Minimal Residual Disease Eradication With Ibrutinib Therapy (MERIT) in Patients With Chronic Lymphocytic Leukemia After Frontline Therapy
Phase: PHASE2
Conditions: Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia
Sponsor: Mayo Clinic

 
 
 
 
 
MC1481 / 15-004991 
 
 
Minimal Residual Disease Eradication With Ibrutinib Therapy 
(MERIT) in Patients With Chronic Lymphocytic Leukemia After 
Frontline Therapy 
 
 
NCT02649387 
 
 
Document Date: 01/17/2025 

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Protocol Version: 17Jan2025 
Mayo Clinic Cancer Center 
 
Minimal Residual Disease Eradication with Ibrutinib Therapy (MERIT) in Patients 
with Chronic Lymphocytic Leukemia After Frontline Therapy  
 
 
 
Study Chairs: 
Asher Alban A. Chanan-Khan, MD  
Mayo Clinic in Florida 
4500 San Pablo Road 
Jacksonville, FL 32224 
904-953-2607 
904-953-2315(FAX) 
 
 
Study Co-chairs: 
Taimur Sher 
 
 
Sikander Ailawadhi 
 
 
Vivek Roy 
 
 
Aneel Paulus * 
 
 
Yan Asmann * 
 
 
Statistician: 
Betsy LaPlant * 
 
 
  
 
 
Drug Availability 
Drug Company Supplied:  Ibrutinib 
 
*Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Activation 
 February 8, 2016 
Addendum 1 
June 28, 2016 
Addendum 2 
Addendum 3 
Addendum 4 
Addendum 5 
Addendum 6 
Addendum 7 
August 15, 2016 
June 26, 2018 
September 20, 2018 
November 15, 2018 
September 9, 2019 
April 7, 2025 
 
 
 
  
 
 
 
 
 
 
 

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Table of Contents 
Minimal Residual Disease Eradication with Ibrutinib Therapy (MERIT) in Patients with Chronic Lymphocytic 
Leukemia After Frontline Therapy ................................................................................................................................ 1 
Table of Contents........................................................................................................................................................... 2 
Schema .......................................................................................................................................................................... 3 
1.0 
Background and Scientific Rationale ........................................................................................................... 4 
2.0 
Goals .......................................................................................................................................................... 11 
3.0 
Patient Eligibility ....................................................................................................................................... 12 
4.0 
Test Schedule ............................................................................................................................................. 15 
5.0 
Grouping Factor: None. ............................................................................................................................. 19 
6.0 
Registration Procedures ............................................................................................................................. 19 
7.0 
Protocol Treatment ..................................................................................................................................... 21 
8.0 
Dosage Modification Based on Adverse Events ........................................................................................ 21 
9.0 
Ancillary Treatment/Supportive Care ........................................................................................................ 26 
10.0 
Adverse Event (AE) Reporting and Monitoring ........................................................................................ 29 
11.0 
Treatment Evaluation ................................................................................................................................. 39 
12.0 
Descriptive Factors..................................................................................................................................... 42 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................................................... 42 
14.0 
Body Fluid Biospecimens .......................................................................................................................... 44 
15.0 
Drug Information ....................................................................................................................................... 49 
16.0  
Statistical Considerations and Methodology .............................................................................................. 53 
17.0  
Pathology Considerations/Tissue Biospecimens: ....................................................................................... 59 
18.0 
Records and Data Collection Procedures ................................................................................................... 61 
19.0  
Budget ........................................................................................................................................................ 63 
20.0 
References .................................................................................................................................................. 64 
Appendix I – Eastern Cooperative Oncology Group (ECOG) Performance Scale ..................................................... 68 
Appendix II – Rai Staging System for CLL ................................................................................................................ 69 
Appendix III – Criteria for Diagnosis of Disease ........................................................................................................ 70 
Appendix IV – Definition of Symptomatic B-Cell ...................................................................................................... 71 
Appendix V – Grading Scale for Hematologic Toxicity in CLL Studies .................................................................... 72 
Appendix VI – Medication Diary ................................................................................................................................ 73 
Appendix VII – Child-Pugh Score............................................................................................................................... 74 
Appendix VIII – Patient Health Questionaire 8 ........................................................................................................... 75 
Appendix IX – Generalized Anxiety Disorder 7-item (GAD-7) scale......................................................................... 76 
Appendix X – Medical Outcomes Study: Social Support Survey (MOS-SSS) ........................................................... 77 
Appendix XI – Linear Analogue Self-Assessment ...................................................................................................... 78 
Appendix XII – Clinical Response Criteria ................................................................................................................. 79 
 
 

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Protocol Version: 17Jan2025 
 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cycle length = 28 days   Last cycle may be up to 56 days to accommodate the Study Drug 
Discontinuation visit. 
2. Q 3 months x 2 years 
 
Generic name: Ibrutinib 
Brand name(s): 
Mayo Abbreviation: PCI-32765   
Availability:  Provided by Pharmacyclics  
Registration 
Treatment1 
Cycles 1-36: 
Ibrutinib days 1-28 
Observation2 
 
Event Monitoring 
 
PD at any time 
Unacceptable adverse  
 
Event 
    events   
 
 
Monitoring 
Patient refusal  
 
 

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1.0 
Background and Scientific Rationale  
 
1.1 
Overview on CLL: CLL is a lymphoproliferative malignant disorder that remains 
incurable in the majority of the patients when using standard therapeutic approaches.  It is 
manifested by the progressive accumulation of functionally-incompetent, mature-looking 
lymphocytes in the blood, bone marrow and lymphoid tissues.  It is a heterogeneous 
disease with a variable clinical spectrum ranging from an indolent variety (Rai Stage 0), 
where the patients enjoy a long-term survival of over 12 years, vs. advance-stage disease 
(Stage III/IV), where the median survival is about 2.5 years.1  Treatment options have 
included alkylating agents (Chlorambucil, Cyclophosphamide) or purine analogues 
(fludarabine, pentostatin) and/or monoclonal antibodies (rituximab, alemtuzumab, 
ofatumumab).  These agents are often used in combination regimens with variable 
responses. Treatment of this disease remains palliative as the clinical course is punctuated 
with frequent relapses and the eventual death of the patient from progressive disease.  
New agents and novel therapeutic strategies are thus needed for the treatment of CLL2  to 
cure the disease, induce a prolonged remission, or maintain remission.  In reviewing the 
natural history of this disease, it is clear that these aims are unlikely until complete 
remission can be achieved in higher proportions of this patient population.  Most 
recently, it has been further reported that eradication of minimal residual disease or 
MRD, which can be detected by flow cytometry or by polymerase chain reaction (PCR) 
is associated with more prolonged disease control and is an important end point that 
determines longer disease free interval.3-5  
   
1.2 
Treatment: Due to the incurable nature of the disease and limited therapeutic options, 
treatment of CLL is often only instituted when patients develop symptomatic or 
persistently progressive disease. The criteria for treatment interventions are outlined in 
the IWCLL/Hallek, December 2008 formulation (see Appendix IV).6  
 
(A) Chemotherapy in CLL:  Traditionally, the initial treatment for CLL patients that 
require therapy7 included either (a) a single agent alkylating agent (chlorambucil) or a (b) 
purine analogue (fludarabine or pentostatin). Compared to chlorambucil, higher overall 
response rate (ORR) and complete remission (CR) rate were observed with fludarabine, 
but there was no superiority in overall survival (OS) or progression-free survival (PFS) 
noted in randomized studies.8,9 Kanti Rai reported on the CALGB randomized 
Chlorambucil vs. Fludarabine vs. the combination of Fludarabine and Chlorambucil.8 
Among the 170 patients treated with fludarabine, 20% achieved a CR, while 43% 
achieved a partial remission (PR).  The median duration of remission and the median PFS 
in this group were 25 and 20 months, respectively.  Despite improvement in the ORR, no 
survival benefit was reported. Thus, up until very recently, the standard of care for this 
disease remained the use of single agent oral chlorambucil or fludarabine with a CR rate 
of 4% and 20%, respectively.  
 
Combining these agents with steroids and/or other chemotherapy agents (such as 
vincristine or an anthracycline) also did not result in improvement in survival.10-12 
Importantly, even early disease stage patients treated with these agents did not alter the 
overall clinical outcome.  Despite evaluation of various combination regimens, purine 
analogues remained the most active agents in patients with CLL, yielding higher overall 
and complete response rates.8,13,14  Eventually all patients with CLL will relapse.  
Although retreatment with fludarabine can result again in response, especially in those 
with an initial clinical response lasting for more than 1 year, continued treatment with 

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fludarabine is difficult due to cumulative marrow toxicity resulting in prolong cytopenia 
and inability to further treat the patient.  Patients who do not achieve durable remission 
after first fludarabine therapy have only a modest response with a second round of 
fludarabine.15  For these patients, the combination of this drug with alkylating agents 
(cyclophosphamide) has been used with improved outcome.13,16,17 Various investigators 
reported combination of fludarabine with cyclophosphamide as salvage regimen in 
patients with CLL.17,18  
 
(B) Monoclonal antibodies and chemoimmunotherapy  
The development of monoclonal antibodies heralded a new era and modified the 
therapeutic approach to treatment of CLL.   
 
Rituximab is a chimeric humanized monoclonal antibody that showed an ORR of 
approximately 50-60% in patients with relapsed and refractory low-grade non-Hodgkin's 
lymphoma.19-21 Because CLL is a B-cell lymphoproliferative disease with expression of 
CD20, rituximab was investigated for the treatment of CLL.  Interestingly, despite 
expression of CD20 on the CLL cells, single agent rituximab (on standard dosing 
schedule) failed to demonstrate any meaningful clinical response. However, more 
frequent dosing e.g., three times weekly for 4 weeks (at 375 mg/m2 per dose) showed  a 
better response rate 45% (3% CR, 42% PR) with a median duration of response of 10 
months .22  Higher doses may have more anti-tumor efficacy but are cost prohibitive, and 
the true long-term benefit remains undetermined.23 
 
While results of single agent rituximab in CLL were disappointing, the results of the 
combination with fludarabine (chemoimmunotherapy) were impressive.24,25 Clinical 
experience of combination of rituximab with fludarabine or fludarabine and 
cyclophosphamide demonstrated higher CR rates.17,22,23,26-30  ORR of fludarabine + 
rituximab combination are in the range of 90% with 47% CR.27,31  In another clinical 
investigation the FC (Fludarabine/Cyclophosphamide) regimen was also combined with 
rituximab.  Phase III randomized clinical trial of FC vs. FCR confirmed superiority of the 
chemoimmunotherapy approach in survival outcomes for patients.32 This strategy of 
chemoimmunotherapy, although yielding higher response rates, is often associated with 
significant toxicity and morbidity to the patients.  Thus these regimens are often preferred 
for younger patients with good performance statuses.  Despite the higher response rates 
and increase rates of reported CR, all patients eventually relapse and die of progressive 
disease or its complications.  Nevertheless, the chemoimmunotherapy approach is now 
the most commonly used front-line treatment approach in CLL.   
 
Obinutuzumab: is a novel CD20 targeting monoclonal antibody that recently received 
approval for the treatment of elderly patients with CLL.  Prior studies of rituximab in 
combination with chlorambucil showed higher ORR and CR rates, and this led to the 
clinical trial comparing Obinutuzumab/chlorambucil vs. rituximab/chlorambucil vs. 
chlorambucil alone.  This study demonstrated a higher ORR in favor of 
chemoimmunotherapy; 77% vs. 65% vs. 31%, respectively.  PFS was also significantly 
improved with Obinutuzumab/chlorambucil combination vs. the other arms.33  
 
Despite these high ORR and CR rates noted with the chemoimmunotherapy approach, all 
patients eventually relapse and develop resistance to therapy. Up until very recently, the 
only approved treatments for these patients were alemtuzumab (monoclonal antibody 
targeting CD52) and ofatumumab (monoclonal antibody targeting CD20). 
 

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Alemtuzumab:  is a humanized monoclonal antibody that targets CD52 and has 
demonstrated a clinical response in over 30% of CLL patients with relapsed or refractory 
disease. Notably, the CR rate remains low (<5%).  An important and limiting adverse 
event of alemtuzumab has been severe immunodeficiency resulting from depletion of 
both T and NK cells along with B cells. This often results in infectious complications and 
has limited its use in the community.34,35  
 
Ofatumumab:  Ofatumumab is another monoclonal antibody that targets CD20, and it is 
one of the three currently available. It has demonstrated efficacy and is approved in 
patients with relapsed or refractory CLL; however, similar to the experience with other 
CD20 monoclonal antibodies, by itself the drug has very low CR rates.36  Currently 
ofatumumab is approved for the treatment of CLL patients who are refractory to 
fludarabine and alemtuzumab.37  
 
(C) Tyrosine kinase inhibitors:  
Ibrutinib (also referred to as PCI-32765 or JNJ54179060) is a first-in-class, potent, orally 
administered covalent inhibitor of Brutons tyrosine kinase (BTK). BTK is a mediator of 
critical B-cell signaling pathways implicated in the pathogenesis of B-cell cancers.  In 
vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in 
the BTK active site, leading to potent inhibition of BTK enzymatic activity.  In cellular 
signal transduction assays with a B-cell lymphoma cell line, ibrutinib inhibited auto-
phosphorylation of BTK, phosphorylation of BTK's physiological substrate, 
phospholipase-Cγ (PLCγ).  It also inhibited the phosphorylation of a further downstream 
kinase, extracellular-regulated kinase (ERK).  Ibrutinib inhibited the proliferation of cell 
lines derived from diffuse large B-cell lymphoma (DLBCL) patients with a median 
effective concentration, EC50, of 1 or 2 nM.  In primary chronic lymphocytic leukemia 
(CLL) cells, ibrutinib reduced proliferation at concentrations of 500 and 1000 nM.  
Preclinical studies have also shown that ibrutinib inhibits numerous processes, e.g., 
NFκB deoxyribonucleic acid (DNA) binding, CpG-mediated CLL cell proliferation, and 
tumor cell migration and adhesions.  At concentrations relevant to exposure levels in 
patients, ibrutinib has remarkable selectivity for inhibition of B-cell receptor (BCR) 
signaling over T-cell receptor (TCR) signaling.38-41 
 
Clinical efficacy:  The clinical benefit of ibrutinib was first shown in the initial clinical 
study PCYC-04753, which was a Phase 1, multicenter, open-label, dose-escalation study 
of ibrutinib in subjects with recurrent B-cell lymphoma, including chronic lymphocytic 
leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), 
DLBCL, and follicular lymphoma (FL), or Waldenströms macroglobulinemia (WM).  It 
was initiated in February 2009.  Thirty-three of the 66 subjects enrolled responded to 
treatment with ibrutinib monotherapy, including 10 CR.  Responses were observed at 
each dose level and across all included histologic types, with highest response rate 
observed in subjects with MCL and CLL/SLL (85.7% each).  The maximum tolerated 
dose (MTD) of ibrutinib was not reached using intermittent dosing cohorts up to 12.5 
mg/kg/day and continuous dosing cohorts at 560 mg.  However, it was noticed that 
subjects treated on the lowest dosing cohort of 1.25 mg/kg/day, which did not reach full 
BTK occupancy, reported the lowest overall response rate (25.0%) compared with all 
other tested dose levels.42  
 
The favorable overall safety profile of ibrutinib and the high incidence of objective 
responses observed in these subjects with advanced and heavily pretreated B-cell 
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survival in B-cell malignancies and was further demonstrated in subsequent Phase 2 
studies in relapsed or refractory MCL and relapsed or refractory CLL/SLL.   
(a) In Study PCYC-1104-CA, 111 subjects with relapsed and/or refractory MCL were 
treated with 560 mg daily continuously until disease progression or until the subject 
could no longer tolerate the treatment.  The overall response rate was 68%, and complete 
response (CR) rate was 21%.  The median duration of response (DOR) was 17.5 months, 
and the median progression-free survival (PFS) was 13.9 months.  Based on these data, 
560 mg daily dosing was chosen for further development in MCL, FL, and DLBCL.43   
 
In Study PCYC-1102-CA, subjects with relapsed or refractory or treatment-naïve 
CLL/SLL were treated with 420 mg or 840 mg daily continuously until disease 
progression or until the subject could no longer tolerate the treatment.  A total of 85 
patients (mostly with high risk CLL) were included in this study (51 received 420mg and 
34 received 840mg dose). Ibrutinib produced an overall response rate of 71 % in both the 
groups. Objective responses appeared independent of poor-risk factors, including adverse 
cytogenetic characteristics.  The median overall survival was 83% and at 26 month the 
progression-free survival was recorded as 75%.  The 840 mg dose level did not appear to 
improve efficacy.  Therefore, 420 mg daily dose was chosen as the recommended dose 
for further development in CLL/SLL.44  The subsequent section will provide more detail 
on some of the important safety aspects of ibrutinib. 
 
Safety:  Over 736 subjects have been treated with either single agent use of ibrutinib (506 
subjects plus 100 healthy volunteers) or in combination with immunotherapy and/or 
chemotherapy (130 subjects) in nonrandomized studies.  In addition, approximately 537 
subjects have been treated with either ibrutinib or placebo in five randomized (controlled 
and open-label) studies.  In the absence of an established MTD, responses have been 
observed in all histologic subtypes treated to date.  Ibrutinib has been well tolerated 
across various dose levels.  The most commonly reported treatment-emergent adverse 
events (AEs) in studies where ibrutinib was administered as monotherapy (n=506) were 
diarrhea (42.1%), fatigue (33.8%), and nausea (26.1%).  The majority of the adverse 
events were of Grade 1 or 2 in severity.  The most commonly reported adverse events 
considered related to ibrutinib were diarrhea (30.2%), fatigue (17.8%), nausea (15.0%), 
and thrombocytopenia (9.9%).  The majority of these adverse events were of Grade 1 or 2 
in severity.  Adverse events of Grade 3 or higher in severity were not common and were 
primarily hematologic in nature including neutropenia (9.7%), thrombocytopenia (6.5%), 
and anemia (4.9%).  Grade 3 or higher pneumonia occurred in 7.7% of subjects.  Serious 
adverse events (SAEs) in the monotherapy studies were commensurate with patient 
population, the disease state or its complications, the most common being pneumonia 
(7.9%) and atrial fibrillation (3.2%).  Adverse events of ibrutinib on cardiac, hepatic, or 
renal function have not been apparent. 
 
