Clinical trial NCT01096992
Conditions: Leukemia
Keywords: Chronic lymphocytic leukemia CLL Bendamustine Fludarabine Fludara Fludarabine Phosphate Rituximab Rituxan
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-04-19; Completion date: 2017-03-31
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of bendamustine, combined with fludarabine and rituximab, that can be given to patients who have CLL that has been treated before.

The goal of Phase 2 of this study is to find out if this drug combination can help to control the disease. The safety of this drug combination will also be studied.

Detailed description:
The Study Drugs:

Fludarabine and bendamustine are designed to damage the DNA (genetic material) of cancer cells, which may cause the cancer cells to die.

Rituximab is designed to attach to cancer cells and damage them, which may cause the cancer cells to die. It is also designed to cause the immune system to attack cancer cells.

Study Drug Dose Levels:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. One (1) to 8 groups with 3-6 participants will be enrolled in the Phase 1 portion of the study, and up to 58 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of bendamustine you receive will depend on when you joined this study. The first group will receive the lowest dose. The next group will receive a higher dose, if the number and type of side effects was low or none. The dose of bendamustine will be increased for each new group until the highest tolerable dose is found.

If you are enrolled in Phase 2, you will receive bendamustine at the highest dose that was tolerated in Phase 1.

All participants in both phases of the study will start out with the same dose levels of fludarabine and rituximab.

If side effects occur, the study doctor may decide to lower your doses of study therapy. If you have side effects during a dose, the study staff will observe you for any other problems for 2 hours after the dose.

Study Drug Administration:

Cycles in this study are 4 weeks. All 3 study drugs are given by vein.

Cycle 1:

* On Days 1-3, bendamustine will be given over 30 minutes.
* On Days 2-4, fludarabine will be given over 30 minutes.
* On Day 4, rituximab will be given over 6-8 hours.

Cycles 2-6:

* On Day 1, rituximab will be given at a higher dose than in Cycle 1. If you tolerated the Cycle 1 dose well, your Cycles 2-6 rituximab doses may be given over 2-4 hours.
* On Days 1-3, fludarabine will be given over 30 minutes.
* On Days 1-3, bendamustine will be given over 30 minutes.

Other Drugs:

You will be given Tylenol (acetaminophen) and Benadryl (diphenhydramine hydrochloride) to take by mouth 30-60 minutes before every dose of rituximab (Cycles 1-6). These drugs are given to lower the risk of side effects.

Study Visits:

Once a week in Cycle 1 and every 2-4 weeks in Cycles 2-6, blood (about 1 tablespoon) will be drawn for routine tests.

Before Cycles 1-6, you will also have a physical exam, including measurement of your vital signs. You will be asked about any side effects you may have had.

Before Cycle 4, the following tests and procedures will be performed:

* You will have a physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a bone marrow aspiration and biopsy to check the status of the disease.
* If the doctor thinks it is needed, you will have a CT scan of the neck, chest, abdomen, and pelvis to check the status of the disease.

Length of Study Participation:

You may receive up to 6 cycles of study treatment. The study treatment will be stopped early if the disease gets worse or you experience any intolerable side effects.

End-of-Treatment Visit:

After Cycle 6 (or earlier if you stop early), the following tests and procedures will be performed:

* You will have a physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a bone marrow aspiration and biopsy to check the status of the disease.
* If the doctor thinks the disease has completely responded, you will have a CT scan of the neck, chest, abdomen, and pelvis to confirm the response.

Follow-Up Visits:

You will have follow-up visits at the end of Month 6 and Year 1 after your last dose of study drugs, and once a year until you start a new cancer treatment. The same tests will be performed as at the end-of-treatment visit. Starting at Year 3, the follow-up tests and procedures can be done by your local doctor if that is more convenient to you.

You should tell your study doctor or staff if you start another cancer treatment after the study. If that occurs, your follow-up in this study will stop.

This is an investigational study. Both fludarabine and bendamustine are commercially available and FDA approved to treat CLL. Rituximab is commercially available and FDA approved to treat lymphoma. The use of these drugs together in this study is investigational.

Up to 82 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Bendamustine, Fludarabine + Rituximab arm 2: Bendamustine 30 mg/m\^2 by vein (fixed), Days 1,2,3 + Fludarabine + Rituximab arm 3: Bendamustine, Fludarabine + Rituximab arm 4: Bendamustine, Fludarabine + Rituximab arm 5: Bendamustine, Fludarabine + Rituximab
Interventions: intervention 1: Bendamustine intervention 2: Fludarabine intervention 3: Rituximab
Intervention descriptions: intervention 1: Phase 1: Starting Dose of 20 mg/m2 IV on Days 1,2,3 (after fludarabine)

Phase 2: 30 mg/m2 by vein (fixed) on Days 1,2,3 (after fludarabine) intervention 2: Course 1: 20 mg/m2 intravenous (IV) on Days 2,3,4 Courses 2-6: 20 mg/m2 IV, Days 1,2,3 intervention 3: Course 1: 375 mg/m2 IV, Day 4 (after fludarabine) Courses 2-6: 500 mg/m2 IV, Day 1

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2009-0546
August 4, 2014
Page 1
Protocol Page
A phase I/II clinical trial of fludarabine, bendamustine, and rituximab (FBR) in 
previously treated patients with chronic lymphocytic leukemia (CLL)
2009-0546
Core Protocol Information
Short Title 
FBR for Relapsed CLL
Study Chair: 
William G. Wierda
Additional Contact:
Annette Jalayer
Laura K. Fowler
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-0428
Unit:
428
Full Title: 
A phase I/II clinical trial of fludarabine, bendamustine, and rituximab (FBR) in previously treated 
patients with chronic lymphocytic leukemia (CLL)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Terminated 03/31/2017
Version:
14
Submitted by:
Laura K. Fowler--8/4/2014 8:23:45 AM
OPR Action:
Accepted by:  Matthew D. Geidel -- 8/4/2014 8:45:44 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol 2009-0546
August 4, 2014
Page 2
Protocol Body
 


Protocol 2009-0546 
August 1, 2014 
Version 8 
Page 1 
 
 
A Phase I/II Clinical Trial of Fludarabine, 
Bendamustine, and Rituximab (FBR) in Previously 
Treated Patients with Chronic Lymphocytic 
Leukemia (CLL) 
 
 
Version 8 
 
August 1, 2014 
 
William G. Wierda, M.D., Ph.D. 
Associate Professor of Medicine 
Department of Leukemia 
Division of Cancer Medicine 
UT MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX  77030 
(713) 745-0428 (ph) 
(713) 794-1602 (fax) 
 
 
 
 
Short Title: 
Phase I/II FBR for Previously Treated Patients with 
CLL 
 


Protocol 2009-0546 
August 1, 2014 
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Page 2 
1.0 
OBJECTIVES 
 
Primary objectives: 
• Phase I – Evaluate the toxicities and tolerability and identify the 
maximum tolerated dose of bendamustine combined with fixed-
dose fludarabine and rituximab (FBR) in previously treated patients 
with CLL. 
 
• Phase II – Evaluate efficacy (2008 International Workshop on 
Chronic Lymphocytic Leukemia [IWCLL] response rate) of the FBR 
regimen at the tolerated dose of bendamustine in previously treated 
patients with CLL.  This will be compared to the historic data of 
treatment regimens for previously treated patients with CLL. 
 
Secondary objectives: 
• Evaluate safety in the Phase II portion at the tolerated dose of 
bendamustine in previously treated patients with CLL. 
 
• Evaluate time to treatment failure (TTF) and time-to-progression 
(TTP) for previously treated patients treated with the FBR 
combination.  These time-to-event endpoints will be compared to 
historic data of treatment regimens for previously treated patients. 
 
• Correlate pretreatment prognostic factors, including ZAP-70 
expression, CD38 expression, β-2 microglobulin, IGHV gene 
mutation status, chromosome abnormalities by FISH, and serum 
thymidine kinase with response and time to event endpoints. 
 
• Evaluate pharmacodynamic endpoints to determine bendamustine-
induced deoxyribonucleic acid (DNA) damage response in 
quiescent CLL lymphocytes and test the hypothesis that fludarabine 
triphosphate will enhance this response by inhibiting DNA repair. 
 
