/4 unexpected toxicity for ibrutinib is about 25%. This monitoring 
rule has 22%, 47%, 68%, 84%, or 93% of probability to amend the study if the rate of grade 3/4 
unexpected toxicity for ibrutinib arm is 15%, 25%, 35%, 45%, or 55%, respectively. 
We will hold weekly teleconferences during the early safety phase to be attended by the study 
investigators or their representatives, the principal investigator, data management, and the 
statistical data center to review adverse events, accrual and other issues that arise over the course 
of the study. This teleconference is only required for those sites with patients on study. 
13.8 
Protocol-Specific Monitoring Plan 
Accrual Monitoring 
Accrual will be monitored closely after activation of Update #06 to ensure trial feasibility. 
Failure to meet accrual goals may be attributed to lower than anticipated preregistration rates 
and/or higher than anticipated drop-out rates between preregistration and registration. 
Ultimately, we will require that the observed preregistration rate is at least 75% of the targeted 
preregistration rate and that the drop-out rate between pre-registration and registration is no 
higher than 60%. Preregistration and registration rates will be reviewed in the first 6 months and 
in months 6-12 to ensure that at least 50% and 75%, respectively, of the projected rates are being 
met. In addition, the drop-out rate between pre-registration and registration and the reasons for 
drop-out will be reviewed with each successive group of 30 patients preregistered. If the drop-
out rate is higher than 60%, the data will be discussed with the central pathology lab, Data 
Monitoring Committee, and the National Cancer Institute to determine whether processes can 
be modified to minimize drop-out and if trial completion remains feasible.  
On-site Monitoring 
On-site audits will be conducted according to the NCI Clinical Trials Monitoring Branch 
guidelines. 
 
 

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associated with inferior PFS and OS following autologous stem cell transplantation. Our 
secondary hypothesis is that planned therapy with ibrutinib will modify this effect. FDG-
PET/CT scans obtained during salvage assessment will be acquired and centrally reviewed. 
We will utilize both traditional revised IWG criteria as well as the Lugano criteria to perform 
our analysis as well as quantitative metabolic measurements. The results of our study may 
validate the prognostic and predictive role of FDG-PET/CT in the relapsed DLBCL setting 
and allow the design of future intervention trials targeting a more selected high-risk patient 
population. 
14.1.2 Objectives 
14.1.2.1 To assess whether pre-AutoHCT positive FDG-PET is associated with inferior 24-
month PFS as well as PFS and OS. 
14.1.2.2 To assess whether pre-AutoHCT FDG-PET results are differentially associated with 
24-month PFS, PFS, and OS in the ibrutinib versus placebo arms. 
14.1.2.3 To evaluate the application of the Lugano criteria and change in quantitative 
measurements between pre-AutoHCT and post AutoHCT FDG-PET (e.g., delta SUV, 
%SUV decline and %MTV decline, and other available applicable quantitative 
measurements) to assess the association between changes in these variables and 
outcomes, such as PFS and OS. 
14.1.3 Methods 
PET/CT using fluorodeoxyglucose (18F) (FDG) performed during salvage therapy 
assessment will be acquired at the time of study entry and will be centrally reviewed. Semi-
quantitative and qualitative PET analysis will be performed by the Alliance imaging 
committee using SUV, mediastinal blood pool, and liver uptake. All patients will then 
receive PET/CT subsequent scans as mandated by the protocol for response assessment.  We 
will ask that all PET/CT scans be performed at the same instrument at each institution.  
These PET/CT scans will be considered standard of care. 
14.1.4 Statistical Design 
Of those who respond to salvage therapy and go on to transplant, about 60% will be PET/CT 
negative by rIWG criteria. Within each arm, PFS and OS will be compared between PET/CT 
positive and negative groups using the two-sample log-rank test with a 2-sided alpha of 5%. 
Assuming that FDG-PET/CT data will be available for 90% of the patients (n=68 per arm), 
we will have 80% power to detect a true hazard ratio (HR) of 0.45, corresponding to a 
difference in median PFS of 1.25 years for PET/CT positive group vs. 2.80 years for 
PET/CT negative group in the placebo arm. In the treatment arm, we will have 80% power 
to detect a true HR of 0.40 or less, corresponding to a difference in median PFS of 2.25 
years for PET/CT positive group vs. 5.68 years for PET/CT negative group in the 
experimental arm. Other design parameters are set at the same values as in the main trial. A 
Cox regression model will be conducted to regress PFS and OS on PET/CT positivity, study 
treatment arm, their interaction and known clinical predictors, so that the real power for 
PET/CT positivity effect will be higher than this power which is based on an unadjusted 
analysis (the 2-sample log-rank test). We will also evaluate the influence of PET/CT status 
on the 2-year PFS rate. Logistic regression models will be used to evaluate the influence of 
PET/CT status on 2-year PFS rate within treatment arms as well as across arms but where 
interaction effects are evaluated. With 136 evaluable patients, we will have 80% power to 
detect an odds ratio (OR) of 0.36 or lower. We will also conduct similar analyses using 
Deauville criteria with cutoffs at scores of 2 and 3, and quantitative measurements, e.g. delta 