Treatment related Lymphocytosis:   
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of ibrutinib, in which the inhibition of BTK-mediated cellular 
homing and adhesion results in a mobilization of tumor cells to the peripheral blood 
(Stevenson 2011). 
 
A reversible increase in lymphocyte counts (ie, ≥50% increase from baseline and above 
absolute count 5000/mcL), often associated with reduction of lymphadenopathy, has been 
observed in most subjects (approximately 69% to 75%) with CLL/SLL treated with 
single agent ibrutinib. This effect has also been observed in some subjects (33%) with 

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MCL treated with single agent ibrutinib. This observed lymphocytosis is a 
pharmacodynamic effect and should not be considered progressive disease in the absence 
of other clinical findings. In both disease types, lymphocytosis typically occurs during the 
first few weeks of ibrutinib therapy (median time 1.1 weeks) and typically resolves 
within a median of 8.0 weeks in subjects with MCL and 18.7 weeks in subjects with 
CLL/SLL.  
 
Lymphocytosis appeared to occur in lower incidence and at lesser magnitude in subjects 
with CLL/SLL receiving ibrutinib in combination with chemoimmunotherapy (ie, 27% of 
subjects receiving ibrutinib + BR in Study 1108) or immunotherapy (ie, 55% of subjects 
receiving ibrutinib + ofatumumab in Group 2 of Study 1109).  
 
A substantial increase in the number of circulating lymphocytes (e.g., >400,000/µL) 
has been observed in a subset of subjects. There have been isolated cases of 
leukostasis reported in subjects treated with ibrutinib. Bleeding-related events: 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both 
with and without thrombocytopenia.  These include primarily minor hemorrhagic events 
such as contusion, epistaxis, and petechiae; and some major hemorrhagic events 
including gastrointestinal bleeding, intracranial hemorrhage and hematuria.  
 
Rash: Rash has been commonly reported in subjects treated with either single agent 
ibrutinib or in combination with chemotherapy.  In a randomized Phase 3 study (PCYC-
1112-CA), rash occurred at a higher rate in the ibrutinib arm than in the control arm. 
Most rashes were mild to moderate in severity. One case of Stevens-Johnson Syndrome 
(SJS), with a fatal outcome, was reported in a subject with CLL. The subject received 
ibrutinib (420 mg/day) and was also receiving various antibiotics and antigout medication 
(allopurinol) known to be associated with SJS.  
 
Cardiac: 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. In particular subjects with a history of cardiac 
arrhythmias should be monitored closely. 
 
Other Malignancies:  Other malignancies, most frequently skin cancers, have occurred 
in subjects treated with ibrutinib. Across the MCL (PCYC-1104-CA) and CLL/SLL 
studies (PCYC-1112-CA and PCYC-1102-CA)), skin cancers and non-skin cancers were 
reported in 5.0% (18/357) and 2.5% (9/357) of subjects who received ibrutinib, 
respectively. 
 
Infection: Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 
25% of subjects with MCL and 35% of subjects with CLL had Grade 3 or greater 
infections per NCI Common Terminology Criteria for Adverse Events (CTCAE). The 
most commonly reported infections include pneumonia, cellulitis, urinary tract infection 
and sepsis. Isolated cases of JC virus reactivation resulting in progressive multifocal 
leukoencephalopathy (PML) have been observed and resulted in death. Two cases in 
relapsed CLL subjects have been reported. One case occurred after multiple prior 
rituximab regimens and less than one year after the last dose of rituximab and high dose 
steroid administration. The second case occurred during concomitant administration of 
rituximab, bendamustine and ibrutinib. 
 

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Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, 
thrombocytopenia, and anemia) were reported in subjects treated with ibrutinib. 
 
Diarrhea: Approximately one-third of subjects treated with ibrutinib monotherapy and 
two-thirds treated with combination therapy reported diarrhea. Other frequently reported 
gastrointestinal events include nausea, vomiting, and constipation. These events are 
rarely severe, with only a small number of Grade 3 events, and no Grade 4 events 
reported to date.  
 
Summary:   
Pooled safety data for subjects treated with ibrutinib monotherapy in 11 nonrandomized 
studies (PCYC-1102-CA, PCYC-1117-CA, PCYC-1112-CA [crossover only], PCYC-
1104-CA, PCI-32765MCL2001, PCI-32765MCL4001, PCYC-1106-CA, PCYC-1111-
CA, PCI-32765FLR2002, PCYC-04753, and PCI-32765-JPN-101) has been evaluated 
(ibrutinib Investigator's Brochure [IB], version 8.0, dated 24 June 2014).    
The most frequently reported treatment-emergent adverse events in more than 10% of 
subjects receiving ibrutinib as monotherapy in nonrandomized studies (N=1061) were 
diarrhea (35.9%), fatigue (28.6%), nausea (20.2%), cough (17.5%), and anemia (15.2%). 
The most commonly reported Grade 3 or 4 adverse events that were hematologic in 
nature were neutropenia (10.7%), thrombocytopenia (6.2%), and anemia (5.5%). 
Pneumonia (5.7%), fatigue (2.9%), hypertension (2.7%), and atrial fibrillation (2.6%) 
were the most frequently reported nonhematologic Grade 3 or 4 adverse events.  
The incidence of treatment-emergent SAEs reported was 41.3% (N=1061);  pneumonia 
(7.0%), atrial fibrillation (2.8%), and febrile neutropenia (2.3%) were the most commonly 
reported treatment-emergent SAEs .  
 
In a randomized Phase 3 study in subjects with CLL/SLL (PCYC-1112-CA), the most 
frequently reported treatment-emergent adverse events in the ibrutinib arm were diarrhea 
(47.7%), fatigue (27.7%), nausea (26.2%), pyrexia (23.6%), anemia (22.6%), and 
neutropenia (21.5%). Adverse events reported at a higher incidence (> 10% difference) in 
the ibrutinib arm than in the ofatumumab arm included diarrhea (ibrutinib: 47.7%, 
ofatumumab: 17.8%), arthralgia (17.4%, 6.8%), and petechiae (13.8%, 1.0%).  
The most commonly reported Grade 3 or 4 adverse events in more than 2% of ibrutinib 
treated subjects that were hematologic in nature were neutropenia (16.4%), 
thrombocytopenia (5.6%), and anemia (4.6%). Pneumonia (6.7%) was the most 
frequently reported nonhematologic Grade 3 or 4 adverse event. The most frequently 
reported SAEs in ibrutinib subjects were pneumonia (8.7%), atrial fibrillation (3.1%), 
pyrexia (3.1%), lung infection (2.6%), lower respiratory tract infection (2.1%) and 
urinary tract infection (2.1%).  
For more detailed information refer to the current version of the IB. 
 
Long-term use and safety:  Analysis of adverse events over a 3-year follow-up period is 
now available (see Investigator Brochure for details, Item 5.3.1.4; IB-
v8_24June2014_v1.2) and shows that most AEs of clinical interest, including 
hematological and non-hematological AEs, either decreased or stayed the same overtime.  

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1.3 
Rationale for the study 
 
MRD:  Over 25 clinical trial evaluations have been completed and established the 
importance of minimal residual disease (MRD).  Analyses of these clinical studies have 
demonstrated a significant PFS benefit among patients who have achieved MRD-negative 
(MRD-) state.  Patients who are in CR and are MRD- tend to have up to 2 years advantage 
in PFS vs. those who are in CR and maintain residual detectable disease.  Data from Dr. 
Peter Hillmen (Leeds, UK)47,48 shows that (a) level of MRD (<0.01% vs. 0.01-1% vs. 
>1%) in marrow is predictive of overall survival outcome in CLL patients, (b) patients 
who achieve MRD- state after first-line therapy have a better PFS and OS than those who 
achieve MRD- after >1 with prior therapies and (c) patients who achieve an MRD- state 
after initial induction therapy have a better PFS and OS than those who remain MRD+.49  
In a multivariate analysis Kwok et al reported that MRD response of <0.01% was the 
most significant independent predictor of clinical outcome (PFS and OS) along with prior 
therapies.  Collectively, these data suggest that attainment of MRD- disease after 
first-line therapy may have an important impact on the clinical outcome of patients 
with CLL.  Thus strategies that can be employed to achieve this goal are highly desirable 
but remain undefined.  The Hillmen data is a retrospective analysis and provided 
additional important insight that the type of prior therapy may not be significant as long 
as patients achieve MRD- post induction therapy. In a clinical study of alemtuzumab 
consolidation Hillmen et al showed that 83% of the patients can be converted to MRD- 
state (NCRI CLL207 study), and this resulted in significant improvement in PFS and 
OS.50 They further reported that MRD+ patients after FCR induction when converted to 
MRD- post-consolidation with alemtuzumab benefited from improvement in PFS, 
validating the critical importance of eradicating MRD post induction therapy.50  Similar 
observations were made by the CLL group at MD Anderson.47  These results have 
prompted investigation of MRD in 2 phase III clinical trials; in UK NCRI-CLL8 study 
MRD eradication is attempted in previously treated CLL patients (1-3 prior therapies) 
with obinutuzumab (GA-101) given for a finite period of 3-6 months.  In the UK NCRI-
CLL10 study FCR will be evaluated against IR (ibrutinib/rituximab) and MRD will be 
used to determine the duration of therapy.  While these clinical trials will answer the 
important question on the eradication of MRD using either a consolidation strategy (with 
GA-101) or upfront induction treatment with a defined regimen, it remains to be 
determined what is the most optimal agent that can be universally employed for MRD 
eradication independent of the frontline induction regimen utilized. Furthermore, can 
a primary maintenance (instead of consolidation) strategy be used to achieve MRD- after 
frontline therapy has failed to achieve this?  
 
In this clinical trial we will prospectively evaluate these questions.  The design of this 
clinical trial allows enrollment of all patients who have completed their initial induction 
regimen independent of the type of regimen (therapy) given to them as long as they are 
MRD+. Thus this study will be able to determine prospectively if attainment of MRD- 
post-induction can potentially be possible with the novel agent ibrutinib given in a 
primary maintenance setting.  Thus this study is unique in the following manner (a) it 
will evaluate the role of single agent ibrutinib in eradication of MRD (b) it will evaluate 
whether the attainment of MRD negativity is possible with ibrutinib and is it independent 
of the frontline therapy given (c) the role and benefit of continuous therapy independent 
of attainment of MRD negativity and the impact of this in durability of MRD- status.  
 
 

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2.0 
Goals    
 
2.1 
Primary 
 
2.11 
Determine the rate of MRD-negative responses (in both blood and bone marrow) 
at any time during treatment with ibrutinib maintenance. 
  
2.2 
Secondary 
 
2.21 
Median time to achieve MRD- (negative) status (in blood and in bone marrow) 
after initiation of ibrutinib maintenance treatment. 
 
 
2.22 
Toxicity profile of ibrutinib as maintenance therapy after frontline induction.   
 
 
2.23 
Durability of the MRD- state (determined from the time of first documentation of 
MRD-  until the first documentation of MRD+(or last date shown to be MRD- for 
a censor).  
 
2.24 
Time to requirement of next therapy for patients who achieve confirmed MRD- 
vs. those who remain MRD+ disease at 48 weeks (end of 12 cycles). 
 
2.25 
Progression free survival (as determined by the IWCLL criteria) among patients 
who achieve confirmed MRD vs. those who remain MRD+ disease at 48 weeks 
(end of 12 cycles). 
 
 
2.3 
Correlative Research 
 
2.31 
To conduct correlative studies for further understanding of the mechanism of 
antitumor activity of ibrutinib in eradication of the MRD. 
 
2.32 
Determine the impact of ibrutinib on depression and anxiety symptoms to better 
understand toxicity profile of ibrutinib maintenance. 
 
2.33 
Determine impact of social support or lack thereof on mood symptoms in CLL 
patients receiving maintenance treatment. 
 

MC1481 
12 
Addendum 7 
 
Protocol Version: 17Jan2025 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria  
 
3.11 
Understand and voluntarily sign an informed consent form. 
 
3.12 
 Age ≥ 18 years. 
 
 
 
3.13 
Able to adhere to the study visit schedule and other protocol requirements 
including willing to provide blood, baseline bone marrow aspirate, and control 
DNA samples for correlative research purposes (see Sections 6.2, 4.0, 14.0, and 
17.0). 
 
3.14 
Diagnosis of B-CLL, confirmed by flow cytometry and as per the criteria 
outlined by the IWCLL/Hallek December 2008 (Refer to Appendix III).  
 
3.15 
Prior frontline therapy for B-CLL must have been discontinued ≥ 56 days but ≤ 
365 days prior to registration. NOTE: Patients on supportive care therapy due to 
use of specific induction regimen such as antibiotics may continue on those 
treatments at the discretion of the treating physician.  
 
3.16 
Patient must have completed a frontline induction therapy (minimum of 2 
treatment cycles). NOTE: Standard Therapies / therapeutic agents are defined as 
those listed in the NCCN guidelines for treatment of CLL (nccn.org). Also, 
patients who received induction regimen as part of a clinical trial and is not 
necessarily mentioned in the NCCN guidelines, will also be eligible as long as 
the patient has completed at least 2 treatment cycles of induction regimen, 
achieved a clinical response (PR or CR) and is able to meet all other criteria for 
the study. However, patients who have previously received ibrutinib or have been 
randomized to ibrutinib containing arms in a clinical trial will not be eligible for 
this study. 
 
3.17 
Patients must have a sustained clinical response (PR, nPR, CCR, CRi, CR) with 
documented residual disease (≥1 CLL cell per 10,000 leukocytes or ≥ 0.01% 
MRD) either in the blood, bone marrow or a lymph node ≥ 3.5 cm by any 
available techniques. 
  
3.18 
ECOG performance status of 0, 1 or 2 at registration (see Appendix I). 
 
3.19 
The following laboratory values obtained ≤ 14 days prior to registration: 
• 
Absolute neutrophil count ≥ 1000/mm3 
• 
Platelet count ≥ 30,000/mm3 
• 
Serum creatinine ≤ 1.5 x ULN. 
• 
Total bilirubin ≤ 1.5 mg/dL or direct bilirubin ≤ 1.0 mg/dL for patients with 
Gilbert’s syndrome 
• 
SGOT (AST) and SGPT (ALT) ≤ 3.5 x ULN  
 
3.19a 
Negative pregnancy test done ≤ 7 days prior to registration, for women of 
childbearing potential only. 
 

MC1481 
13 
Addendum 7 
 
Protocol Version: 17Jan2025 
3.2 
Exclusion Criteria  
 
 
3.21 
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
 
3.22 
Since this study involves an investigational agent whose genotoxic, mutagenic 
and teratogenic effects on the developing fetus and newborn are unknown, any of 
the following will deem the subject ineligible for the study: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.23 
Any condition, including the presence of laboratory abnormalities, which places 
the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. 
3.24 
Use of any other experimental drug or therapy ≤ 28 days prior to registration on 
this study.  NOTE: Patients on low dose prednisone (≤ 10 mg) for treatment of 
conditions other than CLL are eligible. 
 
3.25 
Patients who have received more than 1 prior therapy.  NOTE: (Prior therapy is 
defined as any single agent or combination regimen that is included as treatment 
for symptomatic CLL. Treatment(s) given prior to the symptomatic phase of the 
disease (preventive strategy) will not be considered as prior induction therapy.  
For the purpose of a particular therapy/regimen to be counted towards the 
number of prior treatments a patient must have received at least 2 cycles of the 
induction regimen e.g., a patient who change their treatment regimen after only 1 
cycle (due to toxicity or any other reason) will not be considered to have "2" 
prior therapies.  
 
3.26 
Patients who have progressive disease or relapse (as defined by the IWCLL 
criteria see Section 11.23) at or any time before registration on this study. 
 
3.27  
 . No other prior malignancy is allowed except for the following: adequately 
treated basal cell or squamous cell skin cancer, in situ cervical cancer or any 
other cancer in situ, adequately treated Stage I or II cancer from which the patient 
is currently in complete remission, or any other cancer from which the patient has 
been disease free for three years. 
 
3.28 
Patients who are already MRD- (both in the blood and the bone marrow) after 
frontline therapy and have lymph nodes <3.5cm.   
 
3.29a 
Concomitant use of warfarin or other Vitamin K antagonists [see Section 9.5(d)]. 
 
3.29b Requires treatment with a strong cytochrome P450 modulators (CYP3A inhibitor 
and/or CYP3A inducers) [see Section 9.5(a)].  NOTE: A comprehensive list of 
inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually 
revised and should be checked frequently for updates. 
 
3.29c 
Currently active, clinically significant hepatic impairment Child-Pugh class B or 
C according to the Child Pugh classification (see Appendix VII) 

MC1481 
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Addendum 7 
 
Protocol Version: 17Jan2025 
 
3.29d Major surgery ≤ 4 weeks prior to registration. 
 
3.29e 
Patients who have active infectious hepatitis. 
 
3.29f 
Patients with other diseases that in the opinion of the treating physician pose a 
higher risk for treatment with ibrutinib therapy including active HIV infection 
and bleeding disorders.  

MC1481 
15 
Addendum 7 
 
Protocol Version: 17Jan2025 
4.0 
Test Schedule 
All visits ± 4 days unless otherwise stated. 
 