 
2.0 
BACKGROUND 
 
2.1 
CLL is the most common leukemia in the United States and Western 
Hemisphere (reviewed in 1).  Nearly two-thirds of patients with CLL are 
over 65 years of age, and there is a steady increase in the prevalence of 
this disease in the population over 50 years of age.  Interest in newer 
therapeutic agents was poor until recently, owing to the usual advanced 
age of patients and often indolent course of disease.  However, the natural 
history of the disease is diverse.  Patients with only lymphocytosis have a 
median survival in excess of 10 years; those with evidence of marrow 
failure manifested by anemia or thrombocytopenia have a median survival 


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of only 2 years.  Intermediate survival is predicted for patients with 
lymphadenopathy or organomegaly.  The National Cancer Institute 
Working Group on CLL has described clinical features of “active disease” 
which are helpful in the decision to treat.  These indications for treatment 
include: 1) unintentional weight loss of more than 10% body weight over 
the past 6 months; 2) fever or night sweats in the absence of infection; 3) 
extreme fatigue; 4) worsening anemia or thrombocytopenia; 5) massive 
(>6 cm below the left costal margin) or progressive splenomegaly; 6) 
massive 
(>10 
cm 
in 
the 
longest 
diameter) 
or 
progressive 
lymphadenopathy; 7) progressive lymphocytosis with rapid lymphocyte 
doubling time; 8) marked hypogammaglobulinemia or paraproteinemia2-4. 
 
2.2 
The mainstay of therapy has been systemic chemotherapy consisting 
usually of an alkylating agent and a corticosteroid.  Chlorambucil plus 
prednisone has become the standard initial therapy with response rates 
from 40-77%.  Generally, responses have not been complete 5-9.  Therapy 
in patients who are refractory to alkylating agents is unsatisfactory.  The 
response rates are substantially lower (approximately 30%) with rare 
complete responses 8-12. 
   
2.3 
Fludarabine 
has 
shown 
marked 
activity 
in 
several 
indolent 
lymphoproliferative disorders including CLL, low-grade lymphoma, 
Waldenstroms macroglobulinemia, and prolymphocytic leukemia 13-17. 
 
Treatment of previously treated CLL patients with fludarabine has resulted 
in a 13% complete response rate and 44% partial response rate 13.  
Fludarabine has also been given to patients with previously untreated 
CLL, resulting in even higher response rates with 33% confirmed complete 
response, 39% unconfirmed complete response and 6% partial response 
16. 
 
Despite attainment of clinical complete response, most patients will 
experience a recurrence at a median of approximately 2 years 18.  This is 
likely related to the fact that most patients in complete remission (CR) 
have residual disease that can be assessed by several parameters.  In 
previously untreated patients, 55% of CR patients have residual nodules 
on bone marrow biopsy (now referred to as nodular partial remission 
[nPR]) 16.  At 2 years 87% of CR patients are progression-free, versus 
55% of nPR patients18. 
 
2.4 
Fludarabine and prednisone have been combined and used to treat over 
200 patients with CLL.  Response rates are equivalent to those seen with 
single agent fludarabine for both previously treated and untreated patients 
19.  However, 14 episodes of Listeria sepsis or Pneumocystis carinii 
pneumonia were seen with 4 deaths resulting from these infections.  


Protocol 2009-0546 
August 1, 2014 
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These infections were not seen in 100 prior patients treated with 
fludarabine alone. 
 
2.5 
Cyclophosphamide has been combined with vincristine (VCR) and 
prednisone (COP) to treat lymphoproliferative disorders.  Liepman and 
Votaw first reported on this combination to treat CLL in 1978.  Thirty-six 
patients received this regimen, 23 were previously untreated.  The 
response rate was 72%; 18 of 23 (78%) previously untreated patients 
responded; 8 of 13 (62%) patients previously receiving chlorambucil 
responded to COP 20.  Oken and Kaplan treated 18 patients with CLL with 
CVP (cyclophosphamide 800 mg/m2 I.V. on day 1 or 400 mg/m2 orally for 
5 days, VCR 2 mg I.V. on day 1 and prednisone 60-100 mg/m2 on days 1-
5).  All patients were previously treated and 17 of 18 were refractory to 
chlorambucil.  The response rate was 44% 21. 
 
2.6 
In vitro studies have demonstrated that fludarabine inhibits repair of 
cyclophosphamide-induced DNA inter-strand cross-links in CLL B cells 22.  
This was the basis for a regimen of fludarabine, 25-30 mg/m2, combined 
with cyclophosphamide, 250-500 mg/m2; both drugs were given daily for 
three days in 4-week courses.  Frewin et al 23 first reported their 
experience giving fludarabine 25 mg/m2 and cyclophosphamide 250 
mg/m2 daily for three days in a limited trial of 7 patients with CLL; two 
patients achieved a complete remission and the overall response rate was 
71%. Toxicities included nausea and vomiting, myelosuppression and 
infections.  O’Brien et al 24 gave this treatment to 94 patients who were 
previously treated with either an alkylating agent, fludarabine, or both.  
The complete remission rate was 11% and an overall response rate 
(ORR) of 69% was reported.  Patients that had previously been treated 
with an alkylating agent and were resistant to fludarabine had a markedly 
lower, but noteworthy response rate with 3% complete remissions and a 
39% overall response rate. 
 
2.7 
Rituximab in CLL 
The Food and Drug Administration (FDA) approved Rituximab in 1997 for 
treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma.  
In the pivotal trial, 33 of 166 patients had small lymphocytic lymphoma 
(SLL), International Working Formulation (IWF) A (CLL equivalent).  
Rituximab was given at a dose of 375 mg/m2 weekly for four weeks, and 
produced a response rate of 48%.  For the patients with IWF A disease 
the overall response rate was low; 12% compared to 58% for those with 
IWF B, C, and D (combined) disease 25.  There are several potential 
explanations for the lower activity of rituximab in patients with CLL/SLL.  
Leukemia cells from patients with CLL express lower levels of CD20 than 
that observed on follicular lymphoma cells.  In addition, pharmacokinetic 
analyses conducted during the pivotal trial showed lower plasma levels of 
rituximab in non-responders and, effectively, in most patients with SLL.  


Protocol 2009-0546 
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Finally, circulating CD20 has been demonstrated in the plasma of patients 
with CLL 26.  Soluble CD20 may act as a sink for the therapeutic antibody, 
resulting in more rapid clearance and reducing delivery of the antibody to 
leukemia cells.  Therefore, higher plasma concentrations of rituximab 
could potentially improve response rates in CLL. 
 
Rituximab has been evaluated as a single agent in the treatment of CLL.  
The standard dose of 375 mg/m2 weekly for four weeks was given to 28 
patients with CLL who had been previously treated with chemotherapy 27.  
There were no complete remissions; 25% of patients had partial 
responses, 43% had stable disease, and 32% had progressive disease.  
Smaller studies evaluating rituximab 375 mg/m2 weekly for four weeks in 
previously treated patients with CLL report low overall response rates with 
no complete remissions 27-29. 
 
Two studies of dose-escalated rituximab in CLL yielded encouraging 
results.  O’Brien et al.30 conducted a study of four weekly doses of 
rituximab at 500, 650, 825, 1000, 1500, and 2250 mg/m2.  All patients with 
CLL had been previously treated with chemotherapy.  The overall 
response rate among the 39 evaluable patients was 36% and all 
remissions were partial.  Responses were seen in 5 of 24 (21%) patients 
receiving 500-825 mg/m2, 3 of 7 (43%) patients receiving 1000-1500 
mg/m2, and 6 of 8 (75%) patients receiving 2250 mg/m2 (P=0.03).  Byrd et 
al.31 conducted a dose-intensified study with 375 mg/m2 administered 
thrice weekly for four weeks.  Twenty-seven previously treated patients 
were evaluable for response, 10 (37%) achieved remission.  There 
appears to be increased activity for rituximab in CLL with dose intensified 
schedules; the optimal dose and schedule for rituximab in CLL is yet to be 
determined. 
 
2.8 
Chemoimmunotherapy in CLL 
The increased activity of fludarabine combined with cyclophosphamide 
(FC) and the potential chemo-sensitization between purine analogue, 
alkylating agent, and monoclonal antibody was the rationale for combining 
rituximab 
with 
FC. 
 
