A Phase 2 Study of the Combination of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) Patients
Phase: PHASE2
Conditions: Leukemia
Sponsor: M.D. Anderson Cancer Center

2011-0785
11/13/2012
Page 1
Protocol Page
A Phase 2 Study of the combination of the Bruton's tyrosine kinase inhibitor 
PCI-32765 and rituximab in high-risk Chronic Lymphocytic Leukemia (CLL) and 
Small Lymphocytic Lymphoma (SLL) patients
2011-0785
Core Protocol Information
Short Title 
Phase 2 Study of the combination of BTK inhibitor PCI-32765 and rituximab in high-risk CLL 
and SLL patients
Study Chair: 
Jan A. Burger
Additional Contact:
Jeannice Y. Theriot
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-1865
Unit:
428
Full Title: 
A Phase 2 Study of the combination of the Bruton's tyrosine kinase inhibitor PCI-32765 and 
rituximab in high-risk Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma 
(SLL) patients
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 08/09/2018
Version:
12
Submitted by:
Jeannice Y. Theriot--2/21/2018 1:11:29 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 2/23/2018 8:09:19 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2011-0785
11/13/2012
Page 2
Protocol Body
 

1 
 
Title: A Phase 2 Study of the combination of the Bruton’s tyrosine kinase 
inhibitor PCI-32765 and rituximab in high-risk Chronic Lymphocytic 
Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) patients. 
 
Principal Investigator 
Jan A. Burger, M.D., Ph.D. 
Department of Leukemia, Unit 428 
The University of Texas MD Anderson Cancer Center 
PO Box 301402 
Houston, TX 77230-1402 
e-mail: jaburger@mdanderson.org 
Co-Investigator 
Susan O’Brien, M.D., 
Department of Leukemia, Unit 428 
The University of Texas MD Anderson Cancer Center 
PO Box 301402 
Houston, TX 77230-1402 
 
 
Date of latest update: 10-22-2012 by J. Burger

 
 
2
1.0 
Objectives 
The primary objective is to assess the activity of the combination of the Bruton’s 
tyrosine kinase (Btk) inhibitor PCI-32765 and rituximab in patients with high-risk 
Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).  
For this study, we define high-risk CLL as any CLL patient who has a 17p 
deletion or an 11q deletion or a TP53 mutation. We define high-risk SLL as any 
SLL patient who has a 17p deletion or an 11q deletion or a TP53 mutation. 
Alternatively, any patient with a diagnosis of CLL or SLL who had a short 
remission duration of less than 3 years after prior first-line chemo-immunotherapy 
would be considered a high-risk CLL or SLL patient, regardless of the presence 
or absence of any chromosomal marker. The secondary objective is to assess 
the tolerability of the combination of PCI-32765 and rituximab in CLL/SLL 
patients. 
 
2.0 
Background 
2.1 
Chronic Lymphocytic Leukemia (CLL)  
CLL is the most common form of adult leukemia in the United States. It has been 
estimated that there are approximately 150,000 individuals living with CLL in the 
United States. The use of combination of chemo-immunotherapy as initial 
therapy is associated with high response rates. Unfortunately, once disease 
relapse has been observed, second line treatment is less effective and response 
durations are shorter. An alternative to repeating chemo-immunotherapy is to use 
the monoclonal antibody alemtuzumab. Alemtuzumab is able to induce a 
response in up to 30% of the patients, but is associated with significant 
immunosuppression and infections. Also, it lacks activity in patients that have 
developed bulky lymphadenopathy (larger than 5 centimeters)1. Combination of 
purine-analogue based regimens have limited activity: the combination of 
fludarabine, cyclophosphamide, rituximab, alemtuzumab (CFAR) is associated 
with an overall response rate of 65% in patients that have received prior therapy 
and once patients are fludarabine refractory their median survival is less than 
twelve months based on our published experience 2.  
 
2.2 
High-risk genetic abnormalities (17p deletion, 11q deletion, TP53 
mutation). Standard treatment approaches such as chemo-immunotherapy (e.g., 
fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in frontline 
treatment of the majority of CLL patients. However, there is a small, challenging 

 
 
3
subgroup of patients whose leukemia is characterized by presence of 17p 
deletion or TP53 mutation who respond poorly to chemo-immunotherapy 3, 4 or 
other treatment modalities for CLL. Related to the poor treatment outcome in this 
high-risk subgroup, patients with 17p deletion or TP53 mutation have a short 
median life expectancy of less than 2 to 3 years 5. Accordingly, there is an urgent 
need for alternative therapeutic strategies acting independently of p53 for 
patients with a 17p deletion or TP53 mutation, both in the frontline and salvage 
setting.  Because of the poor outcome and responses to standard therapy, 
patients with 17p deletion or TP53 mutation will not be required to have received 
prior therapy to enroll. 
CLL patients with del(11q22–11q23) represent another challenging clinical 
subset. This genomic aberration occurs in approximately 20% of patients with 
advanced CLL. These patients are usually younger than the typical CLL patient 
(median age: 59 years), and often have extensive lymphadenopathy at the time 
of diagnosis. The clinical course of patients with the 11q deletion is usually 
characterized by rapid disease progression with shorter treatment-free survival; a 
shorter overall survival has been reported in patients younger than 55 years. 
Although patients with 11q deletion have an improved progression-free survival 
(PFS) with chemo-immunotherapy, remission duration and overall survival of 
patients in this subgroup indicate that patients with 11q deletion have an inferior 
outcome compared with patients with favorable genomic abnormalities6. 
Patients 
with 
short 
remission 
duration 
after 
frontline 
chemo-
immunotherapy, for example with the FCR regimen, constitute another high-risk 
group of CLL patients6, and oftentimes such patients also display high-risk 
cytogenetic abnormalities (del17p, del11q). Such patients typically have low 
response rates and remission durations when re-treated with chemo-
immunotherapy6. 
The preliminary experience with PCI-32765 in relapsed CLL patients with 
17p deletion, 11q deletion, or TP53 mutation indicates that PCI-32765 displays 
high clinical activity in this risk group. An analysis presented at the 2010 annual 
meeting of the American Society of Hematology (ASH) showed that single agent 
treatment with PCI-32765 induces 30% partial remissions (PR, n=3), 30% partial 
remissions with lymphocytosis (PR with lymphocytosis, n=3), and stable disease 
in 30% (SD, n=3) of CLL patients with 17p deletion, which is similar to the 
response rates for CLL patients without 17p deletion. Treatment was 
discontinuation in only one out of 10 patients with 17p deletion 7. These data are 

 
 
4
based on a relatively short median follow-up time (2 to 8 months), but 
nonetheless are highly promising and therefore should be verified in a larger 
cohort of CLL patients. Therefore, to address this unmet medical need and to 
generate more robust experience with PCI-32765 in high-risk CLL patients, we 
propose to examine the activity of PCI-32765 and rituximab in 40 CLL patients 
with high-risk disease features which have relapsed disease. 
 
