Clinical trial NCT01253460
Conditions: Leukemia
Keywords: Chronic Lymphocytic Leukemia CLL Small Lymphocytic Lymphoma SLL Cyclophosphamide Rituximab Sapacitabine Cytoxan Neosar Rituxan
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-08-22; Completion date: 2019-02-13
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if sapacitabine given in combination with 2 standard drugs (cyclophosphamide and rituximab) can help to control CLL and SLL. The safety of this drug combination will also be studied.

Detailed description:
The Study Drugs:

Sapacitabine and cyclophosphamide 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 Administration:

If you are found to be eligible to take part in this study, you will receive sapacitabine by mouth 1 time a day on Days 1-3 of each 28-day cycle. Try to take sapacitabine at least 1 hour before or 2 hours after a meal. On Days 1-3 of each cycle, you will also receive cyclophosphamide by vein over 30 minutes, starting 2 hours after you take sapacitabine.

On Day 3 of Cycle 1 and Day 1 of Cycles 2 and beyond, you will receive rituximab by vein over 6-8 hours.

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

Other Drugs:

On Days 1-14 of Cycle 1, you will take allopurinol by mouth 1 time a day to lower the risk of kidney damage.

Before each dose of cyclophosphamide, you will receive Zofran (ondansetron) by vein over a few seconds to lower the risk of nausea.

About 30-60 minutes before each dose of rituximab, you will take Tylenol (acetaminophen) and Benadryl (diphenhydramine hydrochloride) by mouth to lower the risk of side effects such as fever and chills.

Study Visits:

On Day 1 of each cycle:

* Blood (about 1-2 tablespoons) will be drawn for routine tests.
* You will also have a physical exam, including measurement of your vital signs, except Cycle 1.
* You will be asked about any side effects you may have had.

On Days 8 and 22 of Cycle 1, and on Day 15 of every cycle:

* Blood (about 1-2 tablespoons) will be drawn for routine tests.
* You will be asked about any side effects you may have had.

If your disease has had a good response and the doctor thinks it is needed to check the status of the disease, you will have a bone marrow aspiration and biopsy and a CT scan of the chest, abdomen and pelvis prior to Cycle 4 and possibly every other cycle after that (Cycles 6, 8, 10, and so on).

Length of Study:

Once your doctor thinks the disease has had its best response, you may receive 2 more cycles of study therapy after that. You will no longer be able to receive the study drugs if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

The following tests and procedures will be performed after your last cycle of study drugs:

* You will have a physical exam, including measurement of your vital signs.
* Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

At 2 and 6 months and 1 and 2 years after your last dose of study drugs:

* You will be asked about any side effects you may have had and any drugs you may be taking.
* You will have a physical exam, including measurement of your vital signs.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* 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. You will also have a bone marrow aspiration and biopsy to confirm the response.

At 3 years after your last dose of study drugs and 1 time a year from then on:

* You will be asked about any side effects you may have had and any drugs you may be taking.
* You will have a physical exam, including measurement of your vital signs.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* You will have a bone marrow aspiration and biopsy if the doctor decides it is needed to check the status of the disease.

If the doctor thinks it is needed anytime during follow-up, you will have a CT scan of the neck, chest, abdomen, and pelvis to check the status of the disease.

Starting at Year 3, the follow-up tests and procedures can be done by your local doctor if that is more convenient to you. The test results should be sent to MD Anderson.

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

This is an investigational study. Sapacitabine is not FDA approved or commercially available. It is currently being used for research purposes only. Cyclophosphamide and rituximab are FDA approved and commercially available to treat CLL and SLL. The combination of sapacitabine, cyclophosphamide, and rituximab is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses.
Interventions: intervention 1: Cyclophosphamide intervention 2: Rituximab intervention 3: Sapacitabine
Intervention descriptions: intervention 1: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. intervention 2: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. intervention 3: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.