The 
efficacy, 
toxicity, 
and 
tolerability 
of 
chemoimmunotherapy 
with 
the 
combination 
of 
fludarabine, 
cyclophosphamide, and rituximab (FCR) were evaluated in previously 
treated patients with CLL 32. The purpose of this study was to improve the 
CR rate for previously treated patients and evaluate the quality of bone 
marrow response.  One hundred seventy-seven previously treated 
patients with CLL were evaluated. Treatment consisted of rituximab 375 
mg/m2 day 1 of course 1 and 500 mg/m2 day 1 of courses 2 to 6; 
fludarabine 25 mg/m2/d days 2 to 4 of course 1 and days 1 to 3 of courses 
2 to 6; and cyclophosphamide 250 mg/m2/d days 2 to 4 of course 1 and 
days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks.  CR 
was achieved in 25% of 177 patients, and nPR and partial remission (PR) 


Protocol 2009-0546 
August 1, 2014 
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were achieved in 16% and 32% of patients, respectively; the overall 
response rate was 73%. Twelve (32%) of 37 complete responders tested 
achieved molecular remission in bone marrow. Univariable and 
multivariable analyses were used to identify pretreatment patient 
characteristics associated with CR and overall remission, longer time to 
progression, and overall survival.  The FCR regimen was an active and 
well-tolerated treatment for previously treated patients with CLL. 
Myelosuppression was the most common toxicity. FCR induced the 
highest CR rate reported in a clinical trial of previously treated patients 
with CLL. Furthermore, molecular remissions were achieved in a third of 
patients achieving CR. 
 
The FCR regimen has been evaluated in two large Phase III randomized 
trials, one in previously untreated patients (CLL8 trial33) conducted by the 
German CLL Study Group (GCLLSG) and in previously treated patients 
(REACH trial34) conducted as an international trial sponsored by F. 
Hoffmann La-Roche.  Both trials demonstrated superior efficacy for the 
FCR combination over FC in terms of higher complete and overall 
response rates and longer progression-free survival.  The REACH trial 
was conducted mainly in Europe and randomized previously treated 
patients with CLL to either FC or FCR.  Patients could have only had one 
prior treatment that could not have included FC or rituximab.  A total of 
552 patients were randomized, 276 each received FC or FCR; patients 
were equally distributed between treatment arms in terms of pre-treatment 
characteristics.  The doses of FC were the same for both treatment arms, 
fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2, both daily for 3 
days of each course.  For FCR, rituximab was given at 375 mg/m2 x1 for 
course 1 and 500 mg/m2 x1 for courses 2-6.  The CR and OR rates were 
24.3 and 69.9% respectively for patients treated with FCR and 13 and 
58% respectively for patients treated with FC. The median progression-
free survival (PFS) for patients treated with FCR was 30.6 mo, versus 20.6 
mo for patients who were treated with FC. Treatment was well tolerated by 
both arms and there was no significant difference in the rates of grade 3 
and 4 neutropenia, anemia, thrombocytopenia, infectious, or other 
adverse events.  These Phase III data clearly demonstrated superiority for 
the FCR regimen over FC in previously treated patients with CLL. 
 
 
2.9 
Bendamustine in CLL 
Bendamustine has recently been approved by the FDA for treatment of 
patients with CLL35,36.  Bendamustine has a complex structure with 3 
functional groups: an alkylating group, a benzimidazole ring, and a butyric 
acid side chain37.  It clearly has alkylating-agent activity, capable of 
inducing inter-strand and intra-strand DNA cross-links.  It may also have 
anti-metabolite activity conferred by the benzimidazole nucleus.  Work by 
our group22,38,39 demonstrated that DNA excision repair is inhibited by  


Protocol 2009-0546 
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fludarabine, giving rationale to combining alkylating agents with 
fludarabine24.  Clinical trials have confirmed the superior efficacy with the 
combination of fludarabine and cyclophosphamide versus single-agent 
fludarabine40-42. 
 
The German CLL Study Group conducted a single-arm Phase II clinical 
trial of bendamustine with rituximab (BR) in previously treated patients 
(CLL2M) that demonstrated therapeutic activity and acceptable toxicity43. 
In this study, previously treated patients received bendamustine 70 mg/m2 
on days 1 and 2 with rituximab 375 mg/m2 x1 course 1, then 500 mg/m2 x1 
for courses 2-6.  The CR and OR response rates for the 81 patients 
treated on this trial were 14.5 and 77.4%, respectively.  The incidence of 
grade 3 and 4 neutropenia was 12.2%, thrombocytopenia was 9.1%, 
anemia was 6.1% and infection was 5.2%. The response demonstrated an 
indication of therapeutic efficacy and the incidence of toxicities were 
tolerable, considering this was a population of previously treated patients.  
The GCLLSG is currently conducting a randomized frontline trial of FCR 
versus BR. 
 
2.10 Rationale for the FBR Combination 
This proposal takes advantage of the alkylating-agent activity of 
bendamustine and inhibition of DNA repair by fludarabine37 and aims to 
explore the tolerability and toxicities of this combination with rituximab 
(FBR regimen) in the Phase I portion and the therapeutic efficacy in the 
Phase II portion of a clinical trial for previously treated patients with CLL.  
In Phase I, we will evaluate a fixed dose of fludarabine 20 mg/m2 daily x 3 
and rituximab 375 mg/m2 x 1 (course 1) and 500 mg/m2 x 1 (courses 2-6), 
with bendamustine at increasing doses of 20 mg/m2 daily x3, 30 mg/m2 
daily x 3, 40 mg/m2 daily x 3, or 50 mg/m2 daily x 3.  Courses will be every 
4 weeks; 6 courses will be given.  In Phase I, for the first course, 
bendamustine will be given alone on Day 1, then on Days 2 and 3 
fludarabine will be given before bendamustine; fludarabine will be given 
alone on Day 4; rituximab will be given on Day 4 (after fludarabine) of this 
course.  For courses 2-6 of Phase I, fludarabine and bendamustine will be 
given on Days 1-3; rituximab will be given on Day 1.  For Phase II, the 
tolerated dose of bendamustine will be used with fludarabine and 
rituximab in an expanded population to evaluate clinical efficacy.  For 
Phase II, fludarabine and bendamustine will be given sequentially on the 
same day. 
 
We have evaluated the fludarabine, cyclophosphamide, rituximab (FCR) 
combination in over 300 previously untreated patients and nearly 290 
previously treated patients.  Therefore, we have well-characterized, 
historic patient populations with which to compare new treatment 
regimens and assess clinical efficacy of new regimens.  These patient 


Protocol 2009-0546 
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populations will be used as a comparison to evaluate the effectiveness of 
this regimen. 
 
This is a Phase I/II, open label study to identify the tolerated dose of 
bendamustine in combination with fixed-dose fludarabine and rituximab in 
Phase I and in Phase II to evaluate the efficacy of this combination. In the 
Phase II portion, patients will receive up to 6 courses of treatment at the 
tolerated dose of bendamustine identified in Phase I and will be evaluated 
for response. 
 
3.0 
BACKGROUND DRUG INFORMATION  
 
The clinical supplies of fludarabine, bendamustine, and rituximab will be 
commercial drug supply. 
 
3.1 
Fludarabine: 
 
The following information applies to fludarabine (Fludara®).  
 
 
3.1.1 How Supplied:  
Sterile, 50 mg prepared as a white lyophilized powder with sodium 
hydroxide to adjust pH. 
 
 
3.1.2 Solution Preparation:  
Fludarabine for injection should be prepared for parenteral use by 
aseptically adding Sterile Water for Injection USP.  When 
reconstituted with 2 mL of Sterile Water for Injection, USP, the 
solidcake should fully dissolve in 15 seconds or less; each mL of 
the resulting solution will contain 25 mg of fludarabine phosphate, 
25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7.  
The pH range for the final product is 7.2 – 8.2.  In clinical studies, 
the product has been diluted in 100 cc or 125 cc of 5% Dextrose 
Injection USP or 0.9% Sodium Chloride USP. 
 
Reconstituted fludarabine for Injection contains no antimicrobial 
preservative and thus should be used within 8 hours of 
reconstitution.  Care must be taken to assure the sterility of 
prepared solutions.  Parenteral drug products should be inspected 
visually 
for 
particulate 
matter 
and 
discoloration 
prior 
to 
administration. 
 
 
3.1.3 Handling and Disposal:  
Procedures for proper handling and disposal should be considered. 
Consideration should be given to handling and disposal according 
to guidelines issued for cytotoxic drugs. Several guidelines on this 
subject have been published.  There is no general agreement that 


Protocol 2009-0546 
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all of the procedures recommended in the guidelines are necessary 
or appropriate. 
 