Active Monitoring Phase 
 
Days Prior to 
Registration 
Cycle 1 
(Pre) 
Prior to 
subsequent 
Cycles 2-36 
Study Drug 
Discontinuation 
Observation 
Tests & Procedures 
≤28 days 
≤14 
days 
 
 
3-4 weeks from the last 
day of the last cycle 
Every 3 months x 2 
years 
Complete medical history (including prior treatment regimen) 
X 
 
 
 
 
 
Adverse event assessment 
X 
 
 
X 
X 
X 
Physical exam, including weight and vital signs, and PS1 
 
X 
X 
X20 
X 
X 
Clinical Response assessment (Tumor measurement by physical exam)2, 3 
 
X 
 
X 
X 
X 
CT scans (Chest, Abdomen, Pelvis)4 
X 
 
 
 
X 
 
EKG/ECHO5 
X 
 
 
 
 
 
CBC with differential6 
 
X 
X 
X 
X 
X 
Chemistry group (SGOT [AST], SGPT [ALT], serum creatinine, total 
bilirubin, LDH, uric acid, phosphorus, alkaline phosphate, serum 
electrolytes)6 
 
X 
X 
X 
X 
X 
Direct bilirubin15 
 
X 
 
 
 
 
Quantitative Immunoglobulins 
X 
 
 
X7 
X 
 
Quantitative T & B cells, peripheral blood 
 
X 
 
X17 
 
 
Minimal residual disease assesment8 
X 
 
 
X 
X 
X 
Flow Cytometry-CLL Panel9 
X 
 
 
 
 
 
Bone marrow biopsy and/or aspirate10 
X 
 
 
X 
X 
X 
CLL FISH Panel11,  
X 
 
 
 
 
 
Zap 70, CD38, IgHV12 
X 
 
 
 
 
 
Beta 2 microglobulin12 
X 
 
 
 
 
 
Research blood sample collection13, R 
 
X 
 
X 
X 
X 
Research bone marrow aspirate collection14, R 
X 
 
 
X 
X 
X 
Mandatory DNA sample which can be collected from any one of the 3 
sources (buccal swab, skin biopsy or myeloid cells from bone marrow) as 
noted in Section 17.0 
 
X18 
 
 
 
 
Urine Pregnancy test 
 
X16 
 
 
 
 
PHQ-8; GAD; Living Situation; MOS-SSS-4 Question; QOL 
 
X 
 
X19 
 
 

MC1481 
16 
Addendum 7 
 
Protocol Version: 17Jan2025 
1. During the first 2 cycles of treatment, patients will have a focused clinical examination weekly, as necessary, for the monitoring of tumor lysis 
syndrome (TLS).  This can be done in collaboration with local MD/referring physician. 
2. The physical exam should measure the spleen and liver, noting the maximal distance below the respective costal margins and should record the 
bi-dimensional diameter of the largest palpable node in each area of involvement including the following sites:  left neck (sub-mandibular, 
cervical, supra-clavicular), right neck (sub-mandibular, cervical, supra-clavicular), left axillary, right axillary, left groin (inguinal, femoral) and 
right groin (inguinal, femoral). 
3. Clinical response assessment: will be done per IWCLL criteria starting with evaluation of disease state at baseline and for progression of disease 
only every 3 cycles (for 36 cycles) during study treatment and every cycle (every 3 months) during follow-up without therapy. 
4. CT scans should be done as clinically indicated for the management of the patient and in accordance with the IWCLL guidelines. CT scans may 
be done with patient's primary physician (if outside Mayo Clinic), results of these will be entered in the source document.   
5. EKG or ECHO only if clinically indicated.  
6. Hematology (CBC) / Serum Chemistry: During cycle 1 and 2, day 8 and 15 labs will be done at the treating physician discretion based on 
patient's clinical needs and/or can be done based on risk for TLS or for conduct of correlative studies.  Monitoring for TLS is considered 
standard of care. In subsequent cycles CBC/chemistry will be done prior to beginning of each cycle as standard of care and additional testing 
will only be done as clinically indicated to be determined by treating physician.  Laboratory workup may be done with patient's primary 
physician (if outside Mayo Clinic), results of these will be entered in the source document. 
7. Quantitative immunoglobulin will be done at baseline and thereafter can be done every 4 cycles at the discretion of the treating physician and as 
per standard clinical practice. 
8. Minimal residual disease: MRD assessment will be done at baseline, during the treatment phase and then during the observation phase (no 
treatment).  The MRD will be done on peripheral blood and / or bone marrow aspirate using flow cytometry standardized Mayo Clinic panel. In 
general bone marrow aspirate evaluation will only be required when the peripheral blood is recorded at least twice (at two separate evaluation 3 
months apart) to be negative. If blood is positive for MRD assessment, then bone marrow aspirate evaluation for the MRD will not be needed 
and can be deferred.   MRD assessment in the Blood: (a) Baseline: all patients will have MRD assessed in the peripheral blood prior to 
initiating the study. (b) During treatment phase:  all patients will have MRD assessed in the peripheral blood every 3 cycles. If the ibrutinib 
maintenance treatment is held > 21 days for toxicity or for any other reason(s) then the MRD testing will be delayed to accommodate 3 
treatment cycles prior to testing.  (c) During observation period: all patients will have MRD assessed within 4 weeks of completion of the last 
treatment cycles and thereafter every 3 months (if they are MRD negative) and every 6 months (if they are MRD+) for a maximum follow-up of 
2 years or until initiation of subsequent treatment for relapsed disease (whichever happens first).  MRD assessment in the Bone marrow 
aspirate: The schedule of assessment of the bone marrow aspirate for MRD will be different and dependent upon the results of the MRD status 
in the blood. (a) Baseline: If the peripheral blood MRD results are positive then a BM aspirate assessment for MRD will not be needed. If the 
peripheral blood MRD results are negative, then a BM aspirate assessment for MRD will be needed. (b) During the treatment phase:  The 
MRD assessment of the Bone marrow aspirate will only be required once the peripheral blood MRD is recorded to be negative for at least 2 
evaluations that are separated at least 3 months apart. If the blood evaluation demonstrates positivity for MRD, then Bone marrow aspirate 
evaluation will not be required and can be deferred until the peripheral blood is noted to be negative x 2. (c) During the observation period: 
The MRD assessment of the Bone marrow aspirate will only be required if the post treatment peripheral blood assessment (i.e., that done within 
4 weeks of the last treatment dose) was noted to be negative. If the post treatment blood evaluation was noted to be positive, then no bone 

MC1481 
17 
Addendum 7 
 
Protocol Version: 17Jan2025 
marrow aspirate evaluation is required. It is possible, though unlikely, that during observation period the peripheral blood (evaluated every 3 
months) may convert to negative. If this is observed, then a bone marrow aspirate for MRD will be done only if 2 consecutive blood MRD 
assessments are recorded to be negative. Note:  Bone marrow aspirate done solely for MRD will be considered research, however if the 
procedure is done to assess response to therapy (such as to document complete remission as part of clinical care as required by the IWCLL 
guidelines) then it will be considered standard of care.  
• 
See detailed section on the MRD (see Section 11.4).  
9. Flow cytometry-CLL Panel: The objective of this is to confirm diagnosis as per standard of care (pretreatment). Patients who have a flow 
cytometry done at any time prior to starting the clinical trial which validates the diagnosis of B-CLL will not be required to have it repeated.  
10. Bone marrow biopsy/aspirate: At baseline documentation of bone marrow assessment (aspirate and biopsy) will be required to determine the 
extent of marrow involvement and / or confirmation of presence of MRD. This is standard of care as per the IWCLL guidelines to accurately 
assess response to treatment. The BM assessment (aspirate and biopsy) will not be required if (1) a bone marrow assessment (aspirate and 
biopsy) was done post induction treatment and this showed residual disease (or MRD positivity) or (2) if a bone marrow post induction was 
done (with negative disease, or if there was no MRD information) but the peripheral blood at the time of screening show MRD positivity. If no 
bone marrow aspirate/biopsy is done post induction therapy, then a bone marrow aspirate and biopsy will be required prior to starting 
maintenance therapy to assess extent of disease in the marrow and establish appropriate response category post induction (this is consistent with 
the IWCLL guidelines and is standard of care). During the treatment and observation phase, a repeat bone marrow biopsy will only be required 
to establish the response of complete remission as recommended by the IWCLL guidelines and this will be at the discretion of the treating 
physician who will determine the appropriate timing based on clinical response assessment (this is consistent with the IWCLL guidelines and is 
standard of care).  Bone marrow aspirate will be done for assessment of MRD and the timing of this will be followed as noted in detail in foot 
note 8.   
11. FISH (florescent in situ hybridization) in blood or bone marrow (if no CLL cells in the blood): May be performed any time prior to initiation of 
therapy. If already done previously (prior to initial induction therapy), the results will be obtained and recorded, repeat testing will not be 
needed unless clinically indicated and at the discretion of the treating physician. 
12. These tests may be performed any time prior to initiation of therapy. If already done previously (prior to initial induction therapy), the results 
will be obtained and recorded, repeat testing will not be needed unless clinically indicated and at the discretion of the treating physician. 
13.  For blood collected for correlative studies, see Section 14.0.  Samples will be collected at baseline (pre-treatment), prior to cycle 4, prior to 
cycle 7, prior to cycle 13 and at time of relapse. 
14. Bone marrow aspirate (optional) for correlative studies, see Section 14.0.  Samples will be collected only if bone marrow biopsy or aspirate is 
done as part of routine clinical care of the patient (as outlined in footnote 10) or as part of MRD assessment (as noted in footnote 8).  
15. Only for patients with Gilbert’s syndrome and the total bilirubin >1.5 mg/dL. 
16.For women of childbearing potential only.  Must be done ≤ 7 days prior to registration. 
17.Should be performed after 3 cycles, 6 cycles, 12 cycles, and at time of relapse. 
18.  Buccal swab may be collected any time prior to starting treatment.  Skin biopsy is only required if DNA cannot be obtained from the buccal 
swab.  Alternate source could be myeloid cells in the marrow (in cases where bone marrow is obtained). This will be at the discretion of the 
treating physician in consultation with the PI. 

MC1481 
18 
Addendum 7 
 
Protocol Version: 17Jan2025 
19. PHQ-8, GAD-7, Living situation, MOS-SSS-4 Question, and Linear Analogue Self-Assessment: Prior to cycle 4, prior to cycle 7, prior to cycle 13, at 
time of relapse and thereafter every 3 months x4. 
20.  After the first 6 cycles, clinical evaluation and blood tests can be obtained per test schedule and mailed/faxed to Mayo Clinic and patient can 
return at least every 3 cycles for follow up to Mayo.  Patient may be seen more frequently, if clinically necessary. NOTE: All forms, including 
AEs, will need to be filled out every 28 days. 
R.  Research funded. 

MC1481 
19 
Addendum 7 
 
Protocol Version: 20Sep2018 
5.0 
Grouping Factor: None. 
 
6.0 
Registration Procedures 
 
 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at (507) 284-2753 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on the 
MCCC web page (http://hsrwww.mayo.edu/ccs/training) and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully completed 
prior to release of the study agent.  Patient registration via the registration/randomization 
application can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753.  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to "Instructions for Remote Registration" in section "Finding/Displaying 
Information about A Registered Subject." 
 
6.2 
Registration to the Correlative Research 
 
Mandatory: 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.13, 4.0, 14.0 and 17.0). 
 
6.3 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.4 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
507-284-0885).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted, and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 

MC1481 
20 
Addendum 7 
 
Protocol Version: 20Sep2018 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.5 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of CLL at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.6 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist or hematologist. 
 
6.7 
Treatment cannot begin prior to registration and must begin ≤ 14 days after registration. 
 
6.8 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.9 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.9a 
Study drug is available on site. 
 
6.9b 
Patient Questionnaire booklets 
 
Patient questionnaire booklets are available on site. Copies are not acceptable for these 
submissions.  Booklets should be ordered using the Patient Questionnaire Order Form.  
 
 

MC1481 
21 
Addendum 7 
 
Protocol Version: 20Sep2018 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Agent 
Dose 
Route Days Max. No. of cycles 
Ibrutinib 
420 mg QD 
Oral 
1-28 
36 
Cycle length = 28 days 
 
7.11 
Ibrutinib  
• 
420mg PO QD will begin on day one of cycle #1.  
• 
Four weeks will constitute 1 treatment cycle.  
• 
Patients will be evaluated for MRD status every 3 cycles (as discussed 
previously in Section 4.0, footnote 8, see detailed MRD section 11.4).  
• 
A maximum of 36 cycles of maintenance cycles will be given.  
• 
Treatment will be discontinued if (a) patients develop unacceptable side 
effects, (b) if patients develop disease progression while on ibrutinib 
maintenance (recommended to be confirmed on two independent 
occasions at least 2 week apart and consistent with the IWCLL 
guidelines, see Section 11.0),  (c) if patients have completed the 36 
cycles on maintenance therapy, (d) if the patient is removed from the 
study by the treating physician due to concern of overall wellbeing and in 
the best interest of the patient, (e) patients who have residual disease at 
the end of 36 cycles will continue to event monitoring   
 
7.2 
Treatment by Local Medical Doctor (LMD): If patient is tolerating therapy without 
excessive toxicity at a stable dose level after 1 cycle (can be confirmed through 
telecommunication and does not need to be physically evaluated at Mayo Clinic) of 
treatment the patient may be seen by their primary physician (if outside of Mayo Clinic).  
Results would need to be returned to Mayo Clinic.  Patient would need to return to Mayo 
Clinic every 3 cycles for follow-up at Mayo Clinic.  
 
7.3 
After the first 6 months, clinical evaluation and blood tests can be obtained per test 
schedule and mailed/faxed to Mayo Clinic and patient can return at least every 3 cycles 
for follow up to Mayo (patient does not need to be seen every cycle).  Patient may be 
seen more frequently, as clinically necessary. All unused study drug must be returned, 
and all study drug must be accounted for. A 3-month supply of study drug may be 
provided at each cycle. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
Dose Levels (Based on Adverse Events in the Tables below) 
Dose 
Level 
Ibrutinib 
 0* 
420 mg daily 
-1 
280 mg daily 
-2 
140 mg daily 
  * Dose level 0 refers to the starting dose. 

MC1481 
22 
Addendum 7 
 
Protocol Version: 20Sep2018 
 
8.2 
Dose Modification 
 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time 
 
Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 
Discontinue = The specified drug(s) are totally stopped.   
 
 

MC1481 
23 
Addendum 7 
 
Protocol Version: 20Sep2018 
 
Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (section 10.1) 
unless otherwise specified.  
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
AT TIME OF RETREATMENT   
Investigations 
Neutrophil count decreased  
Grade 4 lasting >7 days 
Ibrutinib 
Hold (day 1) or omit (days 2-28) Ibrutinib 
until recovery to Grade ≤1 or baseline; 
may restart at original dose for first 
occurrence.  Each subsequent occurrence 
may restart at next lower dose after 
recovery to Grade ≤1 or baseline.  If AE 
occurs at lowest dose discontinue 
treatment. 
NOTE: 
Baseline cytopenia:  In patients whose 
baseline (i.e., prior to starting protocol 
therapy) ANC is 1000/µL, the above 
Ibrutinib dose modifications, if required, 
would not be applied until Cycle 3. 
Blood and lymphatic 
system disorders 
≥ Grade 3 Febrile 
neutropenia 
Hold (day 1) or omit (days 2-28) Ibrutinib 
until fever resolves and ANC ≥1000/µL, 
then resume Ibrutinib at 
the previous dose. 
Gastrointestinal 
disorders 
≥ Grade 3 Nausea (if 
persistent despite optimal 
antiemetic therapy) 
Hold (day 1) or omit (days 2-28) Ibrutinib 
until recovery to Grade ≤1 or baseline; 
may restart at original dose for first 
occurrence.  Each subsequent occurrence 
may restart at next lower dose after 
recovery to Grade ≤ 1 or baseline.  If AE 
occurs at lowest dose discontinue 
treatment. 
≥ Grade 3 Vomiting (if 
persistent despite optimal 
antiemetic therapy) 
≥ Grade 3 Diarrhea (if 
persistent despite optimal 
anti-diarrheal therapy) 
Other non-
hematologic  
Any other Grade 4 AE or 
any unmanageable Grade 3 
AE 
• 
Dose delay: Ibrutinib may be held for toxicity considerations for a maximum of 28 consecutive 
days. Study medication should be discontinued permanently in the event of a toxicity lasting 
more than 28 days. If Ibrutinib is interrupted for a reason other than toxicity (e.g. unrelated 
illness) it must be restarted within 90 days.  If interrupted for more than 90 days, study 
medication should be discontinued permanently and go to event monitoring.  
• 
Dose re-escalation: Patients who require a dose reduction during a given cycle will remain at that 
dose for at least 2 additional cycles. At the investigator discretion, the dose of ibrutinib may 
be re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the 
toxicity that led to this reduction.  This is particularly reasonable based upon the long-term 
safety data now available in ibrutinib treated patients that show that most of the hematological or 
non-hematological AEs either decreased or remained stable (see investigator brochure section 
5.3).  

MC1481 
24 
Addendum 7 
 
Protocol Version: 20Sep2018 
• 
If multiple adverse events are seen, administer dose based on the greatest reduction required by 
any single adverse event observed.  
• 
Dose modifications are for adverse events attributed to study treatment only.  Dose modifications 
are not required for adverse events if they are deemed unrelated to study treatment.  
• 
Reductions apply to treatment given in the preceding cycle and are based on adverse events 
observed since the prior dose.     
• 
If cough, dyspnea, and other pulmonary symptoms occur, a chest x-ray and high-resolution chest 
CT scan should be obtained. Incentive spirometry studies (to include DLCO) should be 
considered.  Consider Pneumocystis pneumonia or viral pneumonitis.  
 
8.3  
Dose Modification for Hematological Toxicities (Platelet and Hemoglobin only) 
 
Note: hematological toxicity is not based on CTCAE 4.0 except neutrophil but based on 
CLL specific hematological toxicity (this table and Appendix V). 
Dose modification guidelines for drug-related hematological (hemoglobin and 
platelets) adverse events  
 
 

MC1481 
25 
Addendum 7 
 
Protocol Version: 20Sep2018 
 
Toxicity 
Grade 1, 
2 
Decrease from 
pretreatment 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with PI) 
CLL/NHL 
specific 
Hematological 
Toxicity 
(Appendix V) 
 
1 
 
 
 
2 
11-24% 
decrease in 
HGB or PLT 
 
25-49% 
decrease in 
HGB or PLT 
No 
N/A 
N/A 
N/A 
3 
50-74% 
decrease in 
HGB or PLT 
Yes 
Toxicity 
resolves to 
Grade 0-1 
or baseline 
Hold (day 1) or 
omit (days 2-28) 
Ibrutinib until 
recovery to 
Grade ≤1 or 
baseline; may 
restart at original 
dose for first 
occurrence.  
Each subsequent 
occurrence may 
restart at next 
lower dose after 
recovery to 
Grade ≤1 or 
baseline.  If AE 
occurs at lowest 
dose, 
discontinue 
treatment. 
Toxicity does 
not resolve 
within 8 weeks 
of last treatment 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event. 
Go to event 
monitoring if ≥1 
cycle of therapy 
was given, 
otherwise go to 
observation. 
4 
≥75% decrease 
in HGB or PLT  
Yes 
Toxicity 
resolves to 
Grade 0-1 
or baseline 
1  
If, at any level of decrease the platelet count is < 20,000/μL, this will be considered 
grade 4, unless the initial platelet count was ≤ 20,000 μL in which case the patient is 
inevaluable for toxicity referable to platelet counts. 
2 
If, at any level of decrease from the baseline value the platelet and/or hemoglobin 
counts are within normal limits, this will be considered a grade 0. 
 