Protocol documents:
Prot_SAP_000.pdf: 
2010-0516
August 30, 2013
Page 1
Protocol Page
A Phase II Clinical Trial of Sapacitabine, Cyclophosphamide, and Rituximab (SCR) 
for Relapsed Patients with Chronic Lymphocytic Leukemia / Small Lymphocytic 
Lymphoma (CLL/SLL) and Deletion 11q22-23 by FISH
2010-0516
Core Protocol Information
Short Title 
Phase II Sapacitabine, Cyclophsophamide, Rituximab for Rel CLL/SLL with del(11q22-23)
Study Chair: 
William G. Wierda
Additional Contact:
Ana B. Ayala
Laura K. Fowler
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-0428
Unit:
428
Full Title: 
A Phase II Clinical Trial of Sapacitabine, Cyclophosphamide, and Rituximab (SCR) for 
Relapsed Patients with Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma 
(CLL/SLL) and Deletion 11q22-23 by FISH
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 03/29/2018
Version:
16
Submitted by:
Laura K. Fowler--11/15/2016 11:04:22 AM
OPR Action:
Accepted by:  Julie Arevalo -- 11/29/2016 12:54:27 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2010-0516
August 30, 2013
Page 2
Protocol Body
 


Protocol 2010-0516 
June 28, 2012 
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Page 1 
 
 
A Phase II Clinical Trial of Sapacitabine, 
Cyclophosphamide, and Rituximab (SCR) for 
Relapsed Patients with Chronic Lymphocytic 
Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) 
and Deletion 11q22-23 by FISH 
 
 
Version 7 
 
June 28, 2012 
 
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 II SCR for Relapsed CLL with deletion 11q22-23 
 


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1.0 
OBJECTIVES 
Primary objective: 
• 
Evaluate efficacy (2008 International Workshop on Chronic Lymphocytic 
Leukemia [IWCLL] overall response rate) of the SCR regimen in previously 
treated patients with CLL who have deletion 11q22-23 by FISH. 
 
Secondary objectives: 
• 
Evaluate the association between IWCLL response (CR, PR, and OR) to SCR 
and ATM function in previously treated patients with CLL who have deletion 
11q22-23 by FISH. 
 
• 
Evaluate toxicities, safety and tolerability of the SCR regimen in previously 
treated patients with CLL who have deletion 11q22-23 by FISH. 
 
• 
Evaluate the number of courses of SCR to best response and overall number of 
courses SCR administered to each patient. 
 
• 
Evaluate 
time-to-treatment 
failure 
(TTF), 
time-to-progression 
(TTP) 
for 
responders, and overall survival for previously treated patients with CLL who 
have deletion 11q22-23 by FISH treated with SCR. Also, evaluate the association 
between these time-to-event endpoints and ATM function. 
 
• 
Correlate pretreatment prognostic factors, including ZAP-70 expression, CD38 
expression, β-2 microglobulin, IGHV mutation status, response and time-to-event 
outcomes. 
 
• 
Evaluate pharmacodynamic endpoints including 1) quantitate the proportion of 
proliferating cells (proliferating fraction) in blood and/or bone marrow by flow 
cytometry before and during treatment; and 2) quantitate DNA double-strand 
breaks in blood and bone marrow lymphocytes by staining for Rad51 foci and 
evaluating cells by confocal microscopy, and 3) measure changes in apoptosis 
during therapy. 
 
2.0 
BACKGROUND 
2.1 
CLL is the most common leukemia in Western societies (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 and 
development of new therapeutic agents was lagging until recently, owing to the usual 
advanced age of patients and often indolent course of disease.  The natural history of 
the disease is diverse; patients with only lymphocytosis have a median survival in 
excess of 10 years, while those with evidence of marrow failure manifested by anemia or 
thrombocytopenia have a median survival of only 2 years.  Intermediate survival is 
expected for patients with lymphadenopathy or organomegaly.  The National Cancer 
Institute Working Group on CLL described clinical features of “active disease” which are 
helpful in the decision to treat2,3.  These indications for treatment were revised and re-
reported by the International Working Group for CLL (IWCLL)4 and 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 


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splenomegaly; 6) massive (>10 cm in the longest diameter) or progressive 
lymphadenopathy; 7) progressive lymphocytosis with rapid lymphocyte doubling time; 8) 
marked hypogammaglobulinemia or paraproteinemia. 
 