Caution should be exercised in the handling and preparation of 
fludarabine for Injection solution.  The use of latex gloves and 
safety glasses is recommended to avoid exposure in case of 
breakage of the vial or other accidental spillage.   If the solution 
contacts the skin or mucous membrane, wash thoroughly with soap 
and water; rinse eyes thoroughly with plain water.  Avoid exposure 
by inhalation or by direct contact of the skin or mucous membranes. 
 
3.1.4 Stability:   
Fludarabine phosphate is relatively stable in aqueous solution.  
Over a pH range of approximately 4.5 to 8 in aqueous buffer 
solutions stored at 65°C, approximately 11% decomposition 
occurred in one day.  From this pH profile, the optimum pH was 
determined to be approximately 7.7. 
 
At a concentration of 25 mg/ml in distilled water stored at room 
temperature in normal laboratory light, fludarabine phosphate 
exhibited less than 20% decomposition in 16 days. 
 
Diluted to concentration of 1 mg/ml in 5% dextrose injection, USP, 
or in 0.9 sodium chloride injection, USP, less than 3% 
decomposition occurred in 16 days at room temperature under 
normal laboratory light. 
 
CAUTION: The single-use lyophilized dosage form contains no 
antibacterial preservatives.  Therefore, it is advised that the 
reconstituted product be discarded eight hours after reconstitution. 
 
3.1.5 Route of Administration: Intravenous (IV). 
 
3.1.6 Fludarabine Side Effects: 
Common 
• Gastrointestinal: loss of appetite (0 to 34%), nausea (1% to 
5%), vomiting 
• Neurologic: asthenia (9% to 65%), parasthesia (4% to 12%) 
• Respiratory: cough (6% to 44%) 
• Other: fatigue (10 to 38%), fever (11% to 69%), infectious 
disease (12% to 44%), pain (5% to 22%), shivering (11% to 
19%) 
 
Serious 


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• Hematologic: 
decreased 
hemoglobin 
(14% 
to 
60%), 
hemolytic anemia, neutropenia (37% to 59%), pancytopenia, 
thrombocytopenia (17% to 55%) 
• Neurologic: 
neurotoxicity, 
progressive 
multifocal 
leukoencephalopathy 
• Respiratory: pulmonary toxicity 
• Other: graft versus host disease, tumor lysis syndrome 
(.33% to 1%) 
 
3.2 
Bendamustine (Treanda): 
Bendamustine (TREANDA®) for Injection is indicated for the treatment of 
patients with CLL.  Efficacy relative to first line therapies other than 
chlorambucil has not been established. 
 
3.2.1 How Supplied: 
Bendamustine for Injection single-use vial containing 100 mg of 
bendamustine hydrochloride (HCl) as white to off-white lyophilized 
powder. 
 
3.2.2 Solution Preparation:  
Aseptically reconstitute each 100 mg bendamustine vial with 20 mL 
of Sterile Water for Injection, USP. This yields a clear, colorless to a 
pale yellow solution with a bendamustine HCl concentration of 5 
mg/mL.  The lyophilized powder should completely dissolve in 5 
minutes. If particulate matter is observed, the reconstituted product 
should not be used. 
 
Aseptically withdraw the volume needed for the required dose 
(based on 5 mg/mL concentration) and immediately transfer to a 
500 mL infusion bag of 0.9% Sodium Chloride Injection, USP 
(normal saline). The reconstituted solution must be transferred to 
the infusion bag within 30 minutes of reconstitution. After 
transferring, thoroughly mix the contents of the infusion bag. The 
admixture should be a clear and colorless to slightly yellow solution. 
 
Sterile Water for Injection, USP and 0.9% Sodium Chloride 
Injection, USP must be used as outlined above. Compatibility with 
other diluents has not been determined.  Parenteral drug products 
should be inspected visually for particulate matter and discoloration 
prior to administration whenever solution and container permit. Any 
unused solution should be discarded according to institutional 
procedures for antineoplastic agents. 
 
3.2.3 Handling and Disposal:  
Bendamustine is intended for administration as an intravenous 
infusion over 30 minutes. 


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As with other potentially toxic anticancer agents, care should be 
exercised in the handling and preparation of solutions prepared 
from bendamustine.  The use of gloves and safety glasses is 
recommended to avoid exposure in case of breakage of the vial or 
other accidental spillage.  If a solution of bendamustine contacts 
the skin, wash the skin immediately and thoroughly with soap and 
water.  If bendamustine contacts the mucous membranes, flush 
thoroughly with water. 
 
Procedures for the proper handling and disposal of anticancer 
drugs should be considered. Several guidelines on the subject have 
been published. There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or 
appropriate. 
 
3.2.4 Stability 
Bendamustine 
contains 
no 
antimicrobial 
preservative. 
The 
admixture should be prepared as close as possible to the time of 
patient administration.  Once diluted with 0.9% Sodium Chloride 
Injection, USP, the final admixture, is stable for 24 hours when 
stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at 
room temperature (15-30°C or 59-86°F) and room light. 
Administration of bendamustine must be completed within this 
period. 
 
3.2.5 Route of Administration 
Intravenous  
 
3.2.6 Bendamustine Side Effects 
 
 
Common 
 Dermatologic: rash (all grades, 8% to 16%; grade 3 or 4, 
less than 1% to 3%) 
 Endocrine metabolic: weight loss (all grades, 7% to 18%, 
grade 3 or 4, 2 %) 
 Gastrointestinal: constipation (all grades, 29%), grade 3 or 4 
less than 1%), diarrhea ( all grades, 9% to 37%; grade 3 or 
4, 1% to 3%), loss of appetite (all grades, 23%; grade 3 or 4, 
2%), nausea (all grades, 20% to 75%; grade 3 or 4, less 
than 1% to 4%), stomatitis (all grades, 15%; grade 3 or 4, 
less than 1%), vomiting (all grades, 16% to 40%; grade 3 or 
4, less than 1% to 3%) 
 Neurologic: headache (21%) 
 Respiratory: cough (all grades, 4% to 22%; grade 3 or 4, 
less than 1%), dyspnea (all grades,16%; grade 3 or 4, 2%) 


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 Other: dehydration (all grades, 14%; grade 3 or 4, less than 
5%), fatigue (all grades, 9% to 57%; grade 3 or 4, 1% to 
11%), fever (all grades, 24% to  34%; grade 3 or 4, 2% to 
4%) 
 
 
 
Serious 
 
 Cardiovascular: hypertensive crisis 
 Dermatologic: 
dermatologic 
toxicity, 
Stevens-Johnson 
syndrome, toxic epidermal necrolysis 
 Endocrine metabolic: hyperuricemia (all grades, 7%; grade 3 
or 4, 2%) 
 Hematologic: acute myeloid leukemia, anemia (all grades, 
88% to 89%; grade 3 or 4, 11% to 13%), febrile neutropenia 
(6%), leukopenia (all grades, 61% to 94%; grade 3 or 4, 28% 
to 56%), lymphocytopenia (all grades, 68% to 99%, grade 3 
or 
4, 
47% 
to 
94%), 
myelodysplastic 
syndrome, 
myeloproliferative disorder, myelosuppression, grades 3 and 
4 (98%), neutropenia (all grades, 75% to 86%; grade 3 or 4, 
43% to 60%), thrombocytopenia (all grades, 77% to 86%; 
grade 3 or 4, 11 % to 25%) 
 Immunologic: anaphylaxis, hypersensitivity reaction (all 
grades 5%; grade 3 or 4, 1%), infectious disease (all grades 
6%; grade 3 or 4, 2%), sepsis, septic shock 
 Renal: renal failure 
 Respiratory: squamous cell carcinoma of bronchus 
 Other: myelodysplastic syndrome, tumor lysis syndrome 
 
3.3 
Rituximab: 
 
3.3.1 Investigational Drug Nomenclature 
 
• IDEC Pharmaceuticals code designation Rituxan® 
• Generic Name: rituximab 
• IND Number: BB-IND 4904 
 
3.3.2 Clinical Formulation: 
Clinical supplies for this study will be manufactured by Genentech 
Incorporated in South San Francisco, CA. 
 
Rituximab will be provided to the clinical sites packaged in single 
use 10 mL (100mg) and 50 mL (500mg) Type I glass vials at a 
concentration of 10 mg of protein per mL.  The product is 
formulated in 7.35 mg/mL sodium citrate buffer, containing 7 mg/mL 
polysorbate 80, 9.0 mg/mL sodium chloride and Sterile Water for 
Injection.  The pH is adjusted to 6.5. 
 


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Rituximab may be produced by the mammalian (Chinese Hamster 
Ovary) cell suspension culture in a nutrient medium containing 100 
mg/mL of the antibiotic gentamicin.  The antibiotic is not detectable 
in the final product. 
 
