A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)
Phase: PHASE3
Conditions: Anemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: National Cancer Institute (NCI)

E1912 
 
1 
This is an FDA Registration Trial 
E1912: A Randomized Phase III Study of Ibrutinib (PCI-
32765)-based Therapy vs Standard Fludarabine, 
Cyclophosphamide, and Rituximab (FCR) 
Chemoimmunotherapy in Untreated Younger Patients 
with Chronic Lymphocytic Leukemia (CLL) 
STUDY CHAIR: 
ECOG CO-CHAIR: 
SWOG CO-CHAIR: 
CALGB CO-CHAIR: 
STUDY STATISTICIAN: 
LEUKEMIA COMMITTEE CHAIR: 
PATIENT OUTCOMES AND 
SURVIVORSHIP CHAIRS: 
 
PATHOLOGY CO-CHAIR: 
LABORATORY CO-CHAIR: 
Version Date:  January 20, 2023 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
SWOG / SWOG 
 
January 31, 2014  
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
Amendment #1 – 3/14 
CCTG / Canadian Cancer Trials Group 
 
Amendment #2 – 7/14 
NRG / NRG Oncology 
 
Amendment #3 – 8/15 
 
 
Amendment #4 – 1/16 
 
 
Amendment #5 – 11/16 
 
 
Amendment #6 – 12/16 
 
 
Amendment #7 – 8/17 
 
 
Amendment #8 
 
Agent 
IND# 
NSC# 
Supply 
Ibrutinib 
 
748645 
NCI 
Fludarabine 
 
312887 
Commercial 
Cyclophosphamide 
 
26271 
Commercial 
Rituximab 
 
687451 
Commercial 
 
Rev. 3/14 
Rev. 7/14 
Rev. 7/14,  
8/15, 11/16 
NCT02048813

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Chronic lymphocytic leukemia .................................................................. 7 
1.2 
Ibrutinib (NSC 748645) .............................................................................. 8 
1.3 
2015 Ibrutinib Safety Update .................................................................... 9 
1.4 
Rationale ................................................................................................. 11 
1.5 
Quality of Life .......................................................................................... 12 
2. Objectives ......................................................................................................... 13 
2.1 
Primary Objectives .................................................................................. 13 
2.2 
Secondary Objectives .............................................................................. 13 
3. Selection of Patients ......................................................................................... 14 
3.1 
Eligibility Criteria ..................................................................................... 14 
4. Registration Procedures .................................................................................... 19 
4.1 
Protocol Number ..................................................................................... 22 
4.2 
Investigator Identification ....................................................................... 22 
4.3 
Patient Identification .............................................................................. 22 
4.4 
Eligibility Verification .............................................................................. 22 
4.5 
Stratification Factors: .............................................................................. 22 
4.6 
Additional Requirements ........................................................................ 23 
4.7 
Investigational Brochure ......................................................................... 24 
4.8 
Instructions for Patients who Do Not Start Assigned Protocol Treatment24 
5. Treatment Plan ................................................................................................. 25 
5.1 
Administration Schedule ......................................................................... 25 
5.2 
Adverse Event Reporting Requirements ................................................. 34 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for PCI-
32765 (Ibrutinib, NSC 748645) ................................................................ 45 
5.4 
Dose Modifications and Management of Toxicity .................................. 50 
5.5 
Supportive Care ....................................................................................... 56 
5.6 
Duration of Therapy ................................................................................ 58 
5.7 
Duration of Follow-up ............................................................................. 58 
6. Measurement of Effect ..................................................................................... 59 
6.1 
Assessment of Clinical Response ............................................................ 59 
7. Study Parameters .............................................................................................. 66 
7.1 
Therapeutic Parameters .......................................................................... 66 
7.2 
Biological Sample Submissions ............................................................... 69 
8. Drug Formulation and Procurement ................................................................. 71 
8.1 
Ibrutinib (NSC 748645) PCI-32765 .......................................................... 71 
8.2 
Allopurinol (Lopurin, Zyloprim) ............................................................... 74 
8.3 
Rituximab (IDEC-C2B8, Rituxan®) ............................................................ 75 
8.4 
Fludarabine Monophosphate [Fludara; Berlex laboratories] ................. 76 

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8.5 
Cyclophosphamide (Cytoxan®; CTX; CPA; Endoxan®; Neosar®; Cytoxan 
Lyophilized®) ........................................................................................... 77 
9. Statistical Considerations .................................................................................. 80 
9.1 
Study Design and Objectives ................................................................... 80 
9.2 
Accrual ..................................................................................................... 81 
9.3 
Primary Endpoint and Sample Size ......................................................... 81 
9.4 
Phase III Interim Analysis of the Primary Endpoint ................................. 82 
9.5 
Secondary Objectives .............................................................................. 83 
9.6 
Quality of Life .......................................................................................... 84 
9.7 
Correlative Studies .................................................................................. 85 
9.8 
Anticipated Accrual by Gender and Ethnicity ......................................... 87 
9.9 
Randomization Procedure ...................................................................... 87 
9.10 Study Monitoring .................................................................................... 87 
9.11 Safety Monitoring ................................................................................... 88 
10. Correlative Studies ............................................................................................ 89 
10.1 Submissions to the ECOG-ACRIN Leukemia Translational Research 
Laboratory ............................................................................................... 89 
10.2 Submissions to Mayo Clinic for Correlative Studies ................................ 93 
10.3 Studies to be performed: ........................................................................ 95 
10.4 ECOG-ACRIN Sample Tracking System .................................................... 97 
10.5 Banking .................................................................................................... 98 
10.6 Sample Inventory Submission Guidelines ............................................... 98 
10.7 Lab Data Transfer Guidelines .................................................................. 98 
11. Records to Be Kept ............................................................................................ 99 
11.1 Records Retention ................................................................................... 99 
12. Patient Consent and Peer Judgment .............................................................. 100 
13. References ...................................................................................................... 100 
 Appendix I:  Blood Collection Kit Mayo Clinic CLL Laboratory .............................. 103 
Appendix II:  Patient Thank You Letter .................................................................. 106 
Appendix III:  Ibrutinib Patient Medication Calendar ............................................ 107 
Appendix IV:  CRADA/CTA ..................................................................................... 109 
Appendix V:  ECOG Performance Status ............................................................... 111 
 Appendix VI:  Grading Scale for Hematologic Toxicity in CLL Studies .................. 112 
Appendix VII:  Cumulative Illness Rating Scale ...................................................... 113 
 Appendix VIII:  CYP3A Inhibitors and Inducers ..................................................... 114 
 Appendix IX:  Instructions for Reporting Pregnancies on a Clinical Trial ............. 117 
Appendix X:  Timed Up and Go (TUG) Test1,2 ...................................................... 119 
Appendix XI:  RAI Staging ...................................................................................... 120 
 Appendix XII:  CHILD-PUGH SCORE ....................................................................... 121 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206  
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com.. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions. Do 
not submit study data or 
forms to the CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.   
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 

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1. 
Introduction 
1.1 
Chronic lymphocytic leukemia 
Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid 
malignancies, accounting for ~11% of all hematologic neoplasms.1 CLL affects 
approximately 100,000 individuals in the United States (~15,000 new cases/year) 
and is currently an incurable disease. 1,2  While a majority of patients with CLL 
have early stage disease at diagnosis ~70% eventually progress to require 
treatment and a majority will ultimately die from CLL or CLL related 
complications.3-9  
The last 2 decades have been a time of tremendous advances in the treatment of 
patients with CLL. During this interval, randomized trials have established that 
single agent fludarabine is superior to single agent alkylator-based approaches 
and demonstrated that combination of fludarabine and cyclophosphamide 
improves response rates and progression free survival (PFS) for younger CLL 
patients.10-12 More recently, the addition of rituximab to purine nucleoside 
analogue-based chemotherapy has been shown to not only improve response 
rates and PFS but to also prolong overall survival in patients with CLL. 
Despite the improved efficacy of CIT, only 40-45% of patients treated with these 
approaches currently achieve a CR and nearly all patients (including those 
achieving CR) eventually relapse.13-15  Although they are not curative, aggressive 
fludarabine based CIT regimens also result in substantial toxicity including 
profound immunosuppression, prolonged cytopenias (which can restrict salvage 
therapy options at the time of recurrence), and a 5-10% risk of therapy-related 
myelodysplasia (MDS).14, 16, 17 These toxicities are particularly problematic since 
nearly all CLL patients are >age 50 at diagnosis and many patients have 
coexistent health problems that limit their ability to receive CIT.13  Even among 
younger, fit CLL patients >25% are unable to tolerate FCR-based CIT, where 
previous phase 3 trial indicate that 56% of patients experience grade 3-4 
myelosuppression, 25% an infectious complication, and 47% require dose 
reductions.13  Even with these extensive dose reductions, >25% of patients are 
unable to complete the intended 6 cycles of FCR induction13 The end result is 
that, while FCR has been a major advance in the CLL treatment, it is associated 
with profound toxicity that limits the benefit of this approach for many patients. 
These facts continue to foster interest in identifying novel approaches to improve 
both the efficacy and tolerability of CLL therapy. Although pilot studies have 
explored intensification approaches adding additional cytotoxic agents to CIT in 
an effort to improve efficacy (e.g. FCRM, CFAR, OFAR), the substantial toxicity 
of standard CIT renders these intensification approaches unfeasible for most CLL 
patients.18, 19 
While new combinations of existing/traditional chemotherapeutic agents may 
lead to incremental progress in CLL treatment, more substantive improvements 
will likely occur through therapeutic targeting of novel biologic pathways critical to 
the survival and/or chemotherapy resistance of CLL B-cells.  A profound increase 
in the understanding of CLL B-cell biology over the last decade has identified 
numerous potential therapeutic targets. In this regard, interrupting survival 
signals mediated through the B-cell receptor appears to be one of the most 
promising approaches.20 Multiple groups have now demonstrated single-agent 

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activity with a variety of compounds that interrupt B-cell receptor signaling 
pathway including SYK inhibitors21, PI3 kinase inhibitors, mTOR inhibitors, and 
Bruton’s tyrosine kinase inhibitors22, 23. Notably, these agents have generally 
been found to be well tolerated and to have the additional benefit of being orally 
administered.  The activity of these targeted agents in relapsed/refractory CLL 
patients has created substantial interest in exploring how they may be 
incorporated into first-line therapy with the aim of improving efficacy and 
tolerability. 
1.2 
Ibrutinib (NSC 748645) 
Ibrutinib is one of the most promising of these new compounds. Ibrutinib is an 
irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a member of the Tec family 
of tyrosine kinases and a protein which is over-expressed in patients with CLL.  
Btk is a critical protein involved in B cell development, differentiation, and 
signaling as well as B cell proliferation and survival.18 Inhibition of this kinase has 
been shown to cause modest apoptosis in vitro, and significantly inhibits B cell 
signaling both in vitro and in vivo (19 and unpublished data).  The initial phase I 
studies examined dose escalation in various B cell malignancies.  In this study, 
15 patients with CLL were enrolled with objective response observed in 9/15 
patients.(Fowler, ASH 2010)  The drug was well tolerated at all dose levels 
examined, with only 5 out of 47 patients discontinuing therapy for toxicity. 
(Fowler, ASH 2010).  A fluorescent-labeled probe was used to ensure that the 
doses brought forward occupied >90% of Btk,(Pollyea, ASCO 2009) and based 
on this study, a dose of 420 mg daily was established as a tolerable and effective 
dose.  In an ongoing phase Ib/II study, this agent has shown extraordinary 
activity in 61 patients with relapsed or refractory CLL (O’Brien, ASH 2011).  In 
patients with relapsed or refractory CLL and measurable adenopathy, the rate of 
lymph node shrinkage >50% is 89%.  After a median follow-up of ~12 months, 
ORR is 68%.(O’Brien, ASH 2011).  Transient lymphocytosis in this trial of 
Ibrutinib similar to that observed in clinical trials with the PI3 kinase delta inhibitor 
Cal-101 and is likely related to B-cell release from lymph node and spleen 
microenvironment due to disruption of homing signals or chemoattractants.  
Lymphocytosis with Ibrutinib agent has generally begun within the first 2 cycles, 
appears to resolve sooner than has been observed with Cal-101, and has 
resolved over time in virtually all patients.  While this is currently under 
investigation, the magnitude and duration of lymphocytosis does not appear to be 
related to the depth of eventual response nor to response duration or toxicity.  
Response to Ibrutinib also occurs independently of high risk genomic features 
including IVGH mutational status and deletion(17p13.1).  Studies are ongoing 
with this age in both relapsed and previously untreated patients.  The majority of 
patients in both groups remain on therapy and response over time has continued 
to improve as the majority of patients have had slow continued resolution of their 
lymphocytosis.  
Thus far only 3 out of 83 patients have been removed from study for disease 
progression after 10-12 months follow-up. Oral Ibrutinib is well tolerated, with a 
very low rate of hematologic toxicity and few patients discontinuing therapy due 
to AE.  The most common toxicities with Ibrutinib have been diarrhea, cough, 
fatigue, upper respiratory infection, rash, and bruising.   Importantly, they do not 
overlap with the typical toxicities observed with CIT induction. The efficacy seen 

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thus far and tolerability of this agent administered continuously now to many 
patients for a year or more make it an ideal agent for further study. 
The efficacy of Ibrutinib in combination with anti-CD20 monoclonal antibodies is 
also being explored in a multi-cohort phase 2 trial for patients with relapsed CLL 
and other B-cell malignancies at the Ohio State University. In the first cohort of 
27 patients, Ibrutinib (430 mg) begins on day 1 and continues until disease 
progression with anti-CD20 monoclonal antibody treatment beginning month 2.  
All 27 patients completed the first month of therapy without a DLT.  Of the 24 
patients with CLL, a high rate of clinical activity has been observed and 23 
patients remain on treatment (1 patient proceeded to non-ablative stem cell 
transplant).  A second cohort of patients was accrued in whom the anti-CD20 
monoclonal antibody treatment began on cycle 1 day 1 with Ibrutinib (420 mg) 
beginning cycle 1 day 2 (current accrual n=20).  Nineteen patients completed 1 
month of therapy and one patient suffered a subdural hematoma that was fatal.  
This patient was on warfarin and had other risk factors for developing this 
complication. Infusion toxicities with anti-CD20 monoclonal antibody on day 1 
were manageable but in general were more severe than observed in the first 
cohort.  A third cohort of patients where anti-CD20 monoclonal antibody is given 
for 8 weeks prior to beginning Ibrutinib is currently enrolling patients.  
Collectively, the Ohio State experience of giving Ibrutinib concurrent with anti-
CD20 monoclonal antibody therapy suggests a run in with Ibrutinib for the first 
month followed by initiation of anti- CD20 monoclonal antibody beginning month 
two may be better tolerated.  This schedule of administration will be pursued in 
this study. 
1.3 
2015 Ibrutinib Safety Update 
Pooled safety data are available for a total of 423 patients treated with various 
therapies in combination with ibrutinib across 4 studies conducted in B-cell 
malignancies, including 1 randomized-control study (Investigator’s Brochure, 
2015). Therapies used in combination with ibrutinib in these studies included BR 
(bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone).  The most frequent TEAEs occurring in 
these patients are summarized below. 
Ibrutinib Combination Therapy Studies (N=423) 
Most frequently reported 
TEAEs >20% 
Most frequently reported 
Grade 3 or 4 TEAEs (>3%) 
Most frequently reported 
Serious TEAEs (>2%) 
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension 
 
TEAE = treatment-emergent adverse event 
For more detailed information, refer to the current version of the IB. 
Rev. 1/16 

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1.3.1 
Risks 
Bleeding-related events 
There have been reports of hemorrhagic events in patients treated 
with ibrutinib, both with and without thrombocytopenia.  These include 
minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including 
gastrointestinal bleeding, intracranial hemorrhage, and hematuria.  
Use of ibrutinib in patients requiring other anticoagulants or 
medications that inhibit platelet function may increase the risk of 
bleeding.  Patients with congenital bleeding diathesis have not been 
studied. 
Leukostasis 
There were isolated cases of leukostasis reported in patients treated 
with ibrutinib. A high number of circulating lymphocytes (>400000/µL) 
may confer increased risk. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte 
counts (i.e., ≥ 50% increase from baseline and an absolute count  
> 5000/µL), often associated with reduction of lymphadenopathy, has 
been observed in most patients with CLL/SLL treated with ibrutinib. 
This effect has also been observed in some patients with MCL treated 
with ibrutinib. This observed lymphocytosis is a pharmacodynamic 
effect and should not be considered progressive disease in the 
absence of other clinical findings. In both disease types, 
lymphocytosis typically occurs during the first few weeks of ibrutinib 
therapy (median time 1.1 weeks) and typically resolves within a 
median of 8.0 weeks in patients with MCL and 18.7 weeks in patients 
with CLL/SLL. 
A large increase in the number of circulating lymphocytes (e.g., 
>400000/mcL) has been observed in some patients.  Lymphocytosis 
was not observed in patients with WM treated with ibrutinib.  
Lymphocytosis appeared to occur in lower incidence and at lesser 
magnitude in patients with CLL/SLL receiving ibrutinib in combination 
with chemoimmunotherapy. 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in patients 
treated with ibrutinib, particularly in patients with cardiac risk factors, 
acute infections, and a previous history of atrial fibrillation 
(Investigator’s Brochure, 2015). For atrial fibrillation which persists, 
consider the risks and benefits of ibrutinib treatment and follow the 
protocol dose modification guidelines. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, 
thrombocytopenia, and anemia) were reported in patients treated with 
ibrutinib (Investigator’s Brochure, 2015). 

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Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with 
ibrutinib monotherapy and combination therapy. Other frequently 
reported gastrointestinal events include nausea, vomiting, and 
constipation. These events are rarely severe. 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy.  At 
least 25% of patients with MCL and 35% of patients with CLL had 
Grade 3 or greater infections per NCI Common Terminology Criteria 
for Adverse Events (CTCAE) (Investigator’s Brochure, 2015).  The 
most commonly reported infections include pneumonia, cellulitis, 
urinary tract infection and sepsis.  Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy 
(PML) have occurred in patients treated with ibrutinib. 
Second Primary Malignancies 
Other malignancies, most frequently skin cancers, have occurred in 
patients treated with ibrutinib. 
Rash 
Rash has been commonly reported in patients 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. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in 
patients treated with single-agent ibrutinib or in combination with 
chemotherapy.  Patients at risk of tumor lysis syndrome are those with 
comorbidities and/or risk factors such as high tumor burden prior to 
treatment, increased uric acid (hyperuricemia), elevated LDH, bulky 
disease at baseline, and pre‐existing kidney abnormalities. 
1.4 
Rationale 
These early trials with Ibrutinib indicate that this agent is effective and well 
tolerated in patients with relapsed or refractory CLL and that combining Ibrutinib 
with anti-CD20 monoclonal antibodies is both well-tolerated and may improve 
efficacy.  Ibrutinib has also been shown to antagonize microenvironment signals 
in CLL, which may make it particularly effective at clearing bone marrow disease 
which is a frequent site for residual disease at the completion of CIT25. These 
characteristics, in combination with Ibrutinib’s excellent tolerability profile and the 
fact it is an orally administered agent appear to make it ideally suited for testing 
as both induction therapy or as a consolidation strategy for eradicating residual 
disease after CIT induction. 
The present trial is designed to compare targeted therapy using an oral, Bruton’s 
tyrosine kinase inhibitor (Ibrutinib) to fludarabine-based induction (and reserve it 
as a salvage therapy) in younger patients (</= age 70) with previously untreated 
CLL.  The study employs a randomized phase III design. 

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1.5 
Quality of Life 
CLL has important impacts on patient QOL.  Even though most patients with CLL 
are asymptomatic at the time of diagnosis and are observed for several years 
prior to starting treatment, the diagnosis has a substantial impact on emotional 
QOL even before symptoms develop.26  Once patients progress to require 
treatment, they must deal not only with the effects of the disease on QOL but the 
effects of treatment.27, 28  Several studies suggest that QOL may decline during 
the active phase of fludarabine based treatment but that such therapy improves 
QOL over the long run by alleviating disease related symptoms.12, 28, 30  Not 
surprisingly, these studies also provide evidence that patients with a better 
response to treatment have greater improvements in QOL suggesting that 
disease control and improvements in QOL are linked.12  Although it is possible 
that agents such as Ibrutinib may improve the QOL of CLL patients receiving 
first-line therapy relative to fludarabine-based therapy due to their apparent 
favorable toxicity profile, such an advantage may be short lived if they provide 
less effective disease control.  In addition, although the toxicity profile of Ibrutinib 
appears favorable relative to fludarabine-based therapy, the need for chronic 
indefinite administration may result in chronic side effects that ultimately erode 
QOL over the long run compared to a more intense but limited treatment 
schedule.  The present trial will assess QOL of CLL patients receiving Ibrutinib 
and fludarabine-based therapy to explore these aspects. 
While the primary QOL objective is to assess the impact of therapy on QOL 
between two treatment arms, it is also important to assess the impact of 
treatment-related toxicity on QOL during treatment.  Thus we will perform QOL 
assessments at baseline and at two time points during treatment (3 and six 
months after randomization).  We will also evaluate the effects of these two 
treatment approaches over QOL over the longer term by assessing QOL at the 
time of the 
 and then every  months for  years. 
While those patients assigned to the FCR arm will be off active treatment at 
these points, patients assigned to the experimental Ibrutinib-based treatment arm 
will still be taking therapy.  Thus the QOL of patients at these later time points 
may still differ between arms even though response rates may be equivalent. 
Moreover, as previously stated, improved QOL may be linked to improved 
disease control. This study provides us the opportunity to test this hypothesis by 
following patients longitudinally to see if improvements in QOL are sustained for 
a longer period of time in the disease control phase (up to 2 years after 
treatment) as well as to test for long-term differences in QOL between the two 
groups. 
 