8.4  
Dose Modification for Hepatic Impaired Subjects 
 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant 
hepatic impairment at the time of screening (Child- Pugh class B or C) are excluded from 
study participation. For subjects who develop mild liver impairment while on study 
(Child-Pugh class A), the recommended dose reduction for ibrutinib is to a level of 280 
mg daily (two capsules). For subjects who develop moderate liver impairment while on 
study (Child-Pugh class B), the recommended dose reduction is to a level of 140 mg daily 
(one capsule). Subjects who develop severe hepatic impairment (Child-Pugh class C) 
must hold study drug until resolved to moderate impairment (Child-Pugh class B) or 
better. Monitor subjects for signs of toxicity and follow dose modification guidance as 
needed (Refer to Appendix VII). 

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Protocol Version: 20Sep2018 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Growth factors 
Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell growth 
factors (erythropoietin) is permitted per institutional policy and in accordance with the 
ASCO guidelines. They should be utilized as clinically warranted and following 
institutional policies and recommendations.  Growth factors can be used during the 
treatment cycle as clinically indicated.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology (42) Update of 
Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-
Based, Clinical Practice Guidelines.51  
 
9.2 
Supportive care 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  (A) Any blood transfusions 
administered must be irradiated blood products to reduce risk of transfusion-
mediated graft versus host disease in CLL patients receiving T-cell suppressive 
therapy.  Leukocyte reduction of all blood products for patients on protocol is also 
required. All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records.  (B) Antiemetics 
may be used at the discretion of the attending physician. (C) Prophylactic antibiotics and 
antifungals may be prescribed at the treating physicians’ discretion and as clinically 
indicated, or as per the institutional guidelines. (D) Treatment for autoimmune cytopenias 
are permitted for <14 days at doses that do not exceed 100 mg per day of prednisone or 
equivalent. (E) Supportive medications in accordance with standard practice (such as for 
emesis, diarrhea, etc.) are permitted. (F) Short courses (≤14 days) of steroid treatment for 
non-cancer related medical reasons (e.g., joint inflammation, asthma exacerbation, rash, 
antiemetic use and infusion reactions) at doses that do not exceed 100mg per day of 
prednisone or equivalent are permitted. 
 
9.3 
Tumor Lysis Syndrome (TLS) prophylaxis and treatment 
Since patient will have received frontline therapy, it is anticipated that they will no longer 
have bulky disease that pose any risk for TLS.  Patients who are still at risk of TLS as 
determined by the treating physician, may receive Allopurinol 300 mg/day (or an 
equivalent standard agent for prevention of hyperuricemia) orally for the first two weeks 
of the first cycle of protocol therapy. Allopurinol may be continued after the first two 
weeks at the investigator's discretion and as clinically indicated. Subjects should be 
observed closely for signs and symptoms of TLS during the initial cycle of therapy. 
Subjects should be encouraged to drink an abundant amount of fluid prior to treatment. 
Subjects should maintain adequate hydration and urine output. 
 
9.4 
Treatment related lymphocytosis 
Lymphocytosis has been reported with ibrutinib, however since this is a patient 
population who are already expected to be in remission post induction therapy it is not 
known if this lymphocytosis will still happen upon treatment with ibrutinib.  Patients who 
develop this reaction will be monitored as per standard clinical protocol without specific 
intervention unless other specific symptoms / signs of disease progression is noted (such 
as increase in lymph node size that is progressive and persist beyond 3 months of 

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Protocol Version: 20Sep2018 
maintenance therapy, worsening of cytopenia from the time of initiation of maintenance 
therapy that is consistent with the IWCLL guidelines requiring therapeutic intervention, 
development of B symptoms persisting for more than 2 months while on therapy or other 
factors such as organomegaly demonstrating disease progression).  
  
9.5 
Medications to be used with caution 
 
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. 
 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) 
must be used, reduce ibrutinib dose to 140 mg or withhold treatment for the 
duration of inhibitor use. Subjects should be monitored for signs of ibrutinib 
toxicity. 
 
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, 
aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, 
fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) 
must be used, reduce ibrutinib to 140 mg (for 840 mg/day dose, reduce to 280 mg) 
for the duration of the inhibitor use. Avoid grapefruit and Seville oranges during 
ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A (see 
Section 5.3.1.2). 
 
No dose adjustment is required in combination with mild inhibitors.  
 
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A 
induction. 
 
A comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually 
revised and should be checked frequently for updates. 
 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib 
exposure, please refer to the current version of the IB. 
 
(b) Drugs that may have their plasma concentrations altered by ibrutinib:  In vitro 
studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic 
drug-drug interactions with P-gp substrates.  However, it cannot be excluded that 
ibrutinib could inhibit intestinal P-gp after a therapeutic dose. There is no clinical data 
available; therefore, co-administration of narrow therapeutic index P-gp substrates 
(e.g., digoxin) with ibrutinib may increase their blood concentration and should be 
used with caution and monitored closely for toxicity. 
 
(c) QT prolonging agents:  Any medications known to cause QT prolongation should be 
used with caution; periodic ECG and electrolyte monitoring should be considered.  
 
(d) Antiplatelet agents and anticoagulants:  Warfarin or vitamin K antagonists should 
not be administered concomitantly with ibrutinib.  Supplements such as fish oil and 
vitamin E preparations should be avoided.  Use ibrutinib with caution in subjects 
requiring other anticoagulants or medications that inhibit platelet function.   
 
 

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Protocol Version: 20Sep2018 
 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic 
anticoagulation is clinically indicated, treatment with ibrutinib should be held and not be 
restarted until the subject is clinically stable and has no signs of bleeding.  Subjects should 
be observed closely for signs and symptoms of bleeding.  No dose reduction is required 
when study drug is restarted. 
 
9.6  
Prohibited concomitant medications:  Any chemotherapy, anticancer immunotherapy, 
experimental therapy, or radiotherapy are prohibited while the subject is receiving ibrutinib 
treatment.  Corticosteroids for the treatment of the underlying disease is prohibited.  
Corticosteroids for the treatment of non-cancer related reasons for longer than 14 days 
and/or at doses >100mg of prednisone or its equivalent are prohibited.   
 
9.7 
Guidelines for ibrutinib management with surgeries or procedure:  Ibrutinib may 
increase the risk of bleeding with invasive procedures or surgery.  Consider the benefit-
risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending 
upon the type of surgery and the risk of bleeding. The following guidance may be 
applied to the use of ibrutinib in the perioperative period for patients who require surgical 
intervention or an invasive procedure while receiving ibrutinib: (a)  Minor surgical 
procedures - For minor procedures (such as a central line placement, needle biopsy, 
thoracentesis, or paracentesis) ibrutinib should be held for 3 days prior to the procedure 
and should not be restarted for at least 3 days after the procedure. For bone marrow biopsies 
that are performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for 
these procedures.  (b) Major surgical procedures - For any surgery or invasive procedure 
requiring sutures or staples for closure, ibrutinib should be held at least 7 days prior to the 
intervention and should be held at least 7 days after the procedure and restarted at the 
discretion of the investigator when the surgical site is reasonably healed without 
serosanguineous drainage or the need for drainage tubes.  (c) Emergency Procedures - 
For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 

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Protocol Version: 20Sep2018 
9.8 
Psychosocial Assessment:  Assessing psychosocial factor is important in cancer patients. 
The Patient Health Questionnaire 8 (PHQ-8, which is a version of the PHQ-9) will be used to 
screen for depression symptoms. This is a validated tool in cancer patients when scored as a 
continuous measure with a cutoff score of 8 or higher. Item 9 on this scale inquiries about 
“thoughts that you would be better off dead or of hurting yourself in some way”. Cancer 
patients are likely to consider the prospect of death while thinking about their prognosis. This 
makes this question more ambiguous in this population. Kroenke et al have reported that using 
PHQ-8 is desirable in conditions where data is collected in settings where real time further 
follow up questions about response to item 9 on PHQ-9 is not feasible.   After comparing the 
data from PHQ-9 studies they concluded that PHQ-8 is an acceptable alternative to PHQ-9. 
When using cut off score of 10 or higher, PHQ-8 has 99% sensitivity, 92% specificity and 57% 
positive predictive value (2) (See appendix VIII) 
The GAD-7 (Generalized Anxiety Disorder) self-reported scale will be used to assess 
anxiety symptoms (See appendix IX). 
Subjects will be asked about their living situations by asking:  
What best describes your living situation: 
• 
I live with a partner/spouse/family/friends 
• 
I live alone 
• 
I live in a nursing home, hospital, or other long-term care home 
• 
Other 
Social support will be assessed by using 4 questions from the Medical Outcomes Study: 
Social Support Survey (MOS-SSS) (See appendix X). 
These will be collected at baseline at the time of study enrollment and will be repeated 
quarterly.  
10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure.  
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 

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Protocol Version: 20Sep2018 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site:  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)    
 
 
a. Identify the grade and severity of the event using the CTCAE version 4.0.   
b. Determine whether the event is expected or unexpected (see Section 10.2).  
 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
e. Determine if other reporting is required (see Section 10.5). 
 
f. 
Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 

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Protocol Version: 20Sep2018 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) or 
procedure, the following attribution categories are utilized: 
 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 

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Protocol Version: 20Sep2018 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious 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 within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 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. 
Effective Date:  May 5, 2011 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing of expedited adverse 
events and forwarding of suspected unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
 
 

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Protocol Version: 20Sep2018 
10.41 Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of 
standard safety monitoring activities. These events (regardless of seriousness) will 
be reported to Pharmacyclics Drug Safety per SAE reporting timelines.   
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• 
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. 
Any treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of 
any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be 
reported as grade 3 or higher AE per CTCAE v4. 
Events meeting the definition of major hemorrhage will be captured as an event of 
special interest according to Section 11.4.6 above. 
All serious adverse events and AESIs (initial and follow-up information) will be 
reported on FDA Medwatch (Form 3500A) or Suspect Adverse Event Report 
(CIOMS Form 1) IRB Reporting Form and sent via email 
(drugsafety@pcyc.com) or fax ((408) 215-3500) to Pharmacyclics Drug Safety, 
or designee, within 15 days of the event. Pharmacyclics may request follow-up 
and other additional information from the Sponsor Investigator. 
 
 
Regulatory reporting: Reporting an SAE to Pharmacyclics does not relieve the 
investigator’s responsibility of reporting it to FDA or local regulatory 
authority.   Safety reporting responsibility should be clearly stated in the research 
agreement and the protocol. 
 
Follow up information:  Investigators will assist in investigating any SAE/AESI 
and provide follow-up information as requested by Pharmacyclics.  Company 
staff who frequently interact with the investigators may facilitate the follow-up 
activity  
 
10.42 Reporting 
Use FDA Medwatch (Form 3500A) available in forms packet for Investigational 
agents or commercial/investigational agents on the same arm.  Submit to 
Pharmacyclics Drug Safety (see contact information above). 
Mayo Clinic Cancer Center (MCCC) Institutions:   
Submit copies, along with the Event Reporting coversheet, to the following email 
address: CANCERCROSAFETYIN@mayo.edu. This email will be managed by 
the SAE, IND and Safety Reporting Coordinators. 
 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
10.43 EXPECTED Serious Adverse Events:  Protocol Specific Exceptions to 
Expedited Reporting 
 
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.6). * 
 
CTCAE SOC 
Adverse Event 
Grade 
Attribution 
Comments 
Investigations 
Neutrophil count 
decreased 
Grade 3 or 4 
Possible, 
probable, 
definite 
This frequent event in 
patients with CLL will be 
reported through the routine 
reporting mechanism 
Platelet count 
decreased 
Grade 3 or 4 
Possible, 
probable, 
definite 
This frequent event in 
patients with CLL will be 
reported through the routine 
reporting mechanism 
White blood count  Grade 3 or 4 
Possible, 
probable, 
definite 
This frequent event in 
patients with CLL will be 
reported through the routine 
reporting mechanism 
Lymphocyte count 
decreased 
Grade 3 or 4 
Possible, 
probable, 
definite 
This frequent event in 
patients with CLL will be 
reported through the routine 
reporting mechanism 
Blood and 
lymphatic system 
disorders 
Anemia 
Grade 3 or 4 
Possible, 
probable, 
definite 
This frequent event in 
patients with CLL will be 
reported through the routine 
reporting mechanism 
 
*Report any clinically important increase in the rate of a serious suspected adverse 
reaction over that which is listed in the protocol or investigator brochure as an expedited 
event.  
*Report an expected event that is greater in severity or specificity than expected as an    
expedited event. 
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 

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Addendum 7 
 
Protocol Version: 20Sep2018 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events.  In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
 
Mayo Clinic Cancer Center (MCCC) Institutions: 
 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the Reportable Event coversheet and appropriate 
documentation to CANCERCROSAFETYIN@mayo.edu. The Mayo Regulatory 
Affairs Office will review and process the submission to the Mayo Clinic IRB. 
 
10.52 Death 
 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided. 
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 

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Addendum 7 
 
Protocol Version: 20Sep2018 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
 
10.53 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. 
 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o 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. 
 
10.54 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 unless otherwise specified. 
 
10.55 Pregnancy  
 
Before study enrollment, subjects must agree to take appropriate measures to 
avoid pregnancy. However, should a pregnancy occur in a female study subject, 
consent to provide follow-up information regarding the outcome of the 
pregnancy and the health of the infant until 30 days old will be requested. 
 
A female subject must immediately inform the Investigator if she becomes 
pregnant from the time of consent to 30 days after the last dose of study drug. A 
male subject must immediately inform the Investigator if his partner becomes 
pregnant from the time of consent to 3 months after the last dose of study drug. 
Any female subjects receiving study drug(s) who become pregnant must 
immediately discontinue study drug. The Investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the 
fetus.   
 
Although pregnancy itself is not regarded as an adverse event, the outcome will 
need to be documented. Any pregnancy occurring in a subject or subject’s 
partner from the time of consent to 30 days after the last dose of study drug must 
be reported. Any occurrence of pregnancy must be reported to Pharmacyclics 

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Addendum 7 
 
Protocol Version: 20Sep2018 
Drug Safety, or designee, per SAE reporting timelines. All pregnancies will be 
followed for outcome, which is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. Pregnancies with an outcome of live birth, 
the newborn infant will be followed until 30 days old and this must be reported to 
Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. Any 
congenital anomaly/birth defect noted in the infant must be reported as a serious 
adverse event. 
 
10.6 
Required Routine Reporting  
 
10.61 Baseline and Adverse Events Evaluations 
 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation per CTCAE v4.0 grading unless otherwise stated in 
the table below: 
 
System Organ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Platelet count decreased* 
X 
X 
Blood and lymphatic 
system disorders 
Anemia* 
X 
X 
* Grading will be performed by the study statisticians at the time of analysis based 
on the CLL toxicity grading scale for blood counts in Appendix V.  Anemia grade 
per CTCAE will also be recorded for reporting purposes. 
 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.623 Grade 5 AEs (Deaths) 
 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.7 
Late Occurring Adverse Events 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
 

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11.0 
Treatment Evaluation  
NOTE: Information from CT scans is not considered in the standard classification of response.  
 
Note: Treatment-related lymphocytosis is a known phenomenon with ibrutinib and is not 
representative of PD. As noted in the Leukemia Research Foundation Workshop report52: 
"Patients with lymphocytosis and no other evidence of PD should continue therapy until they 
develop other deﬁnitive signs of PD (i.e., at least one feature suggesting worsening of the CLL 
other than lymphocytosis (e.g., anemia, thrombocytopenia, lymphadenopathy, or 
hepatosplenomegaly) or the occurrence of another reason to discontinue therapy.”  
 
PD:  “If PD is suspected, clinical examination, computed tomography, and peripheral blood 
counts should be obtained, and a bone marrow biopsy considered, to provide objective 
assessment of CLL status.  Note: Recommended to be confirmed on two independent occasions at 
least 2 weeks apart and consistent with the IWCLL guidelines. " 
 
Note:  Since this is a maintenance trial in which patients will be enrolled after having a clinical 
response from induction therapy, a further decrease in disease burden as noted by decrease in 
lymph node size or hepatosplenomegaly may not be observed. Thus, patients will be recorded 
with an objective status of “Not PD” as long as they do not demonstrate disease progression (or 
PD, defined below in section 11.2). 
   
11.1 
Overall Schedule of evaluations  
 
(a) Clinical Response: Will be evaluated and documented at baseline (this is defined as 
the response to the induction therapy). Thereafter clinical response will be evaluated for 
progression of disease only every 3 cycles of study treatment (for 36 cycles) and every 
cycle (every 3 months) during follow-up period of without therapy for 2 years.    
 
 
 
(b) MRD status: To be assessed at baseline (document positivity in blood or bone 
marrow) and then every 3 cycles of treatment (for 36 cycles) and thereafter every 3 
months (for MRD-) and every 6 months (for MRD+) during follow-up without therapy 
for 2 years. 
 
 
Note:  Bone marrow aspirate done solely for MRD will be considered research.  As 
outlined by the IWCLL guidelines a bone marrow biopsy / aspirate is required to 
document complete remission. Thus, a bone marrow biopsy / aspirate that is done as part 
of the clinical response to therapy (such as to document complete remission as part of 
clinical care as required by the IWCLL guidelines) will be considered standard of care. 
Additionally, if the bone marrow biopsy or aspirate is done as part of the clinical care of 
the patient (as determined by the treating physician) that procedure will be considered 
standard of care.  
 