3.3.3 Storage 
Rituximab for clinical use should be stored in a secure refrigerator 
at 2-8°C. 
 
3.3.4 Reconstitution and Dilution of Rituximab 
Using a sterile syringe and a 21 gauge or larger needle, transfer the 
necessary amount of rituximab from the vial into a partially filled IV 
pack containing sterile, pyrogen-free 0.9% Sodium Chloride, USP 
(saline solution).  The final concentration of rituximab should be 1 
mg/mL.  Mix by inverting the bag gently.   
 
Caution should be taken during the preparation of the drug.  
Parenteral drug products should be inspected visually for 
particulate matter prior to administration.  Preparations of rituximab 
containing visible particles should not be used.  As with all 
parenteral drug products, aseptic procedures should be used 
during the preparation and administration of rituximab. 
 
NOTE:  DO NOT USE A VACUUM APPARATUS to transfer 
rituximab from the syringe to the infusion pack.  DO NOT USE 
evacuated glass containers, which require vented administration 
sets, because this causes foaming when air bubbles pass through 
the solution. 
 
3.3.5 Rituximab Side Effects: 
Common 
• Cardiovascular: hypertension (all grades, 6%; grades 3-4, 
1%); hypotension (all grades, 10%; grades 3 and 4, 1%) 
• Dermatologic: pruritis 
• Gastrointestinal: nausea, vomiting 
• Neurologic: asthenia (non-Hodgkin’s lymphoma, all grades, 
26%; grades 3 and 4, 1%; rheumatoid arthritis, 2%), 
dizziness (all grades, 10%; grades 3 and 4, 1%), headache 
(all grades, 19%, grades 3 and 4, 1%), sensory neuropathy 
(30%) 
• Other: fever (all grades, 53%; grades 3 and 4, 1%), shivering 
(all grades, 33%; grades 3 and 4, 3%) 
 
Serious 


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• Cardiovascular: cardiac dysrhythmia, cardiogenic shock, 
heart 
failure, 
myocardial 
infarction, 
supraventricular 
arrhythmia, supraventricular tachycardia 
• Dermatologic: 
drug-induced 
pemphigus, 
Lichenoid 
dermatitis, Stevens-Johnson syndrome, toxic epidermal 
necrolysis 
• Gastrointestinal: 
bowel 
obstruction, 
gastrointestinal 
perforation 
• Hematologic: anemia (all grades, 8%; grades 3 and 4, 3%), 
aplastic anemia, transient cytopenia, grades 3 and 4 (48%), 
hemolytic anemia, leukopenia (all grades 14%; grade 3 and 
4, 4%, lymphocytopenia (grades 3 and 4, 40%) neutropenia 
(all grades, 14%; grade 3 and 4, 6%), thrombocytopenia (all 
grades, 12%; grade 3 and 4, 2%) 
• Hepatic: relapsing type B viral hepatitis 
• Immunologic: complication of infusion (first infusion, 77%); 
subsequent 
infusions, 
(14% 
to 
30%), 
immune 
hypersensitivity reaction 
• Neurologic: progressive multifocal leukoencephalopathy 
(rheumatoid arthritis, rare) 
• Renal: nephrotoxicity 
• Respiratory: 
obliterative 
bronchioilitis, 
pneumonitis, 
pulmonary fibrosis 
• Other: infectious disease (all grades, 31%, grades 3 and 4, 
4%), tumor lysis syndrome 
 
• Hepatitis B virus (HBV) reactivation with fulminant hepatitis, 
hepatic failure, and death has been reported in some 
patients 
with 
hematologic 
malignancies 
treated 
with 
rituximab.  The majority of patients received rituximab in 
combination with chemotherapy.  The median time to the 
diagnosis of hepatitis was approximately 4 months after the 
initiation of rituximab and approximately one month after the 
last dose. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 
Inclusion criteria: 
1. Patients must have a diagnosis of CLL/SLL and be previously treated 
2. Patients must have an indication for treatment by 2008 IWCLL Criteria  
3. Age ≥ 16 years 
4. Zubrod performance status ≤ 2 
5. Adequate renal and hepatic function as indicated by all the following: 
a. serum creatinine ≤ 2 mg/dL AND; 
b. alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal AND; 


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c. total bilirubin ≤ 2.5 times upper limit of normal 
6. Patients must give written informed consent 
7. Patients of childbearing potential must be willing to practice birth control 
during the study 
 
4.2 
Exclusion Criteria: 
1. Pregnant or breast-feeding females 
2. Significant co-morbidity indicated by major organ system dysfunction 
3. Active, uncontrolled infection, including active hepatitis 
4. Uncontrolled 
autoimmune 
hemolytic 
anemia 
(AIHA) 
or 
immune 
thrombocytopenia purpura (ITP) 
5. Treatment including chemotherapy, chemoimmunotherapy, monoclonal 
antibody therapy, radiotherapy, high-dose corticosteroid therapy (prednisone 
>/= 60 mg daily, or equivalent), or immunotherapy within 21 days prior to 
enrollment or concurrent with this trial 
 
5.0 
TREATMENT PLAN 
 
After patients sign informed consent and screening is complete, all pretreatment 
evaluations have been done, and eligibility is confirmed, patients may begin 
treatment.  Drug doses for Phase I and Phase II are detailed below.  Phase I will 
consist of fixed doses of fludarabine (20 mg/m2, days 2-4) and rituximab (375-
500 mg/m2, day 4 or 1) with increasing doses of bendamustine as indicated.  
Patients will receive 6 courses and will have response assessment prior to 
course 4 and 3 months after last course of FBR. 
 
Phase I: 
Course 1 
Fludarabine 20 mg/m2 IV (fixed), Days 2,3,4  
Bendamustine 20, 30, 40, or 50 mg/m2 IV, Days 1,2,3 (after 
fludarabine) 
Rituximab 375 mg/m2 IV (fixed), Day 4 (after fludarabine) 
 
Courses 2-6 
Fludarabine 20 mg/m2 IV (fixed), Days 1,2,3 
Bendamustine 20, 30, 40, or 50 mg/m2 IV Days 1,2,3 (after 
fludarabine) 
Rituximab 500 mg/m2 IV (fixed), Day 1 
 
Courses will be every 4 weeks as permitted by recovery of blood 
counts, for total of 6 planned courses. The next course of FBR may 
begin when absolute neutrophil count (ANC) and platelets (PLT) 
have recovered to within 20% of pretreatment levels or ANC ≥  
1,200/μL and PLT ≥ 75,000/μL. For courses 2-6, bendamustine will 
be dose reduced to the next lower dose for patients experiencing 
prolonged myelosuppression defined as Grade 3 or 4 neutropenia 
or thrombocytopenia lasting longer than Day 42 of the course for 


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patients who begin treatment with normal neutrophil or PLT counts.  
For patients who begin treatment with neutropenia (ANC 
<1,000/μL) 
or 
thrombocytopenia 
(PLT 
<100,000/μL), 
dose 
reduction of bendamustine to the next lower dose will occur if 
neutrophil or platelet count does not recover to within 20% of the 
pre-treatment level of the previous course.  For courses 2-6, intra-
patient dose escalation may occur to the next higher dose level for 
which there are 3 patients evaluated for toxicity and a decision for 
dose level expansion or dose escalation has been made.  
Granulocyte Colony Stimulating Factor (G-CSF growth factor) may 
be used in courses 2-6. 
 
To prevent Tumor Lysis Syndrome (TLS) in patients with elevated 
WBC who may develop tumor lysis despite allopurinol therapy, 
consider the use of rasburicase for C1 if ALC >50K and uric acid >5 
and daily labs during chemotherapy to monitor potassium, 
phosphorus, calcium and uric acid. 
 