2.2 
Historically, the mainstay of therapy was systemic chemotherapy consisting of an 
alkylating agent and corticosteroid.  Chlorambucil plus prednisone was the standard 
initial therapy with response rates from 40-77%.  Generally, responses were not 
complete 5-9.  Therapy for patients refractory to alkylating agents was unsatisfactory.  
The response rates were substantially lower (approximately 30%) with rare complete 
responses (CR) 8-12. 
 
2.3 
Fludarabine has marked activity in several indolent lymphoproliferative disorders 
including 
CLL, 
low-grade 
lymphoma, 
Waldenstroms 
macroglobulinemia, 
and 
prolymphocytic leukemia 13-17. 
 
Treatment of previously treated patients with CLL with fludarabine resulted in 13% CR 
and 44% partial remission (PR)13.  Fludarabine was also given to patients with previously 
untreated CLL, resulting in even higher response rates with 33% confirmed CR, 39% 
unconfirmed CR and 6% PR16. 
 
Despite achieving clinical CR, most patients experience recurrence at a median of 
approximately 2 years after frontline fludarabine treatment 18.  This is likely related to the 
fact that even patients in CR have residual disease.  Residual disease can now be 
assessed using highly sensitive flow cytometry or molecular methods that were 
previously not available.  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 were progression-free, versus 55% of nPR 
patients18. 
 
2.4 
Cyclophosphamide was combined with vincristine (VCR) and prednisone (CVP) 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 CVP 
19.  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% 20. 
 
2.5 
In vitro studies demonstrated that fludarabine inhibited repair of cyclophosphamide-
induced DNA inter-strand cross-links in CLL B cells 21.  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 22 first reported 
their experience giving fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily for 
3 days in a limited trial of 7 patients with CLL; 2 patients achieved complete remission 
and the overall response rate was 71%.  Toxicities included nausea and vomiting, 
myelosuppression and infections.  O’Brien et al 23 gave this treatment to 94 patients who 
were previously treated with either an alkylating agent, fludarabine, or both.  The CR rate 
was 11% and an overall response rate (ORR) of 69% was reported.  Patients previously 


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treated with an alkylating agent and were resistant to fludarabine had a markedly lower, 
but noteworthy response rate with 3% complete remissions and 39% ORR. 
 
2.6 
Rituximab and Chemoimmunotherapy 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 International Working Formulation (IWF) A disease or small lymphocytic 
lymphoma (SLL).  Rituximab was given at a dose of 375 mg/m2 weekly for 4 weeks, and 
produced an ORR of 48%.  For the patients with IWF A disease, the ORR was low, 12% 
compared to 58% for those with IWF B, C, and D (combined) disease 24.  There are 
several potential explanations for the lower activity of rituximab in patients with SLL.  
Leukemia/lymphoma cells from patients with CLL/SLL express lower levels of CD20 than 
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.  Finally, circulating CD20 has been demonstrated in the 
plasma of patients with CLL/SLL 25.  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 monotherapy has been evaluated as treatment for CLL.  The standard dose of 
375 mg/m2 weekly for 4 weeks was given to 28 previously patients with CLL26.  There 
were no CRs; 25% of patients achieved PR, 43% had stable disease, and 32% had 
progressive disease.  Smaller studies evaluating rituximab 375 mg/m2 weekly for 4 
weeks in previously treated patients with CLL report low ORR with no CRs 26-28.  Two 
studies of dose-escalated rituximab in CLL yielded encouraging results.  O’Brien et al.29 
conducted a study of 4 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 
ORR among the 39 evaluable patients was 36% and all remissions were PRs.  
Responses were seen in 5 of 24 (21%) patients who received 500-825 mg/m2, 3 of 7 
(43%) patients who received 1000-1500 mg/m2, and 6 of 8 (75%) patients who received 
2250 mg/m2 (P=0.03).  Byrd et al.30 conducted a dose-intense study with 375 mg/m2 
administered thrice weekly for 4 weeks.  Twenty-seven previously treated patients were 
evaluable for response, 10 (37%) achieved remission.  There appeared to be increased 
activity for rituximab in CLL with dose intensified schedules; the optimal dose and 
schedule for rituximab monotherapy for CLL is yet to be determined. 
 