2.2 
PCI-32765 
Antigenic stimulation through the B cell antigen receptor (BCR) promotes the 
expansion of chronic lymphocytic leukemia (CLL) and other malignant B cells 8, 9. 
Bruton’s tyrosine kinase (Btk), a key component of BCR signaling, can be 
blocked by PCI-32765, a small-molecule Btk inhibitor, that displayed activity in 
patients with CLL and other B cell malignancies in the first clinical trial 7. PCI-
32765 is a potent (IC50, 0.5 nM) and selective Inhibitor of Btk that binds 
covalently to a cysteine residue (Cys-481) in the active site of Btk, leading to 
irreversible inhibition of the enzymatic activity of Btk 10. Once daily oral dosing 
results in 24-hour sustained target occupancy. In vitro studies demonstrated that 
inhibition of Btk in CLL cells results in the blockade of BCR related survival 
signals, thereby causing apoptosis 11. Additionally, Dr. Burger’s laboratory has 
demonstrated that inhibition of Btk with PCI-32765 markedly decreases CLL cell 
responses to chemotactic factors elaborated by stromal cells, such as CXCL12 
and CXCL13, resulting in diminished CLL cell migration and homing capabilities 
11. 
A recent analysis of 38 CLL patients from an ongoing Phase Ib/II trial of 
single-agent PCI-32765 in CLL or SLL included patients with relapsed or 
refractory disease following at least 2 treatment regimens, and a cohort of 
patients over 65 years old with treatment naïve disease 7. When measured 
clinically and by CT scan every 2 months, patients treated with PCI-32765 
typically had an immediate and marked nodal response; 87% of patients with 
evaluable nodal disease achieved a nodal response. There have been no cases 
of primary lymph node progression. For the Phase Ia trial with a median follow-up 
of 8 months, there were 13 evaluable patients with 1 CR (8%), 8 PRs (62%) and 
2 patients with a nodal response with lymphocytosis (15%). Two additional 
patients had stable disease. There have been only 3 patients with disease 
progression, and an additional 3 patients discontinued treatment for reasons 
other than progressive disease. Of 32 evaluable patients in the Phase Ib study 

 
 
5
(with less than 2 months median follow-up) there were 8 PRs (25%) and an 
additional 17 patients with a nodal response with lymphocytosis. An additional 
two patients have stable disease. As such, the overall response rate (ORR) from 
the Phase Ib/II trial experience at this point is 38% (1 CR, 16 PRs in 45 patients).  
94% patients experienced an adverse event (AE), 38% patients 
experienced an adverse event grade 3 or greater in severity (nausea, vomiting, 
fatigue, diarrhea, headache, rash). The incidence of >/= grade 3 adverse events 
believed to be related to PCI-32765 was 17%. 14 patients experienced a serious 
adverse event (SAE), with “serious” defined as requirement for hospitalization. 6 
SAE were considered related to study drug by the investigator. These were one 
case of viral lymphadenitis, one case of a subdural hematoma, one case of viral 
infection (follow-up reported as unrelated), one case of decreased appetite, 
dehydration, and asthenia, one case of sepsis, and one case of headache and 
dizziness (follow-up reported as unrelated viral vestibular neuritis) 7. Two patients 
in this pooled analysis have died due to progressive disease. 
Diarrhea, nausea, and fatigue have been the most commonly reported 
adverse events, with most of the reported events occurring early in treatment 
(cycles 1 or 2). Significant myelosuppression has been infrequent; with grade 3 
or greater thrombocytopenia or neutropenia reported in less than 5% of patients. 
Significant hepatic or renal toxicity has been absent. In addition, with longer-term 
follow-up, there has been no evidence of cumulative toxicity, either overall, or 
related to specific events. Because of a) one event of spontaneous subdural 
hematoma in a patient who took ibuprofen and PCI-32765 at the time of 
detection of the subdural hematoma, and b) the controversial role of Btk in 
platelet function and aggregation, we initiated clinical and laboratory assessment 
of platelet function of patients treated with PCI-32765 on the ongoing Phase I/II 
trial. There have been no subsequent bleeding events; some patients, however, 
displayed petechiae or bruises. Therefore, we will implement regular clinical and 
laboratory assessment and exclude patients with a history of bleeding diathesis 
or coagulopathy, recent surgical procedure, stroke, or hemorrhage, and patients 
receiving Coumadin. 
 
2.2 
Rituximab 
Rituximab is a monoclonal antibody that binds to the human CD20 antigen. 
Rituximab 
has 
been 
extensively 
used 
for the 
treatment 
of 
chronic 
lymphoproliferative disorders. As a single agent, it is able to induce a response in 

 
 
6
up to 30% of the patients with relapsed CLL and is synergistic with chemotherapy 
agents and other monoclonal antibodies when used in combination12. The 
rationale for combining PCI-32765 with rituximab is to potentiate the clinical 
efficacy of these agents without increasing their toxicity. This is based on the 
different mechanisms of action and the non-overlapping toxicity profile. When 
used as single agent, PCI-32765 typically induces a “compartment shift” of CLL 
cells from the tissues into the peripheral blood 7. Clinically, this is associated with 
a transient surge in lymphocyte counts and lymph node shrinkage during the first 
weeks of treatment. Because of this lymphocytosis, the patients treated with 
single agent PCI-32765 often times do not achieve remissions, even though they 
are asymptomatic and display partial or complete responses at other disease 
sites. To improve the efficacy of PCI-32765, rituximab is an ideal combination 
partner, because this antibody is very effective in clearing the blood stream of 
CLL cells, but less effective at eradicating disease in lymphatic tissues and bone 
marrow. As such, this protocol combines two agents with complementary single 
agent activity in different disease sites: PCI-32765 has remarkable activity in the 
lymphatic tissues, and rituximab is highly effective in clearing the blood stream of 
CLL cells. 
The side effect profile of these two agents also appears to be entirely 
different and non-overlapping; the toxicity of rituximab consists mainly of infusion 
reactions, nausea and late transient myelosuppression. PCI-32765 has a very 
benign side effect profile with low-grade gastrointestinal side effects, no signs of 
any cumulative toxicity, and no immunosuppression or myelosuppession.  
 
3.0 
Study Design 
This is a single center open label phase II study to evaluate the efficacy and 
safety of the combination of PCI-32765 and rituximab in patients with high-risk 
CLL and SLL who have received prior treatment. Pharmacyclics will supply PCI-
32765, commercial supply of rituximab will be used for this study. PCI-32765 will 
be supplied as capsules containing 140 mg of PCI-32765.  
 