 
11.2 
Evaluation for Progression of Disease 
 
11.21 PROGRESSION (PD):  Patients will continue to receive protocol therapy unless 
they have evidence of disease progression according to the IWCLL criteria6 as 
evidenced by: 
 
11.211  ≥ 50% increase in the sum of the products of at least 2 lymph nodes on 2 
consecutive determinations 2 weeks apart (at least one node must be ≥2 

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Protocol Version: 20Sep2018 
cm) that persist for > 3 months or the appearance of new palpable lymph 
nodes >1.5 cm not due to a tumor flare.  Enlargements or the appearance 
of new nodes due to a tumor flare do NOT qualify as progression.   
 
11.212 ≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin on 2 consecutive 
determinations 2 weeks apart and with a minimum of a ≥ 2 cm increase 
in size from baseline; or appearance of hepatomegaly or splenomegaly 
which was not previously present at baseline and not due to a tumor 
flare. 
 
11.213 Transformation to a more aggressive histology (e.g. Richter’s 
transformation). 
 
 
Note:  If a patient develops DLBCL at any time, it will be considered 
disease progression.  If the patient develops any other hematologic 
malignancy while on study, it will not be considered progressive disease. 
 
11.214 ≥ 50% increase in the absolute number of circulating lymphocytes NOT 
due to infection, tumor flare or drug-associated lymphocytosis (taking as 
reference for progressive disease the smallest absolute lymphocyte count 
recorded since the treatment started).  The absolute lymphocyte count 
must be at least 5000/mm3 to qualify as disease progression. 
 
11.215 In the absence of progression as defined by 1, 2, 3, or 4 above, the 
presence of a ≥ 2 g/dl decrease in HGB, or ≥ 50% decrease in platelet 
count or absolute neutrophil count will NOT exclude a patient from 
continuing the study.  Work-up of such decreases to exclude auto-
immune hemolytic anemia, pure red cell aplasia, or idiopathic 
thrombocytopenic purpura (ITP) should be considered. 
 
11.216 For patients who achieve a CR or nodular PR, progression will be 
defined as recurrence of circulating leukemia cell clone and an ALC 
>5000 or recurrence of adenopathy >1.5 cm not due to a tumor flare. 
 
 

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Protocol Version: 20Sep2018 
 
11.22    Not PD:   The patient was evaluated for progression only in this cycle and a 
formal response evaluation did not occur.  The patient did not meet the criteria 
for progression per section 11.21.   
 
 
11.3 
Minimal Residual Disease (MRD) Response:  MRD will be assessed by flow cytometry.  
 
 
MRD definition   
Patients will be considered MRD-negative when they have blood or marrow less than one 
CLL cell per 10,000 leukocyte (or bone marrow consistent with <0.01% involvement).  
Patients will be recorded to have either MRD+ vs. MRD- disease. 
 
Schedule   
 
(A) Pretreatment   All patients will have MRD assessed by flow cytometry at baseline 
prior to initiation of therapy. This can be done either in the peripheral blood (PB) and/or 
the bone marrow aspirate (BM). (Note: If blood is positive for MRD, then bone marrow 
aspirate analysis is not required for the clinical protocol, however, if peripheral blood is 
positive, then a bone marrow aspirate will be required to document MRD+ status of the 
patient). 
 
(B) On treatment  All patients will have the MRD evaluated by flow cytometry on the 
peripheral blood every 3 treatment cycles while on maintenance therapy. MRD will first 
be done on the PB.  If this is positive, then NO BM analysis will be required, but if the 
PB is negative (on two consecutive evaluation at least 3 months apart) , then a BM 
aspirate analysis for MRD will be done. If the ibrutinib maintenance treatment is held > 
21 days for toxicity or for any other reason(s) then the MRD testing will be delayed to 
accommodate 3 treatment cycles prior to testing.    
 
 
(C) Observation   Patients upon completing maintenance therapy will then be monitored 
for MRD by flow cytometry in the PB only for a maximum of 24 months after the 
completion of the last treatment cycle.  Monitoring schedule will be in the following 
manner:  
(a) If patient becomes MRD+ from a previously noted MRD-at any point  (or those 
who never develop MRD- state) will only be monitored every 6 months for a 
maximum of 2 year or until initiation of therapy for relapsed disease, whichever 
comes first.  
 
(b) MRD- patients who remain MRD- at the time of the start of the observation 
period will be continued to monitor for MRD in the PB every 3 months for a 
maximum of 2 year or until initiation of therapy for relapsed disease whichever 
comes first. 
 
Methodology   
We will employ Mayo Clinic Standard MRD assay.  
 
Flow cytometry:  we will conduct 8 color flow cytometry to assess MRD.   
 
Flow cytometry panel for MRD 
(i) CD19/CD5/CD20/CD23/CD38/CD45/kappa/lambda. (8-color panel) 
 
 
 

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Protocol Version: 20Sep2018 
12.0 
Descriptive Factors 
 
12.1 
Rai Stage:  0 vs. 1 vs. 2 vs. 3 vs. 4. (Appendix II) 
 
12.2 
CD38+ expression:  Positive (≥30%) vs. negative (<30%). 
 
12.3 
Chromosomal anomalies as detected by FISH:  13q- vs. 12+ vs. 11q- vs. 17p- vs. other 
abnormality vs. normal karyotype. 
 
12.4 
IgVH mutation status:  Mutated (≥2%) vs. unmutated (<2%) vs. indeterminate.  
 
12.5 
ZAP-70 expression:  Positive (≥20%) vs. negative (<20%).  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1  
If the patient develops PD at any time during active treatment they will go to event 
monitoring.  If the patient develops unacceptable adverse events, if the treating physician 
feels it is in the patient’s best interest, or if the patient refuses all further study 
participation, study treatment will be discontinued, and the patient will go directly to 
event monitoring. Patients will then be followed in event monitoring per Section 18.0. 
 
13.2  
Patients not progressing on active treatment will continue treatment per protocol up to a 
maximum of 36 cycles. After the completion of 36 cycles, the patient will go to 
observation (maximum duration of observation 2 years).  After completing observation, 
patients will enter event monitoring.  NOTE: Patients who have residual disease at the 
end of 36 cycles will continue to event monitoring. 
 
13.3 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns and as long as the patient was properly registered. The 
patient will go directly to the event-monitoring phase of the study (or off study, if 
applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
 
Note:  Due to the nature of the disease, if the patient is diagnosed with DLBCL within the 
first cycle of treatment, it will be assumed that the DLBCL was present at registration.  
The patient will be deemed ineligible per Sec 3.27. 
 
13.4 
A patient is deemed cancel if he/she is removed from the study for any reason before any 
study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 

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13.5 
If a patient develops DLBCL at any time, it will be considered progressive disease.   The 
patient will go directly to the event monitoring phase of the study per Section 18.0.  If the 
patient develops any other hematological malignancy while on study, it will not be 
considered progressive disease.   
 

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Protocol Version: 20Sep2018 
14.0 
Body Fluid Biospecimens 
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or Body 
Fluid being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Visit 1:Baseline (pre-tx) 
Visit 2: Prior to Cycle 4 
Visit 3: Prior to Cycle 7 
Visit 4: Prior to Cycle 13 
Visit 5: At time of relapse 
Process at 
site?  
(Yes or No) 
Temperature 
 Conditions for 
Storage 
/Shipping  
WES studies and 
Mate-pair DNA 
sequencing 
Mandatory 
Blood  
EDTA 
5 mL (2) 
X 
YES 
Ambient 
Bone marrow 
5 mL (2) 
X1 
BTK signalosome 
analysis only for 
patients with MRD+ 
disease in blood 
and/or marrow2 
Mandatory 
Blood  
Heparin 
(green top) 
5 mL (2) 
X 
YES 
Ambient 
Bone marrow 
5 mL (2) 
X1 
Immunomodulatory 
effect analysis 
Mandatory 
Blood  
Heparin 
(green top) 
6 mL (1) 
X 
YES 
Ambient 
Bone marrow 
6 mL (1) 
X1 
1. Only if bone marrow biopsy or aspirate is done as part of routine clinical care of the patient or as part of MRD assessment. 
2. Sample should also be collected at the time of first documentation of lymphocytosis >5,000cell/mm3. 

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Protocol Version: 20Sep2018 
 
14.2  
Collection and Processing  
 
All samples will be collected and stored at Dr. Chanan-Khan's laboratory (Griffin 
Building, First Floor, Mayo Clinic-Florida, San Pablo Road Jacksonville FL 32224; 
Telephone 904-953-7291).  
 
14.3 
Rationale and Methodology 
 
14.31 Determine the molecular profile predictive of eradication of CLL clone by 
ibrutinib 
Scientific rationale: The current molecular landscape in CLL biology is able to 
identify patients with high vs. low risk disease in context with standard 
therapeutics, such as chemoimmunotherapy. However, recent data on ibrutinib 
seem to demonstrate that the clinical response to ibrutinib is independent of the 
traditional risk factors such as del(17p). This suggests that molecular markers 
currently employed may display a differential sensitivity to ibrutinib therapy. 
Furthermore, certain del(17p) patients upon relapse demonstrate a more 
aggressive clinical path than other del(17p) patients, hinting at underlying 
molecular architecture that is directing clinical responsiveness (or lack thereof) to 
ibrutinib. In this study we expect that ibrutinib treatment of the MRD will result 
in abrogation of the microenvironmental signaling through the BTK pathway and 
thus be able to eliminate residual clone. However, we do not expect all patients to 
be able eradicate MRD with ibrutinib, and this is consistent with the differential 
clinical response noted in prior studies (21% CR only).  
 
Hypothesis:  Therefore, our hypothesis is that it is the primary molecular makeup 
that directs responsiveness of the malignant clone to BTK inhibition by ibrutinib 
and that the extent of sensitivity of the clone will be predictive of ability to 
achieve an MRD-negative disease state.  
 
Methodology & Sample:  to address this, we will perform whole genome 
sequencing and mate-pair DNA sequencing of the malignant clone obtained from 
patient’s blood (2 x 5ml tubes) and / or bone marrow (when available 2 x 5ml 
tubes).  CD19+ cells will be sorted and used for WES.  B-CLL cells are known to 
have two types of mutations: small (site mutations) and large (genomic 
rearrangements such as translocations, inversions, etc.), and the combination of 
mate-pair sequencing and WES will enable the detection of both types of lesions.  
A time series study is ideal for studying clonal evolution, which plays an 
important role in CLL.  This will allow the identification of the sub-clone(s) in 
the MRD+ patients that were able to survive / eradicate with ibrutinib therapy.  
The protocol requires to have normal control DNA. This control DNA can be 
obtained from any one of the samples (which ever is convenient to the patient 
and preferred by the treating MD). Establishing whether molecular architecture is 
associated with response or lack of response to ibrutinib therapy will also be 
attempted by in silico predictive modeling simulation techniques, as previously 
described (Cellworks Inc.) For this analysis, blinded and de-identified data will 
be used to derive response from the in silico modeling algorithm. Control:  It is 
important to have controls, which will represent lack of response to ibrutinib (or 
other anti-CLL therapeutics) to help design in silico algorithms.  For this we will 
collect peripheral blood (2 x 5mL tubes) and/ or bone marrow (when available 2 

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Protocol Version: 20Sep2018 
x 5mL tubes) as well as buccal swab from CLL patients who are not enrolled on 
trial (and thus not on maintenance therapy for MRD eradication), but who have 
received ibrutinib with suboptimal clinical response.  Possible sources for this 
DNA identified include either one of the following;   1. buccal swabs, 2. myeloid 
cells in the marrow (in cases where bone marrow is obtained for clinical reasons) 
or 3. Skin biopsy (if no other source of germline DNA is available).  
 
Statistical support:  WES analysis will be done at Mayo Clinic laboratories, and  
the data will be analyzed in collaboration with Dr. Asman Yan, PhD. 
 
Sample time: sample will be collected any time prior to starting the ibrutinib 
therapy and then at time of relapse.  Additional samples during treatment will be 
collected as noted in Table 14.1. 
 
Expected results:  This data will help us identify (a) unique molecular patterns of 
Clone that correlates with highest sensitivity of response to ibrutinib maintenance 
therapy and achievement of MRD negativity (b) molecular makeup of CLL clone 
associated with the most expeditious eradication of MRD vs. delayed eradication 
vs. persistent MRD and (c) molecular profile of the CLL clone associated with 
the longest durability of MRD negativity and (d) assess for clonal evolution and 
alteration of molecular profile of the CLL clone post exposure/resistance to 
ibrutinib therapy.  
 
Clinical implications: these analyses will allow us to determine which patients 
are exquisitely sensitive to eradication of disease from ibrutinib maintenance 
therapy and thus will benefit from continued ibrutinib therapy and allow the 
identification of patients who may harbor a clone that would increase the 
potential of relapse or development of  resistance to ibrutinib maintenance 
therapy, and thus require more frequent monitoring or perhaps timely use of 
additional therapeutic(s) to prevent development of ibrutinib resistance.  
 
14.32 Determine the role of members of the BTK signalosome in eradication of 
CLL clone by ibrutinib  
Scientific Rationale:  It is evident from the clinical data53,54 that over 70% of the 
patients will respond to ibrutinib therapy; however, 80% of these "clinically 
responsive" patients will retain the CLL clone, while approximately 20% will go 
into CR.  This variability in the depth of clinical response may suggest an 
underlying adaptability of the CLL clone’s mediation through components of the 
BTK signalosome.  Woyach et role reported55 that CLL patients treated with 
ibrutinib demonstrated upregulation of p-Akt and p-Erk (downstream mediators 
of BTK) in some (but not all) patients and suggest that these downstream 
pathways may contribute to the survival of these CLL cells.56  They also 
concluded that these cells may not be dependent upon the proximal BTK 
pathways mediated apoptosis and thus resistant to killing by ibrutinib.  While this 
phenomenon is primarily reported in the displaced CLL cells, we ask the 
question of whether these pathways play any role in inability to eradicate the 
disease altogether from the bone marrow?  
 
Hypothesis:  Depth of response (i.e., eradication of the MRD) is dependent on the 
viability of the downstream mediator of the BTK pathway and its response to 
ibrutinib exposure.   

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Methodology & Sample:  to address this question we will establish the profile of 
BTK signalosome for each patient through determination of the mRNA (RT-
PCR/ nanostring assay) and protein expression (western blot analysis) of 
members of the BTK signaling pathway. alidation of BTK signaling, and the 
predictive ability of BTK (and other signaling pathways) for therapy response / 
or lack of response will be attempted through in silico modeling using a 
previously published (REF) platform (Cellworks Inc.). For this analysis, blinded 
and de-identified data will be used to derive response from the in silico modeling 
algorithm. 
 
Samples: Blood (2 x 5ml green top tubes) and/or bone marrow samples (when 
available 2 x 5ml green top tubes) will be collected at anytime prior to initiating 
the ibrutinib therapy. Serial blood samples (first at the time of first 
documentation of lymphocytosis >5,000cell/mm3 and then prior to starting cycles 
4, 7, and 13 and then at time of relapse) will be collected if patients are noted to 
have lymphocytosis as a result of ibrutinib therapy.  Bone marrow samples will 
only be collected when the procedure is performed as part of the clinical care of 
the patient and will follow the bone marrow biopsy and aspirate schedule noted 
in section 4.  Control:  It is important to have controls, which will represent lack 
of response to ibrutinib (or other CLL therapeutics) to help design in silico 
algorithms.  For this we will collect peripheral blood (2 x 5mL tubes) and/ or 
bone marrow (when available 2 x5mL tubes) as well as buccal swab from CLL 
patients who are not enrolled on trial (and thus not on maintenance therapy for 
MRD eradication), but who have received ibrutinib with suboptimal clinical 
response.  
 
 
Expected results: We anticipate (a) a variability in the expression and 
phosphorylation status of various members of the BTK pathway (Syk, Lyn CD79 
FYN) and their targets (ERK, AKT, NFKB and Bcl-2, Mcl-1, XIAP, MYC, 
CD40 and CFLAR) (b) and predict a correlation of this variability with the 
ability to eradicate the MRD.  
 
14.33 Determine the contribution of immunomodulatory effects of ibrutinib in  
eradication of MRD and maintenance of clinical response 
Scientific rationale:  our prior investigation of lenalidomide in CLL demonstrated 
that while lenalidomide was not directly cytotoxic it mediated its anti-CLL effect 
through activation of an innate (NK cell dependent) coupled by a CD8+ cytotoxic 
immune response.  This resulted in 18% of the patients achieving MRD-negative 
disease with lenalidomide alone.  Thus immune restoration can effectively 
deliver deeper responses in CLL.  Traditional induction regimen incorporates 
chemoimmunotherapy (such as fludarabine and cyclophosphamide) causing 
direct insult to host immunity.  Interestingly, many patients demonstrate 
regeneration of T cell enrich lymphocytic nodules in the bone marrow.  In cancer 
redirection of host immunity from a predominant Th2 to Th1 response can 
deliver antitumor response.  Dubovsky et al57 recently reported in an elegant 
paper that ibrutinib can bind to ITK (IL-2 inducible kinase).  ITK a member of 
the TEC-kinase family mediate TCR signaling through PLCγ, NFAT, NFκB and 
MAPK.  This results in activation and proliferation of CD8+ cells.  We wonder 

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Protocol Version: 20Sep2018 
whether the eradication of MRD in CLL is perhaps also dependent upon its 
immunomodulatory effects.  
 
Hypothesis:  Ibrutinib alters the Th2:Th1 balance in the blood and bone marrow 
microenvironment, skewing towards a more Th1 profile, and this translates into 
its effects on the MRD.  We further hypothesize that the robustness of the Th1 
response will direct ibrutinib's depth of response i.e., MRD negativity post-
induction.   
 