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SUV, %SUV decline and %MTV decline, in place of the dichotomous FDG-PET/CT 
outcome. We will further estimate the positive and negative predictive values, sensitivity 
and specificity of PET/CT by dichotomizing the PFS and OS at 2 years (e.g. case if PFS>2 
years and control otherwise). In order to investigate the prognostic value of FDG-PET 
positivity, we will also conduct these analyses using only the control arm. 
14.2 
Pharmacogenetics (Alliance A051301-PP1) 
A051301-PP1 will evaluate the Pharmacogenetics of High-dose Chemotherapy and Treatment 
Efficacy in Relapsed/Refractory DLBCL.  
14.2.1 Background 
The pharmacogenomic component of this study is conducted as part of the NIH 
Pharmacogenomics Research Network, which is funded through a separate U01 mechanism 
(see http://www.nigms.nih.gov/pharmacogenomics/research_net.html) for details. 
Pharmacogenetic studies will focus on the effects of candidate SNPs on pulmonary toxicity 
after high-dose chemotherapy followed by autologous stem cell transplant. High-dose 
chemotherapy administered in the setting of autologous stem cell transplantation can be 
associated with significant short-term (mucositis, delayed count recovery, infection) and 
long-term 
(BCNU 
pneumonitis, 
secondary 
malignancies) 
toxicities. 
Germline 
polymorphisms may affect the severity of these toxicities in individual patients, as well as 
treatment efficacy. We hypothesize that the null (deletion) allele of GSTT1 is associated 
with pulmonary toxicity in relapsed DLBCL patients treated with high-dose chemotherapy 
administered in the setting of autologous stem cell transplantation. 
Factors believed to contribute to chemical lung injury include oxidative stress and 
inflammation. Higher doses of BCNU are associated with a higher risk of pulmonary 
toxicity [47]. Gene expression and polymorphisms in glutathione reductase and NQO1 
(oxidative stress), TNFa, IL-1R, and others (inflammation) have been associated with lung 
injury [48] [49-53]. GSTT1 encodes the glutathione transferase with the highest activity in 
the denitrosylation and inactivation of BCNU [54]. There is a common copy number 
variation of this locus, with a null allele frequency of 34-74%, based on racial ethnic 
background [55]. Expression of GSTT1 is tightly correlated with gene copy number, with 
lowest expression in homozygous null patients (-/-)[56]. A mouse knockout for GSTT1 is 
viable and has higher serum BCNU levels and higher area under the curve (AUC) after 
BCNU administration [57]. We hypothesize that patients with lower GSTT1 copy number 
will be more susceptible to BCNU-induced pulmonary toxicity due to decreased clearance 
of the drug and/or more oxidative damage in lung tissue.  
Other proteins are likely associated with BCNU pneumonitis as well. O(6)-methylguanine-
DNA methyltransferase (MGMT) is a key enzyme involved in the excision of 06-guanine 
methyl or chloroethyl damage that is induced by BCNU and other agents with a similar 
mechanism of action. Its expression has been implicated in drug resistance and inferior 
clinical outcomes in patients with glioblastoma multiforme treated with these drugs [58-60]. 
MGMT promoter methylation status has been associated with MGMT expression and 
expression associated with activity and drug resistance to BCNU, temozolomide, and DTIC. 
The nonsynonymous SNP rs2308321 (I174V) (MAF 0.159 CEU) has been associated with 
expression, activity, carcinogenesis, and response to DTIC in melanoma. Additionally, the 
promoter SNP rs16906252 (MAF 0.120 CEU) has been associated with methylation status 
in tumor and normal tissue. ATP-dependent drug efflux via transmembrane transporters is 
a major route of elimination of cyclophosphamide and etoposide from the cytoplasm and 
thus, a major determinant of intracellular drug levels [61].  MDR1 glycoprotein (ABCB1) is 
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and has since been shown to be expressed in most tissues and overexpressed in a variety of 
solid and hematologic malignancies. Several lines of work suggest an association between 
ABCB1 expression and inferior clinical outcomes in patients with DLBCL and other 
lymphomas in the front-line setting [62-64]. The polymorphism C3435T (rs1045642) has 
been previously identified to be associated with expression and function of ABCB1 [65]. 
Additionally, it has been implicated in toxicity and clinical efficacy of ABCB1 substrates in 
other studies [66-70]. In exploratory analyses, we will also evaluate the ABCB1 SNP 
rs1045642, and others in XRCC3, GSTP1, MDM2 snp309, and SNPs associated with 
etoposide cytotoxicity (rs460869, rs6588131, and rs16965867) in this patient population.  
14.2.2 Objectives 
14.2.2.1 To assess whether the GSTT1 null polymorphism is correlated with pulmonary 
toxicity after BCNU-containing conditioning regimens as part of autologous stem cell 
transplantation. 
14.2.2.2. Secondary objectives are to assess whether other polymorphisms in the BCNU 
metabolism pathway or BCNU damage repair pathway(s) are associated with 
pulmonary toxicity after BCNU-containing conditioning regimens as part of 
autologous stem cell transplantation. 
14.2.2.3. Additional objectives will assess whether any of the proposed polymorphisms are 
associated with other toxicities. 
14.2.2.4 Exploratory analyses to identify polymorphisms associated with ibrutinib response 
will be performed. 
14.2.3 Methods 
Ten mL whole blood in an EDTA tube will be obtained from consenting study participants 
at baseline, prior to receipt of study treatment. The blood will be sent to the Alliance 
Biorepository at Washington University (WUSTL) for DNA preparation. DNA quality will 
be assessed by UV spectrophotometry and by agarose gel electrophoresis. All DNA samples 
will be stored at WUSTL until they are distributed to the appropriate laboratory for 
genotyping. For the GSTT1 null allele, samples will be genotyped using previously 
established assays (Taqman, based) [55]. Assays for other polymorphisms will be done 
according to previously established assays as well. Phenotypic data will be extracted from 
the Alliance database by the Alliance Statistical Center. Statistical analyses will be 
conducted under the direction of the responsible Alliance faculty statistician. 
14.2.4 Statistical Design 
The primary statistical objective for this companion study is to investigate the association 
between the GSTT1 null allele and BCNU-induced lung toxicity. The response phenotype 
will be quantified using standard CTCAE criteria, and changes in DLCO from baseline. 
Specifically, we hypothesize that patients with null alleles of GSTT1 (-/- or +/-) will have a 
higher risk of pulmonary toxicity after the BCNU-containing conditioning regimens used in 
this protocol. The analysis will be stratified by BCNU dosage, with patients categorized as 
receiving either the “low” (300 mg/m2) or “high” (15 mg/kg) dose, in order to control for 
the different preparatory regimens. 
The number of eligible patients to be registered to this study and randomized is 160. 
Assuming 5% attrition due to ineligibility and dropout gives a sample size of 152 eligible 
patients (76 per arm). We will perform an analysis with adjustment for ancestry, but given 
the limited power to examine this association in minority subjects, the primary analysis 