4.0 
Treatment Plan 
Rituximab (375 mg/m2) will be given intravenously on Day 1, Day 8 (+/- 3 days), 
Day 15 (+/- 3 days), and Day 22 (+/- 3 days), and then continued once every 4 
weeks only on Days 1 (+/- 7 days) during cycles 2 - 6 (+/- 7 days), see Study 
Calendar, unless patients experience toxicities that warrant early discontinuation 

 
 
7
of the rituximab (as determined by the treating physician). There will be no dose 
modifications of rituximab. PCI-32765 will be started on Day 2 of cycle 1 at a 
dose of 420 mg (3 x 140-mg capsules) orally once daily with 8 ounces 
(approximately 240 mL) of water (avoid GRAPEFRUIT JUICE due to CYP450 
3A4 inhibition) and will be continued daily. There will be no dose modifications of 
PCI-32765. The doses and schedule of PCI-32765 is based on prior studies with 
this drug in patients with CLL and other B cell malignancies. At this dose, the 
target enzyme, Btk, is fully inhibited. The rituximab doses and schedule are 
considered standard for treatment of CLL patients. A subject diary will be used to 
aid with PCI-32765 administration compliance. Treatment duration will be 12 
cycles, and it will be possible to continue beyond 12 cycles if there is a significant 
benefit such as an ongoing PR or CR. Response will be evaluated after three, six 
and twelve cycles. (Each cycle consists of 28 days, see Study Calendar). 
 
Rituximab should be held for any Grade 4 toxicity or for any rituximab-related, 
clinically significant, unmanageable Grade 3 adverse events. Rituximab should 
be held until the adverse event returns to baseline or resolves complete. PCI 
32765 should be held for any Grade 3 toxicity. PCI-32765 should be held until 
the adverse event returns to baseline or resolves complete. After Cycle 1, if PCI-
32765 is held for > 28 days, the subject should be discontinued from the study. 
 
Special Handling Instructions 
Allopurinol at the dose of 300mg daily will be given during the first one to two 
weeks of treatment as standard tumor lysis prophylaxis. Unused or expired PCI-
32765 will be disposed per institutional policy. 
Concomitant Medication: Patients receiving Coumadin are ineligible to participate 
in this study. Patients who recently received Coumadin must be off this 
medication for at least 7 days prior to start of the study.   
 
PCI-32765 is metabolized by CYP3A4/5 and CYP2D6. Therefore strong 
inhibitors of CYP3A4/5 and CYP2D6 are prohibited.  Once patients are on study 
they may acquire an illness that requires cocommitant therapy with a drug that 
inhibits these CYPs. In such cases, alternatives to strong CYP3A4/5 inhibitors 
(such as clarithromycin, ketoconazole, itraconazole, nefazodone, and ritonavir) 
and strong CYP2D6 inhibitors (such as bupropion, fluxetine, paroxetine, and 
quinidine) should be sought if possible, for example milder CYP inhibitors. 

 
 
8
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4/5 and 
CYP2D6 inhibitors, inducers, and substrates can be found at 
http://medicine.iupui.edu/flockhart.  This website is continually revised and 
should be checked frequently for updates. 
Concomitant Use of QT Prolonging Agents 
During the course of study drug treatment medications known to cause 
Torsades des Pointes should be avoided.  Medications known to cause QT 
prolongation may be used with caution. 
 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
· 
Laboratory studies have shown that, in vitro, PCI-32765 can prevent 
platelets from aggregating normally; the clinical significance of this finding is 
unknown at this time.  While serious bleeding has been uncommon in patients 
treated to date, it is possible that treatment with the study drug could increase 
the risk of bruising or bleeding, particularly in subjects receiving other 
antiplatelet agents or anticoagulants. 
 
· 
Subjects receiving antiplatelet agents in conjunction with PCI-32765 
should be observed closely for any signs of bleeding or bruising, and PCI-32765 
should be withheld in the event of any bleeding events.  
 
· 
Subjects requiring the initiation of anticoagulation with warfarin or related 
agents during the course of the study should have treatment with PCI-32765 
held, and PCI-32765 should not be restarted until subjects are stably 
anticoagulated   During the co-administration of PCI-32765 and anticoagulant 
therapy, the INR should be monitored carefully and subjects should be observed 
closely for signs and symptoms of bleeding. 
 
For the following hematologic toxicities:  
· 
Grade 4 ANC (< 500/µL) for > 7 days  
· 
Grade 3 or 4 Platelets (< 50,000/µL) in presence of significant bleeding  
· 
Grade 4 Platelets (< 25,000/µL)  
Gastrointestinal toxicities: 
· 
Grade 3 or 4 nausea, vomiting or diarrhea if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy)  
or any other grade 4 or unmanageable grade 3 toxicities: 
 
 
 
 

 
 
9
 
 
 
Antiemetics are permitted if clinically indicated.  Standard supportive care 
medications are permitted.   
 
5.0 
Patient Eligibility 
Inclusion Criteria: 
Patients will be eligible for inclusion in the study if they meet all of the following 
criteria: 
1. Patients must have a diagnosis of high-risk CLL/SLL and be previously 
treated with up to 3 lines of prior therapy. High-risk CLL and high-risk SLL 
is defined by the presence of a 17p deletion or 11q deletion or TP53 
mutation. Any CLL and SLL patient  who has a short remission duration of 
less than 3 years after prior first-line chemo-immunotherapy, such as the 
FCR regimen, also fulfills criteria of high-risk CLL/SLL, regardless of the 
presence or absence of cytogenetic abnormalities.  
2. CLL and SLL patients with 17p deletion or TP53 mutation will not be 
required to have received any prior therapy, given the poor outcome of 
CLL/SLL patients to standard frontline chemo-immunotherapy, such 
patients will be eligible if they are untreated or if they have received up to 
3 lines of prior therapy. 
3. Patients must have an indication for treatment by 2008 IWCLL Criteria 
Occurrence 
Action 
1st 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; may 
restart at original dose level 
2nd 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; restart at 
one dose level lower (280 mg daily) 
3rd 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; restart at 
one dose level lower (140 mg daily) 
4th 
Discontinue PCI-32765 
 
 

 
 
10 
4. Patients age >/= 18 years at the time of signing informed consent. 
Understand and voluntarily sign an informed consent. Be able to comply 
with study procedures and follow-up examinations. 
5. ECOG/WHO performance status of 0-1. 
6. Patients of childbearing potential must be willing to practice highly 
effective birth control (e.g., condoms, implants, injectables, combined oral 
contraceptives, intrauterine devices [IUDs], sexual abstinence, or sterilized 
partner) during the study and for 30 days after the last dose of study drug. 
Women of childbearing potential include any female who has experienced 
menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not 
postmenopausal. Post menopause is defined as follows: Amenorrhea >/= 
12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL; a male of 
childbearing potential is any male that has not been surgically sterilized. 
7. Adequate renal and hepatic function as indicated by all of the following: 
Total bilirubin </=1.5 x institutional Upper Limit of Normal (ULN) except for 
patients with bilirubin elevation due to Gilbert's disease who will be 
allowed to participate; an ALT </=2.5 x ULN; and an estimated creatinine 
clearance (CrCl) of > 30 mL/min, as calculated by the Cockroft- Gault 
equation unless disease related. 
8. Free of prior malignancies for 3 years with exception of currently treated 
basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of 
the cervix or breast.  
9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women 
with childbearing potential. 
 