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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
The primary objective for the trial is to evaluate the ability of Ibrutinib -
based induction therapy to prolong progression free survival (PFS) 
compared to standard FCR chemoimmunotherapy for younger 
patients with CLL. 
2.2 
Secondary Objectives 
2.2.1 
Evaluate overall survival (OS) of patients based on treatment arm.  
2.2.2 
Monitor and assess toxicity of treatment with Ibrutinib-based induction 
relative to standard FCR chemotherapy. 
2.2.3 
To compare quality of life (QOL) in CLL patients during the first 6 
months of treatment among patients receiving Ibrutinib-based 
induction therapy relative to standard FCR chemoimmunotherapy. 
2.2.4 
To compare QOL over the long-term in CLL patients receiving 
continuous therapy using Ibrutinib to that of CLL patients who 
completed FCR therapy. 
2.2.5 
Determine the effect of pretreatment clinical and biological 
characteristics (e.g. disease stage, IGHV mutation status, FISH) on 
clinical outcomes (e.g. complete response, PFS) of the different arms 
2.2.6 
Determine if the minimal residual disease (MRD) status as assessed 
by flow cytometry at different time points during and after treatment is 
an effective surrogate marker for prolonged PFS and overall survival. 
2.2.7 
Compare the genetic abnormalities and dynamics of intra-clonal 
architecture of CLL patients before and after treatment with CIT and 
non-CIT approaches and explore relationships with treatment 
resistance. 
2.2.8 
Explore the effects of FCR and Ibrutinib-based therapy on T-cell 
immune function 
2.2.9 
Conduct confirmatory validation genotyping of single nucleotide 
polymorphisms (SNPs) associated with the efficacy and toxicity of 
fludarabine-based therapy as in a prior ECOG GWAS analysis in the 
E2997 trial. 
2.2.10 
Evaluate the ability of prognostic model that incorporates clinical and 
biologic characters to predict a response to therapy and clinical 
outcome (PFS, OS) 
2.2.11 
Evaluate signaling networks downstream of the B-cell receptor in 
patients receiving Ibrutinib-based therapy. 
2.2.12 
Collect relapse samples to study mechanisms of resistance to both 
FCR and Ibrutinib-based therapy. 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Diagnosis of CLL according to the NCI/IWCLL criteria or SLL 
according to the WHO criteria. 
This includes previous documentation of: 
• 
Biopsy-proven small lymphocytic lymphoma 
OR 
• 
Diagnosis of CLL according to the NCI/IWCLL criteria as 
evidenced by all of the following: 
o Peripheral blood lymphocyte count of greater than 5 x109/L 
o Immunophenotype consistent with CLL defined as: 
• 
The predominant population of lymphocytes share both B-
cell antigens [CD19, CD20 (typically dim expression), or 
CD23] as well as CD5 in the absence of other pan-T-cell 
markers (CD3, CD2, etc). 
• 
Clonality as evidenced by κ or λ light chain restriction 
(typically dim immunoglobulin expression) 
• 
Negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral 
blood or tissue biopsy (e.g. marrow aspirate) or negative 
immunohistochemical stains for cyclin D1 staining on involved 
tissue biopsy (e.g. marrow aspirate or lymph node biopsy. 
3.1.2 
No prior chemotherapy, BTK inhibitor therapy, or monoclonal anti-
body therapy for treatment of CLL or SLL 
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3.1.3 
Has met at least one of the following indications for treatment: 
• 
Evidence of progressive marrow failure as manifested by the 
development of worsening anemia (Hg < 11 g/dl) and/or 
thrombocytopenia (Platelets < 100 x 109/L) 
• 
Symptomatic or progressive lymphadenopathy, splenomegaly, or 
hepatomegaly. 
• 
One or more of the following disease-related symptoms: 
o Weight loss ≥ 10% within the previous 6 months 
o Grade 2 or 3 fatigue attributed to CLL 
o Fevers >100.5oF for 2 weeks without evidence of infection 
o Clinically significant night sweats without evidence of infection 
• 
Progressive lymphocytosis (not due to the effects of 
corticosteroids) with an increase of >50% over a two-month period 
or an anticipated doubling time of less than six months. 
3.1.4 
Age ≥ 18 years and ≤ 70 
3.1.5 
ECOG performance status between 0-2. 
3.1.6 
Life expectancy of ≥ 12 months 
3.1.7 
Ability to tolerate FCR based therapy 
3.1.8 
No deletion of 17p13 on cytogenetic analysis by FISH 
3.1.9 
The following laboratory values obtained </= 14 days prior to 
registration: 
_____ 
Glomerular filtration rate (GFR) > 40 mL/minute as 
calculated by the Cockcroft-Gault Formula: 
CrCl (ml/min) =       (140 – age in years)  
              x actual wt (in kg)              x 0.85 (for female pts) 
      72 x serum creatinine (mg/dl) 
_____ 
Total bilirubin ≤ 2.5 x ULN unless due to Gilbert’s disease. 
For those with a total bilirubin > 2.5 x ULN, a direct bilirubin 
should be performed and must be < 1.5 mg/dL for Gilbert’s 
to be diagnosed. 
_____ 
SGOT (AST)/SGPT (ALT) ≤ 3.0 x the institutional ULN 
_____ 
PT/INR < 1.5 ULN and PTT (aPTT) < 1.5 X ULN 
NOTE: If value is higher due to hepatic involvement by CLL, patient 
is eligible. 
3.1.10 
No active hemolytic anemia requiring immunosuppressive therapy or 
other pharmacologic treatment. Patients who have a positive Coombs 
test but no evidence of hemolysis are NOT excluded from 
participation. 
3.1.11 
No current use of corticosteroids. EXCEPTION: Low doses of steroids 
(< 10 mg of prednisone or equivalent dose of other steroid) used for 
treatment of non-hematologic medical condition (e.g. chronic adrenal 
insufficiency) is permitted. 
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3.1.12 
No previous use of corticosteroids for autoimmune complications that 
have developed since the initial diagnosis of CLL. Prior use of 
corticosteroids for reasons other than treatment of autoimmune 
complications is allowed. 
3.1.13 
No other active primary malignancy (other than non-melanomatous 
skin cancer or carcinoma in situ of the cervix) requiring treatment or 
limiting expected survival to ≤ 2 years.   
NOTE: 
If there is a history of prior malignancy, they must not be 
receiving other specific treatment (other than hormonal 
therapy for their cancer). 
3.1.14 
Able to adhere to the study visit schedule and other protocol 
requirements. 
3.1.15 
No major surgery within 4 weeks (28 days) of first dose of study drug 
or minor surgery within 3 days of first dose of study drug. 
3.1.16 
No radiation therapy ≤ 4 weeks prior to registration 
3.1.17 
Patients with HIV infection may be eligible provided they meet the 
following criteria: 
- CD4-positive cell count ≥ lower limit of institutional normal 
- HIV viral load< 10,000 copies HIV RNA/mL (if not on anti-HIV 
therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)  
- No evidence of hepatitis B or C infection  
- No evidence of resistant strains of HIV  
- No history of AIDS-defining condition  
3.1.18 
Patients must not have any of the following conditions: 
• 
Congestive heart failure or New York Heart Association Functional 
Classification III or IV congestive heart failure 
• 
History of myocardial infarction, unstable angina, or acute 
coronary syndrome within 6 months prior to registration. 
• 
Recent infections requiring systemic treatment; need to have 
completed anti-biotic therapy >14 days before the first dose of 
study drug. 
• 
Cerebral vascular accident or intracranial bleed within the last 6 
months 
• 
Infection with known chronic, active hepatitis C. 
• 
Serologic status reflecting active hepatitis B or C infection. 
Patients that are positive for hepatitis B core antibody, hepatitis B 
surface antigen (HBsAg), or hepatitis C antibody must have a 
negative polymerase chain reaction (PCR) prior to enrollment 
(PCR positive patients will be excluded). 
3.1.19 
Patients are not eligible if they require treatment with a strong 
cytochrome P450 (CYP) 3A inhibitor (see Appendix VIII). For 
additional information regarding use of moderate CYP3A4/5 inhibitors 
see Section 8.1.12. 
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3.1.20 
Patients may not be on any other investigational agents 
3.1.21 
Patients may not have received warfarin or another vitamin K 
antagonist in the preceding 30 days.  
3.1.22 
Women must not be pregnant or breast-feeding since this study 
involves an investigational agent whose genotoxic, mutagenic, and 
teratogenic effects on the developing fetus and newborn are 
unknown. 
Female patients of childbearing potential must have a negative serum 
pregnancy test within 2 weeks prior to registration to rule out 
pregnancy.  Female patients who are of non-reproductive potential 
are those who are post-menopausal by history (i.e. no menses for ≥ 1 
year); OR history of hysterectomy; OR history of bilateral tubal 
ligation; OR history of bilateral oophorectomy) 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________________ 
3.1.23 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception or to abstain from sexual intercourse for 90 days after 
the last dose of study drug. 
3.1.24 
Patient must be able to swallow capsules and not have the following 
conditions: 
• 
disease significantly affecting gastrointestinal function 
• 
resection of the stomach or small bowel 
• 
symptomatic inflammatory bowel disease 
• 
ulcerative colitis 
• 
partial or complete bowel obstruction 
3.1.25 
Patient must not be on any other systemic immunosuppressant 
therapy other than corticosteroids within 28 days of the first dose of 
study drug. 
3.1.26 
Patient must not be vaccinated with live, attenuated vaccines within 4 
weeks of first dose of study drug. 
3.1.27 
Patient must not have any known bleeding disorders (e.g., von 
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3.1.28 
Patient must not have currently active, clinically significant hepatic 
impairment (≥ moderate hepatic impairment according to the 
NCI/Child Pugh classification [Appendix XII 
 
 
 
 
 
Physician Signature 
 
Date 
 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation 
 

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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
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at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for the study 
are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review.  However, sites must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB (via 
IRBManager) to indicate their intention to open the study locally.  The CIRB’s approval of 
the SSW is then communicated to the CTSU Regulatory Office for compliance in the 
RSS.  The Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in a given study so that the study 
approval can be applied to those institutions. Other site registration requirements (e.g., 
laboratory certifications, protocol-specific training certifications, or modality credentialing) 
must be submitted to the CTSU Regulatory Office or compliance communicated per 
protocol instructions. 
Downloading Site Registration Documents   
Site registration forms may be downloaded from the E1912 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1912 
• 
Click on the Site Registration Documents link 
Requirements for E1912 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS. 
 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206  
 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
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3. 
A.  
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within 14 working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To 
access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or 
participating organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient position in the database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria has been met within the protocol stated timeframes. All patients 
have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 