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53. Patwari, P.P., et al., Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats 
polymorphism and respiratory failure in children with community-acquired pneumonia. Pediatr 
Crit Care Med, 2008. 9(6): p. 553-9. 
54. Lien, S., A.K. Larsson, and B. Mannervik, The polymorphic human glutathione transferase T1-
1, the most efficient glutathione transferase in the denitrosation and inactivation of the 
anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochemical pharmacology, 2002. 63(2): 
p. 191-7. 
55. Moyer, A.M., et al., Glutathione S-transferase T1 and M1: gene sequence variation and 
functional genomics. Clinical cancer research : an official journal of the American Association 
for Cancer Research, 2007. 13(23): p. 7207-16. 
56. Butler, M.W. and N.R. Hackett, Glutathione S-transferase Copy Number Variation Alters Lung 
Gene Expression. European Respiratory Journal, 2011. 38(1): p. 15-28. 
57. Fujimoto, K., S. Arakawa, and T. Watanabe, Generation and Functional Characterization of 
Mice with a Disrupted Glutathione S-Transferase , Theta 1 Gene. Drug Metabolism and 
Disposition, 2007. 35(12): p. 2196-2202. 
58. Bocangel, D.B., et al., Multifaceted resistance of gliomas to temozolomide. Clin Cancer Res, 
2002. 8(8): p. 2725-34. 
59. Hegi, M.E., et al., MGMT gene silencing and benefit from temozolomide in glioblastoma. N 
Engl J Med, 2005. 352(10): p. 997-1003. 
60. Kaina, B., et al., MGMT: key node in the battle against genotoxicity, carcinogenicity and 
apoptosis induced by alkylating agents. DNA Repair (Amst), 2007. 6(8): p. 1079-99. 
61. Chabner, B.A. and D.L. Longo, Cancer Chemotherapy & Biotherapy.  3rd Edition2001, 
Philadelphia, PA: Lippincott Williams & Wilkins. 
62. Andreadis, C., et al., Members of the glutathione and ABC-transporter families are associated 
with clinical outcome in patients with diffuse large B-cell lymphoma. Blood, 2007. 109(8): p. 
3409-16. 
63. Jerkeman, M., et al., Assessment of biological prognostic factors provides clinically relevant 
information in patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study. 
Ann Hematol, 2004. 83(7): p. 414-9. 
64. Ohsawa, M., et al., Immunohistochemical expression of multidrug resistance proteins as a 
predictor of poor response to chemotherapy and prognosis in patients with nodal diffuse large 
B-cell lymphoma. Oncology, 2005. 68(4-6): p. 422-31. 