Exclusion Criteria: 
1. Pregnant or breast-feeding females 
2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal 
antibody therapy, radiotherapy, high-dose corticosteroid therapy (more 
than 60 mg Prednisone or equivalent daily), or immunotherapy within 21 
days prior to enrollment or concurrent with this trial 
3. Investigational agent received within 30 days prior to the first dose of 
study drug or have previously taken PCI-32765. If received any 

 
 
11 
investigational agent prior to this time point, drug-related toxicities must 
have recovered to Grade 1 or less prior to first dose of study drug. 
4. Systemic fungal, bacterial, viral, or other infection not controlled (defined 
as exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment). 
5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or 
autoimmune thrombocytopenia (ITP) 
6. Patients with severe hematopoietic insufficiency, as defined by an 
absolute neutrophil count of less than 500/μL and/or a platelet count of 
less than 30,000/μL at time of screening for this protocol. 
7. Any other severe concurrent disease, or have a history of serious organ 
dysfunction or disease involving the heart, kidney, liver or other organ 
system that may place the patient at undue risk to undergo therapy with 
PCI-32765 and rituximab. 
8. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 
months of screening, or any Class 3 or 4 cardiac disease as defined by 
the New York Heart Association Functional Classification 
9. Significant screening ECG abnormalities including left bundle branch block, 
2nd degree AV block type II, 3rd degree block, bradycardia, and QTc > 470 
msec 
10. Any serious medical condition, laboratory abnormality, or psychiatric 
illness that places the subject at unacceptable risk if he/she were to 
participate in the study. 
11. History of stroke or cerebral hemorrhage within 6 months 
12. Evidence of bleeding diathesis or coagulopathy 
13. Major surgical procedure, open biopsy, or significant traumatic injury  
within 28 days prior to Day 1, anticipation of need for major surgical 
procedure during the course of the study. 
14. Minor surgical procedures, fine needle aspirations or core biopsies within 
7 days prior to Day 1. Bone marrow aspiration and/or biopsy are allowed. 
15. Serious, non-healing wound, ulcer, or bone fracture. 
16. Treatment with Coumadin. Patients who recently received Coumadin must 
be off Coumadin for at least 7 days prior to start of the study. 
17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, 
or fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab), 

 
 
12 
bone marrow transplant, experimental therapy, or radiotherapy is 
prohibited during therapy on this study.   
18. Use of medications known to prolong QTc interval or that may be 
associated with Torsades de Pointes (refer to Appendix F) are prohibited 
within 7 days of starting study drug and during study-drug treatment. 
19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors. 
 
6.0 
Pretreatment evaluation 
Pretreatment evaluation will include a physical examination including vital signs, 
ECOG/WHO performance status, height and weight and recording of concurrent 
medications (within 7 days of Day 1). 
Clinical laboratory evaluation will include serum chemistry. This will include 
sodium, potassium, calcium, magnesium, phosphorus, BUN, creatinine, glucose, 
albumin, total protein, alkaline phosphatase, total bilirubin, ALT, uric acid, and 
immunoglobulin levels. Beta-2-microglobulin, coagulation studies (Prothrombin 
Time/PT; Partial Thromboplastin Time/PTT; and International Normalized Ratio/ 
INR) within 7 days of Day 1. Hematology: Complete CBC and differential and 
peripheral blood lymphocyte subset and immunoglobulin levels (within 7 days of 
of Day 1). Flow cytometry assessment for peripheral CLL cells (CLL panel) and 
lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16/56 cells, within 7 
days of Day 1). 
A Urine Pregnancy Test (within 7 days of Day 1) is required for women with 
childbearing potential. 
Bone marrow aspiration and biopsy within 28 days from of Day 1. Bone marrow 
will be evaluated by flow cytometry for clonality and for IgVH mutation studies 
(unless known) ZAP-70 expression (unless known), cytogenetic and genomic 
abnormalities by FISH. Electrocardiogram (within 28 days from of Day 1). 
Patients also will undergo CT scans of the chest, abdomen, and pelvis within 2 
months from Day 1. Furthermore, patients will be asked to fill out the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
C30 (EORTC QLQ-C30) within 7 days of Day 1(Appendix E). 
 
7.0 Evaluation During Study 
 Clinic visits (this will include vital signs and physical exam) at The 
University of Texas, M.D. Anderson Cancer Center are required weekly 
(+/- 3 days) during the first 4 weeks. Patients for whom weekly visits at MD 

 
 
13 
Anderson during the first month of therapy cause a major hardship can 
have their clinic visits and rituximab infusions on day 8 (+/- 3 days), day 15 
(+/- 3 days), and day 22 (+/- 3 days) at their local physician’s office. Such 
exceptions must be approved by the treating physician and the principal 
investigator. Patients return for follow up and then prior to start of cycles 2, 
3, 4, 6, 9 and 12 (+/- 1 month). If patients stay on the study past 12 cycles, 
they return for clinic visits at The University of Texas, M.D. Anderson 
Cancer Center for clinical assessment (this will include vital signs and 
physical exam), and laboratory workup (hematology and clinical 
chemistry) every 3 months (+/- 1 month) for cycles 13 through 36, and 
every 6 months (+/- 1 month) thereafter, until disease progression or study 
discontinuation for other reasons.  
 Hematology and serum chemistry: complete blood counts (white blood cell, 
hemoglobin, platelets and differential) will be monitored once weekly for 
the first four weeks, and then every four weeks thereafter.  
 Serum chemistry: basic metabolic profile (sodium, potassium, chloride, 
CO2, BUN, creatinine and glucose) will be monitored once weekly for the 
first four weeks and then once every four weeks thereafter until the end of 
cycle 12. If patients stay on the study past 12 cycles, they will have these 
laboratory tests (hematology and clinical chemistry) done every 3 months 
(+/- 1 month) for cycles 13 through 36, and every 6 months (+/- 1 month) 
thereafter during their clinic visit.   
 PT, PTT, INR will be monitored after 1, 3, 6, and 12 cycles (+/- 1 month) 
and if patients stay on the study past 12 cycles, once every 12 cycles (+/- 
1 month).  
 beta-2-microglobulin, lymphocyte subset, immunoglobulin levels, bone 
marrow aspiration will be performed and evaluated by flow cytometry after 
3, 6 and 12 cycles and if patients stay on the study past 12 cycles, once 
every 12 cycles (+/- 1 month). If patients’ bone marrow tests are 
consistent with a complete remission, no further bone marrow testing is 
mandatory, and will be ordered at the treating physicians’ discretion.  
 CT scans of the chest, abdomen, and pelvis after 3 or 6 cycles, and 12 
cycles, and once every 12 cycles thereafter. If patients stay on the study 
past 24 cycles, once every 12 cycles only inpatients with measurable 
disease, as determined by the treating physician. 