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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.   
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested  
4.1 
Protocol Number  
4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification  
4.3.1 
Patient’s initials (first and last) 
4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Gender 
4.3.3.2 
Birth date 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.5 
Stratification Factors: 
4.5.1 
Age: < 60 years vs. ≥ 60 years 
4.5.2 
PS 0,1 vs 2 
4.5.3 
Disease stage: 3/4 vs. 1/2 
4.5.4 
Baseline cytogenetic abnormalities on FISH: deletion 11q22.3(ATM) 
vs. other 
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4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: Copies of the consent are not collected by the ECOG-ACRIN 
Operations Office -- Boston. 
NOTE: Copies of the consent are not collected by the ECOG-ACRIN 
Operations Office. However the ECOG-ACRIN Leukemia 
Translational Research Laboratory (LTRL) requires 
institutions to submit a copy of the E1912 consent and a 
copy of the HIPAA authorization form. 
4.6.2 
Bone marrow sections/slides and smears must be submitted for 
central review as outlined in Section 10. 
4.6.3 
Peripheral blood and buccal cells should be submitted for correlative 
studies and/or banking as outlined in Section 10, per patient consent.  
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E1912 be entered and 
tracked via the on-line ECOG-ACRIN Sample Tracking 
System (STS) (see Section 10.4).  
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG-ACRIN 
Operations Office – Boston regarding logistics for 
submission of fresh samples. 
4.6.4 
Data collection for this study will be done exclusively through 
Medidata Rave. Access to the trial in Rave is granted through the 
iMedidata application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access Rave via 
iMedidata the site user must have an active CTEP IAM account 
(check at <https://eapps-ctep.nci.nih.gov/iam>) and the appropriate 
Rave role (Rave CRA, Read-Only, Site Investigator) on either the 
LPO or participating organization roster at the enrolling site.  
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking the link in the upper right pane of the 
iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
menbers’ website, Rave tab under the Rave resource materials 
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(Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at http://www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
ECOG-ACRIN has contracted with Alpha Oncology, a contract 
research organization (CRO) to conduct on-site and remote 
monitoring activities.  The goal of these monitoring activities is to 
provide source document verification (SDV). Alpha Oncology will be in 
contact with sites as patients reach the pre-defined milestones for 
initiation of monitoring activities. 
Alpha Oncology will also be conducting data sweeps. The goal of 
these data sweeps is to assist institutions with timely data entry and 
query resolution. Alpha Oncology will utilize phone requests and email 
notifications to request entry of outstanding data and/or completion of 
open queries.  The objective of these sweeps is to collect data; they 
are not designed as an audit, nor are they intended to generate 
corrections to previously submitted data. 
Alpha Oncology will report only to ECOG-ACRIN per contract and 
information obtained from monitoring will be shared only with ECOG-
ACRIN. 
4.7 
Investigational Brochure 
Ibrutinib is an INVESTIGATIONAL AGENT (IND# 117241). A copy of the 
Investigator's Brochure (IB) can be obtained by calling the Pharmaceutical 
Management Branch at the NCI (240-276-6575) or via email request to 
ibcoordinator@mail.nih.gov. 
NOTE:  
Please have your investigator’s NCI # handy. The IB provides relevant 
and current scientific information about the investigational 
product.Please submit the IB to your IRB/EC according to GCP 
regulations. The IB and any correspondence to the IRB should be 
kept in the study files of E1912. 
4.8 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E1912 Forms Completion Guidelines. Document the reason for 
not starting protocol treatment on the Off Treatment form. Also report the date 
and type of the first non-protocol treatment that the patient receives. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
All questions regarding treatment and dose modifications should be directed to 
the ECOG-ACRIN Study Chair. 
All drugs that will be administered according to weight should be dosed 
according to actual body weight. There is no clearly documented adverse impact 
of treatment of obese patients when dosing is performed according to actual 
body weight. Therefore, all dosing is to be determined solely by (1) the patient’s 
BSA as calculated from actual weight or (2) actual weight without any 
modification unless explicitly described in the protocol. This will eliminate the risk 
of calculation error and the possible introduction of variability in dose 
administration. Failure to use actual body weight in the calculation of drug 
dosages will be considered a major protocol deviation. Physicians who are 
uncomfortable with administering chemotherapy dose based on actual body 
weight should not enroll obese patients on this protocol. 
Intravenous medications in both study arms may be administered via the 
following methods: peripheral IV, Port-a-cath, central line, PIC, or Hickman. 
NOTE: 
BSA will be calculated prior to each cycle based on body weight at the 
start of that cycle.  Accordingly, the dose of drugs based on BSA (e.g. 
fludarabine, cyclophosphamide, rituximab) may vary slightly cycle by 
cycle due to fluctuations in body weight. Changes to doses cycle by 
cycle are allowed but not required unless calculated dose changes by 
greater than 10%. 
NOTE: 
Doses can be rounded using the following guidelines: 
Rituximab 50 mg/m2 round to nearest 5 mg 
Rituximab 325 mg/m2 round to nearest 10 mg 
Rituximab 500 mg/m2 round to nearest 10 mg 
Fludarabine round to nearest 1 mg 
Cyclophosphamide round to nearest 10 mg 
5.1.1 
ARM A: Ibrutinib with Rituximab 
Therapy will consist of daily oral Ibrutinib in combination with 
rituximab. For the first month of therapy patients will receive Ibrutinib 
alone. Beginning with the second cycle, patients will receive 
rituximab. Since the rituximab begins in cycle 2 rather than cycle 1, 
patients will receive rituximab during cycles 2-7 so that they receive 
an identical cumulative dose of rituximab to arm B. After completion of 
cycle 7, patients will continue on daily oral Ibrutinib until disease 
progression. Patients will be assessed with physical examination, 
CBC, and chemistries prior to cycle 1-7 as per Section 7.1. Beginning 
day 1 of cycle 7, patients will be seen every 90 days (+/-7 days). 
NOTE:  
Ibrutinb should be taken with 8 ounces (approximately 240 
ml) of water. The capsules are to be swallowed intact, not 
less than 30 minutes before or 2 hours after a meal. 
Patients should avoid consuming food and beverages 
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containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition.   
NOTE:  
Doses are to be taken at about the same time each day. If 
an ibrutinib dose is missed, it should be made up as soon 
as possible on the same day with a return to the normal 
schedule the following day. 
NOTE: 
Patients require antibiotic prophylaxis for PCP/PJP and 
zoster as delineated in 5.5.2. 
5.1.1.1 
Drugs 
Cycle 1: 
• 
Ibrutinib 420 mg orally once per day for  28 days (+/- 4 
days) 
• 
Patients will be seen every 28 days (+/- 4 days)  
NOTE:  
Patients with a baseline platelet counts below 
20x109/L should receive platelet transfusion 
prior to starting Ibrutinib therapy.  As noted in 
Section 7.0, patients whose baseline platelet 
count is below 20x109/L should have repeat 
CBC on day 3. 
Cycles 2-7: 
• 
Ibrutinib 420 mg orally once per day for  28 days (+/- 4 
days)  
• 
Rituximab, 50 mg/m2 IV on day 1 of Cycle 2,  and 325 
mg/m2 on day 2 of Cycle 2, then 500 mg/m2 on day 1 of 
Cycles 3-7. 
NOTE:  
Patients with a baseline platelet counts below 
20x109/L should receive platelet transfusion 
prior cycle 2, day 1 rituximab therapy.  As 
treatment with anti-CD20 monoclonal anti-
bodies may result in acute but temporary 
reduction in platelets, patients with baseline 
platelet counts < 50x109/L, prior to receiving 
rituximab should have platelet counts repeated 
after the rituximab infusion is ended to see if 
platelet transfusion is necessary. 
• 
Repeat cycles every 28 days (+/- 4 days) for a total of 6 
cycles  
• 
Since monthly visits are required during cycles 1-6, a 1 
month supply of drug should be dispensed to patient 
during these cycles. Since 3 month visits are required 
after cycle 6, a 3 month supply of drug may be 
dispensed for cycle 7 and beyond. 
After cycle 7 
• 
Ibrutinib 420 mg orally once per day continuously until 
disease progression. 
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• 
During this phase patients will be seen every 90 days 
(+/-7 days) 
NOTE: 
Telemedicine is permitted for some visits after 
cycle 7. Please refer to Section 7.1 for more 
details. 
NOTE: 
Please see Section 5.5.8 for dose modifications 
to ibrutinib if patients require treatment with a 
CYP3A inhibitor/inducer or any medication 
known to cause QT prolongation. 
5.1.1.2 
Unless otherwise indicated, premedication prior to all 
doses of rituximab (Cycles 2-7) will include the following: 
• 
Hydrocortisone 100 mg IV (or equivalent dose of other 
corticosteroid) should be administered before the first 
and second doses of rituximab during Cycle 2 of 
therapy.  Thereafter, it should only be administered if 
patients have infusion reactions or nausea that is not 
controlled by alternative anti-emetics. 
• 
Diphenhydramine 50 mg IV or PO (or alternative anti-
histamine) and acetaminophen 650 mg PO should be 
administered 30 minutes prior to rituximab to reduce 
infusion reactions. Patients with allergic reactions to 
diphenhydramine and other anti-histamines may have 
anti-histamines held at the discretion of the treating 
physician. 
5.1.1.3 
The following premedication will be administered prior to 
Cycles 1 and 2: 
• 
All patients will be given PO allopurinol 300 mg/day 
from day 1 to day 14 (a total of 14 days) of Cycles 1 
and 2 unless they are allergic. Treatment with 
allopurinol may continue beyond 14 days during Cycles 
1 and 2 at the discretion of the treating physician.  Use 
of allopurinol with subsequent cycles will be at the 
discretion of the treating physician. 
• 
Use of antiemetic therapy will be left to the discretion of 
the treating physician 
5.1.1.4 
Ibrutinib 420 mg orally once per day on days 1-28 days of 
cycles 1-7.  After the end of cycle 7, patients will remain on 
Ibrutinib 420 mg orally once per day until disease 
progression. During this phase patients will be seen every 
90 days (+/-7 days) 
5.1.1.5 
Rituximab administration: 
On day 1 Cycle 2: rituximab 50 mg/m2 mg will be 
administered IV over a period of 4 hours.  To determine the 
hourly rate of infusion, divide the total volume of rituximab 
solution by 4 and administer at this rate, without escalation, 
for 4 hours. Shortness of breath, rigors and other infusion-
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related toxicities have been noted more frequently during 
the first infusion and in patients with high leukocyte counts. 
Vital signs are recommended to be measured every 15 
minutes for the first 2 hours with the first dose of rituximab. 
If patient is unable to complete rituximab on day 1 of cycle 
2, the residual rituximab dose should be administered on 
day 2. 
On day 2 of Cycle 2: rituximab 325 mg/m2 will be 
administered IV.  Rituximab can usually be initiated at 50 
mg/hr. If hypersensitivity or infusion related events do not 
occur, escalate the infusion rate in 50 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr. Close 
observation for infusion-related toxicities should occur 
throughout the infusion, particularly with each dose 
escalation. 
On day 1 of cycles 3-7:  rituximab 500 mg/m2 will be 
administered IV. If the patient tolerated the most recent 
infusion, rituximab can usually be initiated at 100 mg/hr. If 
hypersensitivity or infusion related events do not occur, 
escalate the infusion rate in 100 mg/hr increments every 
30 minutes to a maximum of 400 mg/hr.  Close observation 
for infusion-related toxicities should occur throughout the 
infusion, particularly with each dose escalation. If the 
patient did not tolerate the most recent infusion, initiate 
rituximab at 50 mg/hr (or lower rate if necessary) and 
follow the Cycle 2 day 2 infusion schedule. If a reaction 
occurs, slow or stop the infusion. If the reaction abates, 
restart infusion at 50% of the previous rate. Close 
observation for infusion-related toxicities should occur 
throughout the infusion, particularly with each dose 
escalation. If patient is unable to complete rituximab on 
day 1 of cycles 3-7, the residual rituximab dose should be 
administered on day 2 of that cycle. 
Rituximab Infusion reactions: 
• 
Shortness of breath, rigors and other infusion-related 
toxicities have been noted more frequently in patients 
with high leukocyte counts and during the first several 
treatments. Close observation for these potential 
toxicities should occur.  The treatment area should be 
sufficiently prepared to allow easy access to supportive 
care medications and measures, such as meperidine 
for IV push, oxygen supplementation and nebulized 
albuterol, warm blankets, IV fluid for bolus, and access 
to crash cart. 
• 
If infusion reactions occur, infusions should be stopped 
until infusion-related symptoms resolve, and then 
resumed at a 50% slower rate. Contact the ECOG-
ACRIN Study Chair or ECOG-ACRIN Committee chair 
with any questions. 
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• 
If transient bronchospasm occurs, rituximab 
administration should be interrupted.  If these 
symptoms persist, albuterol (or other B2 agonist) by 
inhalation and additional hydrocortisone should be 
administered at the discretion of the treating physician. 
• 
In patients with high leukocyte counts, close 
observation for potential toxicities should occur.  If 
marked reduction in circulating lymphocytes is noted, 
close attention to the possibility of acute tumor lysis 
syndrome should occur.   
5.1.2 
As treatment with anti-CD20 monoclonal anti-bodies may result in 
acute but temporary reduction in platelets, patients with baseline 
platelet counts < 50x109/L prior to receiving rituximab should have 
platelet counts repeated after the rituximab infusion is ended to see if 
platelet transfusion is necessary. Criteria for converting patients who 
do not respond to Ibrutinib therapy 
On day 1 of cycle 5 (e.g. after completing cycle 4), patients will be 
assessed with physical examination and CBC as per Section 7.1.  
Patients with progressive disease or those who have not experienced 
at least a ≥ 50% reduction in lymphadenopathy will be considered to 
have failed Ibrutinib based therapy. These patients will be considered 
a treatment failure and will discontinue Ibrutinib-based therapy. If 
deemed appropriate by their treating physician, patients may receive 
salvage therapy (off protocol) with FCR for 6 cycles using the 
schedule outlined for Arm B. 
NOTE: It should be noted that it is common for CLL patients treated 
with Ibrutinib to experience a transient increase in 
lymphocytosis due to redistribution of lymphocytes from the 
lymph nodes and spleen to the peripheral blood circulation.  
This lymphocytosis is NOT a marker of disease progression 
or Richter’s transformation and typically resolves over 
several months.  For this reason, no patient on Ibrutinib will 
be considered to have disease progression based on an 
increased absolute lymphocyte count that occurs during the 
first several months of Ibrutinib based treatment. See 
protocol Section 5.1.2.  Questions regarding an increase in 
the absolute lymphocyte count after initiation of Ibrutinib-
based therapy should be discussed with the study PI. 
5.1.3 
ARM B: FCR for 6 cycles 
Therapy will consist of 6 28–day cycles of fludarabine, 
cyclophosphamide, and rituximab.  The sequence of drug 
administration is as follows:  (1) rituximab, (2) fludarabine, (3) CTX.  
Patients will be assessed with physical examination, CBC, and 
chemistries prior to cycle 1-6 as per Section 7.1.  Patients will also be 
evaluated at the end of cycle 6, 90 days (+/-7 days) after the end of 
cycle 6 and then 12 months post registration as outlined in Section 
7.1. 
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NOTE: 
Patients require antibiotic prophylaxis for PCP/PJP and 
zoster as delineated in 5.5.2. 
5.1.3.1 
Drugs 
Cycles 1 – 6: 
• 
Rituximab, 50 mg/m2 IV on day 1 and 325 mg/m2 on 
day 2 of Cycle 1 and 500 mg/m2 on day 1 of Cycles 2-
6. 
• 
Fludarabine 25 mg/m2, IV, days 1, 2, 3 
• 
Cyclophosphamide 250 mg/m2, IV, days 1, 2, 3 
• 
Repeat cycles every 28 days (+/- 4 days) for a total of 6 
cycles. 
NOTE:  
Patients with a pre-treatment platelet counts 
below 20x109/L should receive platelet 
transfusion prior cycle 1, day 1 rituximab 
therapy.  As noted in Section 7.0, patients 
whose pre-treatment platelet count is below 
20x109/L should have repeat CBC on day 3. 
As treatment with anti-CD20 monoclonal anti-
bodies may result in acute but temporary 
reduction in platelets, patients with baseline 
platelet counts < 50 x109/L prior to receiving 
rituximab should have platelet counts repeated 
after the rituximab infusion is ended to see if 
platelet transfusion is necessary. 
5.1.3.2 
Unless otherwise indicated, premedication prior to all 
doses of rituximab (Cycles 1-6) will include the following: 
• 
Hydrocortisone 100 mg IV (or equivalent dose of other 
corticosteroid) should be administered before the first 
and second doses of rituximab during Cycle 1 of 
therapy.  Thereafter, it should only be administered if 
patients have infusion reactions or nausea that is not 
controlled by alternative anti-emetics. 
• 
Diphenhydramine 50 mg IV or PO and acetaminophen 
650 mg PO should be administered 30 minutes prior to 
rituximab to reduce infusion reactions. Patients with 
allergic reactions to diphenhydramine may receive an 
alternative anti-histamine or have anti-histamines held 
at the discretion of the treating physician. 
5.1.3.3 
The following premedication will be administered prior to 
Cycles 1-6: 
• 
All patients will be given PO allopurinol 300 mg/day 
from day 1 to day 14 (a total of 14 days) of Cycle 1 
unless they are allergic.  Treatment with allopurinol 
may continue beyond 14 days at the discretion of the 
treating physician.  Use of allopurinol with subsequent 
cycles will be at the discretion of the treating physician. 
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• 
Antiemetic medications such as Kytril 1 mg PO (or 
substitute) should be given thirty minutes to 1 hour 
prior to chemotherapy (fludarabine and/or 
cyclophosphamide).  Additional prophylactic antiemetic 
therapy will be left to the discretion of the treating 
physician 
• 
All patients should be well hydrated before each cycle 
of therapy. Patients should be encouraged to drink 
fluids the night before treatment and will receive 
approximately 500 to 1000 mL of IV hydration over 1 
hour prior to chemotherapy on days they receive 
fludarabine and cyclophosphamide.   
• 
On Day 2 of Cycle 1 only, CBC with differential, Ca++, 
PO4, LDH, uric acid, electrolytes, and creatinine are 
required to assess for tumor lysis syndrome prior to the 
second fludarabine dose (see Section 7.1). 
5.1.3.4 
Rituximab administration: 
On day 1 Cycle 1: rituximab 50 mg/m2 mg will be 
administered IV over a period of 4 hours. To determine the 
hourly rate of infusion, divide the total volume of rituximab 
solution by 4 and administer at this rate, without escalation, 
for 4 hours. Shortness of breath, rigors and other infusion-
related toxicities have been noted more frequently during 
the first infusion and in patients with high leukocyte counts. 
Vital signs are recommended to be measured every 15 
minutes for the first 2 hours with the first dose of rituximab. 
If patient is unable to complete cycle 1, day 1 rituximab 
dose, the residual rituximab should be added to cycle 1, 
day 2 dose. 
On day 2 of Cycle 1: rituximab 325 mg/m2 will be 
administered IV.  Rituximab can usually be initiated at 50 
mg/hr. If hypersensitivity or infusion related events do not 
occur, escalate the infusion rate in 50 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr. Close 
observation for infusion-related toxicities should occur 
throughout the infusion, particularly with each dose 
escalation. If patient is unable to complete cycle 1, day 2 
rituximab dose, the residual rituximab may be administered 
on cycle 1, day 3. 
On day 1 of cycles 2-6:  rituximab 500 mg/m2 will be 
administered IV. If the patient tolerated the most recent 
infusion, rituximab can usually be initiated at 100 mg/hr. If 
hypersensitivity or infusion related events do not occur, 
escalate the infusion rate in 100 mg/hr increments every 
30 minutes to a maximum of 400 mg/hr.  Close observation 
for infusion-related toxicities should occur throughout the 
infusion, particularly with each dose escalation. If the 
patient did not tolerate the most recent infusion, initiate 
rituximab at 50 mg/hr (or lower rate if necessary) and 
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follow the Cycle 1 day 2 infusion schedule. If a reaction 
occurs, slow or stop the infusion. If the reaction abates, 
restart infusion at 50% of the previous rate. Close 
observation for infusion-related toxicities should occur 
throughout the infusion, particularly with each dose 
escalation. If patient is unable to complete rituximab on 
day 1 of cycles 2-6, the residual rituximab dose should be 
administered on day 2 of that cycle. 
Rituximab Infusion reactions: 
• 
Shortness of breath, rigors and other infusion-related 
toxicities have been noted more frequently in patients 
with high leukocyte counts and during the first several 
treatments. Close observation for these potential 
toxicities should occur.  The treatment area should be 
sufficiently prepared to allow easy access to supportive 
care medications and measures, such as meperidine 
for IV push, oxygen supplementation and nebulized 
albuterol, warm blankets, IV fluid for bolus, and access 
to crash cart. 
• 
If infusion reactions occur, infusions should be stopped 
until infusion-related symptoms resolve, and then 
resumed at a 50% slower rate. Contact the ECOG-
ACRIN Study Chair or ECOG-ACRIN Committee chair 
with any questions. 
• 
If transient bronchospasm occurs, rituximab 
administration should be interrupted.  If these 
symptoms persist, administration of albuterol (or other 
B2 agonist) by inhalation and additional hydrocortisone 
should be administered at the discretion of the treating 
physician. 
• 
In patients with high leukocyte counts, close 
observation for potential toxicities should occur.  If 
marked reduction in circulating lymphocytes is noted, 
close attention to the possibility of acute tumor lysis 
syndrome should occur.  .   
• 
As treatment with anti-CD20 monoclonal anti-bodies 
may result in acute but temporary reduction in 
platelets, patients with baseline platelet counts  
< 50x109/L prior to receiving rituximab should have 
platelet counts repeated after the rituximab infusion is 
ended to see if platelet transfusion is necessary.   
5.1.3.5 
Fludarabine monophosphate 25 mg/m2/day IV over 30 
minutes on days 1-3 of Cycles 1-6. 
(In Canada, it is permissible to substitute fludarabine 
monophosphate 40 mg/m2/day orally on days 1-6 of each 
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5.1.3.6 
Cyclophosphamide 250 mg/m2/day IV over 30 minutes on 
days 1-3 of Cycles 1-6. 
Criteria for converting patients who do not respond to FCR 
induction to Ibrutinib 
Patients will be assessed with physical examination and 
CBC prior to each cycle as per Section 7.1.  Patients with 
progressive disease(see Section 6.1.3) will be considered 
to have failed FCR-based therapy.  These patients will be 
considered a treatment failure for the primary analysis and, 
salvage therapy can be initiated with the regimen deemed 
most appropriate by their treating physician. 
Patients will be seen every 28 days (+/- 7 days) for the first 
6 months of treatment with Ibrutinib at which point he 
frequency of follow-up can be spaced to every 90 days (+/-
7 days) at the discretion of the treating physician. 
NOTE: 
Telemedicine is permitted for some visits after 
cycle 7. Please refer to Section 7.1 for more 
details. 
5.1.3.7 
Patients who relapse after FCR  
After they complete induction therapy, patients responding 
to FCR will be followed according as per Section 7.1.  The 
criteria for progressive disease during follow-up are 
defined in Section 6.1.3.  Many patients with progressive 
disease are asymptomatic and can be observed until they 
experience: 
• 
Evidence of progressive marrow failure as manifested 
by the development of worsening anemia (Hg<11 g/dl) 
and/or thrombocytopenia (Platelets <100 x 109/L) 
• 
Symptomatic or progressive lymphadenopathy, 
splenomegaly, or hepatomegaly. 
• 
One or more of the following disease-related 
symptoms: 
o Weight loss > 10% within the previous 6 months 
o Grade 2 or 3 fatigue attributed to CLL 
o Fevers > 100.5oF for 2 weeks without evidence of 
infection 
o Clinically significant night sweats without evidence 
of infection 
Patients fulfilling the criteria for progressive disease 
(Section 6.1.3) and in need of salvage therapy as 
determined by the treating physician may be treated with 
the salvage therapy regimen deemed most appropriate by 
their treating physician. 
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5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave.  
On this protocol, all adverse events, of any grade, regardless of 
attribution to study treatment, will be recorded on the E1912 
Adverse Event Form. 
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
NOTE: 
Effective April 1, 2018 expedited adverse event 
reporting done via CTEP-AERS will use CTCAE 
version 5.0 terminology and grading.  Routine 
adverse event reporting and dose modifications 
guidelines will continue to be based on CTCAE 
version 4.0 terminology and grading. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
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• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.   
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred. 
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a 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. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
• 
the AE Team at ECOG-ACRIN (617-632-3610) for Arms A and B 
• 
the CTEP/NCI (301-897-7497) for Arm A and Arm B 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
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Supporting and follow up data:  Any supporting or follow up 
documentation (for Arms A and B) must be uploaded to the 
Supplemental Data Folder in Medidata Rave within 48-72 hours.  In 
addition, supporting or follow up documentation must be faxed to the 
CTEP/NCI (301- 230-0159) for Arm A and) for Arm B in the same 
timeframe. 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including: 
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E1912 and outline 
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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
considered important medical event 
• 
Grade 3 adverse events only if meets serious criteria 
5.2.6 
Expedited Reporting Requirements for Arm A on protocol E1912 
Investigational Agents: Ibrutinib 
Commercial Agents: Rituximab 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
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5.2.7 
Additional instructions, requirements and exceptions for protocol 
E1912 – Arm A 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497..  This will need to be 
discussed on a case by case basis. 
E1912 additional expedited reporting requirements: 
Pregnancy 
• 
Although not an adverse event in and of itself, pregnancies and 
suspected pregnancies (including a positive or inconclusive 
pregnancy test, regardless of age or disease status) occurring in 
a female patient or a female partner of a male patient while the 
subject is on Ibrutinib, or within 90 days of the subjects last does 
of Ibrutinib, are considered immediately reportable events.  The 
pregnancy, suspected pregnancy, or positive/inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 
hours of the Investigator’s knowledge. 
Please refer to Appendix IX for detailed instructions on how to 
report the occurrence of a pregnancy, the outcome of all 
pregnancies, as well as a link to the NCI’s Pregnancy 
Information Form that must be completed. 
Other Adverse Events: 
• 
Any ≥ grade 3 occurrence of the following events must be 
reported via CTEP-AERS regardless whether or not the patient 
was hospitalized or if it appears in the SPEER. Report the event 
within the timeframes outlined in the chart in Section 5.2.6. 
• 
Diarrhea/Nausea/Vomiting 
• 
Fatigue 
• 
Febrile Neutropenia 
• 
Fever 
• 
Headache 
• 
Hematuria 
• 
Infusion related reaction 
• 
Lower or upper gastrointestinal hemorrhage 
• 
Lung infection 
• 
Myalgia 
• 
Rash maculo-papular 
• 
Sepsis 
• 
Upper respiratory infection 
 
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• 
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. 
E1912 specific expedited reporting exceptions: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS 
if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
Risk Mitigation Plan: 
• Investigators should be vigilant about detecting cases of 
suspected pulmonary and/or CNS fungal infections and, 
specifically, aspergillosis. 
• If a case of aspergillosis is suspected or observed in this trial, 
ibrutinib should be discontinued.  
• All suspected and confirmed cases of fungal infections should 
be reported to CTEP within 24 hours. 
 
 
 
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5.2.8 
Steps to determine if an event is to be reported in an expedited 
manner – Arm B 
Identify the type and grade of the event 
using CTCAE v5.0. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.9 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.2.9 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study.  If so, report the 
event via CTEP-AERS. 
Is the event 
reportable?
No 
Yes 
Report event via CTEP-AERS 
Determine the expectedness of the 
event.  An unexpected event is defined 
as one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 
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2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
 