Method and samples:  Blood and/or bone marrow will be evaluated/quantified for 
Th1 and Th2 cells by flow cytometry.  Changes in the cellular profile as well as 
respective cytokine levels (such as IL2, IL12, INFα and IL4, IL5, IL13 and IL10, 
respectively) will be measured (for cytokines we will use a multiplex assay).  
Blood (1 x 5ml green top tubes) and/or bone marrow samples (when available, 1 
x 5ml green top tubes) will be collected at anytime prior to initiating the ibrutinib 
therapy.  Serial blood samples (starting at 0 month and then every 3 cycles at 
time of MRD/clinical response assessment and then at time of relapse) will be 
collected. Control samples will be collected from CLL patients who are not 
enrolled on trial (not on maintenance therapy for MRD eradication), but who 
received ibrutinib and achieved suboptimal clinical response. Peripheral blood (2 
x 5mL tubes) and/ or bone marrow (when available 2 x5mL tubes) as well as 
buccal swabs will be collected. Note that the bone marrow sample will only be 
collected when the procedure is being done for clinical reasons and will follow 
the bone marrow biopsy and aspirate schedule noted in section 4. Changes in 
cytokine levels will also be implemented into the in silico predictive simulation 
modeling algorithm and resulting effect on tumor cell proliferation as well as 
correlation with response to therapy will be assessed.  Expected results:  We 
anticipate that ibrutinib treatment (a) will result in an increase in Th1 cells both 
in the blood and the bone marrow with bone marrow demonstrating a higher 
percentage of Th1 cell activity and that (b) extent of immune cellular response 
will correlate with the robustness of the MRD eradication and that (c) the 
cytokine profile will mimic this cellular pattern and can be used to predict 
immune cellular response to ibrutinib.  
 
Clinical relevance:  CLL patients have been reported to have immune 
dysfunction or restoration of host immunity and immune cellular function with 
drugs such as lenalidomide, but to date there is no approved agent to address this 
aspect of CLL therapy.  Identification / validation of immune restoration ability 
of ibrutinib and its correlation with disease eradiation in the maintenance setting 
will be a highly novel observation and will define a unique role and mechanism 
of ibrutinib in CLL.  
 
14.4 
Clinical relevance of these correlative studies 
1. Identification of patients who are likely to have the maximum benefit from 
ibrutinib maintenance therapy. 
2. Identification of patients who are likely to have a rapidly vs. delayed 
response to ibrutinib maintenance therapy. 
3. Identification of patients who are likely to have a prolonged vs. a short-lived 
response. 

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Protocol Version: 20Sep2018 
4. Identification of additional targets within the BTK pathway that can be 
exploited concurrently to optimize the response from ibrutinib in eradication 
of MRD. 
5. Identification of molecular landscape associated with CLL clone resistant to 
ibrutinib therapy.  
6. Potential development of biomarkers of clinical response/resistance. 
 
15.0 
Drug Information 
 
15.1 
Ibrutinib (Imbruvica™, PCI-32765) 
 
15.11 Background: Ibrutinib is an antineoplastic agent that is an inhibitor of  
Bruton’s tyrosine kinase. 
 
15.12 Formulation: Ibrutinib comes in a capsule: either size 0, gray. 140 mg capsules 
or size 2, yellow immediate-release 70 mg capsules. The capsules also contain 
the following compendial excipients: microcrystalline cellulose, croscarmellose 
sodium, sodium lauryl sulfate, and magnesium stearate. Capsules are packaged in 
high-density polyethylene bottles with an induction seal and a child resistant 
screw-top cap. The number of capsules in each aclar blister pack or per bottle is 
indicated on the label. 
 
15.13 Preparation and storage: All formulations should be stored according to 
the storage conditions indicated on the label. Ibrutinib capsules: 70 mg and 
140 mg  
 
15.14 Administration:  Administer orally with water at approximately the same time 
every day.  Ibrutinib can be taken with or without food.  Swallow capsules 
whole; do not open, break, or chew the capsules.  Ibrutinib should be held at least 
3-7 days pre- and post- surgery depending upon the type of surgery and the risk 
of bleeding.  Hazardous agent; use appropriate precautions for handling and 
disposal. 
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Current data indicates bioavailability is low and displays high 
inter-subject variability.  The median time to reach maximum plasma 
concentration (Tmax) is approximately 2 hours.  Administration of ibrutinib in a 
fasted condition resulted in approximately 60% of exposure as compared to 
administration either in fed condition (30 minutes after a high-fat breakfast), or 
when drug was taken 30 minutes before or 2 hours after a meal. Based on data 
for the effects of food, ibrutinib could be taken with or without food at 
approximately the same time each day. 
b)  Distribution: The plasma protein binding of ibrutinib and its metabolite 
PCI 45227 in human plasma is 97.3% and 91%, respectively.  The 
apparent steady state volume of distribution is approximately 10,000 L. 
c)  Metabolism – Ibrutinib is extensively metabolized by CYP3A4/5 
(major) and CYP2D6 (minor).  The half-life elimination is 4-6 hours.  
Ibrutinib is metabolized in the liver. 

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Addendum 7 
 
Protocol Version: 20Sep2018 
d)  Excretion –The excretion of ibrutinib is predominantly via the feces 
with approximately 80% recovered mostly within 2 days, whereas ~8% is 
excreted in urine. Approximately 1% of the ibrutinib is recovered as 
unchanged drug, all in feces. Overall, these PK characteristics resulted in 
minimal accumulation of both parent compound and metabolite PCI-45227 
on repeated daily dosing of ibrutinib. 
e) Special populations: a small increase in bioavailability was estimated 
with increasing age. Exposure is predicted to increase approximately 14% 
and decrease approximately 20% in subjects of 81 and 49 years of age, 
compared to a typical 67-year old subject. No statistically significant 
effects were observed for the other covariates tested, i.e., sex, race, mild 
and moderate renal impairment, mild hepatic impairment and B-cell 
histology. The recommended doses for patients with mild and moderate 
liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A 
and B, respectively). It is not recommended to administer ibrutinib to 
subjects with severe hepatic impairment (Child-Pugh Class C). 
 
 
15.16 Potential Drug Interactions:  Ibrutinib is primarily metabolized by 
cytochrome P450 enzyme 3A4/5.   Voriconazole and posaconazole can be 
used concomitantly with ibrutinib as per the dosing guidance described in 
the specific clinical study protocol. All other strong inhibitors of CYP3A 
(eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazodone, and cobicistat) 
should be avoided, and an alternative with less CYP3A inhibitory potential 
should be considered. If the benefit outweighs the risk and a strong 
CYP3A inhibitor must be used, see the recommended dose modifications 
described in the specific clinical study protocol.  
 
If a moderate CYP3A inhibitor (eg, fluconazole, erythromycin,  
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, 
fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) is indicated 
in patients with B-cell malignancies, reduce the ibrutinib dose to 280 mg 
for the duration of the inhibitor use or as per recommended dose 
modifications described in the specific clinical study protocol. No ibrutinib 
dose modifications for moderate inhibitors are required in patients with 
cGVHD dosed with ibrutinib 420 mg. 
 
No dose adjustment is required in combination with mild inhibitors. 
Monitor patient closely for toxicity and follow dose modification guidance 
as needed. Avoid grapefruit and Seville oranges during ibrutinib treatment 
as these contain moderate inhibitors of CYP3A. 
 
Administration of ibrutinib with strong inducers of CYP3A decreases 
ibrutinib plasma concentrations by up to 90%. Avoid concomitant use of 
strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin and St. 
John’s Wort). Consider alternative agents with less CYP3A induction. 
 
To minimize the potential for an interaction in the GI tract, narrow 
therapeutic range P-gp or BCRP substrates such as digoxin or 
methotrexate should be taken at least 6 hours before or after ibrutinib. 

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Protocol Version: 20Sep2018 
Ibrutinib may also inhibit BCRP systemically and increase the exposure of 
drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin. 
 
There have been reports of bleeding-related events in subjects treated with 
ibrutinib. 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. 
 
15.17 Known potential toxicities:   
 
• 
Common(1 to <10%: febrile neutropenia, atrial fibrillation 
diarrhea, pyrexia, pneumonia,  
• 
Uncommon/Rare (<1%):, leukocytosis, thrombocytopenia, l, 
vision blurred, stomatitis, gastritis, asthenia, bronchitis, lung 
infection, sinusitis, urinary tract infection, neutrophil count 
decreased, platelet count decreased, dehydration, 
hyperuricemia, myalgia, extremity pain, dizziness, hematuria, 
epistaxis, erythematous rash, maculo-papular rash, hematoma, 
hypertension, cellulitis, infection, lower respiratory tract 
infection, sepsis, skin infection, arthritis, bone pain, flank 
pain, basil cell carcinoma, squamous cell carcinoma, syncope, 
acute kidney injury, pleural effusion, respiratory failure, 
macular rash, hypotension, respiratory tract infection, 
leukostasis syndrome, pancytopenia, atrial flutter, cardiac 
failure, myocardial infarction, colitis, intestinal obstruction, 
oral mucosal blistering, systemic inflammatory response 
syndrome, atypical pneumonia, bacteremia, infectious 
enterocolitis, neutropenic sepsis, periorbital cellulitis, 
pneumonia (pneumocystis jirovecii, bacterial, cryptococcal, 
fungal, haemophilus, influenzal, viral, pseudomonal klebsiella, 
legionella, parainfluenzae viral, streptococcal, organising), 
septic shock, urosepsis, post procedural hemorrhage, subdural 
hematoma, tumor lysis syndrome, pain (pelvic, groin), 
hemorrhage intracranial, lung infiltration, pneumonitis, 
pustular rash, breast cellulitis, bronchopulmonary 
aspergillosis, Escherichia sepsis, viral lower respiratory tract 
infection, pneumococcal sepsis, fungal sinusitis, 
staphylococcal infection, staphylococcal skin infection, 
interstitial lung disease, angioedema, hypertensive crisis , 
chronic sinusitis bacteroides bacteremia, orbital cellulitis, 
staphylococcal cellulitis, Escherichia bacteremia, alveolitis 
allergic, Stevens-Johnson syndrome, Haemophilus 
bacteremia/sepsis, pseudomonal lung infection, bacterial 
sepsis, herpes zoster disseminated, muscle hemorrhage, 
cerebral hemorrhage, deep vein thrombosis, squamous cell 
carcinoma of the skin, basosquamous carcinoma of the skin, 
hepatic failure, ventricular tachyarrhythmia 
• 
Cardiac Arrhythmias: Atrial fibrillation, atrial flutter, and 
cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, 

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Addendum 7 
 
Protocol Version: 20Sep2018 
particularly in subjects with cardiac risk factors, hypertension, 
acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. 
Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness, syncope, chest discomfort or new onset of 
dyspnea) should be evaluated clinically, and if indicated, have 
an ECG performed. For cardiac arrhythmias which persist, 
consider the risks and benefits of ibrutinib treatment, and 
follow the dose modification guidelines 
• 
Cerebrovascular accidents:  Cases of cerebrovascular 
accident, transient ischemic attack, and ischemic stroke 
including fatalities have been reported with the use of ibrutinib 
in the post-marketing setting, with and without concomitant 
atrial fibrillation and/or hypertension.  Regular monitoring and 
appropriate treatment of conditions that can contribute to the 
occurrence of these events is recommended.  
• 
Cutaneous vasculitis has been identified as a new adverse 
reaction in the postmarketing setting 
 
Please refer to the prescribing information or Investigator’s Brochure for a 
more complete comprehensive list of treatment-emergent adverse events. 
 
15.18 Drug procurement:  Drug will be provided free of charge to study participants 
by Pharmacyclics, Inc. 
 
 
15.19 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 section 15.16. 
• 
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. 
• 
Cardiac arrhythmias have been seen with this agent including a-fib, atrial 
flutter and ventricular tachyarrhythmia’s, some of which have led to death.  

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Protocol Version: 20Sep2018 
Instruct patients who experience any palpitations, lightheadedness, syncope, 
or SOB to see medical care immediately.  This is especially important in 
patients who have pre-existing cardiac issues. 
• 
Warn patients of the risk of bleeding. Patients should not take warfarin or 
other vitamin K antagonists while on ibrutinib, unless the protocol allows for 
it. Additionally, patients should be cautioned to avoid fish oil and Vitamin E 
supplements. 
• 
Patients who are concurrently on ibrutinib and ventoclax should be 
monitored closely for excess toxicity. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1  
Overview:  
 
This is a Phase II study designed to assess the eradication of minimal residual disease 
(MRD) as well as the toxicity associated with ibrutinib used as maintenance therapy in 
CLL patients who achieve a PR, nPR, CCR, CRi, or CR post-induction therapy but who 
have residual disease (i.e. MRD positive). 
 
16.11  Primary Endpoint:  
 
The primary endpoint of this trial is the rate of confirmed MRD-negative 
response at any time during treatment with ibrutinib maintenance. A confirmed 
MRD-negative response is defined as an achievement of MRD-negative status in 
both the blood and the bone marrow on two consecutive evaluations at least three 
months apart. Confirmed MRD-negative response will be evaluated using all 
cycles of treatment.  Throughout Section 16.0, confirmed MRD-negative 
response will be considered synonymous with "success" unless specified 
otherwise.  All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be evaluable for confirmed MRD-negative 
response, with the exception of patients who are determined to be a major 
treatment schedule violation. 
 
 
16.2  
Statistical Design: 
 
16.21 Decision Rule:  
 
Prior clinical investigations have evaluated eradication of the MRD with 
consolidation treatment post induction therapy and these suggest the importance 
of MRD eradication after first-line therapy. None of these studies have 
investigated primary maintenance after first-line induction treatment.  Two 
ongoing studies (mentioned in the introduction) have been initiated, but no data 
is available.  Therefore, any indication of benefit with ibrutinib maintenance 
therapy will be considered promising.   
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 5%, representing a response by 
chance alone.  The smallest success proportion that would warrant subsequent 
studies with the proposed regimen in this patient population is 20%.  The 
following one-stage binomial design uses 32 evaluable patients to test the null 

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Protocol Version: 20Sep2018 
hypothesis that the true success proportion in a given patient population is at 
most 5%.   
 
16.211 Final Decision Rule: Enter 32 evaluable patients into the study.  If 3 or 
fewer successes are observed in the first 32 evaluable patients, we will 
consider this regimen ineffective in this patient population and terminate 
this study.  Otherwise, if the number of successes is at least 4, this will be 
considered evidence of promising activity and the treatment may be 
recommended for further testing in subsequent studies. 
 
16.212  Over Accrual:  If more than the target number of patients are accrued, 
then the additional patients will not be used to evaluate the stopping rule 
or used in any decision making process.  Analyses involving over 
accrued patients are discussed in Section 16.34. 
 
16.22  Sample Size:  
 
The phase II study design to be used is fully described in section 16.21.  A 
maximum of 32 evaluable patients will be accrued onto this phase II study unless 
undue toxicity is encountered.  We anticipate accruing an additional 3 patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons.  
Maximum projected accrual is 35 patients. 
 
16.23  Accrual Rate and Study Duration:  The anticipated accrual rate is approximately 
1-2  patients per month.  Therefore, the accrual period for this phase II study is 
expected to be about 2 years.  The final analysis can begin approximately 2.5 
years after the trial begins, i.e. as soon as the final patient accrued to this trial has 
been followed for at least 6 months.  
 
16.24 Power and Significance Level:  Assuming that the number of responses is 
binomially distributed, with a significance level of 7%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) can be 
tabulated as a function of the true success proportion as shown in the table below. 
 
If the true success proportion is… 
0.05 0.10 0.15 0.20 
Then the probability of declaring that the regimen is promising 
and warrants further study is… 
0.07 0.40 0.73 0.91 
 
16.25 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.3 
Analysis Plan:   
 
 
The analysis for this trial will commence at planned time points (see 16.2) and at the time 
the patients have become evaluable for the primary endpoint. Such a decision will be 
made by the Statistician and Study Chair in accordance with CCS Standard Operating 
Procedures, availability of data for secondary endpoints (e.g., laboratory correlates), and 
the level of data maturity.  It is anticipated that the earliest date in which the results will 

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Addendum 7 
 
Protocol Version: 20Sep2018 
be made available via manuscript, abstract, or presentation format is when the last patient 
has been followed for at least 6 months. 
 
16.31 Primary Endpoint:   
 
16.311  Definition: The primary endpoint of this trial is the rate of confirmed 
MRD-negative response. A confirmed MRD-negative response is 
defined as an achievement of MRD-negative status in both the blood and 
the bone marrow on two consecutive evaluations at least 3 months apart. 
Confirmed MRD-negative response will be evaluated using all cycles of 
treatment.  All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for response, 
with the exception of patients who are determined to be a major 
treatment schedule violation. 
 
16.312  Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Ninety-
five percent exact binomial confidence intervals for the true success 
proportion will be calculated. 
  
16.32 Secondary Endpoint: 
 
16.321  Duration of MRD-negative response is defined in patients who have 
achieved a confirmed MRD-negative response as the time from the 
earliest date that the patient was noted as having MRD-negative response 
in both the blood and bone marrow until the first notation of MRD 
positive disease in the blood or the bone marrow.  The distribution of 
duration of MRD-negative response will be estimated using the method 
of Kaplan-Meier.58  
 
16.322 Time to MRD-negative response is defined in patients who have 
 
achieved a confirmed MRD-negative response as the time from the date 
 
of registration to the earliest date that the patient was noted as having 
 
MRD-negative response in both the blood and bone marrow.  Time to 
 
MRD-negative response will be summarized descriptively (median, 
range). 
 
16.323 Time to requirement of next therapy:   A landmark analysis will be 
conducted to evaluate time to requirement of next therapy for patients 
who achieve a confirmed MRD-negative response in both the blood and 
bone marrow vs. those who remain MRD-positive, as assessed at 48 
weeks (end of 12 cycles; +/- 4 weeks).  Patients who discontinue 
treatment before 48 weeks are excluded from this analysis.  Time to 
requirement of next therapy will be defined as the time from the 48 week 
MRD evaluation until the time of initiation of subsequent treatment for 
progressive CLL.  The distribution of time to requirement of next therapy 
will be estimated using the Kaplan-Meier method and log-rank statistics 
will be utilized to evaluate differences between the two groups. 
 
16.324  Progression-free survival:  A landmark analysis will be conducted to 
evaluate progression-free survival for patients who achieve a confirmed 

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Addendum 7 
 
Protocol Version: 20Sep2018 
MRD-negative response in both the blood and bone marrow vs. those 
who remain MRD-positive, as assessed at 48 weeks (end of 12 cycles; 
+/- 4 weeks).  Patients who discontinue treatment before 48 weeks are 
excluded from this analysis.  Progression-free survival will be defined as 
the time from the 48 week MRD evaluation until the time of disease 
progression per the IWCLL criteria or death due to any cause.  The 
distribution of progression-free survival will be estimated using the 
Kaplan-Meier method and log-rank statistics will be utilized to evaluate 
differences between the two groups. 
 