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 31. 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) were achieved in 16% and 32% of patients, respectively; 


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the overall response rate was 73%. Twelve (32%) of 37 complete responders tested 
achieved molecular remission in bone marrow.  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.  Despite the succession of incremental improvements 
in the duration of response to such chemoimmunotherapy during the last decade, the 
relapse rate appears to be uninterrupted, and the long-term prognosis for survival 
remains poor32. 
 
The FCR regimen was evaluated in two large phase III randomized trials, one in 
previously untreated patients (CLL8 trial33) conducted by the German CLL Study Group 
(GCLLSG) and one 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 longer progression-free 
survival (PFS) associated with higher CR and ORR.  A more recent updated analysis of 
survival in the CLL8 trial demonstrated superior overall survival for patients treated with 
FCR versus FC, making this the standard frontline treatment for fit individuals with 
CLL35.  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 ORR were 24.3 and 69.9% 
respectively for patients treated with FCR and 13 and 58% respectively for patients 
treated with FC. The median PFS for patients treated with FCR was 30.6 versus 20.6 
mos for patients 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 and led to FDA approval of rituximab in combination with chemotherapy for frontline 
and salvage treatment for CLL. 
 
2.7 
Deletion 11q22-23 and ATM in CLL 
The majority of leukemia cells in blood and bone marrow are not proliferating, therefore, 
it is challenging to generate leukemia metaphase karyotypes for patients with CLL.  
Fluorescent in situ hybridization (FISH) enables chromosome analyses in interphase 
cells as well as cells in metaphase and substantially increases the sensitivity for 
identifying specific genomic aberrations in CLL.  Indeed, FISH analysis of 325 CLL 
cases showed chromosome abnormalities in over 80% of CLL cases, including 13q 
deletion, the most common abnormality, occurring in 55% of cases36.  Other 
abnormalities, in order of frequency, were deletion 11q22-23 (18%), trisomy 12 (16%), 
deletion 17p13 (7%), and deletion 6q (6%).  This study also reported the prognostic 
significance of these abnormalities.  Deletion 13q14, as a single aberration, was 
associated with the longest median survival (133 months) while deletion 11q22-23 (79 
months) and deletion 17p13 (32 months) were associated with poor prognosis, high-risk 
disease.  Trisomy 12 and diploid karyotype were intermediate prognosis.  Other studies 
have reported the poor clinical outcomes associated with deletion 11q22-23, particularly 


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Fig. 1.  Structures of dCyd, Sapacitabine, CNDAC and CNddC. 
 
in patients younger than 55 years old36-38.  Characteristically, patients 11q22-23 deletion 
present with advanced disease and bulky lymphadenopathy37. 
 
Deletion at chromosome 11q22.3 is associated with deletion of the Ataxia Telangiectasia 
Mutated (ATM) gene.  ATM protein plays an important role in cellular responses to 
double strand DNA breaks in a process involving a number of factors, including p5339,40.  
In addition to deletions, mutations of ATM are not uncommon in CLL41,42.  One study 
showed that some patients with CLL have germline ATM mutations, suggesting that a 
“carrier state” may predispose to the development of CLL42.  Mutation of ATM in the 
residual allele for patients with deletion 11q22-23 was demonstrated in 36% (19/52) of 
untreated patients, and additional mutations in ATM arising subsequent to treatment 
(2/10, 20%)43. 
 
We noted that 41% (50/121) of patients who relapsed after first remission from FCR had 
deletion 11q22-23, whereas this was present in only 10% of our frontline population44.  
Although these results suggest that the region containing ATM is important for response 
to chemoimmunotherapy, our recent findings suggest an alternative treatment is needed 
that is effective in cells that lack ATM function. 
 
2.8 
Sapacitabine Preclinical Studies 
Sapacitabine/
CNDAC 
causes DNA 
double-stand 
breaks.  
CNDAC 
(2'-
C-cyano-2'-
deoxy-1-beta-
D-arabino-
pentofuranos
yl-cytosine) 
(Fig.1) is a 
deoxycytidine analog that was conceptualized as a DNA strand breaking nucleoside45.  
We recently reported that the orally administered prodrug formulation, Sapacitabine, 
has activity in treating relapsed acute leukemia46.  Investigations of the metabolism and 
mechanism of action of CNDAC demonstrated that the nucleoside is transported into 
the cell and phosphorylated to the tri-phosphate, which is a substrate for both DNA 
replication and repair47.  Upon incorporation into DNA, it becomes chemically unstable 
because of the strong electron-withdrawing properties of the cyano group, and 
undergoes β-elimination to generate a nick in one strand of DNA that is terminated on 
the 3’-strand by the dideoxy analog, CNddC 47.  This is not a substrate for ligation, 
although the lesion is repaired to some extent by the transcription-coupled nucleotide 
excision pathway48.  We’ve measured as many as 7 x 104 such nicks in DNA of single 
cells following incubation with clinically relevant CNDAC concentrations49. 
 