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Adverse events reported on ibrutinib (PCI-32765) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that ibrutinib (PCI-32765) 
caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (hemorrhagic diathesis); Blood and lymphatic system disorders - Other (lymphadenitis); 
Blood and lymphatic system disorders - Other (pancytopenia); Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac disorders - Other (bundle branch block left); Cardiac disorders - Other (extrasystoles); 
Chest pain - cardiac; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Sinus 
bradycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain  
EYE DISORDERS - Dry eye; Eye disorders - Other (eye discharge); Eye disorders - Other 
(macular edema); Eye disorders - Other (ocular hyperemia); Eye disorders - Other (retinal 
hemorrhage); Eye pain; Floaters; Glaucoma; Keratitis; Periorbital edema; Photophobia; Vision 
decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Cheilitis; Colitis; Dyspepsia; 
Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (gluteal intramuscular bleed); Gastrointestinal disorders - 
Other (irritable bowel syndrome); Gastrointestinal disorders - Other (tongue discoloration); Oral 
dysesthesia; Oral pain; Pancreatitis; Periodontal disease; Small intestinal obstruction; 
Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other (early 
satiety); General disorders and administration site conditions - Other (multiple organ dysfunction 
syndrome); General disorders and administration site conditions - Other (sensation of foreign 
body); General disorders and administration site conditions - Other (temperature intolerance); 
Generalized edema; Injection site reaction; Localized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory 
response syndrome) 
INFECTIONS AND INFESTATIONS - Conjunctivitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related reaction; 
Injury, poisoning and procedural complications - Other (excoriation) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT 
corrected interval prolonged; INR increased; Investigations - Other (cardiac murmur); 
Investigations - Other (increase CRP); Lymphocyte count decreased; Weight gain; Weight loss; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - 
Other (cachexia); Metabolism and nutrition disorders - Other (hypoproteinemia); Metabolism 
and nutrition disorders - Other (lactose intolerance) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone 
pain; Flank pain; Generalized muscle weakness; Joint effusion; Joint range of motion 
decreased; Musculoskeletal and connective tissue disorder - Other (groin pain); Musculoskeletal 
and connective tissue disorder - Other (muscle rigidity); Musculoskeletal and connective tissue 
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disorder - Other (pain in jaw); Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Dysgeusia; 
Encephalopathy; Leukoencephalopathy; Memory impairment; Nervous system disorders - Other 
(mental impairment); Nervous system disorders - Other (parosmia); Nervous system disorders - 
Other (PML); Paresthesia; Reversible posterior leukoencephalopathy syndrome; Somnolence; 
Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Insomnia; Restlessness 
RENAL AND URINARY DISORDERS - Cystitis noninfective; Renal and urinary disorders - 
Other (calculus bladder); Renal and urinary disorders - Other (polyuria); Urinary frequency; 
Urinary retention; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dyspareunia; Reproductive system 
and breast disorders - Other (hematospermia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Hiccups; 
Laryngeal inflammation; Pleural effusion; Productive cough; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (nasal ulcer); Sinus disorder; Sinus pain; Voice 
alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Nail discoloration; Nail 
loss; Photosensitivity; Pruritus; Skin atrophy; Skin hyperpigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hot flashes; Thromboembolic event; Vascular disorders - 
Other (peripheral coldness) 
NOTE: 
Ibrutinib (PCI-32765) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the 
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5.4 
Dose Modifications and Management of Toxicity 
Should unanticipated circumstances arise that might require minor variances 
from the prescribed dosing and schedule of the protocol therapy or 
recommended supportive care in order to ensure safety and allow patients to 
continue to receive treatment on study, the ECOG-ACRIN Study Chair should be 
contacted in advance for discussion and approval. 
NOTE: Ibrutinib to be held in the event of major and minor surgeries: major 
surgeries: Hold ibrutinib for 7 days prior to and seven days after major 
surgeries. Minor surgeries: Hold Ibrutinib for 3 days prior and 3 days 
after minor surgeries. 
5.4.1 
Assessment of Toxicity 
• 
An evaluation of potential treatment-induced toxicity in patients 
with CLL can be difficult. Moreover, some conventional criteria are 
not applicable to studies involving patients with hematologic 
malignancies in general, and CLL in particular. An example is 
hematologic toxicity: patients with advanced CLL may exhibit a 
deterioration in blood counts which may represent either 
treatment-related toxicity or progressive bone marrow failure from 
disease itself. 
• 
Toxicity grades below are described using the NCI Common 
Terminology Criteria for Averse Events (CTCAE) version 4.0 
with the exception of hematologic toxicity. Grading Of 
Hematologic Adverse Events In This Protocol Will Be 
Performed As Detailed In Appendix VI. 
• 
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 website (http://ctep.cancer.gov). 
• 
If the following signs and symptoms are medically manageable, 
they are not to be a consideration with respect to a patient’s 
dosing or continuation in the study: nausea/vomiting, diarrhea, 
drug-related fever or chills, and hair loss. 
5.4.2 
Fludarabine and Cyclophosphamide Dose Levels for Hematologic 
Dose Modifications Arm B. 
NOTE: 
Patients who require a dose reduction during a given cycle 
will remain at that dose for future cycles and will not be re-
escalated to higher dose levels 
If the modifications below indicate that either Fludarabine or 
Cyclophosphamide should be held, all drugs in the cycle should be 
held (e.g. the entire cycle delayed) until patient fulfills the indicated 
criteria for retreatment. Accordingly, there will not be any “missed” 
doses of medication. 
There are no dose modifications for rituximab.  If rituximab needs to 
be held, patients can continue to receive other treatment as 
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NOTE: 
Patients on Arm B who require a dose reduction during a 
given cycle will remain at that dose for future cycles and 
will not be re-escalated to higher dose levels. 
In patients whose baseline (i.e., prior to starting protocol 
therapy) ANC is <1000/µL, the FCR dose modifications, if 
required, would not be applied until Cycle 3. 
5.4.4 
Dose Modifications for Febrile Neutropenia 
• 
Arm A 
For febrile neutropenia, hold Ibrutinib until fever resolves and ANC ≥ 
1000/µL, then resume Ibrutinib at the previous dose. If Ibrutinib is 
delayed for febrile neutropenia, rituximab should also be delayed. 
• 
Arm B 
For febrile neutropenia, hold fludarabine and cyclophosphamide until 
fever resolves and ANC ≥ 1000/µL, then resume both at one dose 
level lower than the previous dose (see table in Section 5.4.2). If dose 
reduction to less than dose level -2 is required for febrile neutropenia, 
discontinue treatment with fludarabine, cyclophosphamide, and 
rituximab. If fludarabine and cyclophosphamide are delayed for febrile 
neutropenia, rituximab should also be delayed. If counts have not 
recovered to adequate levels to permit retreatment by 8 weeks (56 
days) from day 1 of the most recent cycle, then the patient will 
discontinue active treatment. 
NOTE: 
Patients on Arm B who require a dose reduction during a 
given cycle will remain at that dose for future cycles and 
will not be re-escalated to higher dose levels 
5.4.5 
Dose Modifications for Thrombocytopenia 
• 
Arm A 
Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, < 50,000/mL]); or 
in subjects with baseline thrombocytopenia a platelet decrease of 
50% to 74% from baseline that is associated with clinically significant 
bleeding follow the actions outlined in the table: 
Occurrence  
Action 
1st  
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; 
may restart at original dose level (420 mg daily) 
2nd  
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (280 mg daily) 
3rd  
Hold Ibrutinib until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (140 mg daily) 
4th  
Discontinue Ibrutinib 
For grade 4 thrombocytopenia (platelets < 25 x 109/L [ie,  
< 25,000/mL]); or in subjects with baseline thrombocytopenia a 
decrease of > 75% from baseline or < 20 x 109/L, whichever is higher 
(note Section 5.1.1.1 for those with a baseline platelet count less than 
20x109/L) follow the actions outlined in the table:  
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Occurrence  
Action 
1st  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
may restart at original dose level (420 mg daily) 
2nd  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (280 mg daily) 
3rd  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (140 mg daily) 
4th  
Discontinue Ibrutinib 
If the dose of ibrutinib is reduced, at the Investigator’s discretion, the 
dose of ibrutinib may be re-escalated after 2 cycles of a dose 
reduction in the absence of a recurrence of the toxicity that led to the 
reduction.  Dose changes must be recorded in the study 
documentation. 
• 
Arm B  
Platelets must be ≥ 100,000/µL or > 80% of baseline value (i.e.,  
> 80% of the value before protocol therapy started) on day 1 of a 
cycle. For platelets < 100,000/µL or < 80% of baseline, hold 
fludarabine and cyclophosphamide until platelets ≥ 100,000/µL or  
> 80% of baseline, then resume both at one dose level lower than the 
previous dose. If dose reduction to less than dose level -2 is required 
for thrombocytopenia, discontinue treatment with fludarabine, 
cyclophosphamide, and rituximab. If fludarabine is delayed for 
thrombocytopenia, rituximab should also be delayed. Note Section 
5.1.3.1 for those with a baseline platelet count less than 20x109/L. If 
counts have not recovered to adequate levels to permit retreatment 
by 8 weeks (56 days) from day 1 of the most recent cycle, then the 
patient will discontinue active treatment. 
In patients whose baseline (i.e., prior to starting protocol 
therapy) platelet count < 100,000/µL, these dose modifications, if 
required, would not be applied until Cycle 3. 
5.4.6 
Dose Modifications for Atrial Fibrilation (Arm A) 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any 
grade, consider the risks and benefits of ibrutinib treatment. If 
clinically indicated, the use of anticoagulants or antiplatelet agents 
may be considered for the thromboprophylaxis of atrial fibrillation. 
If the dose of ibrutinib is reduced, at the Investigator’s discretion, the 
dose of ibrutinib may be re-escalated after 2 cycles of a dose 
reduction in the absence of a recurrence of the toxicity that led to the 
reduction. Dose changes must be recorded in the study 
documentation. 
5.4.7 
Autoimmune Hemolytic Anemia or Thrombocytopenic Purpura 
Patients on Arm B developing autoimmune hemolytic anemia (AIHA) 
or autoimmune thrombocytopenia (AIT) during fludarabine therapy will 
be removed from protocol therapy, and treated with alternative agents 
at the discretion of the local physician. In this event, please consult 
with the ECOG-ACRIN Study Chair.  
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NOTE: 
Patients remain “on study” until an endpoint, either 
progression or death, is reached. 
5.4.8 
Non-Hematologic Toxicity (not including nausea, vomiting, diarrhea, 
drug-related chills and hair loss except where specified) 
• 
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.  Dose modifications are not required for adverse events 
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 Ibrutinib is interrupted for a reason other than toxicity (e.g. 
unrelated illness) the first instance of interruption must be 
restarted within 42 days. Subsequent study medication 
interruptions lasting more than 42 days ibrutinib should be 
discontinued permanently. 
• 
If the dose of ibrutinib is reduced, at the Investigator’s discretion, 
the dose of ibrutinib may be re-escalated after 2 cycles of a dose 
reduction in the absence of a recurrence of the toxicity that led to 
the reduction.  Dose changes must be recorded in the study 
documentation. 
• 
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. 
• 
If treating provider feels that a dose reduction needs to be made 
based on first occurrence (e.g. without restarting at original dose 
level) this must be discussed with study PI who can who can 
approve this request at their discretion. 
• 
Arm A 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent 
despite optimal antiemetic or anti-diarrheal therapy) or any 
other Grade 4 toxicity or any unmanageable Grade 3 toxicity 
follow the actions outlined in the table: 
Occurrence  Action 
1st  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
may restart at original dose level (420 mg daily) 
2nd  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (280 mg daily) 
3rd  
Hold Ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (140 mg daily) 
4th  
Discontinue Ibrutinib 
If the dose of ibrutinib is reduced, at the Investigator’s discretion, the 
dose of ibrutinib may be re-escalated after 2 cycles of a dose 
Rev. 8/15 
Rev. 1/16 
Rev. 1/16 
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reduction in the absence of a recurrence of the toxicity that led to the 
reduction.  Dose changes must be recorded in the study 
documentation. 
• 
Arm B 
• 
For non-hematologic toxicity ≥ grade 2 attributable to 
fludarabine, reduce fludarabine by 50%.  
• 
For non-hematologic toxicity ≥ grade 2 attributable to 
cyclophosphamide, reduce cyclophosphamide by 50%.  
• 
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. 
5.4.9 
Anti-coagulant therapy for patients on Arm A 
Subjects requiring the initiation of therapeutic anticoagulation therapy 
(e.g., 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. For this 
study, non-vitamin K based anti-coagulation is preferred. If Coumadin 
or other vitamin K antagonist is being considered, it should be 
discussed with the study chair. 
5.4.10 
Infusion reactions 
As discussed in 5.1.1.5 (Arm A) and 5.1.3.4 (Arm B), rituximab 
infusion reactions are relatively common and in most patients can be 
managed with interruption of the infusion, supportive measures, and 
reinitiation of rituximab at a slower rate of infusion once symptoms 
resolve.  Based on multiple phase 3 trials showing inclusion of anti-
CD20 impacts overall survival of CLL patients receiving first-line 
treatment, effort should be made to incorporate the supportive 
measures in 5.1.1.5 (Arm A) and 5.1.3.4 (Arm B) and continue to 
include rituximab in the treatment regimen rather than omit this agent.  
In the rare circumstances where severe recurrent infusion reactions or 
other severe rituximab related toxicity occurs (e.g. rituximab induced 
pneumonitis), rituximab may be omitted and the remaining agents 
(Arm A: Ibrutinib, Arm B: fludarabine and cyclophosphamide) 
continued if deemed appropriate by the treating physician. Such 
cases should be discussed with the study Principle Investigator. 
5.4.11 
Dose Modification for Hepatic Impaired Subjects (Child-Pugh Criteria) 
for Arm A 
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. 
Please see the Child-Pugh scoring system outlined in Appendix G to 
determine whether dose modifications are warranted according to the 
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following instructions. For patients who develop mild liver impairment 
while on study (Child-Pugh class A), the recommended dose for 
ibrutinib is 280 mg daily (two capsules). For patients who develop 
moderate liver impairment while on study (Child-Pugh class B), the 
recommended dose is 140 mg daily (one capsule). Patients who 
develop severe hepatic impairment (Child-Pugh class C) must hold 
study drug until resolved to moderate impairment (Child-Pugh class 
B) or better and may be re-treated according to resolved hepatic 
conditions (i.e., 140 mg or 280 mg for moderate or mild impairment, 
respectively). Monitor patients for signs of toxicity and follow dose 
modification guidance as needed. 
5.5 
Supportive Care  
5.5.1 
All patients must receive daily allopurinol (300 mg/day PO) for days 1-
14 of cycle 1 of therapy on both treatment arms unless they are 
allergic. Patients on Arm A (Ibrutinib/Rituximab) will also receive 
allopurinol (300 mg/day PO) for days 1-14 of cycle 2 since that is the 
first cycle they receive rituximab. The need for allopurinol with 
subsequent induction cycles is left to the discretion of the treating 
physician.  For patients with an allergy to allopurinol that precludes 
administration, patients can be followed closely for tumor lysis 
syndrome without allopurinol and the use of rasburicase as needed at 
the discretion of the treating physician. 
5.5.2 
Patients on both study arms will receive Bactrim DS 1 tablet (or 
alternative Pneumocystis pneumonia prophylaxis) on 
Monday/Wednesday/Friday AND acyclovir 400 mg p.o. twice per day 
(or equivalent) beginning with cycle 1 and continuing until the time of 
response evaluation (52 weeks after start of cycle 1; see Section 7.1).  
Even if patients discontinue protocol treatment. they should remain on 
these prophylactic anti-biotics until this timepoint. 
5.5.3 
Neutrophil growth factors are permitted per American Society of 
Clinical Oncology (ASCO) guidelines (JCO 24:3187-3205). Use of 
colony stimulating factors (e.g., filgrastim, sargramostim, PEG-
filgrastim) in this protocol is permitted during therapy as required for 
the treatment of febrile neutropenia. Colony stimulating factors may 
not be used to avoid dose reductions (e.g. to boost counts 
immediately before a starting a treatment cycle). The use of colony 
stimulating factors must be noted on flow sheets. 
5.5.4 
Any blood transfusions administered must be irradiated blood 
products to reduce risk of transfusion mediated graft versus host 
disease in CLL patients receiving potentially T-cell suppressive 
therapy. 
5.5.5 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.6 
As of 2012, the Center for Disease Control (CDC) recommends 
routine use of the 13-valent pneumococcal conjugate vaccine 
(PCV12; Prevnar 13) for all adults with CLL and other 
immunocompromising conditions.  Per the CDC, this should be 
administered in addition to the standard 23-valent pneumococcal 
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vaccine (PCV-23; Pneumovax 23) received by most adults. Since 
most CLL patients have not yet received Prevnar 13, all study patients 
who have:  
i) 
not previously received the Prevnar 13 pneumococcal vaccine  
ii) are ≥ 12 months from their last Pneumovax (or have never 
received a Pneumovax) 
iii) are willing to receive vaccination 
should receive Prevnar 13 vaccination at the time of their 12 month 
response evaluation. Additional information on the CDC guidelines 
can be found at: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6140a4.htm 
5.5.7 
Supportive medications in accordance with standard practice (such as 
for emesis, diarrhea, etc.) are permitted. Use of red blood cell growth 
factors (erythropoietin) is permitted per institutional policy and in 
accordance with the ASCO guidelines (Smith et al., 2006).  . 
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 
100 mg per day of prednisone or equivalent are permitted. 
Treatment for autoimmune cytopenias for patients on Arm A are 
permitted for at doses that do not exceed 100 mg per day of 
prednisone or equivalent. Patients on Arm B who develop 
autoimmune cytopenias must discontinue therapy as per 5.4.7. 
The following may be considered: localized hormonal or bone sparing 
treatment for non-B-cell malignancies, and localized radiotherapy for 
medical conditions other than the underlying B-cell malignancies. 
5.5.8 
If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 140 
mg or withhold treatment temporarily. Patients should be monitored 
for signs of ibrutinib toxicity.  If a moderate CYP3A inhibitor must be 
used, reduce ibrutinib to 140 mg for the duration of the inhibitor use. 
No dose adjustment is required in combination with mild inhibitors. 
Please Appendix VIII for a list of CYP3A inhibitors. 
5.5.9 
Any medications known to cause QT prolongation should be used 
with caution; periodic monitoring with electrocardiograms (ECGs) and 
electrolytes should be considered. 
5.5.10 
In vitro studies indicated that ibrutinib is not a substrate of P-
glycoprotein (P-gp) or other transporters, except OCT2.  Ibrutinib is a 
mild inhibitor of P-gp and BCRP.  Ibrutinib is not expected to have 
systemic drug-drug interactions with P-gp substrates. However, it 
cannot be excluded that ibrutinib could inhibit intestinal P-gp and 
BCRP after a therapeutic dose. There is no clinical data available; 
therefore, to avoid a potential interaction in the GI tract, narrow 
therapeutic range P-gp or BCRP substrates such as digoxin or 
methotrexate, should be taken at least 6 hours before or after 
ibrutinib.  Inhibition of the BCRP pathway may increase exposure to 
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5.5.11 
For minor procedures (such as a central line placement, needle 
biopsy, lumbar puncture [other than shunt reservoir access], 
thoracentesis, or paracentesis), ibrutinib should be held for at least 3 
days prior to the procedure and should not be restarted for at least 3 
days after the procedure.  For bone marrow biopsies that are 
performed while the patient is on ibrutinib, it is not necessary to hold 
ibrutinib for these procedures. 
For major surgery ibrutinib should be held for at least 3 days prior to 
the procedure and should be held after the procedure until the 
surgical site is reasonably healed, or for at least 7 days after the 
surgical procedure, whichever is longer. 
For emergency procedures, ibrutinib should be held after the 
procedure until the surgical site is reasonably healed, or for at least 7 
days after the urgent surgical procedure, whichever is longer. 
5.5.12 
Leukocytosis/Leukostasis 
A high number of circulating malignant cells (>400,000/mcL) may 
confer increased risk of leukostasis; these patients should be closely 
monitored. Administer supportive care such as hydration and/or 
leukophoresis as indicated. Ibrutinib should be temporarily held, and 
study principle investigator should be contacted. 
5.5.13 
Supplements such as fish oil and vitamin E preparations should be 
avoided. 
5.6 
Duration of Therapy 
Patients will receive protocol therapy unless: 
5.6.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E1912 Forms Completion Guidelines. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patient experiences unacceptable toxicity. 
5.6.4 
Non-protocol therapies are administered.  
5.7 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 10 years from the date of registration. All patients 
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6. 
Measurement of Effect 
Patients should be reevaluated for progression every 4 weeks (+/-10 days) during the 
first 6 months of the study by physical exam and CBC.  Although formal response 
evaluation will not occur until the 12 month response evaluation (or off study evaluation), 
patients will be evaluated prior to cycles 1-6 and 3 months after the end of cycle 6 of 
therapy to identify individuals who have experienced disease progression.   
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.   
NOTE: 
With the exception of SLL patients without palpable lymph nodes (see 
Section 6.1.1.1) Information from CT scans is not considered in the standard 
classification of response which is based on the results of CBC, physical 
exam, and bone marrow examination.  Accordingly, data from CT scans will 
be collected to document response and or persistence of non-palpable nodes 
at the time of formal response evaluation but will not be used in the primary 
response categorization. 
6.1 
Assessment of Clinical Response  
The major criteria for determination of the response to therapy in patients with 
CLL are based on physical examination and evaluation of peripheral blood and 
bone marrow. It is recommended that the laboratory and radiographic studies 
which are abnormal pre-study be repeated to document the degree of maximal 
response.  
Physical exam must measure the spleen and liver noting the maximal distance 
below the respective costal margins at rest in the mid-clavicular line and must 
record the bidimensional diameter of the largest palpable node in each lymph 
node area of involvement including the following 6 sites: cervical/supra-clavicular 
(right and left) axillary (right and left), inguinal (right and left). 
6.1.1 
Complete remission requires all of the following for a period of at least 
2 months (e.g. 2 occasions at least 4 weeks apart): 
6.1.1.1 
Absence of lymphadenopathy by physical examination on 
2 occasions at least 4 weeks apart and appropriate 
radiographic techniques (e.g. all lymph nodes ≤ 1.5 cm). 
For patients whose only measurable disease at the time of 
enrollment is on CT scan (i.e. SLL with no palpable nodes), 
a CT scan is required and all lymph nodes must be ≤ 1.5 
cm before classifying the patient a CR. 
6.1.1.2 
Absence of hepatomegaly or splenomegaly by physical 
examination. 
6.1.1.3 
Absence of constitutional symptoms (fevers, nights sweats, 
weight loss, fatigue) due to disease. 
6.1.1.4 
Normal CBC as exhibited by: 
6.1.1.4.1 
Polymorphonuclear leukocytes ≥ 1500/μl. 
6.1.1.4.2 
Platelets > 100,000/μl (untransfused). 
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6.1.1.4.3 
Hemoglobin > 11.0 gm/dl (untransfused). 
6.1.1.4.4 
Peripheral blood lymphocytes ≤ 4000/μl. 
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. 
6.1.1.5 
One marrow aspirate and biopsy should be performed 52 
weeks after Day 1 of cycle 1 (see Section 7.1) among 
patients with clinical and laboratory evidence of a CR to 
document that a complete remission has been achieved. 
The marrow sample must be at least normocellular with  
< 30% of nucleated cells being lymphocytes. If it is 
hypocellular, a repeat determination should be made in 2-4 
weeks. Samples are to be analyzed by a pathologist and 
the presence or absence of nodules noted, although not 
included in the current definition of CR. Only a single BM 
exam is needed to document CR. 
NOTE: 
In a subset of patients who are otherwise in a 
CR, 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 a nPR (nodular PR) which 
is a sub-classification of PR. 
6.1.1.6 
Any other laboratory assays (e.g., quantitative 
immunoglobulins) will not be used currently as an index for 
response but will be recorded for clinical correlations. 
6.1.2 
To be considered in PR, the patient must exhibit the features in 
Sections 6.1.2.1, 6.1.2.2, and 6.1.2.3 (if abnormal prior to therapy) as 
well as one or more of the remaining features (Sections 6.1.2.4, 
6.1.2.5, 6.1.2.6) for at least 2 months (e.g. 2 occasions at least 4 
weeks apart). In addition to the parameters listed below, the presence 
or absence of constitutional symptoms will be recorded.  
6.1.2.1 
≥ 50% decrease in peripheral blood lymphocyte count from 
the pretreatment baseline value. 
6.1.2.2 
≥ 50% reduction in lymphadenopathy. For patients whose 
only measurable disease at the time of enrollment is on CT 
scan (i.e. SLL with no palpable nodes), a CT scan 
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demonstrating ≥ 50% reduction of target nodes enlarged at 
baseline is required before classifying the patient a PR. 
6.1.2.3 
≥ 50% reduction in size of liver and/or spleen as measured 
by physical exam noting the maximal distance below the 
respective costal margins of the palpable 
hepatosplenomegaly during rest. 
6.1.2.4 
Polymorphonuclear leukocytes ≥ 1500/μl or 50% 
improvement over baseline. 
6.1.2.5 
Platelets > 100,000/μl or 50% improvement over baseline. 
6.1.2.6 
Hemoglobin > 11.0 gm/dl or 50% improvement over 
baseline without transfusions. 
6.1.3 
Progressive disease (PD) 
Progressive Disease (PD) will be characterized by at least one of the 
following: 
6.1.3.1 
≥ 50% increase from nadir value since start of treatment in 
the sum of the products of at least 2 lymph nodes on 2 
consecutive examinations 2 weeks apart (at least 1 node 
must be ≥ 2 cm) and that is not due to tumor flare reaction. 
Appearance of new palpable lymph nodes > 1.5 cm not 
due to tumor flare reaction. 
6.1.3.2 
≥ 50% increase from nadir value since start of treatment in 
the size of liver and/or spleen as determined by 
measurement below the respective costal margin that is 
not due to tumor flare reaction. Appearance of palpable 
hepatomegaly or splenomegaly which was not previously 
present that is not due to tumor flare reaction. 
6.1.3.3 
≥ 50% increase in the absolute number of circulating 
lymphocytes (taking as a reference for progressive disease 
the smallest absolute lymphocyte count recorded since the 
treatment started) not due to tumor flare reaction. The 
absolute lymphocyte count must be at least 5x109/L to 
qualify as disease progression. 
NOTE: It is common for CLL patients to experience a 
transient increase in lymphocytosis due to 
redistribution of lymphocytes from the lymph 
nodes and spleen to the peripheral blood 
circulation. This lymphocytosis is NOT a marker 
of disease progression or Richter’s transformation 
and typically resolves over several months.  For 
this reason, prior to the 12 month response 
evaluation, patients on both arms will not be 
considered to have disease progression based on 
an increased absolute lymphocyte count if they 
simultaneously have unequivocal improvement in 
at least one other disease-related parameter 
including lymph node size, spleen size, 
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hematologic parameters (Hgb or platelet count), 
or disease-related symptoms. Questions 
regarding an increase in the absolute lymphocyte 
count after initiation of therapy should be 
discussed with the study PI. 
6.1.3.4 
Unscheduled CT Scans:  Since this is an open label trial, it 
is possible that an imbalance in unscheduled CT scans 
could emerge between arms and influence assessment of 
disease progression.  To address this issue, all 
unscheduled CT scans performed on both arms as well as 
the reason for unscheduled CT scans will be recorded.  
This information will be collected to identify differences in 
the frequency of such unscheduled CT scans between 
arms and allow us to detect potential bias in ascertainment 
of disease progression (see Section 9.3.1.2). 
6.1.3.5 
Progression by physical exam only:  It is anticipated that 
most cases of disease progression will initially be identified 
by an objective increase in the absolute lymphocyte count 
(ALC) on a complete blood count or simultaneous increase 
in ALC and progressive lymphadenopathy.  
Given the unblinded nature of the trial however, it is 
possible that a difference in the interpretation of palpable 
lymphadenopathy could occur between arms.  To address 
this possibility, we will record the pattern of relapse by 
classifying all patients experiencing progression as: 
• 
Progression due to rising ALC only 
• 
Progression determined by lymphadenopathy on 
physical exam only 
• 
Progression due to both rising ALC and physical  
• 
Exam 
This information will be evaluated to identify potential bias 
due to differences in the interpretation of palpable 
lymphadenopathy between arms (Section 9.3.3). 
6.1.3.6 
In the absence of progression as defined above, the 
presence of a ≥ 2 gm/dl decrease in hemoglobin, or ≥ 50% 
decrease in platelet count and/or absolute granulocyte 
count will not exclude a patient from continuing on study. 
Bone marrow aspirate and biopsy are strongly encouraged 
to better define the cause of the suppressed counts.  
6.1.3.7 
Transformation to a more aggressive histology (e.g. 
Richter's syndrome or prolymphocytic leukemia with > 55% 
prolymphocytes). 
6.1.3.8 
For patients who achieve a CR or nodular PR  
< progression will be defined as recurrence of circulating 
leukemia cell clone in the peripheral blood and an absolute 
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lymphocyte count > 5x109/L and/or recurrence of palpable 
lymphadenopathy > 1.5 cm by physical exam. 
6.1.4 
Stable Disease (SD) 
6.1.4.1 
Patients who have not achieved a CR or a PR, or who 
have not exhibited findings consistent with Progressive 
Disease will be considered as having Stable Disease. 
6.1.5 
Complete Clinical Remission (CCR) 
6.1.5.1 
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. 
6.1.6 
Evaluation of Minimal Residual Disease (MRD): An important aspect 
of this trial is that evaluation of minimal residual disease using a 
sensitive flow cytometry method capable of detecting approximately 1 
CLL cell per 10,000 leukocytes following induction. 
An International, standardized approach for flow cytometric evaluation 
of residual disease in patients with CLL was recently developed (32). 
This approach reliably detects residual CLL B-cells at the level of 1 
leukemic cell per 10,000 leucocytes. Notably, analysis of peripheral 
blood was equally or more sensitive to marrow in 92% of samples 
except when patients had received treatment with monoclonal 
antibodies (such as rituximab) within 3 months of evaluation. 
This approach uses a pre-antibody ammonium chloride red cell lysis 
approach to separate peripheral blood white blood cells from RBCs 
followed by staining of 1-2 x 106 leukocytes with a panel of antibodies 
for flow cytometry analysis.  For each test, 300,000 to 500,000 events 
were collected to ensure the desired sensitivity of the assay. 
While the 4 color based strategy was the standard proposed by the 
international group, 5- to even 8-color flow cytometry based assays 
are being used in many laboratories and are expected to have a 
similar degree of sensitivity (level of 1 leukemic cell per 10,000 
leucocytes) while enhancing the accuracy of the assay.  
Assessments for MRD in the present study will be conducted as a 
research assay in the Mayo Clinic Rochester Department of 
Hematopathology under the direction of Dr. 
 using a 
flow cytometry strategy able to detect residual leukemia at the level of 
1 leukemic cell per 10,000 leukocytes in accord with the International 
Standard (32). For each test, 200,000 to 500,000 events are collected 
to ensure the desired sensitivity of the assay. 
All patients will undergo assessment of MRD using sensitive flow 
cytometry 52 weeks (+/- 14 days) after day 1 of cycle 1 (see Section 
7.1). Since the assessment of MRD 52 weeks after day 1 of cycle 1 
will occur more than 3 months of rituximab therapy, MRD assays will 
be performed on peripheral blood. MRD testing for research purposes 
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6.1.7 
Quality of Life 
CLL and CLL treatment can have a substantial affect on patient 
quality of life. 
While Ibrutinib appears to have a favorable toxicity profile relative to 
fludarabine based therapy, the need for chronic indefinite 
administration may result in chronic side effects that ultimately erode 
QOL over the long run (compared to a more intense but limited 
duration treatment schedule). In addition, the benefit of lower toxicity 
may not ultimately improve QOL if this treatment is less effective at 
controlling the disease.   
To explore these aspects, the present study is designed to assess the 
QOL of patients on both treatment arms longitudinally. Mandatory 
quality of life will be assessed at the following 8 time-points: 
• 
Baseline 
• 
After 3 cycles of therapy 
• 
After 6 cycles of therapy 
• 
At response evaluation (52 weeks after day 1 of 
cycle 1) 
• 
Every  months for  years after 
 