 
 
14 
 Optional Quality of Life questionnaires (EORTC QLQ-C30) will be 
collected after 2 weeks, and after cycles 1, 3, 6, and 12. Please refer to 
plan for monitoring patients in the study calendar for further details. 
 Optional correlative laboratory studies will be done before study entry 
(within 7 days of Day 1), and after 1 week (+/- 3 days), 2 weeks (+/- 3 
days), 4 weeks (+/- 3 days), and after cycles 3, 6, and 12, and in patients 
who fail to respond to therapy at the time of treatment failure (as 
determined by the treating physician) or at the time of relapse. 
 Post Treatment Evaluations: Follow-up evaluations will occur at 60 days 
(+/-   14   days) following completion of study drug administration. Patients 
who achieve complete remissions or partial remissions with stable disease 
and discontinue therapy will be followed long-term every 120  days (+/-   
60   days) for up to 5 years or until disease progression or start of a new 
treatment. The post treatment laboratory evaluations include hematology 
and serum chemistry with a complete blood counts (white blood cell, 
hemoglobin, platelets and differential) and a basic metabolic profile 
(sodium, potassium, chloride, CO2, BUN, creatinine and glucose). 
 
 

15 
 
 
8.0 
Criteria for Response 
The International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria 
will be used 13 (Appendix I). Responses will be assessed after 3, 6 and 12 cycles. 
 
9.0 
Evaluation of Toxicity 
Adverse events are reported as per UTMDACC and Leukemia Phase 2-3 studies. 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might 
have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate 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. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 

 
 
16 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the  Sponsor, IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy on Reporting 
Serious Adverse Events”.  Unless stated otherwise in the protocol, all 
SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in 
the IND Office.   
 
 The MDACC “Internal SAE Report Form for Prompt Reporting” will be 
used for reporting to the IND Office.  
 
 Serious adverse events will be captured from the time the patient signs 
consent until 30 days after the last dose of drug. Serious adverse events 
must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 

 
 
17 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
 
The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the 
attribution for each event for all subjects enrolled on the trial 
 
PDMS/CORe will be used as the electronic case report form for this 
protocol and protocol specific data will be entered into PDMs/CORe. 
 
Adverse Drug Reaction Reporting 
AS PER UTMDACC AND LEUKEMIA PHASE II-III STUDIES (APPENDIX C 
AND APPENDIX D), Toxicity will be scored using CTCAE Version 4.03 for 
toxicity and adverse event reporting. A copy of the CTCAE Version 4.03 can be 
downloaded from the CTEP homepage (http://ctep.info.nih.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE Version 4.03. All 
adverse clinical experiences whether observed by the investigator or reported by 
the patient, must be recorded, with details about the duration and intensity of 
each episode, the action taken with respect to the test drug, and the patient’s 
outcome. The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
The investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, 
the investigator must provide details about the action taken with respect to the 
test drug and about the patient’s outcome. Abnormal lab values are only 
significant if they require intervention or treatment. 
 
Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of 
standard safety monitoring activities by the Sponsor.  These events will be 
reported to the Pharmacyclics within 24 hours of awareness following the 
procedure described for SAEs and will require enhanced data collection.  All 
Events of Special Interest will be submitted without a serious criterion selected if 
no other serious criterion is met.  
List of Events of Special Interest 
Major Hemorrhage 

 
 
18 
Defined as any hemorrhagic event, that is Grade 3 or greater in severity, or that 
results in one of the following: intraocular bleeding causing loss of vision, the 
need for a transfusion of two or more units of red cells or an equivalent amount of 
whole blood, hospitalization or prolongation of hospitalization.  
Events meeting the definition of major hemorrhage will be captured as an event 
of special interest (see above). 
 
10.0 Statistical Design 
Endpoint and Design: The primary objective of this phase II study is to assess 
the activity of the combination of the Bruton’s tyrosine kinase (Btk) inhibitor PCI-
32765 and rituximab in Chronic Lymphocytic Leukemia (CLL) in high-risk CLL 
patients that have received prior therapy. Untreated CLL patients with high-risk 
disease based on the presence of a 17p deletion or TP53 mutation will also be 
eligible. The primary endpoint is progression-free survival (PFS). Denote the 
median (T) = mH, for the historical data (H) and mE, for the experimental (E) trial, 
where T is time to progression in month. We assume that, T is distributed 
exponentially with median mH, with the historical regimen and median mE, with 
the new treatment. Under a Bayesian model, we will further assume that mH, 
follows an inverse gamma (IG) prior with parameters (18, 85) reflecting the 
historical data (i.e., 20 patients with chromosome 17 abnormalities who had a 
median PFS of 5 months)6, and mE, follows IG(2.25, 6.25) with the same mean 
as mH, but with a much larger variance of 100 to reflect much greater uncertainty 
about PFS. Progression free survival is defined as the time interval from 
treatment to progressive disease or death, whichever happens earlier. Patients in 
complete remission (CR), partial remission (PR) or stable disease (SD) are all 
counted as progression-free. Due to the characteristic activity of PCI-32765, 
which typically induces a transient lymphocytosis during the first months of 
therapy7, which is not causing any symptoms and which is due to a re-distribution 
of CLL cells from the tissue compartments (bone marrow, secondary lymphatic 
tissues) into the peripheral blood, increases in lymphocyte counts can be 
expected (although in this combination with rituximab are less likely) and will not 
be considered as a sign of progressive disease. 
 
Interim Analysis on PFS: We will accrue 40 patients and will monitor the PFS 
continuously, accrual will be terminated early if Pr(mH + 2 months < mE | data) < 

 
 
19 
0.01.  The design operating characteristics based on 1000 simulations are 
summarized in Table 1. (Accrual of 40 patients with a rate = 3/month, 6 months 
additional follow-up). For example, the trial will stop early with 97.5% chance 
(23.3 patients in average) if the median PFS is 3 months, but stop early with 
7.8% chance (38.6 patients in average) if the median PFS is 6 months. 
 