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65. Hoffmeyer, S., et al., Functional polymorphisms of the human multidrug-resistance gene: 
multiple sequence variations and correlation of one allele with P-glycoprotein expression and 
activity in vivo. Proc Natl Acad Sci U S A, 2000. 97(7): p. 3473-8. 
66. Siddiqui, A., et al., Association of multidrug resistance in epilepsy with a polymorphism in the 
drug-transporter gene ABCB1. N Engl J Med, 2003. 348(15): p. 1442-8. 
67. Fellay, J., et al., Response to antiretroviral treatment in HIV-1-infected individuals with allelic 
variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet, 2002. 
359(9300): p. 30-6. 
68. Paule, B., et al., MDR1 polymorphism role in patients treated with cetuximab and irinotecan in 
irinotecan refractory colorectal cancer. Med Oncol, 2009. 
69. Kwon, W.S., et al., G-T haplotype (2677G>T/A and 3435C>T) of ABCB1 gene polymorphisms 
is associated with ethnic differences to paclitaxel sensitivity in cancer cells with different gene 
expression pattern. Cancer Lett, 2009. 277(2): p. 155-63. 
70. Chang, H., et al., Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T 
with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann 
Oncol, 2009. 20(2): p. 272-7. 
71. Alessandrino, E.P., et al., Pulmonary toxicity following carmustine-based preparative regimens 
and autologous peripheral blood progenitor cell transplantation in hematological malignancies. 
Bone marrow transplantation, 2000. 25(3): p. 309-13. 
72. Rubio, C., M.E. Hill, and S. Milan, Idiopathic pneumonia syndrome after high-dose 
chemotherapy for relapsed Hodgkin's disease. British journal of ‚Ä¶, 1997. 75(March 1994): p. 
1044-1048. 
73. Till, B.G. and D.K. Madtes, BCNU-associated pneumonitis: portrait of a toxicity. Leukemia & 
lymphoma, 2012. 53(6): p. 1019-20. 
74. Polley, M., et al., Statistical and practical considerations for clinical evaluation of predictive 
biomarkers. J Natl Cancer Inst, 2013. 105(22): p. 1677-1683. 
75. Hu, S., et al., MYC/BCL2 protein coexpression contributes to the inferior survival of activated 
B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression 
signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. 
Blood, 2013. 121(20): p. 4021-4031. 
76. Johnson, N.A., et al., Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell 
Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone. J Clin Oncol, 2012. 30(28): p. 3452-3459. 
77. Green, T.M., et al., Immunohistochemical double-hit score is a strong predictor of outcome in 
patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, 
doxorubicin, vincristine, and prednisone. J Clin Oncol, 2012. 30(28): p. 3460-7. 
78. Savage, K.J., et al., MYC gene rearrangements are associated with a poor prognosis in diffuse 
large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood, 2009. 114(17): p. 
3533-7. 
79. Johnson, N.A., et al., Lymphomas with concurrent BCL2 and MYC translocations: the critical 
factors associated with survival. Blood, 2009. 114(11): p. 2273-9. 
80. Aukema, S.M., et al., Double-hit B-cell lymphomas. Blood, 2011. 117(8): p. 2319-31. 