Phase II: 
Course 1 
Fludarabine 20 mg/m2 IV (fixed), Days 2,3,4 
Bendamustine 30 mg/m2 IV (fixed), Days 1,2,3 (after fludarabine) 
Rituximab 375 mg/m2 IV (fixed), Day 4 (after fludarabine) 
 
 
 
Courses 2-6 
Fludarabine 20 mg/m2 IV (fixed), Days 1,2,3 
Bendamustine 30 mg/m2 IV (fixed), Days 1,2,3 (after fludarabine) 
Rituximab 500 mg/m2 IV (fixed), Day 1 
 
Courses will be every 4 weeks as permitted by recovery of blood 
counts, for a total of 6 planned courses. The next course of FBR 
may begin when ANC and PLT counts have recovered to within 
20% of pretreatment level or ANC >/= 1,200/μL and PLT >/= 
75,000/μL. Bendamustine will be dose reduced to the next lower 
dose for patients experiencing prolonged myelosuppression defined 
as Grade 3 or 4 neutropenia or thrombocytopenia lasting longer 
than Day 42 of the course for patients who begin treatment with 
normal neutrophil or PLT counts.  For patients who begin treatment 
with neutropenia (ANC <1,000/μL) or thrombocytopenia (PLT 
<100,000/μL), dose reduction of bendamustine to the next lower 
dose will occur if neutrophil or platelet count does not recover to 
within 20% of the pre-treatment level of the previous course.  G-
CSF growth factor may be used for courses 1-6 of Phase II. 
 
Dose adjustment for toxicity during Phase II: 
 


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Dose Level 
 
-1 
Fludarabine 20 mg/m2 IV (fixed), Days 1,2 
Bendamustine 30 mg/m2, IV, Days 1,2, 
Rituximab 500 mg/m2 IV (fixed), Day 1 
 
 
-2 
Fludarabine 20 mg/m2 IV (fixed), Days 1,2 
Bendamustine 20 mg/m2 IV (fixed), Days 1,2 
Rituximab 500 mg/m2 IV (fixed), Day 1 
 
The dose of fludarabine may be adjusted in Phase II for patients 
with renal insufficiency with reduction according to the fludarabine 
package insert. 
 
5.1 
Suggested premedications:  Anti-emetic (ondansetron 8 mg IV or 
equivalent) premedication will be given 30 min prior to chemotherapy 
(fludarabine/bendamustine).  Premedication for rituximab will consist of 
325 mg-650 mg acetaminophen orally and 25-50 mg diphenhydramine 
hydrochloride orally or intravenously.  Steroids may also be used at the 
discretion of the treating physician.  Other premedications or modifications 
of the above may be appropriate based on the physician or patient 
experience.   
 
5.2 
Suggested supportive medications:  Allopurinol is recommended for at 
least the first week of course 1 for tumor lysis prophylaxis.  Valacyclovir 
(or equivalent) is recommended for herpes virus prophylaxis and Bactrim 
DS (or equivalent) for PCP prophylaxis.  For patients who were previously 
exposed to hepatitis B and are seropositive, consideration should be given 
for lamivudine prophylaxis. 
 
For courses 2-6, growth factor (Neulasta or Neupogen, Erythropoietin 
[EPO]) will be allowed and doses of bendamustine may be adjusted as 
indicated above.   
 
5.3 
Administration of fludarabine 
Fludarabine will be administered intravenous over 30 minutes after 
indicated premedication given.  On days where fludarabine and 
bendamustine are to be given, fludarabine will be given prior to 
bendamustine. 
 
5.4 
Administration of bendamustine 
Bendamustine will be administered IV over 30 minutes.   
 
5.5 
Administration of rituximab:  
 
During the rituximab infusion, the patient’s vital signs (blood pressure, 
pulse, respiration, temperature) should be monitored.  Available at the 


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bedside prior to rituximab administration will be appropriate measures for 
management of anaphylactic reactions. 
 
 
The recommended first dose administration of rituximab is 50 mg/hr for 
the first hour.  If no toxicity is seen, the dose rate may be escalated 
gradually (50 mg/hour increments at 30-minute intervals) to a 
maximum of 500 mg/hr.  If the first dose of rituximab is well tolerated, the 
starting flow rate for the administration of doses 2-6 may be 100 mg/hour 
then increased gradually (100 mg/hour increments at 30-minute 
intervals). 
 
If the first infusion of rituximab is well-tolerated, then for subsequent 
infusions (courses 2-6), accelerated administration of rituximab may be 
given. This consists of 20% of the full dose given over the first 30 min 
followed by the remaining 80% of the full dose given over the subsequent 
hour if the first 30 min is tolerated. For accelerated administration place 
doses less than 1,000 mg in 250 mL of normal saline and run 100mL for 
the first 30 minutes then the remaining 200 mL over 30 minutes (or until 
completed). For doses >1000 mg , the infusion should be 500 mL, with 
200 mL/hour for the first 30 minutes, then 400 mL/hour for 60 minutes (or 
until completed). 
 
 
Patients may experience transient fever and rigors with infusion of 
chimeric anti-CD20 (rituximab) antibody.  When these side effects are 
noted, the antibody infusion should be slowed or interrupted, the patient 
should be observed and the severity of the side effects should be 
evaluated.  The patient should be treated according to the best available 
local practices and procedures.  Following observation, when the patient’s 
symptoms improve, the infusion should be continued, initially, at half the 
previous rate (see Table 1. below).  Upon resolution of all side effects and 
in the judgment of the investigator, the patient’s dose may be gradually 
escalated (50 mg/hr increments at 30 minute intervals) to a maximum rate 
of 300 mg/hr.  Following the antibody infusion, the IV line should be kept 
open for medications, as needed.  If complications occur during the 
rituximab infusion, the patient should be observed for two hours after the 
completion of the infusion. 
 
Since transient hypotension has been reported during rituximab infusions, 
consideration 
should 
be 
given 
to 
withholding 
anti-hypertensive 
medications the day of the rituximab infusion. 
 
 Table  1.   Modification of rituximab infusion rate for side effects 
 Dose Rate           Fever          Rigors                     Mucosal                    % Drop in 
                                                                      Congestion/Edema             Systolic Pressure 
 
Decrease             > 38.5C        Mild/                                       


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 to ½                                       Moderate            Mild/Moderate                  > 30 mm Hg 
 
5.6 
Patients achieving a stable partial response or demonstrating continued 
response after 3 courses will be given an additional 3 courses.  No patient 
will receive more than 6 courses. 
 
5.7 
Patients demonstrating progressive disease or no response after 3 
courses of treatment will come off study. 
 
5.8 
Dose adjustment to the next lower level will be made if pneumonia, 
septicemia, or other life-threatening infection occurs with any course.  If 
recovery of the platelet count to the level prior to treatment exceeds 35 
days, the dose will be decreased 1 level.  If grade 3 or 4 toxicities to other 
organ systems develop, the dose level will be lowered 1 or 2 levels 
respectively. 
 
5.9 
Carriers of hepatitis B should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis 
throughout their study participation. 
 
6.0 
PRETREATMENT EVALUATION 
 
Patients will undergo screening to evaluate and confirm eligibility.  Upon 
confirming eligibility, patients will proceed with treatment on this trial.  
Screening evaluation, including laboratory tests will be done within 2 
weeks of starting treatment. 
 
6.1 
Screening will consist of medical history and physical examination and 
pertinent laboratories including SMA12 and CBC with differential, serum β-
2 microglobulin, as well as a pregnancy test (serum or urine) for females 
of childbearing potential.  This will confirm eligibility and provide baseline 
measurements of lymph node, spleen, and liver size and blood counts that 
will be used for response assessment. 
 
6.2 
Patients will be screened for hepatitis exposure and infection by serum 
HBcAb, HBsAb and HBsAg. Patients will have bone marrow aspirate and 
biopsy with samples sent for differential and morphology within 2 months 
of starting treatment.  Patients will have their prognostic factors 
characterized on pretreatment blood or bone marrow including presence 
of cytogenetic abnormalities (FISH for 13q-, +12, 11q-, and 17p-), 
expression of ZAP70 and CD38, and serum thymidine kinase.  If already 
known, the following prognostic factors do not need to be reevaluated 
since they are not expected to change: leukemia cell IGHV gene 
mutational status and ZAP-70 expression. 
 


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6.3 
Any appropriate radiological and radioisotopic examinations should be 
performed as clinically indicated. 
 
6.4 
Optional blood (20 mL) will be taken to isolate and store pretreatment 
mononuclear cells, DNA, RNA, and plasma.  Optional bone marrow will be 
taken (5 mL) to isolate and store cells, DNA, ribonucleic acid (RNA) and 
marrow plasma.  Gene methylation analyses will be performed on these 
pre-treatment samples to correlate with treatment outcome.  
 