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Fig. 2.  Generation of single- 
and double-strand breaks 
after 
incorporation 
of 
CNDAC into DNA.  
  
 
 
incorporation
3’
5’
replication
3’
5’
β-elimination
3’
5’
1st S
3’
5’
5’
3’
2nd S
one-ended DSB
3’
5’
5’
3’
CNDAC
CNddC
incorporation
3’
5’
3’
5’
replication
3’
5’
3’
5’
β-elimination
3’
5’
1st S
3’
5’
3’
5’
5’
3’
5’
3’
2nd S
one-ended DSB
3’
5’
3’
5’
5’
3’
5’
3’
CNDAC
CNddC
These nicks are not inhibitory to DNA synthesis; cells pass through mitosis and 
progress to a subsequent S phase.  However, upon 
doing so, as the replication fork encounters a nick in 
the DNA, a one-ended double strand break occurs at 
the replication fork (Fig. 2)49.  This is evidenced by a 
significant increase in number of chromosomal 
breaks after cells pass into the second mitosis.  
Likely, this damage is principally repaired by the 
homologous recombination repair (HRR) pathway, as 
the clonogenicity of cells lacking genes that function 
in this pathway such as ATM, XRCC3 and BRCA2, is 
sensitized as much as 100-fold.  In contrast, cells 
deficient in non-homologous end-joining proteins 
(DNA-PKcs, Ku80), an alternative mechanism of 
double-strand break repair, are not affected.  This is 
likely because the non-homologous end-joining 
mechanism joins two double-stranded ends, whereas 
HRR uses the homologous sequence to initiate 
repair and extension of a one-ended double-strand 
break50,51.  The presence of sister chromatid 
exchanges, which arise more significantly after cells 
pass into the second S phase after exposure to 
CNDAC, is diagnostic of homologous recombination 
activity49.  Taken together, these results demonstrate 
that CNDAC kills cells by a unique mechanism of 
action, that cells are able to repair the damage to 
DNA to a limited extent, and that homologous 
recombination is likely a major factor in cell survival. 
 
The results described above demonstrate that cells 
that lack homologous recombination repair function 
are specifically sensitized to the actions of CNDAC, 
the active form of the clinical prodrug, Sapacitabine.  
We hypothesize that patients with CLL who lack ATM function, and therefore are not 
able to conduct homologous recombination repair, will be specifically sensitized to 
treatment containing Sapacitabine. 
 
2.9 
Sapacitabine Clinical Studies 
The palmitoyl side chain on CNDAC allows for improved oral absorption of Sapacitabine 
and protects the N4 amino group from deamination, which is a major route of inactivation 
of the molecule.  Following oral administration, Sapacitabine is converted to 1-(2-C-
cyano-2-deoxy-β (-D-arabino-pentafuranosyl) cytosine (CNDAC) by amidases and 
esterases in the gut, plasma, and liver.  CNDAC is further converted to CNDAC-mono 
phosphate by deoxycytidine kinase (dCK) and this is thought to be the rate-limiting step 
in the formation of CNDAC-triphosphate (CNDACTP), the most active metabolite in 
terms of cytotoxicity.  CNDAC-phosphates are degraded by cytidine deaminase (CDA) 
and 5’nucleotidase.  Both Sapacitabine and CNDAC are active against a wide range of 
human cancer cell lines in vitro and animal models in vivo.  To date, 3 phase I trials with 
Sapacitabine have been reported, 2 in advanced solid tumors and 1 in patients with 
AML/MDS. In the first phase I trial in solid tumors, increasing doses of oral Sapacitabine 