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APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 

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APPENDIX II 
CYP3A INDUCERS AND INHIBITORS 
Because lists of these agents are constantly changing, please consult and review any drugs for their 
potential to induce CYP3A enzymes. Examples of resources that may be utilized include the product 
information for the individual concomitant drug in question, medical reference texts such as the 
Physicians’ Desk Reference, the FDA website, or your local institution’s pharmacist. Please review 
the current literature for other agents which may have interactions with ibrutinib. For the most 
comprehensive effect of CYP3A inhibitors or inducers on ibrutinib/placebo exposure, please refer to 
the current version of the IB. 
Ibrutinib/placebo is metabolized primarily by CYP3A4. Concomitant use of ibrutinib/placebo with 
drugs that strongly or moderately inhibit CYP3A can increase ibrutinib/placebo exposure. Dose 
adjustment of ibrutinib/placebo due to concomitant use of CYP3A inhibitors should follow the table 
below. 
Dose Modification Guidance for CYP3A Inhibitors/Inducers 
Patient Population 
Co-administered Drug 
Recommended Ibrutinib/Placebo 
Dose for the Duration of the Inhibitor 
Usea 
B-Cell 
Malignancies 
Mild CYP3A inhibitors 
420 mg or 560 mg once daily per 
indication. No dose adjustment required. 
Moderate CYP3A inhibitors 
280 mg once daily. 
Voriconazole  
Posaconazole at doses less than or 
equal to suspension 200 mg BID  
140 mg once daily. 
Other strong CYP3A inhibitors 
Posaconazole at higher dosesb  
Avoid concomitant use and consider 
alternative with less CYP3A inhibitory 
potential. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib. 
If the benefit outweighs the risk, and 
long-term dosing with a CYP3A 
inhibitor is required (more than seven 
days), reduce ibrutinib dose to 140 mg 
once daily for the duration of the 
inhibitor use. 
Chronic Graft 
versus Host 
Disease 
Mild CYP3A inhibitors 
420 mg once daily. No dose adjustment 
required. 
Moderate CYP3A inhibitors  
420 mg once daily. No dose adjustment 
required. 
Voriconazole  
Posaconazole at doses less than or 
equal to suspension 200 mg BID  
280 mg once daily. 

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Posaconazole at higher dosesb 
140 mg once daily. 
Other strong CYP3A inhibitors 
 
Avoid concomitant use and consider 
alternative with less CYP3A inhibitory 
potential. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib/placebo. 
If the benefit outweighs the risk and 
long-term dosing is required (more than 
seven days), reduce ibrutinib dose to 140 
mg once daily for the duration of the 
inhibitor use. 
a  
Monitor for adverse reactions to ibrutinib and interrupt or modify dose as recommended (see Section 8.2). 
b  
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole 
IV injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily).  
After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib/placebo. 
Avoid concomitant use of systemic strong CYP3A inducers (e.g., carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
For further information, please refer to the current version of the IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This 
website is continually revised and should be checked frequently for updates. 
Short courses (≤ 14 days) of steroid treatment for non-cancer related medical reasons (e.g., joint 
inflammation, asthma exacerbation, rash, antiemetic use, engraftment syndrome and infusion 
reactions) at doses that do not exceed 100 mg per day of prednisone or equivalent are permitted. For 
suspected BCNU pneumonitis requiring longer term steroid therapy, ibrutinib/placebo should be held 
until patients are clinically stable and resumed with caution without a dose modification. 
 