• 
 
The QOL of patients in the treatment arms will be compared at these 
time points to assess affect of treatment arm on QOL both during 
active the first several months of treatment and over the long term. 
Primary Endpoint 
Quality of life (QOL) will be assessed using FACT-G and the leukemia 
subscale. The primary objective of the QOL study is to compare 
treatment toxicity-related QOL in patients receiving the experimental 
Ibrutinib -based therapy to those receiving standard FCR. The primary 
interest is the FACT-Leu Trial Outcome Index (TOI), which is 
comprised of the FACT-G physical well-being (PWB) and functional 
well-being (FWB) subscales and the leukemia subscale. The FACT-
Leu TOI contains a total of 31 items, with scores ranging from 0 to 
124. It will be administered at the following time points: at the time of 
randomization, three months and six months after randomization, and 
every six months thereafter. The primary endpoint is the change in 
FACT-Leu TOI score from the time of randomization to 12 months 
after beginning therapy between the FCR arm and the Ibrutinib arm.  
To better understand the impact of CLL on an individual’s QOL, the 
entire FACT-G Leukemia questionnaire will be administered to all 
patients at the time of study enrollment, i.e., prior to initiating therapy.  
The FACT-G Leukemia is a 43-item instrument, containing the 
subscales previously described above.  In addition, it also contains a 
social and an emotional well-being subscale. 
Adherence: 
In addition to longitudinally measuring QOL, we will also assess 
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therapy. Adherence will be assessed using both the pill diary 
(Appendix III) completed with each cycle as well as the Morisky 
Adherence Scale.). The Morisky scale will be completed by patients 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans or x-rays used to document measurable or evaluable disease must be done within 2 weeks of 
registration. 
2. Prestudy CBC with differential, LFTs must be done ≤ 2 weeks before registration. 
3. All required prestudy chemistries must be done ≤ 2 weeks before registration - unless specifically required on Day 1 
as per protocol. If abnormal, they must be repeated within 48 hours prior to registration. 
 
Active Monitoring Phase 
Tests/Procedures 
Pre-
treatment 
During Treatment14 
12 Month 
Response 
Evaluation 
Continuation17 Follow 
Up15 
 
Tests & Observations 
 
 
 
 
 
 
 
History and progress note14 
X 
X18 
X 
X 
X 
X 
X 
Performance status14 
X 
X18 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Weight/Body Surface Area1 
X 
X 
 
 
X 
 
 
Physical examination14, 21 
X 
X18 
X 
X 
X 
X 
X 
Tumor measurement by physical exam14-21 
 X2 
X2, 18 
 X2 
 X2 
 X2 
 X2 
X2 
Drug toxicity measurement 14 
X 
X18 
X 
X 
X 
X 
 
Comorbidity Index 
 X3 
 
 
 
 
 
 
Timed Up and Go (TUG) Test13 
X 
 
 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
 
 
CBC with differential5,14 
X 
 X4 
 X4 
X 
X 
X 
X 
Serum creatinine and creatinine clearance16 
X 
 X5 
 
 
 
 
 
Uric acid, potassium, phosphate, LDH, Ca+ 
X 
 X5 
 
 
 
 
 
AST, ALT, total bilirubin, alkaline phosphatase14 
X 
X 
X 
X 
X 
X 
 
Peripheral blood immunophenotyping by flow 
cytometry on peripheral blood or bone marrow7 
X 
 
 
 
 
 
 
Serum pregnancy test 
 X6 
 
 
 
 
 
 
CLL FISH panel (on peripheral blood or bone 
marrow aspirate) 
 X7 
 
 
 
 
 
 
Bone marrow aspirate and biopsy14 
 X8 
 
 
 
 X8 
 
 
Beta-2-microglobulin14 
X 
 
 
 
X 
 
 
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Active Monitoring Phase 
Tests/Procedures 
Pre-
treatment 
During Treatment14 
12 Month 
Response 
Evaluation 
Continuation17 Follow 
Up15 
 
PT/INR, PTT (aPTT) 
X 
 
 
 
 
 
 
Quantitative Immunoglobulins (IgG, IgA, IgM) 14 
X 
 
 
 
X 
 
 
Hepatitis B (HB) surface antigen, surface Ab 
and core Ab testing; 
 X9 
 
 
 
 
 
 
Hepatitis C Anti-body testing 
  X11 
 
 
 
 
 
 
Direct Coombs test  
X 
 
 
 
 
 
 
CT scan chest, abdomen, pelvis12 
X 
 
 
 
X 
 
 
Biological Sample Submissions 
See Section 7.2 
 
QOL Questionnaires10, 14 
  X10 
  X10 
  X10 
 
  X10 
  X10 
X10 
Footnotes for Test Schedule 
1. Drug doses need not be changed unless the calculated dose changes by >10% 
2. Physical exam must measure the spleen and liver noting the maximal distance below the respective costal margins at rest in the mid-clavicular 
line and must record the bidimensional diameter of the largest palpable node in each lymph node area of involvement including the following 6 
sites:  cervical/supra-clavicular (right and left) axillary (right and left), inguinal (right and left). 
3. Cumulative illness rating scale – see Appendix VII (JCO 16: 1582–1587). 
4. For cycle 1, patients with pretreatment platelet counts < 20x109/L, should have a CBC repeated on Day 3. If this platelet count is below 
20x109/L, the responsible physician should be contacted and platelets should be transfused, if clinically indicated. As treatment with anti-CD20 
monoclonal anti-bodies may result in acute but temporary reduction in platelets, patients with baseline platelet counts < 50x109/L prior to 
receiving rituximab should have platelet counts repeated after the rituximab infusion is ended to see if platelet transfusion is necessary. 
5. In Arm B patients, all tests noted should be collected prior to treatment on Day 2 of Cycle 1 to monitor for tumor lysis. 
6. For women of childbearing potential only. Must be done ≤ 14 days prior to registration. 
7. Must be done ≤ 3 months prior to registration. It is acceptable for FISH to be performed on either peripheral blood or bone marrow tissue. 
8. Bone marrow biopsy is required. If the patient has had a bone marrow biopsy obtained for clinical purposes ≤ 3 months prior to registration this 
can be used for baseline purposes and a repeat is not required provided slides from this clinical bone marrow can be submitted. At time of 
response evaluation a bone marrow biopsy is required for all patients with evidence of response (CR, PR) or stable disease but is not required 
for those with disease progression. Bone marrow slides for central review must be submitted as outlined in Section 10. 
9. All patients must be screened for hepatitis B infection before starting treatment. Those patients who test positive for hepatitis B are ineligible. 
Tests must be done ≤ 4 weeks prior to registration. See Section 3.1.18. 
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10. Quality of life will be evaluated at baseline, after the first 3 cycles of therapy; after 6 cycles of therapy; at the time of the 12 month response 
evaluation, and then every  months for  years regardless of whether or not the patient progresses.  QOL will also be assessed 
 
 
11. If Hepatitis C anti-body testing is positive, PCR to evaluate active Hepatitis C. Patients with active Hepatitis C are ineligible (see Section 
3.1.17). Tests must be done ≤ 4 weeks prior to registration. 
12. Baseline CT scan requirement can be waived if the patient has had a CT scan ≤ 4 weeks prior to registration. In such cases, the clinical CT 
scan obtained within the last 4 weeks may serve as the baseline CT scan for measurement purposes. At time of response evaluation CT scan 
of the chest, abdomen and pelvis is required for all patients with evidence of response (CR, PR) or stable disease but is not required for those 
with disease progression. 
13. Please see Appendix X for instructions for the Timed Up and Go (TUG) Test.  
14. If patient comes off treatment due to any reason other than progression or completion of treatment per protocol (Arm B), please complete all of 
the noted tests/procedures with 2 weeks in lieu of a 
. 
15.  Every  months (
 days) until progression. After progression, patient will switch to standard follow-up schedule: every  months for first  
years, every  months for years 
, and then every 
 months for years 
 
16. Creatinine clearance as estimated by the Cockcroft-Gault equation. See Section 3.1.9 
17. All patients on Arm A currently taking Ibrutinib 
18. If pre-registration value is < 21 days from treatment start date, test does not need to be repeated on day 1 cycle 1. 
19. Laboratories required on day 1 of cycles 1-6 of Arm B should be collected prior to start of chemotherapy. For patients on Arm A, these 
laboratories should be collected prior to the start of rituximab. 
20. Telemedicine visits will be allowed after cycle 6 but every 2nd or 3rd visit must be in person.  Note that if a visit is completed by telemedicine, 
medication may need to be shipped to the patient and if so, the CTEP Oral IND Agent Shipment Guidance (found at  
https://ctep.cancer.gov/content/docs/CTEP Oral IND Agent Shipment Guideline.pdf) must be adhered to.  
21. If visit is conducted as telemedicine visit (see footnote 20) no physical exam or tumor measurement by physical exam are required at that visit. 
 
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7.2 
Biological Sample Submissions  
1. Bone marrow sections/slides and smears must be submitted for central 
histological review at baseline and at the time of the twelve (12) month 
response evaluation as outlined in Section 10. 
2. Peripheral blood and buccal cells should be submitted as outlined below for 
correlative studies and/or banking, per patient consent. 
NOTE: Institutions outside of the United States and Canada must confer with 
the receiving laboratory and the ECOG-ACRIN Operations Office – 
Boston regarding logistics for submission of fresh samples. 
NOTE: Patients must sign informed consent before the submission of the 
samples. If submitting baseline samples prior to patient enrollment to 
the trial, please use the Generic Specimen Submission Form (#2981) 
and call the receiving laboratories prior to shipping. Once the patient is 
randomized please call the receiving laboratories with the ECOG-
ACRIN patient sequence number and retroactively log the sample 
information into the ECOG-ACRIN Sample Tracking System.   
NOTE: It is required that biological sample submissions be logged into the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.4) for 
purposes of monitoring compliance. 
NOTE: Please note there are sample submissions to two separate laboratories. 
 
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Biological Materials 
Ship To: 
MANDATORY for Central Review 
Bone Marrow Biopsy Sections/Slides5 
X 
 
 
X 
 
 
LTRL2 
Bone Marrow Smears (Wright-Giemsa 
stained) 
X1 
 
 
 
 
 
LTRL 
From Patients Who Answer “YES” to “I agree to participate in the laboratory research studies that are being done as part of this clinical trial.” 
Peripheral Blood (sodium heparin (5) 10mL 
green top tubes) 
X1 
X 
X 
X 
X 
X 
Mayo Clinic3 
Peripheral Blood (serum, (2) 10mL red top 
tubes) 
X1 
 
 
X 
X7 
 
Mayo Clinic3 
From Patients Who Answer “YES” to “I agree to provide additional specimens for research.” 
 
 
Peripheral Blood (serum, (2) 10mL red top 
tubes, 15-20mL) 
X1 
 
 
 
 
 
LTRL 
Peripheral Blood (heparin, (4) 10mL green 
or purple [EDTA] top tubes, 30-40mL) 
X1 
 
 
 
 
 
LTRL 
Buccal Rinse (preferred) or Swab6 
X1 
 
 
 
 
 
LTRL 
1. After randomization, prior to treatment. 
2. Submit to the ECOG-ACRIN Leukemia Translational Research Laboratory (LTRL). Signed E1912 patient consents and HIPAA authorizations 
must be submitted to the LTRL prior to or at time of submission of baseline samples per Dr. 
 institutional regulations. 
3. Collection and shipping kits are being provided for the peripheral blood being submitted to Mayo Clinic. 
4. [Deleted in Addendum #2] 
5. Bone marrow biopsy sections/slides for central review can be from the clinical biopsy performed within three (≤ 3) months prior to registration if 
the on-study baseline bone marrow biopsy was not performed. Sections/slides are to be submitted within one (1) month of randomization. 
6. Buccal rinse (preferred) or swabs are strongly encouraged to be collected prior to the start of treatment, but can be collected at any other time 
during the study, if necessary. 
7. Collect at month 
 only. 
 