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were administered to patients once daily 3 times a week (Mon, Wed, Fri), for 
consecutive 4 weeks, followed by a 2-week rest period52.  The following dose levels 
were evaluated: 1.5, 12,20,25,30,50,67,90,120,160, and 220 mg/m2/day. Forty patients 
were enrolled with a variety of solid tumors, including colorectal (most common), 
prostate, breast, and lung cancer. Severe hematologic toxicities (G3-4) were not 
uncommon, 
10 
patients 
experienced 
G3-4 
neutropenia, 
2 
experienced 
G4 
thrombocytopenia, and 2 experienced G3 anemia. Dose-limiting neutropenia was 
observed at 220mg/m2/day; the maximum tolerated dose (MTD) was 160mg/m2/day for 
the schedule in this trial. Non-hematologic toxicities (G3) related to treatment included 
nausea, vomiting, anorexia, asthenia, and dehydration but were not dose-limiting.  No 
tumor responses were noted in this trial.  Peak plasma concentrations of the active form 
CNDAC were achieved 2.2±0.9 hr after drug administration and the terminal elimination 
half-life was 1.7±1.5 hr.  CNDAC was metabolized by cytidine deaminase to the inactive 
product CNDAU. 
 
In the second phase I trial for advanced solid tumors, oral Sapacitabine was 
administered 5 days per week for 4 weeks, followed by 2 weeks off treatment 
observation (6 weeks treatment course)53. The following dose levels were evaluated: 
1,2.5,5,7.5,10,13,17.5,23.5,30,50, and 67mg/m2/day. The MTD was 40mg/m2/day, 5 
days each week for 4 weeks followed by 2 weeks of treatment. The most common dose-
limiting toxicity (DLT) was grade 4 neutropenia, which occurred at doses of 40mg/m2/day 
and higher. Other G3-4 toxicities in order of frequency included asthenia and diarrhea. 
No tumor responses were noted in this trial. 
 
A phase I trial was conducted in patients with acute myeloid leukemia (AML) and 
myelodysplastic syndrome (MDS). In this study, oral Sapacitabine was given twice daily 
for 7 days every 3-4 weeks or twice daily on days1-3 and 8-10 every 3-4 weeks.  
Sapacitabine was escalated from 75-375 mg twice daily for 7 days and from 375-475 mg 
twice daily on days1-3 and 8-10 every 3-4 weeks. The DLT for both schedules was 
gastrointestinal (diarrhea, colitis, small-bowel obstruction). The MTDs were 375mg twice 
daily for 7 days and 425 mg twice daily on days1-3 and 8-10 every 3-4 weeks. The 
recommended phase II single-agent dose for these hematologic diseases was 325 mg 
twice daily for 7 days and 425 mg twice daily for 3 days on days 1-3 and 8-10 of each 3-
4 week course. Responses were observed in 13 patients (28%); 4 were complete 
remissions, and 9 were marrow complete responses. 
 
The recommended Phase II dose for monotherapy has been established for 4 dosing 
schedules using the Cyclacel BL formulation: a) 50 mg b.i.d. x 14 days every 3 weeks 
(solid tumors); b) 75 mg b.i.d. x 7 days every 3 weeks (solid tumors); c)   325 mg b.i.d. x 
7 days every 3 weeks (leukemias/MDS); and  d)  425 mg b.i.d. x 3 days/week x 2 weeks 
every 3 weeks (leukemias/MDS). The predominant dose-limiting toxicity (DLT) was 
myelosuppression in solid tumor patients which consisted of neutropenia, febrile 
neutropenia, neutropenic sepsis, and thrombocytopenia.  Myelosuppression was 
generally reversible after interruption of drug dosing.  To date, the predominant DLTs 
reported in patients with advanced leukemias or MDS were gastrointestinal toxicities 
which included abdominal pain/small bowel obstruction, diarrhea and neutropenic 
enteritis.  Common non-hematological toxicities were fatigue, nausea, vomiting, 
diarrhea, constipation, anorexia, abdominal pain, fever, pneumonia, cough, dyspnea, 


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dizziness, epistaxis, peripheral edema, alopecia and hypokalemia which were generally 
mild to moderate. 
 