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APPENDIX III ALLIANCE A051301 MEDICATION CALENDARS 
PATIENT MEDICATION DIARY (Cycle 1) – Ibrutinib/Placebo 
 
Today’s date: ______________________________ 
Cycle #: 1 
Total Daily Dose: ____________ 
Number of capsules given: ___________ 
Patient Name: ___________________ (initials acceptable) Patient Study ID: _________________ 
(To be completed by RN) 
INSTRUCTIONS TO THE PATIENT: 
1. 
You will take your dose of ibrutinib/placebo once a day on days -6 to -1. 
2. 
Record the date, the number of capsules you took, and when you took them. Record doses as soon 
as you take them; do not batch entries together at a later time. 
3. 
If you have any comments or notice any side effects, please record them in the Comments column. 
If you make a mistake while you write, please cross it out with one line, put your initials next to it, 
and then write the corrected information next to your initials.  Example: 10:30 am SB 9:30 am 
4.    Ibrutinib/placebo should be taken at the same time each day. If you miss a dose of 
ibrutinib/placebo, you should take it as soon as possible, as long as it is on the same day. You 
should not take two doses of ibrutinib/placebo on the same day to make up for missed doses. 
5. 
Please return this form to your physician when you go for your next appointment. 
DAY 
DATE 
TIME 
# of capsules taken 
Comments 
Example 
03/09/2015 
9:00 
AM 
4 capsules 
 
-6 
 
 
 
 
 
-5 
 
 
 
 
 
-4 
 
 
 
 
 
-3 
 
 
 
 
 
-2 
 
 
 
 
 
-1 
 
 
 
 
 
 
Physician’s Office will complete this section: 
Date patient started protocol treatment: _____________________ 
 
Date patient was removed from study: ______________________ 
 
Total number of capsules administered to the patient this cycle: __________________ 
 
Total number of capsules returned by the patient this cycle: ________________ 
 
Patient signature: ______________________________________ 
Date: ____________________ 
 
 
Physician/RN signature: _________________________________ 
Date: ____________________ 

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PATIENT MEDICATION DIARY (Cycles 2-13) – Ibrutinib/Placebo 
 
Today’s date: ______________________________ 
Cycle #: 
 
Total Daily Dose: ____________ 
Number of capsules given: ___________ 
Patient Name: ___________________ (initials acceptable) Patient Study ID: _________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each 4 week-period while you take ibrutinib/placebo. 
2. 
You will take your dose of ibrutinib/placebo once a day on days 1-28.  
3. 
Record the date, the number of capsules you took, and when you took them. Record doses as soon 
as you take them; do not batch entries together at a later time. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
If you make a mistake while you write, please cross it out with one line, put your initials next to it, 
and then write the corrected information next to your initials.  Example: 10:30 am SB 9:30 am 
5.    Ibrutinib/placebo should be taken at the same time each day. If you miss a dose of 
ibrutinib/placebo, you should take it as soon as possible, as long as it is on the same day. You 
should not take two doses of ibrutinib/placebo on the same day to make up for missed doses. 
6. 
Please return this form to your physician when you go for your next appointment. 
DAY 
DATE 
TIME 
# of capsules taken 
Comments 
Example 
03/09/2015 
9:00 
AM 
4 capsules 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 

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22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
Physician’s Office will complete this section: 
 
Date patient started protocol treatment: _____________________ 
 
Date patient was removed from study: ______________________ 
 
Total number of capsules administered to the patient this cycle: __________________ 
 
Total number of capsules returned by the patient this cycle: ________________ 
 
 
Patient signature: ______________________________________ 
Date: ____________________ 
 
 
Physician/RN signature: _________________________________ 
Date: ____________________ 
 

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APPENDIX IV COLLABORATIVE AGREEMENT PROVISIONS 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(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: 
1. 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 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 patient or patient’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. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject 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 NCI, 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 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 Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available 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. 
4. 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. 
5. 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. 
6. 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 

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