Table1. Simulation study with maximum 40 patients: 
 
True median PFS Pr(stop) Mean number of patients (25%, 75%) 
3 months 
0.975 
23.3 (14, 33) 
4 months 
0.632 
31.8 (24, 40) 
5 months 
0.240 
36.6 (40, 40) 
6 months 
0.078 
38.6 (40, 40) 
7 months 
0.038 
39.1 (40, 40) 
8 months 
0.018 
39.6 (40, 40) 
 
Interim Analysis on Toxicity: The probability of toxicity (grade 3 or 4) will be 
monitored based on the Bayesian model (beta-binomial) by assuming a priori 
probability of toxicity following beta(1,1). The trial will be terminated if 
Prob(toxicity > 0.25 | data) > 0.90. Following this rule, the trial will be terminated if 
(# patients with toxicities)/(# patients evaluated) >=  2/3, 3/6, 4/9, 5/12, 6/15, 7/18, 
8/22, 9/25, 10/28,11/31, 12/35, 13/38, or 14/40. The operating characteristics for 
toxicity are summarized in Table 2. 
 
Table 2. Operating characteristics based on 10000 simulation study 
True Prob(tox) 
Pr(stop 
early) 
 Median # Pts (25%, 75%)  
0.05 
<0.01 
40 (40, 40) 
0.10 
0.04 
39 (40, 40) 
0.15 
0.11 
36 (40, 40) 
0.25 
0.41 
28 (9, 40) 
0.35 
0.79 
17 (4, 28) 
0.45 
0.97 
9 (3, 10) 
0.55 
>0.99 
6 (3, 7)  
 

 
 
20 
Statistical Analysis: Descriptive statistical analysis will be calculated, including 
histograms or box-plots, proportions, range, means and standard deviations. A 
95% credible interval on response rate will be estimated based on a beta-
binomial distribution. Fisher’s exact test and Wilcoxon rank test will be used in 
univariate analyses of categorical (Stage, for example) and continuous variables 
(Age, for example), respectively. The data analysis will be performed based on 
the Intent-to-treat. Survival or times to progression functions will be estimated 
using the Kaplan-Meier method. Toxicity will be reported by type, frequency and 
severity. Worst toxicity grades per patient will be tabulated for selected adverse 
events and laboratory measurements. The Department of Biostatistics will 
provide and maintain a website (“Clinical Trial Conduct”) for enrolling patients on 
this study and evaluating the efficacy monitoring rules described above. The 
Clinical Trial Conduct website resides on a secure server, and access is gained 
through usernames and passwords provided to personnel responsible for 
enrolling patients and updating patient data.  The website is accessed through a 
browser using secure socket layer (SSL) technology. Personnel responsible for 
enrolling patients on trials will be trained in the use of the trial website, with 
emphasis on the importance of timely updating of follow-up times and recording 
of events. The monitoring rules described below will be automatically evaluated 
each time patient data are updated on the trial website. If the stopping rule is 
met, the study statistician, research nurse, and principal investigator will each 
receive an email notification that the stopping boundary has been met. 
 
11.0 Amendments, Deviations, Regulatory 
Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator 
and reviewed by Pharmacyclics. Amendments should only be submitted to 
IRB/EC after consideration of Pharmacyclics review. Written verification of 
IRB/EC approval will be obtained before any amendment is implemented. 
Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a 
subject, a deviation will be made only for that subject. A decision will be made as 
soon as possible to determine whether or not the subject (for whom the deviation 
from protocol was effected) is to continue in the study. The subject’s medical 
records will completely describe the deviation from the protocol and state the 

 
 
21 
reasons for such deviation. In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. 
Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical 
Practice (GCP) and in the US Code of Federal Regulations. Investigators must 
enter study data into MDACC’s PDMS. The Investigator will permit study-related 
monitoring visits and audits by MDACC’s ORERM, Pharmacyclics  or its 
representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, 
TPP), providing direct access to the facilities where the study took place, to 
source documents, to CRFs, and to all other study documents. The Investigator, 
or a designated member of the Investigator’s staff, must be available at some 
time during monitoring visits to review data and resolve any queries and to allow 
direct access to the subject’s records (e.g., medical records, office charts, 
hospital charts, and study related charts) for source data verification. The data 
collection must be completed prior to each visit and be made available to 
MDACC ORERM and the Pharmacyclics  representative so that the accuracy 
and completeness may be checked. 
Institutional Review Board/Ethics Committee Approval 
The protocol for this study has been designed in accordance with the general 
ethical principles outlined in the Declaration of Helsinki. The review of this 
protocol by the IRB/EC and the performance of all aspects of the study, including 
the methods used for obtaining informed consent, must also be in accordance 
with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 
of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects 
and Part 56 Institutional Review Boards. The Investigator will be responsible for 
preparing documents for submission to the relevant IRB/EC and obtaining written 
approval for this study. The approval will be obtained prior to the initiation of the 
study. The approval for both the protocol and informed consent must specify the 
date of approval, protocol number and version, or amendment number. Any 
amendments to the protocol after receipt of IRB/EC approval must be submitted 
by the Investigator to the IRB/EC for approval. The Investigator is also 
responsible for notifying the IRB/EC of any serious deviations from the protocol, 
or anything else that may involve added risk to subjects. Any advertisements 
used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
 

 
 
22 
Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee 
prior to any study related procedures as per GCPs as set forth in the CFR and 
ICH guidelines. Documentation that informed consent occurred prior to the 
subject’s entry into the study and the informed consent process should be 
recorded in the subject’s source documents. The original consent form signed 
and dated by the subject and by the person consenting the subject prior to the 
subject’s entry into the study, must be maintained in the Investigator’s study files. 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the 
conduct of the study and the distribution of the study drug, that is copies of CRFs 
and source documents (original documents, data, and records (e.g., hospital 
records; clinical and office charts; laboratory notes; memoranda; subject’s diaries 
or evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical study; 
documents regarding subject treatment and study drug accountability; original 
signed informed consents, etc.)) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years 
after discontinuing clinical development or after the last marketing approval). The 
Investigator agrees to adhere to the document/records retention procedures by 
signing the protocol. 
 
Premature Discontinuation of Study 
The responsible local clinical Investigator, as well as Pharmacyclics, has the right 
to discontinue this study at any time for reasonable medical or administrative 
reasons in any single center. Possible reasons for termination of the study could 
be but are not limited to: 
1. 
Unsatisfactory enrollment with respect to quantity or quality. 
2. 
Inaccurate or incomplete data collection. 
3. 
Falsification of records. 
4. 
Failure to adhere to the study protocol. 
 