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8/15 
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8. 
Drug Formulation and Procurement 
Drug Ordering: Pharmacyclics is supplying Ibrutinib (PCI-32765), through the Division of 
Cancer Treatment and Diagnosis, NCI, for this protocol. Maintenance of NCI drug 
accountability records is required. Ibrutinib (NSC 748645 IND 117241) may be 
requested by the Principal Investigator (or their authorized designees) at each 
participating institution. 
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under 
the name of one lead investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of 
an “active” account status and a “current” password.   
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated.  PMB does not permit the transfer of 
agents between institutions. 
NOTE: 
If a visit is completed by telemedicine, medication may need to be shipped to 
the patient and if so, the CTEP Oral IND Agent Shipment Guidance (found at  
https://ctep.cancer.gov/content/docs/CTEP Oral IND Agent Shipment Guid
eline.pdf) must be adhered to. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at (240) 276-6575. 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 
276-6575.” 
8.1 
Ibrutinib (NSC 748645) PCI-32765 
8.1.1 
Chemical name: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-
pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one 
8.1.2 
Classification Selective, irreversible, small molecule inhibitor of 
Bruton’s tyrosine kinase (BTK). 
8.1.3 
CAS Registry Number:  936563-96-1 M.W.:  440.5 g/mole 
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8.1.4 
Mode of Action 
Ibrutinib binds covalently to a cysteine residue in the BTK active site, 
leading to potent and irreversible inhibition of BTK enzymatic activity 
of B-cell receptors (BCR). B-cell maturation is mediated by BCR 
signal transduction and BTK is an essential part of the signaling 
pathway. 
8.1.5 
Description 
White to off-white crystalline solid 
8.1.6 
Storage and Stability 
Ibrutinib Hard Gelatin Capsules should be stored at 15 – 25°C. Shelf 
life surveillance of the intact bottles is ongoing. 
8.1.7 
Administration 
Orally, with 8 ounces (approximately 240 ml) of water. The capsules 
are to be swallowed intact, not less than 30 minutes before or 2 hours 
after a meal. Patients should avoid consuming food and beverages 
containing grapefruit juice or Seville oranges for the duration of the 
study due to CYP3A4/5 inhibition. Doses are to be taken at about the 
same time each day.  If an ibrutinib dose is missed, it should be made 
up as soon as possible on the same day with a return to the normal 
schedule the following day. 
8.1.8 
Preparation  
Ibrutinib is supplied as hard gelatin capsules containing micronized 
Ibrutinib and the following excipients: microcrystalline cellulose; 
croscarmellose sodium; sodium lauryl sulfate; may contain 
magnesium stearate. 
8.1.9 
Availability / How supplied 
Ibrutinib is supplied by Pharmacyclics, Inc., and distributed by the 
CTEP, DCTD, NCI. Capsules are packaged in 60-ml high-density 
polyethylene (HDPE) bottles with an induction seal and a child 
resistant screw top cap. Each bottle contains 92 capsules. 
8.1.10 
Dose Specifics 
Arm A 420 mg PO, each day, days 1-28. Capsules are 140mg 
strength in a size 0, gray, hard gelatin capsule. 
8.1.11 
Side Effects 
See CAEPR, Section 5.3.1 
8.1.12 
Potential Interactions 
Ibrutinib is metabolized primarily by CYP3A4/5. Due to this potential 
increase in Ibrutinib exposure, concomitant use of ibrutinib and drugs 
that strongly or moderately inhibit CYP3A4/5 can increase ibrutinib 
exposure and should be avoided (see Appendix VIII). Patients should 
also be advised to avoid vitamin E and fish oils. Strong inducers of 
CYP3A4/5 should be avoided A comprehensive list of inhibitors, 
inducers, and substrates may be found at 
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http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is 
continually revised and should be checked frequently for updates. 
Alternative agents with mild or no CYP3A4/5 inhibition should be 
considered.  Co-administration of ketoconazole, a strong CYP3A4/5 
inhibitor, in 18 healthy subjects, increased dose normalized exposure 
(Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, respectively. 
Therefore, concomitant administration of ibrutinib with strong inhibitors 
of CYP3A4/5 (see Appendix VIII) should be avoided. 
If a strong CYP3A4/5 inhibitor must be used, the Medical Monitor 
should be consulted before the use, and a dose reduction of ibrutinib 
to 140 mg daily or temporary hold of ibrutinib should be considered.  
Subjects should be closely monitored for potential treatment-related 
toxicities. If Ibrutinib is temporary held or the dose reduced due to 
administration of strong CYP3A4/5 inhibiters, patients may return to 
the previous dose of Ibrutinib once they are no longer taking strong 
CYP3A4/5 inhibiters. Moderate CYP3A4/5 inhibitors  
(see Appendix VIII) should be used with caution. If the benefit 
outweighs the risk and a moderate CYP3A4/5 inhibitor must be used, 
reduce ibrutinib to 140 mg for the duration of the inhibitor use. No 
dose adjustment is required when ibrutinib is administered in 
combination with mild inhibitors. Grapefruit juices and Seville oranges 
may also increase ibrutinib plasma concentrations and should be 
avoided for the duration of ibrutinib treatment 
Warfarin and other vitamin K antagonists are not permitted in 
combination with Ibrutinib. Patients should also be advised to avoid 
fish oil and vitamin E supplements while taking ibrutinib. 
Although short term use (< 4 weeks) of pulse steroids are permitted, 
long term use of prednisone at a dose > 20 mg per day (or equivalent) 
is not permitted. 
Supplements such as fish oil and vitamin E preparations should be 
avoided. 
Patients with congenital bleeding diathesis have not been studied.  
For guidance on ibrutinib and the use of anticoagulants during 
procedures/surgeries, see Section 5.4. 
If therapeutic anticoagulation is clinically indicated, treatment with 
ibrutinib should be held and not be restarted until the patient is 
clinically stable and has no signs of bleeding.  Patients should be 
observed closely for signs and symptoms of bleeding. No dose 
reduction is required when study drug is restarted. See also Section 
5.4.9. 
In addition to the above considerations, any non-study protocol 
related chemotherapy, anticancer immunotherapy, experimental 
therapy, or radiotherapy are prohibited while the patient is receiving 
ibrutinib therapy. 
Corticosteroids for the treatment of the underlying malignancy are 
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8.1.13 
Overdose 
Any dose of study drug administered in excess of that specified in this 
protocol is considered to be an overdose. Signs and symptoms of an 
overdose that meet any SAE criterion must be reported as a SAE in 
the appropriate time frame and documented as clinical sequelae to an 
overdose. 
There is no specific experience in the management of ibrutinib 
overdose in patients. No maximum tolerated dose (MTD) was reached 
in the phase 1 study in which subjects received up to 12.5 mg/kg/day 
(1400 mg/day). Healthy subjects were exposed up to single dose of 
1680 mg. One healthy subject experienced reversible Grade 4 hepatic 
enzyme increases (AST and ALT) after a dose of 1680 mg. Subjects 
who ingested more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment. 
8.2 
Allopurinol (Lopurin, Zyloprim) 
8.2.1 
Availability 
Commercially available as 100 mg and 300 mg tablets. Please refer to 
the agent’s package insert for additional information. 
8.2.2 
Preparation 
A 20 mg/mL suspension may be made by crushing eight 300 mg 
tablets and mixing with 120 mL of either 1:1 mixture of Ora-Sweet® 
and Ora-Plus® or a 1:1 mixture of Ora-Sweet®SF and Ora-Plus®. the 
resulting suspenion is stable for 60 days refrigerated. 
8.2.3 
Storage & Stability 
Store tablets in a tight container at 15°-30°C.  
8.2.4 
Administration 
300 mg/day by mouth days 1 through 14 (total of 14 days) of cycles 1 
and 2 unless allergic. See Section 5.1.1.3. 
Administer by mouth. Fluid intake should be sufficient to yield a daily 
urine output of 2 liters.  
8.2.5 
Toxicity 
Dermatologic toxicity, including pruritic maculopapular rash, urticaria, 
exfoliative dermatitis, and hemorrhagic dermatides which may be 
accompanied by alopecia, fever, and malaise. Stevens-Johnson 
syndrome (exfoliative dermatitis with mucous membrane involvement) 
has been reported. Patients with compromised renal function may be 
at a greater risk of development of rashes. Skin reactions may be 
delayed as long as two years after initiation of therapy. 
Gastrointestinal side effects, including nausea, diarrhea, and 
abdominal pain may occur. Drowsiness may also occur. 
8.2.6 
Drug Interactions 
Concomitant usage of allopurinol and drugs that can increase serum 
urate concentrations, e.g., diuretics and alcohol, may necessitate an 
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increase in allopurinol dosage. Administration of allopurinol with 
ampicillin or amoxicillin may increase the risk of skin rash. Allopurinol 
and chlorpropamide may result in an increased risk of hypoglycemia, 
whereas allopurinol with co-trimoxazole is associated with increased 
risk of thrombocytopenia. 
8.3 
Rituximab (IDEC-C2B8, Rituxan®) 
8.3.1 
Availability 
Rituximab is commercially available in 10 mL and 50 mL single-use 
vials containing 100 mg or 500 mg rituximab solution, respectively, at 
a concentration of 10 mg/mL. Please refer to the agent’s package 
insert for additional information. 
8.3.2 
Storage & Stability 
Intact vials should be stored under refrigeration (2°-8°C). Dilute 
solutions for infusion (1-4 mg/mL) are stable for 24 hours under 
refrigeration, and for an additional 24 hours at room temperature. 
8.3.3 
Preparation 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W 
to a final concentration of 1-4 mg/mL. The solution should be mixed 
by gently inverting the bag. 
8.3.4 
Administration 
Arm A: 
Cycles 2 through 7 
Rituximab, 50 mg/m2 IV on day 1 of Cycle 2, and 325 mg/m2 on day 2 
of Cycle 2,  
then 500 mg/m2 on day 1 of Cycles 3-7. 
Arm B  
Cycles 1 through 6 
Rituximab, 50 mg/m2 IV on day 1 and 325 mg/m2 on day 2 of Cycle 1  
and 500 mg/m2 on day 1 of Cycles 2-6. 
8.3.5 
Side Effects 
Refer to package insert for rituximab for additional information. 
Likely side effects include: Chills ,Fever ,Reaction that can occur 
during or following infusion of the drug. The reaction may include 
fever, chills, rash, low blood pressure, and difficulty breathing, 
Lowered white blood cell count, Less likely side effects include: 
Lowered red blood cell count (may cause anemia , weakness, fatigue) 
Fever associated with dangerously low levels of a type of white blood 
cell (neutrophils), Heart attack caused by a blockage of a blood vessel 
supplying part of the heart , Fast heartbeat, Belly pain, Diarrhea, 
Nausea or the urge to vomit, Vomiting, Swelling of the arms and/or 
legs, Fatigue or tiredness, Pain, Allergic reaction by your body to the 
drug product that can occur immediately or may be delayed. The 

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reaction may include hives, low blood pressure, wheezing, swelling of 
the throat, and difficulty breathing. Allergic reaction to other 
medications, injected proteins, or antisera (blood product) used to 
treat certain medical conditions (such as an infectious or poisonous 
substance), Infection, Awakening of viruses which have been 
latent/dormant, Infection in HIV positive patients, Lowered platelet 
count that might interfere with clotting (may make you more likely to 
bruise or bleed), Decrease in the total number of white blood cells 
(leukocytes), Increased blood sugar level, Decreased blood level of 
calcium, Decreased blood level of potassium, Joint pain, Back pain, 
Muscle pain, Pain in the area of the tumor, Dizziness (or sensation of 
lightheadedness, unsteadiness, or giddiness), Headache or head 
pain, Abnormal drowsiness or sluggishness, an unusual lack of 
energy, Convulsion or seizure, Sudden or traumatic injury to the 
kidney, Stuffy or runny nose, sneezing, Sudden constriction of the 
small airways of the lung that can cause wheezing and shortness of 
breath, Cough, Shortness of breath, Decrease in the oxygen supply to 
a tissue, Inflammation of the lungs that may cause difficulty breathing 
and can be life-threatening, Sore throat, Excess sweating, Itching, 
Skin rash, Swelling of body tissue underneath the skin, Hives, Sudden 
reddening of the face and/or neck, High blood pressure, Low blood 
pressure. Rare but serious side effects include: Serious, life-
threatening allergic reaction requiring immediate medical treatment by 
your doctor. The reaction may include extremely low blood pressure, 
swelling of the throat, difficulty breathing, and loss of consciousness. 
Group of signs and symptoms due to rapid breakdown of tumor that 
can occur after treatment of cancer has started that causes increased 
levels of blood potassium, uric acid, and phosphate, decreased levels 
of blood calcium, and kidney failure. Disease affecting brain tissue, 
caused by the JC virus. Severe potentially life-threatening damage to 
the lungs which can lead to fluid in the lungs. Severe reaction of the 
skin and gut lining that may include rash and shedding or death of 
tissue. Potentially life-threatening condition affecting less than 10% of 
the skin in which cell death causes the epidermis (outer layer) to 
separate from the dermis (middle layer). Life-threatening condition 
affecting greater than 30% of the skin in which cell death causes the 
epidermis (outer layer) to separate from the dermis (middle layer)  
8.4 
Fludarabine Monophosphate [Fludara; Berlex laboratories] 
8.4.1 
Availability 
IV: Fludarabine monophosphate is commercially available as a sterile 
powder in 50 mg vials containing 50 mg of mannitol and sodium 
hydroxide to adjust the pH to 7.7. Please refer to the agent’s package 
insert for additional information. 
PO: An oral formulation of fludarabine will be used by Canadian 
institutions. Fludarabine is available in 10 mg tablets. 
8.4.2 
Storage & Stability 
Intact vials should be stored under refrigeration (2°-8°C). 
Reconstituted fludarabine phosphate contains no antimicrobial 

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preservative and thus should be used within 24 hours of 
reconstitution. Solutions diluted in D5W or NS are stable for 48 hours 
at room temperature or under refrigeration. 
8.4.3 
Preparation 
IV: Vials of fludarabine are reconstituted with 2 mL of sterile water for 
injection to yield a 25 mg/mL solution. The product should be further 
diluted for intravenous administration in 100 or 125 mL 5% dextrose 
or in 0.9% saline.  
8.4.4 
Administration 
Fludarabine 25 mg/m2 IV days 1, 2, 3 
IV: Fludarabine will be administered as an IV infusion over 30 
minutes. 
8.4.5 
Toxicity 
Myelosuppression (dose limiting toxicity), fever, nausea and/or 
vomiting, skin rashes, myalgia, fatigue, autoimmune hemolytic anemia 
(may be life-threatening), and pulmonary toxicity (both pneumonia 
and pulmonary hypersensitivity reactions have been reported; fatal 
pulmonary toxicity has been described, especially when fludarabine 
was used in combination with pentostatin). Severe or fatal CNS 
toxicity presenting with loss of vision and progressive deterioration of 
mental status has been described primarily after high doses of 
fludarabine monophosphate, or at usual doses (25-30 mg/m2) in 
elderly patients. Very rarely described complications include 
transfusion-associated graft versus host disease, thrombotic 
thrombocytopenic purpura, and liver failure. Tumor lysis syndrome 
has been observed, especially in patients with advanced bulky 
disease. Opportunistic infections (protozoan, viral, fungal, and 
bacterial) have been observed. Please refer to the package insert for 
additional information. Please also see Section 8.5.6 for a list of 
possible side effects when used in combination with 
cyclophosphamide. 
8.4.6 
Drug Interactions 
Chronic use of corticosteroids with fludarabine should be avoided due 
to a significant increase in opportunistic infections. 
8.5 
Cyclophosphamide (Cytoxan®; CTX; CPA; Endoxan®; Neosar®; Cytoxan 
Lyophilized®) 
8.5.1 
Availability 
Commercially available as a powder for injection in 100 mg, 200 mg, 
500 mg, and 1 gram and 2 gram vials. Please refer to the agent’s 
package insert for additional information. 
8.5.2 
Storage & Stability 
Intact vials should be stored at room temperature. Reconstituted and 
diluted solutions are stable for 24 hours at room temperature and 6 
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8.5.3 
Preparation 
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 
5, 10, 25, 50, or 100 mL of sterile water for injection or normal saline 
to give a final concentration of 20 mg/mL. Vigorous shaking and/or 
gentle warming may be necessary for non-lyophilized preparations. 
Bacteriostatic water for injection (paraben preserved only) may be 
used; benzyl alcohol derivatives may NOT be used. Further dilute in 
D5W or normal saline for IV infusion. 
8.5.4 
Administration 
Cyclophosphamide 250 mg/m2 IV, days 1, 2, 3 
Administer by slow IV push or IV infusion over 30 minutes. 
All patients should be adequately hydrated before and several days 
after each cycle of treatment. This is especially important to minimize 
hemorrhagic cystitis as well as the occurrence of tumor lysis 
syndrome in patients with bulky adenopathy or leukocytes  
> 50,000/µL. 
8.5.5 
Toxicity 
Myelosuppression, hemorrhagic cystitis, syndrome of inappropriate 
antidiuretic hormone (SIADH), fatigue, hyperuricemia, azospermia, 
amenorrhea, cardiotoxicity (myocardial necrosis) with high doses. 
8.5.6 
Possible side effects, Fludarabine combined with Cyclophosphamide 
Some of the Risks and Side Effects with Fludarabine and 
Cyclophosphamide are listed below (additional information can be 
found in the package insert): 
Likely: Lowered white blood cell count (neutrophils/granulocytes) that 
may lead to infection,Lowered platelets which may lead to an increase 
in bruising or bleeding, Lowered red blood cells which may cause 
anemia, tiredness, or shortness of breath, Lowered number of another 
type of white blood cells (lymphocytes) that may lead to infection, 
Fatigue, Nausea, Vomiting, Time away from work, Hair loss, 
“Shingles.” If you develop a condition known as shingles (Herpes 
zoster infection of the skin), a skin rash caused by the chicken pox 
virus, it will be important that you notify your physician immediately. 
There is a medication available to treat shingles effectively, but only if 
the medication is started within 24-48 hours after the rash has 
developed, Should these side effects occur, they can be treated with 
blood products (transfusions), antibiotics, and a reduction in the 
amount of chemotherapy given to you. Until your immune system has 
recovered from treatment, any blood products you may receive should 
be irradiated. Less Likely: Allergic reaction, Severe allergic reaction 
that causes fever, aches and pains in the joints, skin rash, and 
swollen lymph glands, Stuffy or runny nose, sneezing, Sore throat, 
Abnormal fast heartbeat, Excessive sweating, Flushing, Itching, Rash, 
Swelling of the lips, eyes, tongue, and throat which can be severe, 
Hives, Diarrhea, High blood sugar, Low blood potassium, Dizziness, 
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and/or muscle pain, Headache, Wheezing, Cough, Shortness of 
breath, Inflammation of the lung which may cause difficulty breathing 
and difficulty getting oxygen, Infertility or sterility, Irregular menstrual 
periods. Some women may not resume their periods, Abnormal 
production of a hormone that regulates salt and fluid excretion, 
Increased production of tears associated with the administration of 
cyclophosphamide, Metallic taste, Bladder irritation which may cause 
blood to appear in your urine. To minimize this side effect, patients 
are encouraged to drink fluids to promote frequent urination on the 
days of cyclophosphamide administration and one day afterwards. 
Rare But Serious: Destruction of red blood cells that may lead to 
anemia. Should this occur, it can be treated with blood transfusions, 
Changes in vision or changes in degree of alertness both of which can 
be severe or fatal, Rash which may become severe, Potentially life-
threatening condition affecting less than 10% of the skin in which cell 
death causes the outer skin layer to separate from the middle layer, 
Life-threatening condition affecting greater than 30% of the skin in 
which cell death causes the outer layer of skin to separate from the 
middle layer, Severe lung dysfunction resulting in the ability to breathe 
which can be life-threatening, Allergic reactions to blood transfusions, 
Tumor lysis syndrome - a rapid decline in the number of tumor cells 
that can lead to kidney failure and/or chemical imbalances that may 
have a serious effect on other organs like your heart. If this were to 
occur, you would receive close monitoring and blood tests, as well as 
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9. 
Statistical Considerations 
9.1 
Study Design and Objectives 
This is a randomized phase III study designed to evaluate the ability of Ibrutinib-
based induction therapy to improve the efficacy and tolerability of fludarabine-
based chemoimmunotherapy for patients </= 70 years old with untreated 
symptomatic CLL. Five hundred and nineteen (519) patients will be randomized 
2:1 to the Ibrutinib arm (A, 346 patients) and the FCR control arm (B, 173 
patients).  
The primary objective is to definitively evaluate whether patients who receive 
Ibrutinib-Rituximab have significantly longer PFS than those receiving FCR. With 
the planned sample size, we will have 80% power to detect a true hazard ratio of 
1.5 (FCR vs. Ibrutinib) while controlling the one-sided type I error at 2.5%. 
Overall survival will be used as a secondary endpoint. If PFS is found to be 
significantly longer in the Ibrutinib-Rituximab arm than the FCR arm, with an 
additional 34 months of follow-up, we will have 
% power to detect a true 
hazard ratio of 
 (FCR vs Ibrutinib) in terms of 
 while controlling the one-
sided type I error at 
%. 
Interim analyses will be performed. The study will be monitored for early stopping 
in favor of superior PFS in the experimental Ibrutinib arm, or for evidence of lack 
of benefit. 
Because of the expected lower toxicity and non-curative nature of the Ibrutinib 
therapy, quality of life (QOL) is an important secondary study objective for this 
study. Questionnaires will be administered to learn the QOL impact of disease as 
well as treatment in this patient population. If both PFS and OS are found to be 
significantly longer in the Ibrutinib arm than in the FCR arm, QOL results will be 
considered for labeling in the EU. 
Summaries of other secondary objectives of the study are listed below. Details 
can be found in the Objectives section of the protocol. 
• 
Evaluate patient overall survival (OS); 
• 
Monitor and assess toxicity;  
• 
Determine the effect of pre-treatment characteristics on outcome; 
• 
Determine if the minimal residual disease (MRD) status is an effective marker 
for prolonged PFS and OS; 
• 
Explore changes in genetic abnormalities and intra-clonal architecture pre 
and post treatment and their relationship with treatment resistance. 
• 
Explore the effects of therapy on immune function; 
• 
Validate SNPs found to be associated with efficacy and toxicity of 
fludarabine-based therapy in the E2997 trial; 
• 
Develop and evaluate a prognostic model to predict clinical outcome; 
• 
Evaluate signaling networks downstream of the B-cell receptor in patients 
receiving Ibrutinib-based therapy. 
• 
Study mechanisms of resistance to FCR and Ibrutinib-based therapy. 
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9.2 
Accrual 
Based on previous studies conducted through the North American Intergroup 
collaboration (e.g. CALGB10404) in similar patient populations, we expect the 
annual accrual rate to be approximately 180 patients per year. It will take 
approximately 35 months to accrue the 519 patients for the study. Assuming 
median PFS for the Ibrutinib and FCR arms to be 78 and 52 months, 
respectively, the Ibrutinib vs. FCR comparison requires approximately 
 months 
of follow-up to reach full information of 203 events.  
9.3 
Primary Endpoint and Sample Size 
The primary goal is to definitively evaluate whether patients who receive 
Ibrutinib-Rituximab have significantly longer progression-free survival (PFS) than 
those who do not. PFS is defined as the time from randomization to progression 
or to death without documentation of progression. We wish to have good power 
to detect a true hazard ratio of 1.5 (FCR vs. Ibrutinib-rituximab) controlling the 
one-sided type I error at 2.5%. Assuming PFS follows an exponential distribution, 
adjusted for sequential monitoring described below, a sample size of 519 
patients randomized 2:1 to arms A (Ibrutinib-rituximab) and B (FCR) with 346 and 
173 patients in the two arms, respectively will yield a nominal 80% power to 
detect a hazard ratio of 1.5 (median PFS of 52 vs. 78 months in FCR vs. 
Ibrutinib-rituximab) using a nominal one-sided alpha=0.025 logrank test for the 
Ibrutinib-based regimen vs. FCR comparison. The required number of events for 
full information is 203. 
A stratified logrank test applied to all patients as randomized will be the primary 
analysis, with age (< 60 years vs. >= 60 years), ECOG performance status (0/1 
vs. 2), disease stage (3/4 vs. 1/2), and baseline cytogenetic abnormalities 
(deletion of 11q22.3(ATM) vs. others) as stratification factors. The same analysis 
applied to eligible patients only will also be performed as a sensitivity analysis. 
Cox proportional hazards models will be used to assess possible effects of 
clinical and biological characteristics on outcome, including age, gender, disease 
stage, cytogenetic abnormalities, ECOG performance status, and important 
mutations. Treatment and covariate interactions will also be examined. 
9.3.1 
Since this is an unblinded trial, it is possible a difference in 
unscheduled CT scans could emerge between arms.  All unscheduled 
CT scans performed on both arms as well as the reason for 
unscheduled CT scans will be recorded to identify differences in the 
frequency of unscheduled CT scans between arms (See Section 
6.1.3.4).  
9.3.2 
It is anticipated that most cases of disease progression will initially be 
identified by an objective increase in the absolute lymphocyte count 
(ALC) on CBC or simultaneous increase in ALC and progressive 
lymphadenopathy.  
9.3.3 
Given the unblinded nature of the trial however, it is possible that a 
difference in the interpretation of palpable lymphadenopathy could 
occur between arms.  As detailed in Section 6.1.3.5, to address this 
possibility, we will record the pattern of relapse by classifying all 
patients experiencing progression as: 
• 
Progression due to rising ALC only 

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• 
Progression determined by lymphadenopathy on physical exam 
only 
• 
Progression due to both rising ALC and physical exam 
These data will be used to evaluate the progression events on each 
arm of the study to assess whether there is a higher rate of 
progression by “physical exam only” in one study arm.  Since we 
anticipate follow-up will be fairly mature before a large number of 
progression events occur on each arm, we will monitor differences in 
the pattern of progression at  month intervals from the outset of the 
trial and take action if the difference becomes larger than the greater 
of 
 patients or 
%.  If this occurs, the research team will assess 
whether there needs to be changes to the criteria for progression for 
those patients in who progression is based solely on physical exam. 
Collectively, these data will allow us to determine if there is an 
imbalance in progression based only on the findings of physical exam 
or a difference in the frequency of unscheduled CT scans and to 
detect potential bias in classification of disease progression on this 
basis. 
9.4 
Phase III Interim Analysis of the Primary Endpoint 
We will perform the first interim analysis 24 to 27 months after full accrual. If the 
study has reached the planned full information (i.e. 203 PFS events) by this time, 
then the first analysis would be the only analysis. If the study is not at full 
information, then interim analyses will be performed annually until full information 
is reached. Under the current accrual rate of 
 per month and assumed 
hazard rates for the two arms, interim and final analyses are expected to occur at 
 and 
 months after study activation. The upper boundary for the first interim 
analysis is 2.807, corresponding to one-sided p-value of 0.0025. The upper 
boundary for the final analysis will be determined using the Lan-DeMets error 
spending function to preserve the overall type-I error rate. Upper boundaries at 
the planned analyses times are shown in Table 1. If the upper boundary is 
crossed at the interim analysis, there is sufficient evidence of efficacy to stop the 
study in favor of the alternative. 
Table 1: The Interim PFS Efficacy Analyses for Ibrutinib-Rituximab vs. FCR 
Time from Study 
Start (Months) 
Information 
Time 
Events Under 
H1 
Boundary 
* Actual information time at interim analysis may be less due to data collection and 
processing. 
The study will also be monitored for early stopping for harm and inefficacy. At 
25% information, the DSMC may consider stopping the study for harm if the 
lower 95% confidence bound for the hazard ratio (Ibrutinib/FCR) is above 1. 
Inefficacy monitoring is scheduled to start after approximately 49% of the full 
information becomes available with repeated analyses at each semi-annual 
DSMC meeting. Linear 20% Inefficacy Boundary (LIB20) proposed by Freidlin et 
al. (2010) will be used [8]. At each interim analysis, if the estimated hazard ratio 
is larger than the cut-off value given in the LIB20 boundary, the study would be 