16.325  Adverse Events:   Platelets and hemoglobin will be graded according to 
the Grading Scale for Hematologic Adverse Events in CLL Studies in 
Appendix V.  The maximum grade for each type of adverse event, 
regardless of causality, will be recorded and reported for each patient, 
and frequency tables will be reviewed to determine adverse event 
patterns.  Adverse events will continue to be recorded and reported up to 
30 days after the last day of study drug treatment. 
 
16.33 Correlative Analyses. The reports on the correlative will be descriptive as they 
are exploratory in nature.  
 
16.332  Study of the impact of ibrutinib treatment on mood is exploratory in 
nature. Reports of these correlative analyses will be descriptive.  
 
16.34   Over Accrual: If more than the target number of patients are accrued, then the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 
16.35 Data & Safety Monitoring 
 
16.351 The principal investigator(s) and the study statistician will review the 
study at least every quarter to identify accrual, adverse events, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.352 Adverse Event Stopping Rule: The stopping rule specified below is 
based on the knowledge available at study development.  We note that 
the rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event 
profile of the treatments under investigation.  The study team may 
choose to suspend accrual because of unexpected adverse event profiles 
that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment 
(e.g., an adverse event with attribute specified as "possible," "probable," 
or "definite") that satisfy either of the following: 

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Addendum 7 
 
Protocol Version: 20Sep2018 
 
• 
If 3 or more of the first 12 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to 
treatment. 
 
• 
If after the first 12 patients have been treated, 25% of all patients 
experience a grade 4 or higher non-hematologic adverse event at 
least possibly related to treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed 
"unrelated" or "unlikely to be related," to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.4   Results Reporting on ClinicalTrials.gov  
At study activation, this study will have been registered within the "ClincialTrials.gov" 
website.  The Primary and Secondary Endpoints along with other required information 
for this study will be reported on ClinicalTrials.gov.  For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 2.5 years after the study opens to accrual.  The definition of "Primary Endpoint 
Completion Date" (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
 
16.5 
Inclusion of Women and Minorities 
 
16.51 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.52 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race or gender, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.53 The geographical region served by Mayo Clinic has a population that includes 
approximately 3% minorities.  Based on prior Mayo Clinic studies involving 
similar disease sites, we expect about 3-5% of patients will be classified as 
minorities by race, and about 30% of patients will be women.  Expected sizes of 
racial by gender subsets are shown in the following table: 
 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 0 
 1 
 1 
Not Hispanic or Latino 
 11 
 23 
 34 
Ethnic Category: Total of all subjects 
 11 
 24 
 35 
Racial Category 
American Indian or Alaskan Native 
 0 
 0  
 0 
Asian 
 0 
 0 
 0 
Black or African American 
 1 
 1 
 2 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 10 
 23 
 33 
Racial Category: Total of all subjects 
 11 
 24 
 35 
 
Ethnic 
Categories: 
Hispanic or Latino - a person of Cuban, Mexican, Puerto 
Rican, South or Central American, or other Spanish culture or 
origin, regardless of race. The term "Spanish origin" can also be 
used in addition to "Hispanic or Latino." 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native - a person having origins 
in any of the original peoples of North, Central, or South 
America, and who maintains tribal affiliations or community 
attachment. 
Asian - a person having origins in any of the original peoples of 
the Far East, Southeast Asia, or the Indian subcontinent 
including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American - a person having origins in any of 
the black racial groups of Africa. Terms such as "Haitian" or 
"Negro" can be used in addition to "Black or African American." 
Native Hawaiian or other Pacific Islander - a person having 
origins in any of the original peoples of Hawaii, Guam, Samoa, 
or other Pacific Islands. 
White - a person having origins in any of the original peoples of 
Europe, the Middle East, or North Africa. 

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Addendum 7 
 
Protocol Version: 20Sep2018 
17.0  
Pathology Considerations/Tissue Biospecimens:  
 
17.1       Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of Tissue to 
Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Visit 1: 
Baseline 
only 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
Control DNA 
Mandatory 
Patient must be 
willing to provide 
one of the 
following 
samples: 
 
 
 
 
Saliva/buccal 
swab from oral 
cavity 
NA 
X 
No 
Ambient 
Skin biopsy (only 
if buccal swab is 
not able to deliver 
adequate DNA) 
3mm punch 
biopsy 
X 
yes 
Ambient 
Myeloid cells 
from the bone 
marrow (only if 
buccal swab is not 
able to deliver 
adequate DNA 
and a bone 
marrow is done as 
part of routine 
standard clinical 
test) 
aspirate 
X 
yes 
Ambient 

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Addendum 7 
 
Protocol Version: 20Sep2018 
17.2 
Correlative Tissue Collection  
 
17.21 Standard 3mm skin biopsy tissue.  Kits will not be provided for this protocol.  
 
17.22 Oral buccal swab for normal DNA sample 
 
17.221 The oragene kit will be used for collection saliva/buccal swab.  
 
  
If slides will be submitted, include thickness of tissue, and type of slide 
(charged or uncharged).  Do not coverslip unstained slides. 
 
 
17.222 Sample can be shipped overnight at ambient temperature  
 
 
 
17.223 samples will be shipped to DR. Chanan-Khan’s laboratory in Griffin 
Building 4500 San Pablo Rd. Jacksonville FL 32224 
 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
18.0 
Records and Data Collection Procedures   
 
18.1   Submission Timetable 
 
Initial Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 
4.0) 
On-Study  
≤2 weeks after registration 
Adverse Event - Baseline  
Measurement - Baseline 
Research Blood Submission - Baseline (See section 14.0) 
Research Bone Marrow Aspirate Submission - Baseline 
(See section 14.0) 
Bone Marrow Biopsy  
FISH Results - Baseline  
Quantitative Flow Cytometry  
Pre-induction and pre-registration immunophenotyping/pre-
registration MRD reports including CD38 and ZAP-701, 2 
IgVH Mutation Analysis Report1 
Other Laboratory Results  
CLL FISH Report1 
Bone Marrow Biopsy Report1 
CT Scan Report1 
Research Tissue Submission - Baseline 
Psychology and QOL Assessments - Baseline 
 
End of Active Treatment/Cancel Notification  
Submit <2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
1. Submit copy of the report, Attention: QAS for MC1481, Fax (507) 284-1902. 
2. For patients who previously had full flow immunophenotyping performed and at pre-study workup had limited 
repeat flow immunophenotyping, submit a copy of both reports. 
 
 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
Test Schedule Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Evaluation/Treatment  
X2 
X 
 
Evaluation/Observation  
 
 
X1 
Nadir/Adverse Event  
X 
X 
X 
Measurement  
X 
X 
X 
Quantitative Flow Cytometry  
X4 
X 
X 
Research Blood Submission  
X4 (see Section 14.0) 
X 
 
Research Bone Marrow Aspirate 
Submission  
X4 (see Section 14.0) 
X 
 
Bone Marrow Biopsy  
X4 
X4 
X4 
Other Laboratory Results  
X 
X 
X 
Immunophenotyping/MRD Report3 
X4 
X4 
 
Bone Marrow Biopsy Report3 
X4 
X4 
 
CT Scan Report3 
X4 
X4 
 
Psychology and QOL Assessments 
X4 
X4 
 
End of Active Treatment/Cancel 
Notification  
 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
 
1. Complete at each evaluation during Observation (see Section 4.0). 
 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
 
3. Submit copy of the report, Attention: QAS for MC1481, Fax (507) 284-1902. 
 
4. Complete when required per the test schedule. 
 
 
 

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Addendum 7 
 
Protocol Version: 20Sep2018 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
q. 3 months until PD or 
subsequent treatment 
for CLL2 
At PD or subsequent 
treatment for CLL2 
q. 6 mos. after PD 
or subsequent 
treatment for CLL 
Death 
New Primary
Event 
Monitoring  
X 
X 
X 
X 
At each 
occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Submit copy of documentation of progression to the Operations Office, Attention: QAS for MC1481, 
Fax (507) 284-1902. 
 
19.0  
Budget 
 
19.1 
Costs charged to patient:  All routine clinical care.  Ibrutinib will be provided free of 
charge by Pharmacyclics. 
 
19.2 
Tests to be research funded:  Correlative studies outlined in Sections 14.0.   
 
19.3 
Other budget concerns: Protocol administration, study coordinator time, data 
management, and statistical analysis efforts will be funded by Pharmacyclics. 
 
 

MC1481 
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Addendum 7 
 
Protocol Version: 20Sep2018 
 
20.0 
References 
 
1. 
Aksentijevich I, Flinn IW. Chronic lymphocytic leukemia: advances in biology and therapeutics. 
Curr Opin Oncol. Jan 2003;15(1):16-22. 
2. 
Dighiero G, Binet JL. When and how to treat chronic lymphocytic leukemia. N Engl J Med. Dec 
14 2000;343(24):1799-1801. 
3. 
Moreno C, Villamor N, Colomer D, et al. Clinical significance of minimal residual disease, as 
assessed by different techniques, after stem cell transplantation for chronic lymphocytic 
leukemia. Blood. Jun 1 2006;107(11):4563-4569. 
4. 
Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent 
predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate 
analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. Mar 20 2012;30(9):980-988. 
5. 
Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously 
untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German 
Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. Sep 10 2012;30(26):3209-3216. 
6. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. Jun 15 
2008;111(12):5446-5456. 
7. 
Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group 
guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. 
Blood. Jun 15 1996;87(12):4990-4997. 
8. 
Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary 
therapy for chronic lymphocytic leukemia. N Engl J Med. Dec 14 2000;343(24):1750-1757. 
9. 
Keating MJ. Chronic lymphocytic leukemia. Semin Oncol. Oct 1999;26(5 Suppl 14):107-114. 
10. 
Schmitt B, Wendtner CM, Bergmann M, et al. Fludarabine combination therapy for the treatment 
of chronic lymphocytic leukemia. Clin Lymphoma. Jun 2002;3(1):26-35. 
11. 
Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized 
trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst. May 19 1999;91(10):861-868. 
12. 
Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP 
in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. Oct 15 
2001;98(8):2319-2325. 
13. 
Plunkett W, Gandhi V, Huang P, et al. Fludarabine: pharmacokinetics, mechanisms of action, and 
rationales for combination therapies. Semin Oncol. Oct 1993;20(5 Suppl 7):2-12. 
14. 
Weiss MA, Maslak PG, Jurcic JG, et al. Pentostatin and cyclophosphamide: an effective new 
regimen in previously treated patients with chronic lymphocytic leukemia. J Clin Oncol. Apr 1 
2003;21(7):1278-1284. 
15. 
Keating MJ, O'Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic 
leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. Aug 15 
1998;92(4):1165-1171. 
16. 
Koehl U, Nowak B, al. e. Fludarabine and cyclophosphamide: synergistic cytoxicity associated 
with inhibition of interstrand cross-link removal. Proc Am Assoc Cancer Res. 1997;38:2. 
17. 
O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide 
combination regimen in chronic lymphocytic leukemia. J Clin Oncol. Mar 1 2001;19(5):1414-
1420. 
18. 
Marotta G, Bigazzi C, Lenoci M, Tozzi M, Bocchia M, Lauria F. Low-dose fludarabine and 
cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to 
conventional therapy. Haematologica. Dec 2000;85(12):1268-1270. 

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19. 
Piro LD, White CA, Grillo-Lopez AJ, et al. Extended Rituximab (anti-CD20 monoclonal 
antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. 
Ann Oncol. Jun 1999;10(6):655-661. 
20. 
McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal 
antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose 
treatment program. J Clin Oncol. Aug 1998;16(8):2825-2833. 
21. 
Czuczman MS, Fallon A, Mohr A, et al. Rituximab in combination with CHOP or fludarabine in 
low-grade lymphoma. Semin Oncol. Feb 2002;29(1 Suppl 2):36-40. 
22. 
Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell 
chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity 
and acceptable toxicity. J Clin Oncol. Apr 15 2001;19(8):2153-2164. 
23. 
O'Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic 
lymphocytic leukemia. J Clin Oncol. Apr 15 2001;19(8):2165-2170. 
24. 
Golay J, Lazzari M, Facchinetti V, et al. CD20 levels determine the in vitro susceptibility to 
rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 
and CD59. Blood. Dec 1 2001;98(12):3383-3389. 
25. 
Bellosillo B, Villamor N, Lopez-Guillermo A, et al. Complement-mediated cell death induced by 
rituximab in B-cell lymphoproliferative disorders is mediated in vitro by a caspase-independent 
mechanism involving the generation of reactive oxygen species. Blood. Nov 1 2001;98(9):2771-
2777. 
26. 
Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with 
concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-
cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 
9712). Blood. Jan 1 2003;101(1):6-14. 
27. 
Byrd JC, Park K. Rituximab added to fludarabine improves response in previously untreated 
chronic lymphocytic leukemia: Preliminary reesult from CALGB 9712. Proc Am Soc Clin Oncol. 
2001;20:280a (Abstract 1116). 
28. 
Hainsworth JD, Litchy S, Barton JH, et al. Single-agent rituximab as first-line and maintenance 
treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a 
phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. May 1 
2003;21(9):1746-1751. 
29. 
Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic 
lymphocytic leukemia. Blood. Sep 1 2001;98(5):1326-1331. 
30. 
Marotta G, Lenoci M, Fabbri A, Tozzi M, Lauria F. Efficacy of rituximab in the treatment of 
refractory chronic lymphocytic leukemia patient with bone marrow aplasia. Hematol J. 
2002;3(6):299-301. 
31. 
Garcia-Manero G, Cortes J. Combination fludarabine, cyclophosphamide and rituximab for 
previously treated patients with chronic lymphocytic  leukemia. Blood. 2000;96:757a. 
32. 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, 
phase 3 trial. Lancet. Oct 2 2010;376(9747):1164-1174. 
33. 
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and 
coexisting conditions. N Engl J Med. Mar 20 2014;370(12):1101-1110. 
34. 
Faderl S, Coutre S, Byrd JC, et al. The evolving role of alemtuzumab in management of patients 
with CLL. Leukemia. Dec 2005;19(12):2147-2152. 
35. 
Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients 
with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy 
within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). 
Leukemia. Jun 2004;18(6):1093-1101. 

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36. 
Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A. Ofatumumab is active 
in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 
2 international study. Blood. Nov 10 2011;118(19):5126-5129. 
37. 
Barth MJ, Czuczman MS. Ofatumumab: a novel, fully human anti-CD20 monoclonal antibody 
for the treatment of chronic lymphocytic leukemia. Future Oncol. Dec 2013;9(12):1829-1839. 
38. 
Davids MS, Brown JR. Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase. 
Future Oncol. May 2014;10(6):957-967. 
39. 
Ibrutinib (Imbruvica) for chronic lymphocytic leukemia. Med Lett Drugs Ther. Apr 14 
2014;56(1440):29-30. 
40. 
Lee HZ, Miller BW, Kwitkowski VE, et al. U.s. Food and drug administration approval: 
obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic 
lymphocytic leukemia. Clin Cancer Res. Aug 1 2014;20(15):3902-3907. 
41. 
Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and 
reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. May 22 
2014;123(21):3286-3295. 
42. 
O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with 
chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, 
phase 1b/2 trial. Lancet Oncol. Jan 2014;15(1):48-58. 
43. 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-
cell lymphoma. N Engl J Med. Aug 8 2013;369(6):507-516. 
44. 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic 
lymphocytic leukemia. N Engl J Med. Jul 4 2013;369(1):32-42. 
45. 
Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with 
chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. Apr 4 2014. 
46. 
Rossi D, Gaidano G. Lymphocytosis and ibrutinib treatment of CLL. Blood. Mar 20 
2014;123(12):1772-1774. 
47. 
Hillmen P. MRD in CLL. Clin Adv Hematol Oncol. May 2006;4(5):6-7; discussion 10; suppl 12. 
48. 
Rawstron AC, Hillmen P. Assessing minimal residual disease in chronic lymphocytic leukemia. 
Curr Hematol Malig Rep. Jan 2008;3(1):47-53. 
49. 
Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic 
lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin 
Oncol. May 1 2005;23(13):2971-2979. 
50. 
Hillmen P. Minimal residual disease and survival in chronic lymphocytic leukemia. Clin Adv 
Hematol Oncol. Jul 2005;3(7):522-524. 
51. 
Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of 
hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American 
Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol. Oct 15 
2000;18(20):3558-3585. 
52. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol. Aug 10 2012;30(23):2820-2822. 
53. 
Byrd JC, O'Brien S, James DF. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J 
Med. Sep 26 2013;369(13):1278-1279. 
54. 
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic 
lymphoid leukemia. N Engl J Med. Jul 17 2014;371(3):213-223. 
55. 
Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase 
inhibitor ibrutinib. N Engl J Med. Jun 12 2014;370(24):2286-2294. 
56. 
Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4 somatic mutation activates AKT and 
ERK, and promotes resistance to ibrutinib and other agents used in the treatment of 
Waldenstrom's Macroglobulinemia. Leukemia. Jun 10 2014. 
57. 
Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of 
ITK driving a Th1-selective pressure in T lymphocytes. Blood. Oct 10 2013;122(15):2539-2549. 

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58. 
Kaplan E, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc. 
1958;53:457-481. 
59. 
Thekkumpurath P, Walker J, Butcher I, Hodges L, Kleiboer A, O'Connor M, et al. Screening for 
major depression in cancer outpatients: the diagnostic accuracy of the 9-item patient health 
questionnaire. Cancer. 2011;117(1):218-27. 
60. 
Kroenke K, Spitzer RL. The PHQ-9: A New Depression Diagnostic and Severity Measure. 
Psychiatric Annals 32:9/September 2002 
61. 
Nes, Lise Solberg, Heshan Liu, Christi A. Patten, Sarah M. Rausch, Jeff A. Sloan, Yolanda I. 
Garces, Andrea L. Cheville, Ping Yang, and Matthew M. Clark. "Physical Activity Level and 
Quality of Life in Long Term Lung Cancer Survivors." Lung Cancer 77.3 (2012): 611-16. Web. 
 

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Appendix I 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 

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Appendix II 
Rai Staging System for CLL 
 
Modified 3-stage System 
Rai Stage 
Clinical Features 
Low Risk 
0 
Lymphocytes (L) in blood 
> 5000/mm3 and marrow > 30% only 
 
 
Intermediate Risk 
I 
L+ enlarged lymph nodes (LN) 
 
II 
L + spleen and/or liver (LN + or -) 
High Risk 
III 
L + anemia (Hb < 11 g/dl) 
 
IV 
L + Thrombocytopenia < 100,000/µl. 
 