 

 
 
23 
12.0 Optional Correlative Laboratory Studies 
Optional correlative laboratory studies will be done before study entry (within 7 
days of Day 1), and after 1 week (+/- 3 days), 2 weeks (+/- 3 days), 4 weeks (+/- 
3 days), and after cycles 3, 6, and 12. Also, to better understand mechanism of 
failure to respond to therapy with PCI-32765, samples will be collected and 
examined in patients who fail to respond to therapy at the time of treatment 
failure (as determined by the treating physician) or at the time of relapse. The 
aim of these laboratory studies is to determine changes in CLL cell surface 
markers, responsiveness of the leukemia cells to B cell receptor stimulation, and 
plasma chemokine levels. For these studies, two 8 mL tubes of EDTA blood will 
be collected within 7 days of Day 1, and after 1 week (+/- 3 days), 2 weeks (+/- 3 
days), 4 weeks (+/- 3 days), and after cycles 3, 6, and 12. (approximately 1 
tablespoon per timepoint). In collaboration with our colleagues from the German 
Cancer Research Center in Heidelberg (DKFZ Heidelberg, M.D. Anderson sister 
institution network project) and the Dana-Farber Cancer Institute (DFCI), Boston 
(Dr. Catherine Wu), we will assay for mutations within the CLL cells in patients 
responding or not responding to therapy with PCI-32765. For these studies, four 
8 mL tubes of EDTA blood (approximately 2 tablespoon per timepoint) will be 
collected at study entry (within 7 days of Day 1) and at the time of treatment 
failure (as determined by the treating physician) or at the time of relapse. Also, a 
sputum sample will be collected during follow-up. Samples collected as part of 
the optional procedures will be stored at Dr. Burger's laboratory and then sent to 
the DKFZ and the Dana-Farber Cancer Institute for biomarker testing.  Before 
samples are sent to the DKFZ and the Dana-Farber Cancer Institute, patient 
names and any personal identifying information will be coded to protect patients’ 
privacy. 

24 
 
 
Evaluation or Procedure 
Screening 
 (30 days) 
Screening 
(14 Days) 
Screening  
(7 Days) 
Treatment Plan 
If Patient Stays on Study past 12 Cycles 
Clinical Assessments 
(Day -30) 
(Day -14) 
(Day -7 to 
-1) 
Day 7, 
14, 21, 
28 
(+/-3 
Days) 
Cycle 2, 3, 4, 
6, 9, 12 (+/-1 
month) 
Cycle 
1,3,6,12 
 (+/- 1 
month) 
Cycles 
1,6,12 
(+/- 1 
month) 
Cycles 
3,6, 12 
(+/- 1 
month) 
Cycles 13-36 
every 3 
months 
(+/- 1 month) 
Follow Up After 
Cycle 36 every 6 
months  
(+/- 1 month) 
Once every 
12 cycles 
 (+/- 1 
month) 
Informed Consent 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical Evaluationa 
 
 
X 
 
 
 
 
 
 
 
 
ECOG/WHO Eval 
 
 
X 
 
 
 
 
 
 
 
 
Height/Weight 
 
 
X 
 
 
 
 
 
 
 
 
Concomitant Medications and 
Treatment 
 
 
X 
 
 
 
 
 
 
 
 
Serum Chemistryb 
 
 
X 
 
 
 
 
 
 
 
 
PT/PTT/INRc 
 
 
X 
 
 
 
 
 
 
 
 
Hematologyd 
 
 
X 
 
 
 
 
 
 
 
 
 
CLL Panele 
 
 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and 
biopsyf 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
CT Scansh 
X 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Test 
 
 
X 
 
 
 
 
 
 
 
 
Optional correlative laboratory 
studies (blood samples)q 
 
 
X 
X 
Xr 
 
 
 
 
 
 
Clinical Visits at UT MD 
Anderson Cancer Centeri 
 
 
 
X 
X 
 
 
 
X 
X 
 
Hematology and Serum 
Chemistryj  
 
 
 
Xk 
 
 
 
 
X 
X 
X 
PT, PTT, INR 
 
 
 
 
 
Xl 
 
 
 
 
X 
Beta-2-microglobulin, 
lymphocyte subset, 
immunoglobulin levelsm 
 
 
 
 
 
 
 
X 
 
 
X 

 
 
25 
Bone Marrow Aspirationn 
 
 
 
 
 
 
 
X 
 
 
X 
CT Scanso 
 
 
 
 
 
 
X 
X 
 
 
X 
Optional Quality of Life 
Questionanairep 
 
 
 
 
 
X 
 
 
 
 
 
Optional correlative laboratory 
studies (blood samples)q 
 
 
X 
X 
Xr 
 
 
 
 
 
 
 
a) 
Includes vital signs (within 7 days of Day 1). 
b) 
Includes sodium, potassium, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, uric acid, and immunoglobulin 
levels, Beta-2 microglobulin  within 7 days of Day 1. 
c) 
Prothrombin Time/PT; Partial Thromboplastin Time/PTT; and International Normalized Ratio/INR within 7 days of Day 1. 
d) 
Complete CBC and differential and peripheral blood lymphocyte subset and immunoglobulin levels (within 7 days of registration). 
e) 
Flow cytometry assessment for peripheral CLL cells and lymphocyte subpopulations (CD3, CD4, CD8, CD19,CD16/56 cells) within 7 days of Day 1. 
f) 
Within one month from registration. Bone marrow will be evaluated by flow cytometry for clonality and for IgVH mutation studies (unless known) ZAP-70 expression (unless known), 
cytogenetic and genomic abnormalities by FISH. 
g) 
Within one month  
h) 
CT scans of the chest, abdomen and pelvis  within two months from Day 1. 
i) 
Includes vital signs and physical exam at The University of Texas MD Anderson Cancer Center during the first 4 weeks, and then after, cycles  2,3,4,6,9 and 12 (+/- 1 month). If patients stay 
on the study past 12 cycles, they return for clinic visits at UT MD Anderson for clinical assessment and laboratory workup (hematology and clinical chemistry) every 3 months (+/- 1 month) 
for cycles 13 through 36, and every 6 months (+/1 month) thereafter. 
j) 
Complete blood counts (white blood cell, hemoglobin, platelets and differential) and Serum chemistry: basic metabolic profile (sodium, potassium, chloride, CO2, BUN, creatinine and 
glucose)   will be monitored once weekly for first 4 weeks (+/-3 Days), and then every 4 weeks thereafter.  If patients stay on the study past 12 cycles, they will have these laboratory tests 
(hematology and clinical chemistry) done every 3 months (+/- 1 month) for cycles 13 through 36, and every 6 months (+/- 1 month) thereafter during their clinic visit. 
k) 
Once every 4 weeks thereafter until the end of cycle 12. 
l) 
PT, PTT, INR will be monitored after 1,3,6 and 12 cycles (+/- 1 month) and if patients stay on study past 12 cycles, once every 12 cycles (+/- 1 month). 
m) 
Will be performed and evaluated by flow cytometry after 3, 6 and 12 cycles (+/- 1 month) and if patients stay on study past 12 cycles, once every 12 cycles (+/- 1 month). 
n) 
If patients’ bone marrow tests are consistent with a complete remission, no further bone marrow testing is mandatory, and will be ordered at the treating physicians’ direction. 
o) 
CT scans of chest and abdomen after 3 or 6, and 12 cycles (+/- 1 month), and once every 12 cycles thereafter.  If patients stay on the study past 24 cycles, once every 12 cycles only 
inpatients with measurable disease, as determined by the treating physician. 
p) 
Questionnaire collected at baseline, after 3, 6, 12  and every 6 cycles. 
q) 
Optional correlative laboratory studies (blood samples) will be done before study entry, and after weeks 1, 2, 3, 4 (+/- 3 days). 
r) 
Optional correlative laboratory studies(blood samples) at 12 weeks (cycle 3) (+/- 1 month) only and again in patients who fail to respond to therapy after 6 months or at the time of relapse. 
 