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stopped early for lack of efficacy. In this study, the LIB20 boundary goes from  
on the hazard ratio scale (from 
 on the log hazard ratio scale). 
9.5 
Secondary Objectives 
Overall survival, defined as the time from randomization until death due to any 
cause, will be used as a secondary endpoint. Previous data showed that the time 
to 25% of FCR patients dying was 62.5 months [2]. Assuming an 
 
, with a total of 519 patients and adjusted for sequential 
monitoring described below, we will have 80% power to detect a true hazard ratio 
of 1.67 (FCR vs. Ibrutinib regimen) using a nominal one-sided alpha=0.025 log-
rank test. The required number of deaths for full information is 125. A hierarchical 
testing strategy will be used, in that the difference in OS between the two arms 
will be tested only if PFS for the Ibrutinib arm is significantly longer than that of 
the FCR arm, which gives us a one-sided family wise type I error rate of 
%.  
We will perform the first interim analysis for OS at the final analysis time for PFS, 
expected at 
 months after study activation. To preserve the overall type I error 
rate, critical values at the interim efficacy analyses will be determined using a 
truncated version of the Lan-DeMets error spending rate function corresponding 
to the O’Brien-Fleming (O-F) boundary. The upper O-F boundaries at the 
planned analyses times are shown in Table 2. If the upper O-F boundary is 
crossed at an interim analysis, that would be sufficient evidence of efficacy in 
favor of the alternative. 
Table 2: The Interim OS Efficacy Analyses for Ibrutinib-Rituximab vs. FCR 
Time from Study 
Start (Months) 
Information 
Time 
Events 
Under H1 
Truncated O-F 
Boundary 
A stratified logrank test applied to all patients as randomized will be the primary 
analysis for OS, with age (< 60 years vs. >= 60 years), ECOG performance 
status (0/1 vs. 2), disease stage (3/4 vs. 1/2), and baseline cytogenetic 
abnormalities (deletion of 11q22.3(ATM) vs. others) as stratification factors. The 
same analysis applied to eligible patients only will also be performed as a 
sensitivity analysis. Cox proportional hazards models will be used to assess 
possible effects of clinical and biological characteristics on outcome, including 
age, gender, disease stage, cytogenetic abnormalities, ECOG performance 
status, and important mutations. Treatment and covariate interactions will also be 
examined. 
As per NCI CTCAE Version 4.0, the term toxicity is defined as adverse events 
that are classified as either possibly, probably, or definitely related to study 
treatment.  The maximum grade for each type of toxicity will be recorded for each 
patient, and frequency tables will be reviewed to determine toxicity patterns.  In 
addition, we will review all adverse event data that is graded as 3, 4, or 5 and 
classified as either “unrelated or unlikely to be related” to study treatment in the 
event of an actual relationship developing. 

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9.6 
Quality of Life 
Primary Endpoint 
Quality of life (QOL) will be assessed using FACT-G and the leukemia subscale. 
The primary objective of the QOL study is to compare treatment toxicity-related 
QOL in patients receiving the experimental Ibrutinib-based therapy to those 
receiving standard FCR. The primary interest is the FACT-Leu Trial Outcome 
Index (TOI), which is comprised of the physical well-being (PWB) and functional 
well-being (FWB) components of the FACT-G and the leukemia subscale. The 
FACT-Leu TOI contains a total of 31 items, with scores ranging from 0 to 124. 
The 31-item FACT-Leu instrument will be administered at the following time 
points: at the time of randomization, three months and six months after 
randomization, at the 12 month response evaluation, and every 
 months 
thereafter for 
 years. The primary endpoint is the change in FACT-Leu TOI 
score from the time of randomization to 12 months after beginning therapy 
between the FCR arm and the Ibrutinib arm. An analysis of the cases with both 
baseline and month 12 evaluations by randomized treatment group will be 
performed as the primary analysis. If both PFS and OS are found to be 
significantly longer in the Ibrutinib arm than in the FCR arm, results from this 
analysis will be considered for labeling in the EU. 
The FACT-Leu TOI is reported to have a standard deviation (SD) ranging from 
18.1 to 21.7. Assuming 
% 1-year survival, correlation o
 between 
FACT-Leu TOI scores at randomization and 1 year after beginning therapy, and 
compliance rates (proportion of patients alive at one year who complete the 
baseline and 1-year QOL assessments) of 
%,
% and 
%, the difference in 
FACT-Leu TOI mean change score between the Ibrutinib arm and the FCR arm 
we can detect with 
% power at two-sided significance level of 
 ranges from 
, and are shown in Table 3. 
Table 3. Differences in FACT-Leu TOI mean change scores 
Standard 
deviation 
(SD) 
Correlation 
SD of 
change 
Difference 
detected 
% compliance 
n1=156, n2=78 
Difference 
detected 
% compliance 
n1=202, n2=101 
Difference 
detected 
% compliance 
n1=250, n2=125 
Secondary Endpoints 
The change in FACT-Leu TOI score from the time of randomization to  months 
after beginning therapy will be compared between arm A and arm B to assess 
the short-term effect of the two therapies on QOL. 
The change in FACT-Leu TOI score from the time of randomization to  months 
after beginning therapy will be compared between the two treatment arms in 
order to provide additional information regarding the toxicity of the different 
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computed for patients in the test set and used to predict their clinical outcome. 
Similarly, patients in the test set can also be classified to be responders or non-
responders based on the classification rule. This process of training and testing 
can be repeated many times. The performance of the risk score and the 
classification rule can be evaluated using C-statistics and ROC curves.  
Baseline and relapse samples will be collected to allow exploratory sequencing 
of Bruton’s tyrosine kinase and downstream targets to study mechanisms of 
resistance to both FCR and Ibrutinib-based therapy. We will examine change 
across time from baseline to progression and explore clonal evolution, and 
epigenetic changes in methylation. Descriptive statistics will be used to find 
genes that play important roles in drug resistance. 
9.8 
Anticipated Accrual by Gender and Ethnicity 
Based on previous data from E2997 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
5 
7 
Not Hispanic or Latino 
151 
361 
512 
Ethnic Category: Total of all subjects 
153 
366 
519 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
7 
7 
Black or African American 
17 
48 
65 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
136 
311 
447 
Racial Category: Total of all subjects 
153 
366 
519 
9.9 
Randomization Procedure 
Patients will be randomized 2:1 to the Ibrutinib arm (A) and the FCR control arm 
(B) using permuted blocks with stratification and dynamic balancing on main 
institutions [6]. The stratification factors are age (<60 vs. >= 60), ECOG 
performance status (0/1 vs. 2), disease stage (3/4 vs. 1/2), and baseline 
cytogenetic abnormalities (deletion 11q22.3 (ATM) vs. other). 
9.10 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 

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blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Center. 
9.11 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required.  
References for Statistical Section: 
1.  Simon RM, Subramanian J, LI MC, Menezes S. Using cross-validation to evaluate 
predictive accuracy of survival risk classifiers based on high-dimensional data. Brief 
Bioinform 2011; 12(3): 203–214.  
2. Hallek M, Fischer K, Fingerle-Rowson G, et al. (2010) Addition of rituximab to 
fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a 
randomised, open-label, phase 3 trial. Lancet; 376(9747):1164-1174. 
3. Schluchter MD (1992) Methods for the analysis of informatively censored longitudinal 
data. Statistics in Medicine; 11, 1861-1870. 
4. Schluchter MD, Greene T and Beck GJ (2001) Analysis of change in the presence of 
informative censoring application to a longitudinal clinical trial of progressive renal 
disease. Statistics in Medicine; 20:989-1007. 
5. Anderson JR, Cain KC, Gelber RD (1983) Analysis of survival by tumor response. J 
Clin Oncol. 1983;1:710-719. 
6. Zelen M (1974) The randomization and stratification of patients to clinical trials. 
Journal of Chronic Diseases, 27:365-375. 
7.  Andersen PK & Gill RD. Cox's regression model for counting processes: a large 
sample study. The annals of statistics, 1982; 10(4), 1100-1120. 
8.  Freidlin, B., Korn, E. L., & Gray, R. (2010). A general inefficacy interim monitoring 
rule for randomized clinical trials. Clinical Trials, 7(3), 197-208. 
 
 

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10. 
Correlative Studies 
NOTE: 
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System. An STS 
shipping manifest form must be generated and shipped with the sample 
submissions. See Section 10.4. 
NOTE: 
Institutions outside of the United States and Canada must confer with the 
receiving laboratory and the ECOG-ACRIN Operations Office – Boston 
regarding logistics for submission of fresh samples. 
NOTE: 
Please note there are sample submissions to two separate laboratories 
outlined in Sections 10.1 and 10.2. 
NOTE: 
Patients must sign informed consent before the submission of the samples. If 
submitting baseline samples prior to patient enrollment to the trial, please use 
the Generic Specimen Submission Form (#2981) and call the receiving 
laboratories prior to shipping. Once the patient is randomized please call the 
receiving laboratories with the ECOG-ACRIN patient sequence number and 
retroactively log the sample information into the ECOG-ACRIN Sample 
Tracking System.   
10.1 
Submissions to the ECOG-ACRIN Leukemia Translational Research 
Laboratory 
Derivatives from peripheral blood or bone marrow from patients entered on 
studies of hematologic malignancies are stored in ECOG-ACRIN's Leukemia 
Tissue Bank for future laboratory studies. The bank provides the scientific 
community a source of leukemia specimens that are collected, processed, and 
maintained following quality control and quality assurance guidelines. The bank 
will accommodate requests from investigators within and outside ECOG-ACRIN 
in a timely and efficient manner, with respect to tissue type, tissue preparation, 
and most importantly, biologic characteristics of specimens. 
10.1.1 
Sample Collection and Submission Schedule 
NOTE: 
All cooperative groups should send specimens to the 
ECOG-ACRIN Leukemia Translational Research 
Laboratory. 
All samples should be clearly labeled with the ECOG-ACRIN protocol 
number E1912, the patient’s initials, ECOG-ACRIN patient sequence 
number (if available), date of collection, and type of sample (PB or 
BM). 
• 
Bone marrow biopsy smears must be submitted at baseline for 
central review. 
• 
Bone marrow sections/slides must be submitted at baseline and at 
the time of the twelve (12) month response evaluation for central 
histological review. 
NOTE: 
Submission of pathology samples for central review is 
mandatory in order for the patient to be considered 
evaluable. Failure to submit pathology samples may render 
the case unevaluable. 
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NOTE: 
Bone marrow biopsy sections/slides are distinct from 
bone marrow smears. 
• 
Peripheral blood and buccal cells should be submitted at baseline 
for banking per patient consent. 
NOTE: 
Dr. 
 institutional regulations require that she 
receive copies of patient consents and HIPAA 
authorization forms along with the baseline samples. 
If you have any questions, please contact the LTRL at  
(718) 920-4100.  
Biological Materials 
MANDATORY for Central Review 
Bone Marrow Biopsy Sections/Slides4 
X 
X 
Bone Marrow Smears (Wright-Giemsa stained) 
X 
 
From Patients Who Answer “YES” to “I agree to provide additional specimens for research.” 
Peripheral Blood (serum, (2) 10mL red top tubes, 15-20mL) 
X 
 
Peripheral Blood (heparin, (4) 10mL green or purple [EDTA] 
top tubes, 30-40mL) 
X 
 
Buccal Rinse (preferred) or Swab3 
X 
 
1. Submit after randomization, prior to treatment. 
2. [Deleted in Addendum #2] 
3. Buccal rinse (preferred) or swabs are strongly encouraged to be collected prior to the start of 
treatment, but can be collected at any other time during the study, if necessary.  
4. Baseline bone marrow biopsy sections/slides should be submitted within one (1) month of 
randomization. 
10.1.2 
Sample Preparation Guidelines 
The following samples must be submitted: 
Bone Marrow Smears 
• 
At least two (2) Wright-Giemsa stained bone marrow smears  
Bone Marrow Biopsy Sections/Slides 
• 
Submit eight (8) unstained slides cut at five (5) microns. Label the 
slides with the ECOG-ACRIN patient sequence number, date of 
collection, and order of sections. Do not bake or place cover slips 
on the slides. 
NOTE: 
Bone marrow biopsy sections/slides can be from the 
clinical biopsy performed within three (≤ 3) months 
prior to registration if the on-study baseline bone 
marrow biopsy was not performed. 
NOTE: 
Bone marrow biopsy sections/slides are distinct 
from bone marrow smears. 
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A copy of the institutional pathology report on the bone marrow must 
be submitted via Medidata Rave.  The pathology report must include 
cytogenetic results and any results from fluorescence-in-situ (FISH) 
hybridization and/or molecular studies done at the submitting 
institution.  These documents are to be submitted via Medidata Rave. 
If Rave is unavailable please fax to the LTRL at (718) 920.1161. 
10.1.2.1 
The following should be submitted at baseline to be 
banked for use in future research studies: 
• 
Two (2) 10mL red top serum tubes of peripheral blood 
(15-20mL) 
• 
Heparinized or EDTA peripheral blood ([4] 10mL green 
or purple top tubes, 30-40mL) 
• 
Buccal rinse (preferred) or swabs 
NOTE: 
If samples designated for banking only are not 
submitted, please note the reason in the 
Comments section of the Sample Tracking 
System. 
Buccal Cell Samples 
• 
Most commonly, institutions will have buccal swab kits 
for the collection of cells for HLA-typing. Alternatively, 
Scope, a commercial brand mouthwash, or normal 
saline in a small sealed bottle can be given to the 
patient for a mouthwash 
• 
Aseptic techniques must be used to collect buccal cells 
from patients on-site and buccal cells must not be 
contaminated with cells from any other source. Patients 
should not brush their teeth or consume food prior to 
buccal cell collection.   
• 
If a cytobrush is used, the collection end should not be 
touched and the patient should not scrape his/her 
cheek too vigorously. The inside of the cheek should 
be scraped 6 times. Several models of cytobrushes are 
available, such as the Omni swab or Bio-Swab from 
Arrowhead Forensics or the Cyto-Pak CytoSoft Brush 
from Medical Packaging Corp. 
• 
If mouthwash (e.g. Scope) or normal saline is used, the 
patient should pour approximately 10cc of mouthwash 
or saline into his/her mouth and vigorously swish it 
against the cheeks for 10 seconds and deliver the 
solution into a labeled 15cc polypropylene test tube. 
Among mouthwashes, the Scope brand fares best in 
collecting buccal cells for the preparation of high-
quality DNA in high yield.  
It is important that buccal cells do not dry out during 
shipping. Institutions are advised to seal the container 
containing the buccal cells tightly. Ship containers on 
ice-packs, together with the patient’s peripheral blood. 

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Delivery” marked on the overnight courier slip. Also, please label the 
package with a handwritten note that says: Deliver to Hospital Main 
Lobby/Security.  
If samples need to be drawn late at night, on Sunday, or on a holiday 
when Federal Express does not operate, keep the samples in a 
refrigerator between 10 and 15 degrees Celsius until the next day 
when it can be shipped. 
10.1.3.1 
Sample Processing and Routing 
Bone marrow biopsy sections/slides will be forwarded to 
Dr. 
 at Mayo Clinic for central histological 
review. 
10.2 
Submissions to Mayo Clinic for Correlative Studies 
All samples should be clearly labeled with the ECOG-ACRIN protocol number 
E1912, the patient’s initials (last name, first name), ECOG-ACRIN patient 
sequence number (if available), and date of collection. 
Kits are available to order, and will include materials necessary for the 
preparation and shipment of samples. Kits should be ordered at least 24 hours in 
advance of each sample time point. To order kits e-mail 
 at 
 Please include the following information: site 
name, mailing address, contact person and number of kits requested.  
Any questions concerning sample collection and shipment can be directed to 
 
 at 
. 
10.2.1 
Sample Collection and Submission Schedule 
Peripheral blood samples are requested at the intervals indicated 
below. 
Biological 
Materials 
From Patients Who Answer “YES” to “I agree to participate in the laboratory research studies that 
are being done as part of this clinical trial.” 
 
Peripheral 
Blood 
(sodium 
heparin (5) 
10mL green 
top tubes) 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
(serum, (2) 
10mL red 
top tubes) 
X 
 
 
X 
X2 
 
1. After randomization, prior to treatment. 
2. Month 
only. 
NOTE: 
For patients who consent to the correlative studies, please submit ALL sequential 
blood samples at ALL time points. 
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The blood samples in prepared kits should be shipped to the following 
address: 
 
Mayo Clinic CLL Laboratory 
613 Stabile 
200 First Street, SW 
Rochester, MN 55905 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
Blood samples will be forwarded to Dr. 
 at Mayo Clinic 
for analysis as described in Section 10.3. 
10.3 
Studies to be performed: 
10.3.1 
IGHV Mutation Analysis  
The IGHV mutation status will be assessed at baseline to allow 
exploration of how IGHV mutation status correlates with clinical 
outcomes (CR, PFS) of the different treatment arms. 
10.3.2 
Minimal Residual Disease Assessment by Flow Cytometry 
MRD status will be assessed in patients on both treatment arms at the 
time of the 12 month response evaluation (52 weeks after day 1 of 
cycle 1) to determine the ability of this conventional MRD time-point to 
predict clinical outcome (PFS, OS).  Blood samples for MRD 
assessment by flow cytometry will also be collected on both treatment 
arms 24 and 36 months from randomization. An early MRD 
assessment is also planned at 3 months in the FCR arm of the study.  
Although samples will be collected and archived from all time-points in 
patients on both treatment arms, the initial planned MRD 
assessments at these other time-points will be tailored to address 
hypotheses specific to each arm.  The initial planned time-points of 
assessment are: 
MRD assessment time-points 
3 mo 
12 mo 
24 mo 
36 mo 
FCR (Arm B) 
X 
X 
X 
X 
Ibrutinib/rituximab (Arm A) 
 
X 
X 
X 
As noted, this plan will include assessment of MRD status after the 
first 3 cycles of FCR in arm B to confirm studies suggesting that ~25% 
of patients achieve an MRD negative disease state after 3 cycles of 
FCR. 
Although a sample to permit MRD assessment at that time-point will 
also be collected for patients on the Ibrutinib arm, it is expected nearly 
all patients treated with Ibrutinib/rituximab have overt residual disease 
after only 3 months of therapy. Collectively, these longitudinal studies 
of MRD on both treatment arms will allow better characterization of 
when MRD levels nadir and help define the optimal timing of MRD 
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Immunity following pneumococcal disease is directed primarily against 
the capsular polysaccharide of the bacteria serotype involved.  
Antibody mediated killing of Streptococcus pneumoniae by 
phagocytes is an important mechanism of protection.  The two most 
common serologic methods for quantifying and evaluating the function 
of antibodies induced by pneumococcal vaccination are IgG 
quantification by enzyme-linked immunosorbent assay (ELISA) and 
measurement of opsonophagocytic activity (OPA) of antibodies from 
sera of vaccinated individuals.  The OPA assay is a functional 
antibody assay that is important for the evaluation of candidate 
vaccines and is a requirement for the licensure of new pneumococcal 
conjugate vaccine formulations. OPA reflects in vivo mechanisms of 
defense against pneumococcal infection.  The measurement of 
functional antibodies has been shown to better correlate with 
protection in infant populations and it is also likely to be a better 
indicator for elderly populations than the measurement of antibodies 
specific to the capsular polysaccharides by ELISA assay (Clin Infect 
Dis 47:1328).  While there is no defined correlate of protection for 
pneumococcal vaccines, it is thought that OPA titers are associated 
with protection against invasive pneumococcal disease. The primary 
endpoint for Prevnar 13 adult clinical trials that led to the FDA 
approval of Prevnar 13 relied on immunogenicity endpoints of OPA 
geometric mean ratio (GMT) and proportion achieving at least 4-fold 
increase in OPA titer (MMWR Morb Mortal Wkly Rep. 61:394-395).  
• 
Exploratory outcome for vaccine immunogenicity: OPA titers 
against 6 pneumococcal serotypes (1, 3, 5, 6A, 7F, 19A) included 
PCV13 vaccine at 90 days (15 month post registration sample) 
after immunization (fold change from pre-vaccination baseline 
sera responses). 
• 
We will report pre-vaccination and day 90 post-vaccination (15 
month post registration sample) OPA GMT titers for each serotype 
(1, 3, 5, 6A, 7F, 19A) in vaccine group and vaccine group + 
Lenalidomide.  
• 
Overall Prevnar response will be defined as 4-fold rise in GMT for 
≥ 4 of the 6 serotypes measured at 90 days post-vaccination. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: 
Please note that the STS software creates pop-up windows, so 
you will need to enable pop-ups within your web browser while 
using the software. A user manual and interactive demo are 
available by clicking this link: 
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http://www.ecog.org/general/stsinfo.html Please take a moment to 
familiarize yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
Study Specific Notes 
The Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of sample submission, along with the Patient Information 
Form (Appendix I – to Mayo Clinic only). Indicate the appropriate Lab ID# on the 
submission form: 
• 
0002 = ECOG-ACRIN Leukemia Translational Research Laboratory 
• 
0156 = Mayo Clinic Hematology Research Laboratory 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Banking 
The residuals and/or derivatives of specimens collected for this study will be 
retained at the ECOG-ACRIN Leukemia Translational Research 
Laboratory/ECOG-ACRIN Leukemia Tissue Bank for possible use in ECOG-
ACRIN approved future studies. If future use is denied or withdrawn by the 
patient, the samples will be removed from consideration for use in any future 
study. 
10.6 
Sample Inventory Submission Guidelines 
Inventories of all samples collected, aliquoted, and used will be submitted 
electronically via secure web application to the ECOG-ACRIN Operations Office 
– Boston on a monthly basis or upon request by any laboratory holding and/or 
using any specimens associated with this study. 
10.7 
Lab Data Transfer Guidelines 
The data collected or generated on the above mentioned correlative studies will 
be submitted electronically via secure data portal to the ECOG-ACRIN 
Operations Office – Boston by the central laboratory on a quarterly basis. 
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11. 
Records to Be Kept 
Please refer to the E1912 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 