Subjects in the intermediate risk group must have evidence of active disease as demonstrated by at least 
one of the following criteria: 
 
Massive or progressive splenomegaly and/or lymphadenopathy; (Massive splenomegaly is here defined 
by spleen tip > 6 cm below costal margin.) 
 
Presence of weight loss > 10% over the preceding 6 month period; 
 
Grade 2 or 3 fatigue; 
 
Fevers > 100.5°F or night sweats for longer than 2 weeks without evidence of infection; 
 
Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling 
time of less than 6 months; 
 
Worsening anemia or thrombocytopenia. 
 
 
 

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Appendix III Criteria for Diagnosis of Disease 
 
Specific diagnosis of B-Cell CLL meeting the following criteria at any time during the course of disease 
(e.g., at initial diagnosis, at relapse, etc.): 
 
• 
An absolute lymphocytosis of > 5,000/mm3. 
 
• 
Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes by manual 
differential. 
 
• 
The aspirate smear must show > 30% of nucleated cells to be lymphoid or the bone marrow core 
biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL. The overall 
cellularity must be normocellular or hypercellular. 
 
• 
Local institution lymphocyte immunophenotype must reveal a predominant B-cell monoclonal 
population sharing a B-cell marker (CD19, CD20, CD23, CD24) with the CD5 antigen in the 
absence of other pan-T-cell markers. While the absence of CD23 expression will not exclude 
subjects, it should prompt close re-examination of the lymphocyte morphology to exclude the 
diagnosis of mantle cell lymphoma in the leukemic phase. 
 

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Protocol Version: 20Sep2018 
Appendix IV  Definition of Symptomatic B-Cell 
Active disease should be clearly documented for protocol therapy. At least one of the following criteria 
should be met:  
Evidence of progressive marrow failure as manifested by the development of or worsening of anemia 
(Hb < 11.0 g/dL) and/or thrombocytopenia (Platelets < 100 x 109) 
Massive (e.g., at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly  
Massive nodes (e.g., at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy  
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte 
doubling time (LDT) of less than 6 months. LDT can be obtained by linear regression 
extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation 
period of 2 to 3 months. In patients with initial blood lymphocyte counts of less than 30 x 109/L 
(30 000/µL), LDT should not be used as a single parameter to define a treatment indication. In 
addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., 
infections) should be excluded.  
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other 
standard therapy.  
Constitutional symptoms, defined as any one or more of the following disease-related symptoms or 
signs:  
 
Unintentional weight loss of 10% or more within the previous 6 months;  
 
significant fatigue (e.g., inability to work or perform usual activities);  
 
fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of 
infection;  or  
 
night sweats for more than 1 month without evidence of infection.  
 

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Appendix V 
Grading Scale for Hematologic Toxicity in CLL Studies 
Non Hematologic Toxicity will be scored using NCI CTCAE (version 4.0) for toxicity and adverse event 
reporting.   
Hematologic toxicity will be assessed using IWCLL/Hallek December 20086 
 
Grading scale for hematologic toxicity in CLL studies  
 
 Grade*  
 Decrease in platelets  or Hb  (nadir) from pretreatment 
value, %  
 Absolute neutrophil count/µL  
(nadir)  
 
 0  
 No change to 10%  
  2000  
 1  
 11%-24%  
  1500 and < 2000  
 2  
 25%-49%  
  1000 and < 1500  
 3  
 50%-74%  
  500 and < 1000  
 4  
  75%  
 < 500  
 
 
* Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result of 
toxicity at any level of decrease from pretreatment will be recorded as grade 5.  
Platelet counts must be below normal levels for grades 1 to 4. If, the platelet count is < 20 x 109/L (20 
000/µL) at any level of decrease, this will be considered grade 4 toxicity unless a severe or life-
threatening decrease in the initial platelet count (eg, 20 x 109/L [20 000/µL]) was present pretreatment.  In 
this case, the patient will not be evaluable for toxicity referable to platelet counts.  
Hb levels must be below normal levels for grades 1 to 4. Baseline and subsequent Hb determinations 
must be performed before any given transfusions. The use of erythropoietin is irrelevant for the grading of 
toxicity but should be documented.  
If the absolute neutrophil count (ANC) reaches < 1 x 109/L (1000/µL), it should be judged to be grade 3 
toxicity. Other decreases in the white blood cell count or in circulating neutrophils are not to be 
considered because a decrease in the white blood cell count is a desired therapeutic endpoint. A gradual 
decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity. If the ANC was < 
1 x 109/L (1000/µL) before therapy, then the patient will not be evaluable for toxicity referable to the 
ANC. The use of growth factors such as G-CSF is not relevant to the grading of toxicity but should be 
documented. 
 
 

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Appendix VI – Medication Diary 
 
Patient Instructions 
 
• 
Please indicate on the calendar below every day that you take your study medication by placing the dose 
taken on the line under the date.  
• 
If you miss a dose, place a check “0” under the date, but remember to take your prescribed dose at the next 
regularly scheduled time. 
• 
Bring all bottles and any unused study medication along with this diary when you return for your next 
appointment. 
 
Medication(s) 
Dose 
Ibrutinib 
420 mg 
 
 
 
 
 
 
 
 
 
Date:__________________ 
Participants Signature_________________________________ 
 
 
 
 
 
Area Below Only To Be Completed only by Coordinator 
 
Number of pills returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
 
 
 
Discrepancy Yes____ No_____ 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 

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Protocol Version: 20Sep2018 
Appendix VII – Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of te oesophagus for 
bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 

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Appendix VIII – Patient Health Questionaire 8 
 
 
 
 

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Appendix IX – Generalized Anxiety Disorder 7-item (GAD-7) scale 
 
  
 
 

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Appendix X – Medical Outcomes Study: Social Support Survey (MOS-SSS) 
 
 
 
 

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Appendix XI – Linear Analogue Self-Assessment 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix XII – Clinical Response Criteria 
Clinical Response Definitions:   
The International Working Group criteria (IWCLL)6 will be used to assess response to therapy.  
 
A. 
COMPLETE RESPONSE (CR) requires all of the following for a period of at least  
2 months.  
 
1. Absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) by physical 
examination. 
 
2. No hepatomegaly or splenomegaly by physical examination. 
 
3. Absence of constitutional symptoms. 
 
4. CBC demonstrating: 
o Neutrophils >1500/ul. 
o Platelets >100,000/ul (without transfusion). 
o Hemoglobin >11.0 gm/dl (without transfusion). 
o Peripheral blood lymphocytes <4000/uL. 
 
Note: Patients who fulfill all criteria for a CR but who have a persistent 
anemia, thrombocytopenia, or neutropenia related to drug toxicity rather 
than residual CLL will be classified as CR with incomplete marrow 
recovery (CRi) according to the international criteria.6 
 
5. Bone marrow aspirate and biopsy should be performed within two months 
after documentation of clinical and laboratory evidence of a complete 
response to document that a complete response (CR) has been achieved as 
per standard practice based upon IWCLL.  The marrow sample should 
ideally be at least normocellular with <30% of nucleated cells being 
lymphocytes.  Samples are to be analyzed by a pathologist and the presence 
or absence of nodules noted.  Repeat bone marrow aspirate and biopsy are 
not necessary to document sustained CR. 
 
NOTE:  Patients who fulfill all criteria for a CR but who have hypocellular 
marrow will be classified as a CR with incomplete marrow recovery (CRi). 
 
In a subset of patients who are otherwise in a complete response, bone 
marrow nodules can be identified histologically.  In such cases, special stains 
will be performed to determine whether such nodules represent "regenerative 
nodules" or residual "clonal nodules".  The presence of regenerative nodules 
is consistent with CR while the presence of residual clonal nodules will be 
classified as an nPR (nodular PR) which is a sub-classification of PR.   Per 
the PR criteria, patients must fulfill one or more of the blood count 

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Protocol Version: 20Sep2018 
parameters (Section 11.224, 11.225, 11.226) but are not required to meet all 
3 of these conditions. 
 
Note:  In a patient who achieves clinical and laboratory evidence of a 
complete response, the objective status should be recorded as a CCR on the 
cycle where the formal response evaluation occurred until a bone marrow 
biopsy and aspirate have been performed.  At that time, the objective status 
should be amended to classify the patient as a CR, CRi, or nPR on the cycle 
where the formal response evaluation occurred. 
 
6. Patients who have clinical and laboratory evidence of CR but who have not 
yet had a bone marrow biopsy to distinguish between CR and nPR will be 
classified as having a Complete Clinical Response (CCR) until the marrow 
biopsy is obtained.  Patients must meet all of the blood count parameters 
listed in section 11.214. 
 
7. In some settings MRD assays may be considered as a surrogate of response 
as discussed in section 11.3.  No other laboratory assays (e.g., quantitative 
immunoglobulins) will be used currently as an index for response but will be 
recorded for clinical correlations. 
 
8. For patients whose only measurable disease at the time of enrollment is on 
CT scan, a CT scan showing absence of lymphadenopathy (e.g. lymph nodes 
>1.5 cm) is required before classifying patients a CR. 
 
B. 
PARTIAL RESPONSE (PR) requires the patient exhibits at least two of the features 
in Sections 11.221, 11.222, and 11.223 below (if abnormal prior to therapy) as well 
as one or more of the remaining features (Sections 11.224, 11.225, 11.226) for at 
least 2 months.  In addition to the parameters listed below, the presence or absence of 
constitutional symptoms will be recorded.  
 
1. ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment 
baseline value. Note: This criteria will not be applicable if patients are 
experiencing ibrutinib associated lymphocytosis as noted above in section 
11.0. (LRF workshop)52  
 
2. ≥ 50% reduction in the sum of the products of the maximal perpendicular 
diameters of the largest measured node or nodal masses in the right and left 
cervical, axillary, and inguinal lymph node regions on physical examination.  
 
3. ≥ 50% reduction in size of liver and/or spleen as measured by physical exam 
noting the maximal distance below the respective costal margins of palpable 
hepatosplenomegaly during rest.   
 
4. Neutrophils >1500/ul or 50% improvement over baseline. 
 
5. Platelets >100,000/ul or 50% increase over baseline. 

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6. Hemoglobin >11.0 gm/dl or 50% increase over baseline without transfusions. 
 
7. For patients whose only measurable disease at the time of enrollment is on CT scan, 
a CT scan demonstrating > 50% reduction of target nodes enlarged at baseline is 
required before classifying patients a PR. 
 
C. 
PROGRESSION (PD):  Patients will continue to receive protocol therapy unless 
they have evidence of disease progression according to the IWCLL criteria6 as 
evidenced by: 
 
1. 
 ≥ 50% increase in the sum of the products of at least 2 lymph nodes on 2 
consecutive determinations 2 weeks apart (at least one node must be ≥2 
cm) that persist for > 3 months or the appearance of new palpable lymph 
nodes >1.5 cm not due to a tumor flare.  Enlargements or the appearance 
of new nodes due to a tumor flare do NOT qualify as progression.   
 
2. 
≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin on 2 consecutive 
determinations 2 weeks apart and with a minimum of a ≥ 2 cm increase 
in size from baseline; or appearance of hepatomegaly or splenomegaly 
which was not previously present at baseline and not due to a tumor 
flare. 
3. 
Transformation to a more aggressive histology (e.g. Richter’s 
transformation). 
 
 
Note:  If a patient develops DLBCL at any time, it will be considered 
disease progression.  If the patient develops any other hematologic 
malignancy while on study, it will not be considered progressive disease. 
 
4. 
≥ 50% increase in the absolute number of circulating lymphocytes NOT 
due to infection, tumor flare or drug-associated lymphocytosis (taking as 
reference for progressive disease the smallest absolute lymphocyte count 
recorded since the treatment started).  The absolute lymphocyte count 
must be at least 5000/mm3 to qualify as disease progression. 
 
5. 
In the absence of progression as defined by 1, 2, 3, or 4 above, the 
presence of a ≥ 2 g/dl decrease in HGB, or ≥ 50% decrease in platelet 
count or absolute neutrophil count will NOT exclude a patient from 
continuing the study.  Work-up of such decreases to exclude auto-
immune hemolytic anemia, pure red cell aplasia, or idiopathic 
thrombocytopenic purpura (ITP) should be considered. 
 
6. 
For patients who achieve a CR or nodular PR, progression will be 
defined as recurrence of circulating leukemia cell clone and an ALC 
>5000 or recurrence of adenopathy >1.5 cm not due to a tumor flare. 
 

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Protocol Version: 20Sep2018 
D.     
Not PD:   The patient was evaluated for progression only in this cycle and a 
formal response evaluation did not occur.  The patient did not meet the criteria 
for progression per section 11.23.   
 
Note: Formal response evaluation should occur every 2 cycles during treatment, 
with the first response evaluation occurring at the end of cycle 2. Formal 
response evaluation should occur every cycle during observation. Objective 
status should be classified as PD vs. Not PD on cycles when a formal response 
evaluation does not occur. 
 
 
 
 
 
 
 

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E. 
Summary Definition of objective response for patients with B-CLL 
 
 
CCR1 
CR2 
CRi3 
nPR4 
PR5 
PD6 
PHYSICAL EXAMINATION 
Nodes7 
None 
None 
None 
None 
≥50%  
≥50% , new nodes 
Liver/spleen8 
Not palpable Not palpable 
Not palpable 
Not palpable 
≥50%  
≥50% , newly palpable 
Symptoms 
None 
None 
None 
None 
N/A 
N/A 
PERIPHERAL BLOOD 
ANC 
>1500/µL 
>1500/µL 
See footnote 3 >1500/µL or 
>50% 
improvement 
from baseline 
>1500/µL or >50% 
improvement from 
baseline 
See footnote 6 
Platelets 
>100,000/ 
µL 
>100,000/µL 
See footnote 3 >100,000/µL 
or >50% 
improvement 
from baseline 
>100,00/µL or >50% 
improvement from 
baseline 
See footnote 6 
Hemoglobin 
>11.0 g/dL 
without 
transfusion 
>11.0 g/dL 
without 
transfusion 
See footnote 3 >11.0 g/dL or 
>50% 
improvement 
from baseline 
without 
transfusion 
>11.0 g/dL or >50% 
improvement from 
baseline without 
transfusion 
See footnote 6 
Lymphocytes 
<4000/µL 
<4000/µL 
<4000/µL 
<4000/µL 
≥50%  
≥50%  to at least 
5,000/µL 
BONE MARROW 
N/A 
Normocellular3; 
<30% 
lymphocytes; 
no nodules 
<30% 
lymphocytes; 
no nodules 
<30% 
lymphocytes; 
bone marrow 
nodules4 
N/A 
N/A 
1. Clinical complete response (CCR) requires fulfillment of all physical exam and peripheral blood criteria as noted in the table above.  No 
bone marrow biopsy is required to call a patient a CCR; however, patients should have a bone marrow analysis performed within two  
month of the formal response evaluation where clinical and laboratory evidence of complete response was first seen as instructed in the 
test schedule to confirm CR as per standard guidelines by the IWCLL.   
2. Complete response (CR) requires fulfillment of all physical exam and peripheral blood criteria for a duration of ≥2 months.  A bone 
marrow aspirate and biopsy are required to document the response as a complete within two month of the formal response evaluation 
where clinical and laboratory evidence of complete response was first seen (see Section 11.21).  

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Protocol Version: 20Sep2018 
3.    Patients who fulfill all criteria for a CR but who have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity 
rather than residual CLL or have hypocellular marrow will be classified as CR with incomplete marrow recovery (CRi).  
4. Nodular partial response (nPR) is essentially a patient who appeared to have a CR but nodules were present in the bone marrow.  It 
requires fulfillment of all physical exam and lymphocyte criteria for CR; however, when the bone marrow is done to confirm CR, 
nodules of malignant lymphocytes are found.  Patients must fulfill one or more of the blood count parameters (ANC, Platelets, 
Hemoglobin) but are not required to meet all 3 of these conditions.  See Section 11.215 regarding the distinction between clonal and 
regenerative nodules.  
5. Partial response (PR) requires fulfillment of at least two of the above-noted decrease in circulating lymphocytes, regression in 
adenopathy and regression in hepatosplenomegaly, and at least one other parameter listed above for a duration of ≥ 2 months.  See 
Section 11.22. 
6. Progression:  Fulfilling the criteria as noted in section 11.23.  Prior to the formal response evaluation, baseline on study measurements 
will be used to determine disease progression (e.g. not cycle by cycle comparisons).  Once patients undergo formal response evaluation, 
the nadir value at either baseline or time of response will be used for evaluating future disease progression. In the absence of other 
indices of clinical progression, the presence of a ≥ 2 g/dL decrease in hemoglobin or a ≥ 50% decrease in platelet count and/or absolute 
neutrophil count will not exclude a patient from continuing on the study. Although not mandatory, bone marrow aspirate and biopsy are 
strongly encouraged to better define the cause of the suppressed counts (e.g., treatment versus disease-related). 
7. Measurement of lymphadenopathy will be determined on physical exam by adding the sum of the products of the maximal 
perpendicular diameters of measured lesion(s).  No simultaneous increase in the size of any lesions or the appearance of any new lesions 
may occur for 2 consecutive evaluations at least 1 month apart   Minor fluctuations are acceptable as long as they don't exceed 50% of 
previous measurement.  However, if they do exceed 50% of the previous measurement, treatment should be held for 2 consecutive 
cycles to rule out the possibility of nodes that wax and wane.  For purposes of determining CCR and nPR, all nodes on physical exam 
need to be ≤ 1.5 cm in maximal dimension or documented to be free of CLL by biopsy. NOTE: Information from CT scans regarding 
lymphadenopathy is not considered in the standard classification of response with the exception of the patients fitting criteria of section 
11.218 and 11.227. 
8. Measurement of hepatosplenomegaly will be determined by noting the maximal distance below the respective costal margins of palpable 
hepatosplenomegaly during rest (e.g., not during deep inspiration). NOTE: Information from CT scans regarding hepatosplenomegaly is 
not considered in the standard classification of response with the exception of the patients fitting criteria of section 11.218 and 11.227.