 
 
 
 
 

 
 
26 
Time and Events Schedule:  Screening 
Evaluation or Procedure 
Screening 
 (60 days) 
Screening 
(30 Days) 
Screening 
(14 Days) 
Screening  
(7 Days) 
Clinical Assessments 
(Day -60) 
(Day -30) 
(Day -14) 
(Day -7 to -1) 
Informed Consent 
 
 
 
 
X 
 
Physical Evaluationa 
 
 
 
X 
ECOG/WHO Eval 
 
 
 
X 
Height/Weight 
 
 
 
X 
Concomitant Medications and Treatment 
 
 
 
X 
Serum Chemistryb 
 
 
 
X 
PT/PTT/INRc 
 
 
 
X 
Hematologyd 
 
 
 
X 
 
CLL Panele 
 
 
 
X 
Bone Marrow Aspiration and biopsyf 
 
X 
 
 
Electrocardiogramg 
 
X 
 
 
CT Scansh 
X 
 
 
 
Pregnancy Test 
 
 
 
X 
Optional correlative laboratory studies (blood samples)q 
 
 
 
X 
 
a) 
Includes vital signs (within 7 days of Day 1). 
b) 
Includes sodium, potassium, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, uric acid, and immunoglobulin 
levels, Beta-2 microglobulin  within 7 days of Day 1. 
c) 
Prothrombin Time/PT; Partial Thromboplastin Time/PTT; and International Normalized Ratio/INR within 7 days of Day 1. 
d) 
Complete CBC and differential and peripheral blood lymphocyte subset and immunoglobulin levels (within 7 days of registration). 
e) 
Flow cytometry assessment for peripheral CLL cells and lymphocyte subpopulations (CD3, CD4, CD8, CD19,CD16/56 cells) within 7 days of Day 1. 
f) 
Within one month from registration. Bone marrow will be evaluated by flow cytometry for clonality and for IgVH mutation studies (unless known) ZAP-70 expression (unless known), 
cytogenetic and genomic abnormalities by FISH. 
g) 
Within one month  
h) 
CT scans of the chest , abdomen and pelvis within two months from Day 1. 
i) 
q) Optional correlative laboratory studies (blood samples) will be done before study entry, and after weeks 1, 2, 3, 4 (+/- 3 days). 

 
 
27 
 
Treatment Plan 
If Patient Stays on Study past 12 Cycles 
Procedure 
Day 7, 14, 
21, 28 
(+/-3 
Days) 
Cycle 2, 3, 4, 6, 9, 
12 (+/-1 month) 
Cycle 
1,3,6,12 
 (+/- 1 
month) 
Cycles 1,6,12 
(+/- 1 month) 
Cycles 3,6, 
12 
(+/- 1 month) 
Cycles 13-36 every 3 
months 
(+/- 1 month) 
Follow Up After Cycle 36 
every 6 months  
(+/- 1 month) 
Once 
every 12 
cycles 
 (+/- 1 
month) 
Clinical Visits at UT MD Anderson 
Cancer Centeri 
X 
X 
 
 
 
X 
X 
 
Hematology and Serum Chemistryj  
Xk 
 
 
 
 
X 
X 
X 
PT, PTT, INR 
 
 
Xl 
 
 
 
 
X 
Beta-2-microglobulin, lymphocyte 
subset, immunoglobulin levelsm 
 
 
 
 
X 
 
 
X 
Bone Marrow Aspirationn 
 
 
 
 
X 
 
 
X 
CT Scanso 
 
 
 
 
X 
 
 
X 
Optional Quality of Life 
Questionanairep 
 
 
X 
 
 
 
 
 
Optional correlative laboratory studies 
(blood samples)q 
X 
Xr 
 
 
 
 
 
 
 
 
 

28 
 
13.0 References 
1. 
Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab 
(Campath-1H) in patients who have failed fludarabine: results of a large 
international study. Blood. May 15 2002;99(10):3554-3561. 
2. 
Wierda W, O'Brien S, Faderl S, et al. A retrospective comparison of three 
sequential 
groups 
of 
patients 
with 
Recurrent/Refractory 
chronic 
lymphocytic leukemia treated with fludarabine-based regimens. Cancer. 
Jan 15 2006;106(2):337-345. 
3. 
Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, 
cyclophosphamide, and rituximab regimen as initial therapy of chronic 
lymphocytic leukemia. Blood. Aug 15 2008;112(4):975-980. 
4. 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to 
fludarabine and cyclophosphamide in patients with chronic lymphocytic 
leukaemia: a randomised, open-label, phase 3 trial. Lancet. Oct 2 
2010;376(9747):1164-1174. 
5. 
Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk 
chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ 
Program. 2010;2010:481-488. 
6. 
Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, 
and rituximab chemoimmunotherapy is highly effective treatment for 
relapsed patients with CLL. Blood. Mar 17 2011;117(11):3016-3024. 
7. 
Burger JA, O'Brien S, Fowler N, et al. The Bruton's Tyrosine Kinase 
Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising 
Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small 
Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies. 
Blood. November 19, 2010 2010;116(21):32a. 
8. 
Burger 
JA, 
Ghia 
P, 
Rosenwald 
A, 
Caligaris-Cappio 
F. 
The 
microenvironment in mature B-cell malignancies: a target for new 
treatment strategies. Blood. Oct 15 2009;114(16):3367-3375. 
9. 
Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling 
in diffuse large B-cell lymphoma. Nature. Jan 7 2010;463(7277):88-92. 
10. 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase 
inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of 
autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. Jul 
20 2010;107(29):13075-13080. 
11. 
Ponader S, Buggy J, O'Brien S, Wierda WG, Keating M, Burger JA. 
Bruton's Tyrosine Kinase Inhibitor PCI-32765 Abrogates BCR- and 
Nurselike Cell-Derived Activation of CLL Cells In Vitro and In Vivo. Blood. 
November 19, 2010 2010;116(21):26a. 
12. 
Faderl S, Thomas DA, O'Brien S, et al. Experience with alemtuzumab plus 
rituximab in patients with relapsed and refractory lymphoid malignancies. 
Blood. May 1 2003;101(9):3413-3415. 
13. 
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 

 
 
29 
Cancer Institute-Working Group 1996 guidelines. Blood. Jun 15 
2008;111(12):5446-5456.