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12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
22. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 
CA: a cancer journal for clinicians. 2011;61(2):69-90. Prepublished on 2011/02/08 
as DOI 10.3322/caac.20107. 
23. 
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. 2008;111(12):5446-5456. 
24. 
Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of 
prognostic testing in patients with chronic lymphocytic leukemia. Cancer. 2010. 
25. 
Call T, Phyilky R, Noel P, et al. Incidence of chronic lymphocytic leukemia in 
Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in 
initial stage at diagnosis. Mayo Clinic Proceedings. 1994;69:323-328. 
26. 
Cavotsky D, Fooks J, Richards S. Prognostic factors in chronic lymphocytic 
leukaemia: the importance of age, sex and response to treatment in survival. Br J 
Haematol. 1989;72:141-149. 
27. 
Dighiero G, Maloum K, Desablens B, et al. Cholorambucil in indolent chronic 
lymphocytic leukemia.  Frech Cooperative Group on Chronic Lymphocytic 
Leukemia. N Engl J Med. 1998;338:1506-1514. 
28. 
Diehl LF, Karnell LH, Menck HR. The American College of Surgeons Commission 
on Cancer and the American Cancer Society. The National Cancer Data Base 
report on age, gender, treatment, and outcomes of patients with chronic 
lymphocytic leukemia. Cancer. 1999;86(12):2684-2692. 
29. 
Molica S, Levato D, Dattilo A. Natural history of early chronic lymphocytic 
leukemia. A single institution study with emphasis on the impact of disease-
progression on overall survival. Haematologica. 1999;84(12):1094-1099. 
30. 
Molica S, Levato D. What is changing in the natural history of chronic lymphocytic 
leukemia. Haematologica. 2001;86:8-12. 
31. 
Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus 
cyclophosphamide compared with fludarabine for patients with previously 
untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 
2007;25(7):793-798. 
32. 
Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide 
versus fludarabine alone in first-line therapy of younger patients with chronic 
lymphocytic leukemia. Blood. 2006;107(3):885-891. 
33. 
Catovsky D, Richards S, Matutes E, et al. Fludarabine Plus Cyclophosphamide 
Improves Response and Progression-Free Survival in Chronic Lymphocytic 
Leukemia.  A Report from the LRF CLL4 Trial. Lancet. 2007;370:230-239. 
34. 
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. 2010;376(9747):1164-1174. 

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35. 
Tam CS, O'Brien S, Wierda W, et al. Long term results of the fludarabine, 
cyclophosphamide & rituximab regimen as initial therapy of chronic lymphocytic 
leukemia. Blood. 2008. 
36. 
Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with 
pentostatin, cyclophosphamide, and rituximab shows significant clinical activity 
with low accompanying toxicity in previously untreated B chronic lymphocytic 
leukemia. Blood. 2007;109(2):405-411. 
37. 
Keating M, O'brien S, Albitar M, et al. Early Results of a Chemoimmunotherapy 
Regimen of  Fludarabine, Cyclophosphamide, and Rituximab as Initial Therapy for 
Chronic Lymphocytic Leukemia. J Clin Oncol. 2005;23:4079-4088. 
38. 
Ferrajoli A, O'Brien S M, Wierda W, al e. Treatment of patients with CLL 70 years 
old and older: a single center experience of 142 pateints. Leuk Lymphoma. 
2005;46(S86). 
39. 
Bosch F, Abrisqueta P, Villamor N, et al. Rituximab, Fludarabine, 
Cyclophosphamide, and Mitoxantrone a New, Highly Active Chemoimmunotherapy 
Regimen for Chronic Lymphocytic Leukemia. J Clin Oncol. 2009. 
40. 
Wierda W, O'Brien SM, Faderl S, et al. CFAR, an active frontline regimen for high-
risk patients with CLL, including those with Del 17p. Blood. 
2008;112:2095(abstract). 
41. 
Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor 
signaling in chronic lymphocytic leukemia. Blood. 2011;118(16):4313-4320. 
Prepublished on 2011/08/06 as DOI 10.1182/blood-2011-06-338855. 
42. 
Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib 
disodium has significant clinical activity in non-Hodgkin lymphoma and chronic 
lymphocytic leukemia. Blood. 2010;115(13):2578-2585. Prepublished on 
2009/12/08 as DOI 10.1182/blood-2009-08-236471. 
43. 
Furman R, Byrd JC, Brown JR, et al. CAL-101, An Isoform-selective inhibitor of 
phosphatidylinositol 3-Kinase P110d, demonstrates clinical activity and 
pharmacodynamic effects in patients with relapsed or refracotry chronic 
lymphocytic leukemia. Blood. 2010;116:Abstract #55. 
44. 
Zent CS, LaPlant BR, Johnston PB, et al. The treatment of recurrent/refractory 
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus 
results in clinical responses and mobilization of CLL cells into the circulation. 
Cancer. 2010;116(9):2201-2207. Prepublished on 2010/02/19 as DOI 
10.1002/cncr.25005. 
45. 
Mohamed AJ, Yu L, Backesjo CM, et al. Bruton's tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. 
Immunological reviews. 2009;228(1):58-73. Prepublished on 2009/03/18 as DOI 
10.1111/j.1600-065X.2008.00741.x. 
46. 
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a 
promising therapeutic target for treatment of chronic lymphocytic leukemia and is 
effectively targeted by Ibrutinib. Blood. 2011;117(23):6287-6296. Prepublished on 
2011/03/23 as DOI 10.1182/blood-2011-01-328484. 
47. 
Shanafelt TD, Bowen D, Venkat C, et al. Quality of life in chronic lymphocytic 
leukemia: an international survey of 1482 patients. British Journal of Haematology. 
2007;39:255-264. 

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48. 
Else M, Smith AG, Cocks K, et al. Patients' experience of chronic lymphocytic 
leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. 
British Journal of Haematology. 2008;143(5):690-697. Prepublished on 2008/11/20 
as DOI 10.1111/j.1365-2141.2008.07407.x. 
49. 
Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M. 
Health-Related Quality of Life in Younger Patients With Chronic Lymphocytic 
Leukemia Treated With Fludarabine Plus Cyclophosphamide or Fludarabine Alone 
for First-Line Therapy: A Study by the German CLL Study Group. J Clin Oncol. 
2007. 
50. 
Levy V, Porcher R, Delabarre F, Leporrier M, Cazin B, Chevret S. Evaluating 
treatment strategies in chronic lymphocytic leukemia: use of quality-adjusted 
survival analysis. J Clin Epidemiol. 2001;54(7):747-754. 
51. 
Eichhorst BF, Busch R, Stilgenbauer S, et al. First line therapy with fludarabine 
compared to chlorambucil does not result in a major benefit for elderly patients with 
advanced chronic lymphocytic leukemia. Blood. 2009. 
52. 
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of 
neoplastic diseases of the hematopoietic and lymphoid tissues: report of the 
Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin 
Oncol. 1999;17(12):3835-3849. 
53. 
Rawstron AC, Villamor N, Ritgen M, et al. International Standardized Approach for 
Flow Cytometric Residual Disease Monitoring in Chronic Lymphocytic Leukemia. 
Blood. 2006;In Press. 
 

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Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix I: 
 
Blood Collection Kit Mayo Clinic CLL Laboratory 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND HOLIDAYS** 
 
Kit Contents: 
• 
Small Styrofoam box and cardboard mailing sleeve 
• 
Patient Information Form 
• 
FedEx air bill with pre-printed return address 
• 
Five 10mL Sodium Heparin (green) collection tubes 
• 
Two10mL Red Top collection tubes 
• 
Absorbent tube holder 
• 
Zip lock specimen bag 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
Peripheral blood – Draw: 
• 
50mL into five (5) Sodium Heparin tubes (All Time Points) 
• 
20mL in two (2) Red Top tubes (Baseline, Twelve Month Response, and Fifteen 
Months After Randomization) 
2. All specimens are to be clearly labeled with the protocol number E1912, the patient’s initials 
(last, first, middle), ECOG-ACRIN patient sequence number (if available) and date of 
collection. 
3. Place the tubes in the absorbent holder and seal in the zip lock specimen bag. 
4. Place the filled specimen bag in the Styrofoam container. 
5. Loosely pack with paper toweling. 
6. Place the Styrofoam container and the Sample Tracking System shipping manifest form 
within the cardboard mailing sleeve. 
7. Prepare the package for shipping, applying packing tape as needed. Complete the sender 
portion of the return FedEx Air bill and adhere to the exterior lid of the box. Ship specimens 
via priority overnight delivery (next day delivery by 10am) the same day collected. 
8. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off 
location. 
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The ECOG-ACRIN Sample Tracking System will automatically contact the CLL 
Laboratory. If your patient has not yet been registered and/or you did not use the ECOG-
ACRIN Sample Tracking System please call 
 at 
 or e-mail 
 to notify the laboratory when samples are being 
shipped. Indicate the ECOG-ACRIN protocol number, the FedEx tracking number, and name 
and phone number of the contact person. The blood samples in prepared kits should be shipped 
to the following: 
 
Mayo Clinic CLL Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN  55905 
 
Patient Information Form 
It is required that samples submitted from patients participating in E1912 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (see Section 10.4). This form is 
used only in the event that the STS is inaccessible and then the shipments are to be logged in 
retroactively, indicating the actual dates of collection and shipment. 
Specimen Date:      /        /           
Institution/Affiliate:                 
Physician:                             
Patient Initials (last name, first 
name):                 
ECOG-ACRIN Protocol #: E1912                                                                                      
ECOG-ACRIN Patient Sequence 
#:                                                                                                 
Contact Person:                                                                                                 
Institution:                                                                                                 
Address:  
 City                                           State                  Zip 
Phone #:                                                                                                 
FAX #:  
Please indicate which samples are being shipped at this time and the Treatment Arm (2, 6 and 
7): 
1. Baseline 
2. After Three (3) Cycles of Therapy 
• 
Arm A 
• 
Arm B 
3. After Six (6) Cycles of Therapy (Prior to Cycle Seven) Arm A or (End of Cycle 6) Arm B 
4. Twelve (12) Month Response Evaluation 

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Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix II: 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN, we thank you again. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix III: 
 
Ibrutinib Patient Medication Calendar 
Ibrutinib should be taken with 8 ounces of water. 
 
Pill Calendar Directions 
1. 
Take your scheduled dose of each capsule. 
2. 
Doses are to be taken at about the same time each day. If an ibrutinib dose is 
missed, it should be made up as soon as possible on the same day with a return 
to the normal schedule the following day. If you forget to take your medication for 
a day (or several days), please just restart your medicine at the usual dose and 
do not attempt to ‘make-up’ any missed doses. 
3. 
Please bring the empty bottle or any leftover capsules and your  
medication calendar to your next clinic visit. 
 
 
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Ibrutinib Patient Medication Calendar 
This is a calendar on which you are to record the time and number of capsules you take each 
day.  You should take your scheduled dose of each capsule. Note the times and the number 
of capsules that you take each day.  If you develop any side effects, please record them and 
anything you would like to tell the doctor in the space provided.  Bring any unused capsules and 
your completed medications calendar to your doctor’s visits. 
 
DAY 
Date 
 
 
Month   Day   
Year 
Time 
capsules 
taken 
 
 
AM       PM 
Number of 
capsules 
taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 

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Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix IV: 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industry) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design 
of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order. Additionally, all Clinical 
Data and Results and Raw Data will be collected , used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, 
if applicable, the Standards for Privacy of Individually Identifiable Health Information set 
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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission 
for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, 
in addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review 
as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of 
any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov   
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
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Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix V: 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix VI: 
 
Grading Scale for Hematologic Toxicity in CLL Studies 
The following toxicity grading guidelines apply for patients with baseline hematologic toxicity. 
Decrease from 
Grade2 
Pretreatment value (%) 
Platelets3, 5 
Hemoglobin4, 5 
No change - 10% 
0 
0 
11-24% 
1 
1 
25-49% 
2 
2 
50-74% 
3 
3 
≥ 75% 
4 
4 
1. Grades: 1–mild; 2–moderate; 3–severe; 4–life–threatening.  Grade 5 (fatal) toxicity can 
potentially occur at any level of decrease from pretreatment values and will be recorded 
as such. 
2. 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. 
3. Baseline and subsequent hemoglobin determinations must be immediately prior to any 
given transfusions. 
4. 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. 
Hallek BD, 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 
111:54465456, 2008. 
Hematologic Toxicity Grading Worksheet 
Decrease in platelets 
or hemoglobin from  
pretreatment value 
Grade 
Platelets 
Hemoglobin 
Baseline 
 
 
 
No Change – 10% 
0 
 
 
11 – 24% 
1 
 
 
25 – 49% 
2 
 
 
50 – 74% 
3 
 
 
≥ 75% 
4 
 
 
Rev. 8/15 
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Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix VII: 
 
Cumulative Illness Rating Scale 
 
Extermann et al JCO 16: 1582–1587, 
 

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Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix VIII: 
 
CYP3A Inhibitors and Inducers 
The medications or substances that are listed in the table below are strong or moderate 
inhibitors of CYP3A4. 
Strong and moderate inhibitors of CYP3A4/5 should also be avoided while taking ibrutinib. 
If patients require treatment with strong or moderate inhibitors of CYP3A4 that are used after 
registration see Section 8.1.11 for additional information on monitoring and Ibrutinib dosing. 
Please also consult a frequently updated reference for a comprehensive list of inhibitors, 
inducers, and substrates. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
INDINAVIR 
Efavirenz 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Aprepitant 
St. John’s Wort 
Erythromycin 
Troglitazone 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 
NOT azithromycin 
 
Chloramphenicol 
 
Boceprevir 
 
Ciprofloxacin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
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Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
star fruit 
 
Telaprevir 
 
Troleandomycin 
 
Voriconazole 
 
Receiving any medications or substances that are inducers of CYP3A4. 
Use of the following above are prohibited ≤ 7 days prior to registration. 
INHIBITORS OF CYP3A4/5: 
1. use of strong CYP3A4/5 inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, 
telithromycin, ketoconazole, itraconazole, and nefazodone) should be avoided while on Ibrutinib. 
2.  Moderate CYP3A4/5 inhibitors (aprepitant, erythromycin, fluconazole, verapamil, and diltiazem) 
should be used with caution while on Ibrutinib. 
3. Grapefruit juices and Seville oranges may also increase Ibrutinib plasma concentrations and should 
be avoided for the duration of Ibrutinib treatment. 
 
 

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For Patient Use While Taking Ibrutinib (PCI-32765) 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
 
Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 
Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 
You should avoid supplements such as fish oils and vitamin E; 
check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines that 
interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered “strong 
inducers/inhibitors or substrates of CYP______.” 
 Before prescribing new medicines, your regular prescribers should go 
to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a list of drugs 
to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ and 
can be contacted at _________________________________ 

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Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix IX: 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
Although not an adverse event in and of itself, pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of age or disease status) 
occurring in a female patient or a female partner of a male patient while the subject is on 
Ibrutinib, or within 90 days of the subjects last does of Ibrutinib, are considered immediately 
reportable events.  The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy 
test must be reported via CTEP-AERS within 24 hours of the Investigator’s knowledge.  The 
outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female until completion of the pregnancy and must report 
the outcome of the pregnancy and neonatal status via CTEP-AERS.  
• 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Center. Please contact the ECOG-ACRIN Operations Center to ask for a 
conference call to be set up with the appropriate individuals. 
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• 
It is recommended the female be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com for it will need to be discussed on a case by 
case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after birth” 
that is felt by the investigator to be at least possibly due to the investigational agent/intervention. 
However, for this protocol, any neonatal death that occurs within 28 days of birth, without regard 
to causality, must be reported via CTEP-AERS AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Ibrutinib must also be reported via CTEP-
AERS. 
It must be reported via CTEP-AERS as Grade 4 “Death Neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159).  This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/PregnancyReportFor
m.pdf) 
Rev. Add8 
Rev. Add8 

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Version Date: January 20, 2023 
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E1912: A Randomized Phase III Study of Ibrutinib (PCI-32765)-based Therapy vs Standard 
Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix X: 
 
Timed Up and Go (TUG) Test1,2 
1. Equipment: arm chair, tape measure, tape, stop watch. 
2.   Begin the test with the subject sitting correctly in a chair with arms, the subject’s back should 
resting on the back of the chair. The chair should be stable and positioned such that it will 
not move when the subject moves from sitting to standing. 
3.   Place a piece of tape or other marker on the floor 3 meters away from the chair so that it is 
easily seen by the subject. 
4.   Instructions: “On the word GO you will stand up, walk to the line on the floor, turn around 
and walk back to the chair and sit down. Walk at your regular pace. 
5.   Start timing on the word “GO” and stop timing when the subject is seated again correctly in 
the chair with their back resting on the back of the chair. 
6.   The subject wears their regular footwear, may use any gait aid that they normally use during 
ambulation, but may not be assisted by another person. There is no time limit. They may 
stop and rest (but not sit down) if they need to. 
7.   Normal healthy elderly usually complete the task in ten seconds or less. Very frail or weak 
elderly with poor mobility may take 2 minutes or more. 
8.  The subject should be given 1 untimed practice effort followed by a single timed effort before 
testing. 
9.   Results correlate with gait speed, balance, functional level, the ability to go out, and can 
follow change over time. 
10. Interpretation  ≤ 10 seconds = normal 
≤ 20 seconds = good mobility, can go out alone, mobile without a gait aid. 
< 30 seconds = problems, cannot go outside alone, requires a gait aid. 
A score of more than or equal to fourteen seconds has been shown to indicate high risk of 
falls. 
 
 
1. Podsiadlo D, Richardson S. The Time “Up & Go”: A Test of Basic Functional Mobility for Frail Elderly 
Persons. Journal of the American Geriatrics Society 1991; 39(2): 142­148 
 
2. Shumway ­ Cook A, Brauer S, Woollacott M. Predicting the Probability for Falls in Community­Dwelling 
Older Adults Using the Timed Up & Go Test. Physical Therapy 2000 Vol 80(9): 896­903. 
Saskatoon Falls Prevention Consortium, Falls Screening and Referral Algorithm, TUG, Saskatoon 
Falls Prevention consortium, June, 2005 
Rev. 3/14 

ECOG-ACRIN Cancer Research Group 
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Version Date: January 20, 2023 
120 
E1912: A Randomized Phase III Study of Ibrutinib (PCI-32765)-based Therapy vs Standard 
Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix XI: 
 
RAI Staging 
Both CLL and SLL patients should be staged according to the Rai system.  
NOTE: 
the presence or absence of lymphadenopathy, spleneomegaly, and 
hepatomegaly in assignment of Rai stage is based on physical exam only 
(not CT scan results). 
CLL Patients: CLL patients should be classified as stage 0-IV according to the most 
unfavorable characteristic present according to below: 
Stage 0 
Lymphocytosis only without 
lymphadenopathy, hepatosplenomegaly, 
anemia (hemoglobin < 11 g/dL) or 
thrombocytopenia (platelets < 100 × 
10^9/L) 
Stage I 
Lymphadenopathy without 
hepatosplenomegaly, anemia, or 
thrombocytopenia. 
Stage II 
Splenomegaly +- lymphadenopathy 
Stage III 
Anemia (hemoglobin <11 g/dL) with or 
without lymphadenopathy, hepatomegaly, 
or splenomegaly) 
Stage IV 
Thrombocytopenia (platelets < 100 × 
10^9/L) with or without lymphadenopathy, 
hepatomegaly, splenomegaly, or anemia. 
SLL Patients: Since, by definition, patients with SLL have lymphadenopathy and an 
absolute lymphocyte count < 5, they cannot be classified as stage 0. Accordingly, 
patients with SLL should be classified as stage I-IV according to the most unfavorable 
characteristic present according to below: 
Stage I 
Lymphadenopathy without 
hepatosplenomegaly, anemia, or 
thrombocytopenia. 
Stage II 
Splenomegaly +- lymphadenopathy 
Stage III 
Anemia (hemoglobin < 11 g/dL) with or 
without lymphadenopathy, hepatomegaly, 
or splenomegaly) 
Stage IV 
Thrombocytopenia (platelets < 100 × 
10^9/L) with or without lymphadenopathy, 
hepatomegaly, splenomegaly, or anemia. 
Rev. 8/15 
Rev. 11/16 

ECOG-ACRIN Cancer Research Group 
E1912 
 
Version Date: January 20, 2023 
121 
E1912: A Randomized Phase III Study of Ibrutinib (PCI-32765)-based Therapy vs Standard 
Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in 
Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL). 
 
Appendix XII: 
 
CHILD-PUGH SCORE 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
Source: 
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964. pp. 50-64. 
Pugh RN, Murray-Lyon IM, Dawson L, et al . “Transection of the oesophagus for bleeding 
oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
Rev. 1/16