7.0 
EVALUATION DURING STUDY 
 


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Table 2.  Schedule of Events – Phase I / II 
Test and 
Evaluations 
Screeni
ng Visit 
Day ≤ -
14 
C1
D1
C1
D2
C1
D3
C1
D4
C1
D8
C1
D1
5 
C1
D22
C2-
6 
D1
C2-
6 
D2
C2-
6 
D3 
C2-6 
D15 
Prio
r to 
C4
End 
of 
Tx
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval history 
 
X 
 
 
 
 
 
 
X**
 
 
 
 
 
PE including VS 
X 
X 
 
 
 
 
 
 
X**
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBcAb, 
HBsAb, HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bendamustine 
(Ph I/II doses) 
 
X 
X
X
 
 
 
 
X 
X 
X 
 
 
 
Fludarabine 
(20mg/m2) 
 
 
X
X
X 
 
 
 
X 
X 
X 
 
 
 
Rituximab 
(mg/m2) 
 
 
 
 375
 
 
 
500
 
 
 
 
 
Adverse event 
screening 
 
X 
 
 
 
X
X 
X 
X 
 
 
X 
 
 
CBC with diff, 
PLT 
X 
X 
 
 
 
X
X 
X 
X**
 
 
X 
 
 
SMA 12 
X 
X 
 
 
 
X* X*
X* X**
 
 
 
 
 
PK & PD, 
optional 
samples**** 
X 
X 
X
X
X 
 
 
 
X 
 
X 
 
 
 
 
Response 
assessment 
(2008 IWCLL 
criteria, staging 
CT scan, and 
BM for 
MRD)*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
After 
C6, 
then 
6, 
12, 
24 
mo
BM=bone marrow evaluation; C=course; D=day; PE=physical examination; 
VS=vital 
signs; 
CBC=complete 
blood 
count; 
PK=pharmacokinetic; 
PD=pharmacodynamic; 
IWCLL=International 
Working 
Group 
for 
CLL; 
MRD=minimal residual disease; All courses are 4 weeks, depending on recovery 
of ANC and PLT; Tx=treatment; X*=for Phase I only; **indicates ± 3 days; 
***before C4 and after 6 courses or the last course if fewer than 6 given; ****not 
all samples will be collected in all patients at all time-points 
 
7.1 
Patients will be followed with CBC, platelet count and differential weekly 
(±3 days) for the first course and q2 – 4 weeks (±3 days) during therapy 


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thereafter for both Phase I and II.  An SMA 12 (bilirubin, creatinine, 
albumin, LDH) will be done weekly (±3 days) for the first course for Phase 
I.  For Phase I, courses 2-6 and for patients on Phase II, SMA 12 will be 
done before each course and as clinically indicated.  Physical examination 
every follow-up visit at MD Anderson Cancer Center (MDACC). 
 
7.2 
Before course 4 and after 6 courses of treatment or the last course if fewer 
than 6 given, a full evaluation for response assessment will be performed 
including CBC, platelet and differential count, SMA (bilirubin, creatinine, 
albumin, LDH), and bone marrow aspiration and biopsy with samples sent 
for differential, flow cytometry, and morphologic analysis.  Bone marrow 
will be evaluated by flow cytometry for minimal residual disease (4-color 
flow will be done).  A confirmatory CT of neck, chest, abdomen, and pelvis 
will be done for patients in clinical complete remission. 
 
7.3 
Myelosuppression and associated complications are expected events 
during leukemia therapy and are part of the treatment success (marrow 
emptying of leukemia cells).  Therefore, myelosuppression and associated 
complications 
such 
as 
fever, 
infections, 
bleeding, 
and 
related 
hospitalizations, will not be reported as individual ADRs, but will be 
summarized in the updated and final reports.  Only prolonged Grade 3-4 
myelosuppression, as defined by the 2008 IWCLL criteria specific for 
leukemia, i.e., marrow cellularity <5% on day 42 or later (6 weeks) from 
start of therapy without evidence of leukemia, will be reported as ADR and 
considered in defining the maximum tolerated dose (MTD) and dose-
limiting toxicity (DLT) of particular agents or regimens. 
 
7.4 
Repeat response assessments by physical examination, blood counts, 
and bone marrow evaluation, including for MRD will be done 6, 12, and 24 
months after last treatment course until relapse.  Evaluation for MRD may 
be done on blood.  Blood or marrow for MRD evaluation may be taken by 
referring physician and mailed to UTMDACC.  Follow-up will be annually 
thereafter and bone marrow examinations will be done at the discretion of 
the treating physician for those visits. 
 
7.5 
Optional blood (10 ml) may be taken to determine rituximab levels prior to 
rituximab dose with each course and on day 4 (±2 days) of course 1 and 
day 3 (±1 day) of courses 2-6. 
 
Optional blood may be taken by the referring physician in a green-top 
(heparin) tube and shipped overnight to UTMDACC.  For shipping, each 
tube will be labeled with the patients’ name, MDACC MRN, date and time 
of drawing.  Samples will be shipped same day they are drawn.  Tubes will 
be covered with absorbent wrap and placed in a plastic bag then into a 
shipping kit provided.  Pre-printed shipping labels will be provided for 
shipping. 


Protocol 2009-0546 
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Samples will be shipped to: 
Attention of Ruth LaPushin 
MD Anderson Cancer Center 
1515 Holcombe Blvd 
T6.3849 
Houston, Texas 77030 
Phone:  713-792-3690 
 
7.6 
Optional blood (20 mL) may be taken at response assessment (end of 
treatment) and follow-up visits after completion of treatment to monitor for 
immune reconstitution.  Immune reconstitution samples will be evaluated 
for T cell and normal B cell populations, T cell receptor repertoire, T cell 
functional subsets defined by multi-color flow cytometry.  Optional blood 
may be taken by referring physician in a green-top tube (heparin) and 
mailed to UTMDACC. 
 
8.0 
TOXICITY EVALUATION AND RESPONSE CRITERIA 
 
Non-hematologic toxicity will be described and graded by the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 3.  Hematologic 
toxicity will be graded according to the 2008 IWCLL criteria for grading (Table 3)4. 
 


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Table 3. – Grading of Myelosuppression 
Grade 
Decrease in PLT* or 
HGB** (nadir) from 
pretreatment value, % 
Absolute neutrophil 
count (ANC)/μl*** 
(nadir) 
0 
< 10% 
≥ 2000 
1 
11 – 24% 
≥ 1500 – < 2000 
2 
25 – 49% 
≥ 1000 – < 1500 
3 
50 – 74% 
≥ 500 – < 1000 
4 
≥ 75% 
< 500 
Death occurring as a result of toxicity at any level of decrease from pretreatment 
will be recorded as grade 5. 
* 
PLT counts must be below normal levels for grades 1-4.  If, at any level of 
decrease, the PLT count is < 20K/μl, this will be considered grade 4 toxicity, 
unless there was severe or life-threatening low initial PLT count (< 20K/μl) 
pretreatment, in which case the patient is not evaluable for toxicity referable 
to PLT count. 
** HGB levels must be below normal levels for grades 1-4.  Baseline and 
subsequent HGB determinations must be performed before any given 
transfusions. 
*** If the ANC reaches <1000/μl, it should be judged to be grade 3 toxicity.  If the 
ANC was <1000/μl before therapy, the patient is not evaluable for toxicity 
referable to the ANC. 
 
Responses will be evaluated by the updated 2008 IWCLL Response Criteria 
(Table 4), including staging with CT scan and bone marrow evaluation for 
minimal residual disease for patients in complete remission4.  Bone marrow will 
be evaluated for minimal residual disease by 4-color flow cytometry for patients 
in clinical complete remission.  For patients in clinical complete remission, a 
confirmatory CT scan of neck, chest, abdomen, and pelvis will be done.  Lymph 
nodes 1.5 cm in diameter or smaller will be considered normal and consistent 
with complete remission. 
 


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Table 4.  2008 IWCLL Response Criteria Summary 
SITE 
CR 
PR 
Nodes 
None 
> 50% decrease 
Liver/Spleen 
Not palpable 
> 50% decrease 
Symptoms 
None 
N/A 
PMN 
>1,500/μl 
> 1,500/μl or >50% improvement from 
baseline 
Platelets 
>100,000/μl 
>100,000/μl or 50% improvement from 
baseline 
Hemoglobin (non-
transfused) 
>11.0 gm/dl 
>11.0 g/dl or >50% improvement from 
baseline 
Lymphocytes 
<4,000/μl
>50% decrease 
Bone Marrow 
aspirate 
<30% 
lymphocytes 
N/A for PR 
Bone Marrow 
biopsy 
No lymphocyte 
infiltrate 
< 30% lymphocytes with residual 
disease  on biopsy for nodular PR 
Bone Marrow 
aspirate flow 
Research 
N/A 
CT scan of chest, 
abdomen, pelvis 
Lymph nodes  
<1.5 cm 
Lymph nodes >/= 50% reduced (sum 
product of lymph nodes 
 
9.0 
REMOVAL FROM STUDY 
 
9.1 
Progressive or Relapsed Disease 
 
Progressive disease (PD) will be characterized by at least one of the 
following: 
 
a. > 50% increase in the sum of the products of at least two nodes on two 
consecutive examinations two weeks apart (at least one node must be 
> 2 cm).  Appearance of new palpable lymph nodes. 
 
b. > 50% increase in the size of liver and/or spleen as determined by 
measurement below the respective costal margin; appearance of 
palpable hepatomegaly or splenomegaly, which was not previously 
present. 
 
c. > 50% increase in absolute number of circulating lymphocytes and at 
least 10,000/μl. 
 
9.2 
Patient request. 
 
9.3 
Active HBV infection or hepatitis. 
 
10.0 STATISTICAL CONSIDERATIONS 


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10.1 Phase I 
A standard 3+3 design will be used to evaluate for tolerability and toxicities 
of combined bendamustine (increasing doses), fludarabine, and rituximab 
in previously treated patients with CLL. The DLT and MTD will be 
evaluated based on the information from the first course (4 weeks) of the 
combination therapy. 
 
DLT will be defined as treatment-related, Grade ≥ 3 non-hematologic 
toxicity.  Hematologic toxicity grade ≥ 3 that lasts longer than 42 days will 
be considered a DLT (see Section 8). Since TLS is associated with 
therapeutic activity of this regimen and since it is medically manageable, 
TLS will not be considered a DLT (see Section 5). Fixed doses of 
fludarabine and rituximab will be given.  There will be up to 4 dose levels 
for bendamustine including: 20, 30, 40 and 50 mg/m2 daily x3.  
 
Applying the “3+3” design, the first cohort of 3 patients will be treated at 
the first dose level and evaluated for toxicity. The algorithm is as follows: 
(1) If 0 out of 3 patients experiences DLT, the next cohort of 3 patients will 
be treated at the next higher dose level. (2) If 1 out of 3 patients develop 
DLT, an additional 3 patients will be treated at the same dose level. At this 
level, if 1 out of 6 patients had DLT, the dose escalation continues. If 2 out 
of 6 patients experience DLT, the dose level exceeds the MTD and 3 more 
patients will be treated at the next lower dose if there are less than 6 
patients already treated at that dose.  (3) If greater than 1 out of 3 patients 
experiences DLT, the dose level exceeds the MTD and 3 more patients 
will be treated at the next lower dose if there are less than 6 patients 
already treated at that dose.  In summary, MTD is defined as the highest 
dose level in which 6 patients have been treated with less than or equal to 
1 patient experiencing DLT.  Toxicity evaluation will be completed within 1 
course of therapy for all 3 patients.  No patient will be enrolled in the next 
dose level until the toxicity is fully assessed in all 3 patients enrolled at the 
previous dose level.  For courses 2-6, intra-patient dose escalation may 
occur to the next higher level for which there are 3 patients evaluated for 
toxicity and a decision for dose level expansion or dose escalation has 
been made. Given these 4 dose levels, the maximum number of patients 
required is 24 for this Phase I trial. The 6 patients treated at the tolerated 
dose will be included in the Phase II analysis. 
 
10.2 Phase II 
The efficacy will be assessed in the Phase II part, using the Simon’s two-
stage MinMax design. Overall response will be assessed 2 months after 
the 6th or last course if patients are not able to receive all 6 intended  
courses of treatment. The treatment will be considered promising if the 
complete remission rate is 40% or higher, and will be considered unworthy 
of further investigation if the complete remission rate is 25% or lower. The 


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sample size of 64 is chosen to differentiate between the complete 
remission rate of 40% and 25% with 90% power at a significance level of 
0.1. In particular, 39 patients will be enrolled at the first stage. If 9 or fewer 
of the first 39 patients respond, the trial will be terminated; otherwise 
another 25 patients will be treated for a total of 64 patients. If 20 or fewer 
patients respond among 64 patients, the treatment will be concluded 
ineffective. The probability of early termination due to futility is 0.48. 
 
In addition, the probability of toxicity will be monitored based on the 
Bayesian model (beta-binomial), assuming a priori that p = Prob(toxicity) ~ 
beta(1,1). The trial will be terminated if Prob(p > .30 | data) > .80. This rule 
will be applied continuously starting from the 6th evaluable patient and will 
stop the trial if [number of toxicities]/[number of patients evaluated] is 
greater than or equal to: 3/6, 4/8, 5/10, 6/13, 7/16, 8/19, 9/22, 10/25, 
11/28, 12/31, 13/34, 14/37, 15/40, 16/43, 17/46, 18/49, 19/52, 20/55, 
21/58, 22/61.  
 
The expected rate of accrual onto the trial is 0.2 patients per month. The 
maximum sample size in Phase I is 24. The patients in Phase I at a dose 
level of MTD will be used for the Phase II part since this dosage is used in 
the Phase II. The maximum number of patients expected to enter in to this 
Phase I/II is 82 (= 24+ 64 -6). 
 
Phase II will include 64 patients to evaluate the efficacy and tolerability of 
the FBR combination in previously treated patients with CLL.  We will 
estimate the complete, partial, and overall response rate with 95% 
confidence interval.  In addition, we will determine the median PFS and 
TTF and 95% confidence interval.  We will also evaluate associations 
between the prognostic factors and response and time-to-event endpoints. 
Efficacy endpoints for Phase I and II will be evaluated by the 2008 IWCLL 
criteria.  We will evaluate the complete, nodular partial and partial 
response rates.  We aim to improve the complete remission rate from the 
expected 25% for the FCR regimen to 40% as the primary objective. 
Safety end-points will be tolerability and toxicity of therapy.  The tolerated 
dose of bendamustine will be the highest dose at which fewer than 2 of 6 
patients experience grade 3, non-hematologic, non-infusion related toxicity 
involving a major organ system.  The maximum tolerated dose will have 
been exceeded if 2 or more of 6 patients experience grade 3 or higher, 
non-hematologic, non-infusion related toxicity a major organ system. 
 
11.0 PHARMACODYNAMIC AND PHARMACOKINETIC ENDPOINTS 
 
These investigations will be performed in Drs. Gandhi and Plunkett’s 
laboratory.  Patients with more than 5,000 WBC/µl of peripheral blood who 
agree 
to 
participate 
in 
pharmacokinetic 
and 
pharmacodynamic 


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investigations will be evaluated. Not all samples will be collected in all 
patients at all time-points. 
Please page Yuling Chen (713-404-2550), Min Fu (713-606-2212), or call 
713-792-3336 to inform of registration date and to arrange for blood 
sampling. 
Blood samples (10 ml) will be collected at the following times: 
Day 1 Bendamustine alone: 
• Pre treatment (0 h), 2 h, 4 h, and 6 h, after the start of the first bendamustine 
infusion.   
Day 2 Fludarabine followed by bendamustine: 
• 24 h (prior to fludarabine), 26.5 h, 28.5 h, and 30.5 h  (2 h, 4 h, and 6 h, after 
start of bendamustine infusion).   
Day 3 Fludarabine followed by bendamustine: 
• 48 h (prior to fludarabine) 
These samples will be processed to collect plasma and cells.  Plasma will be 
stored for future pharmacokinetic analyses, if needed, by Cephalon.  Cells will be 
processed for the following endpoints. 
1. DNA damage response using H2AX phosphorylation as a biomarker 
2. Cell death measurements by Annexin V assay 
3. Quantitation of intracellular level of fludarabine triphosphate by HPLC 
(only in 28.5 hr sample) 
4. Cell pellet for immunoblot assays for DNA damage response, DNA repair, 
and recovery of DNA damage. 
These assays will primarily measure bendamustine induced DNA damage 
response and recovery of the DNA repair.  In addition, we will determine if 
circulating leukemia cells undergo apoptosis.  These studies will also compare if 
there is an increase in DNA damage response and/or cell death when 
bendamustine is infused alone (day 1) versus when bendamustine is 
administered with fludarabine (day 2).  For these comparative analyses, each 
patient serves as his or her own control.  Augmentation of DNA damage 
response will be compared with intracellular fludarabine triphosphate peak (peak 
occurs 4 h after fludarabine infusion44.  Correlations will be sought between these 
laboratory endpoints and cytoreduction and/or clinical response to therapy. 


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