Given the clinical activity of Sapacitabine in advanced leukemia46, we are encouraged 
to extend additional clinical investigations to a patient population having a deletion in 
11q22-23, those defined by the loss of ATM function.  The goal of this effort is to create 
a tumor-specific therapy that will benefit a specific patient population. 
 
2.11 Rationale for the SCR Combination in CLL with Deletion 11q22-23 
Although current chemoimmunotherapy for untreated CLL is highly effective at inducing 
CR, there is a steady relapse rate.  Subsequent salvage treatment for these patients is 
associated with lower response rate, and there is now clear evidence that with repeated 
treatment, many patients develop disease resistant to therapy and that many of these 
patients succumb to their CLL.  Several biological characteristics at diagnosis or 
initiation of treatment, including IGHV mutation status, serum markers, inappropriate 
protein expression and cytogenetic changes predict for outcome.  Of these, so far 
cytogenetic changes provide a clue to disease etiology, or pathophysiology, as 
molecular studies have indicated several of the underlying factors that are affected.  This 
trial focuses on 1 of these changes, expression of the DNA damage response gene, 
ATM, which is deleted in the common abnormality at chromosome 11q22-23.  
Remarkably, more than 40% of patients whose disease relapses after treatment with 
FCR, our most effective therapy, exhibit this abnormality, whereas only 15-20% of the 
treatment-naïve CLL population seen at M. D. Anderson exhibit this deletion prior to 
frontline treatment.  Studies suggest as many as half of patients with deletion 11q22-23 
have lost ATM function in the gene at the residual allele due to gene mutations.  The 
investigational agent, Sapacitabine, causes DNA damage by a novel mechanism that 
requires ATM function for repair.  Therefore, there is strong rationale to select patients 
with 11q22-23 deletion for Sapacitabine therapy, since their disease may be selectively 
sensitized to this agent.  This trial will test this hypothesis. 
 
This is a phase II trial of Sapacitabine combined with cyclophosphamide and rituixmab 
(SCR) for previously treated patients with CLL and 11q22-23 deletion by FISH.  The 
primary objective will be to evaluate the overall response rate of the regimen; secondary 
endpoints will be to evaluate tolerability and toxicities, determine association between 
response and ATM function, determine time-to-treatment failure, progression-free 
survival, and overall survival.  Sapacitabine will be provided by Cyclacel 
Pharmaceuticals.  The IND under which this clinical trial will be conducted will be held by 
MD Anderson Cancer Center with cross-filing on the Cyclacel Pharmaceuticals master 
file. 
 
3.0 
BACKGROUND DRUG INFORMATION 
3.1 Sapacitabine 
3.1.1 Chemical 
Name: 
1-(2-C-cyano-2-deoxy-β-D-arabino-pentafuranosyl)-N4-  
palmitoylcytosine 
 


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3.1.2 Chemical structure 
 
 
3.1.3 Formulation: The Cyclacel BL formulation comprises liquid-filled capsules of a 
suspension of the crystalline Form B of the active pharmaceutical ingredient in 
miglyol 812N and is supplied as 25 mg, 50 mg and 75 mg strength capsules.  For 
this clinical trial, 50 mg capsules will be used.  Capsules are packaged in high-
density polyethylene bottles, with low-density polyethylene snap-on tamper 
resistant closures.  The capsules should be stored at room temperature (15-
25oC) in a closed container, protected from light in a secure, limited-access 
storage area.  The 25, 50 and 75 mg capsules currently have a 60 -month retest 
date. 
Unit Formula 
Ingredient 50 mg 
Sapacitabine B Form 50 mg 
Miglyol 812N Ph.Eur/GRAS 200 mg 
Gelatin Capsule and gelatin banding USP/Ph.Eur. Size 2 
Ph.Eur = European Pharmacopoeia; GRAS: Generally regarded as safe; USP = 
United States Pharmacopoeia 
 
3.1.4 Route of administration: Oral 
 
3.1.5 Source of Drug: Sapacitabine is an investigational drug supplied by Cyclacel 
under Investigational New Drug #53748. 
 
3.1.6 Drug Procurement 
FDA regulations require investigators to establish a record of the receipt, use, 
and disposition of all investigational agents.  Investigators may delegate 
responsibility for drug ordering, storage, accountability, and preparation to their 
designees.  Cyclacel’s requirements for procurement, accountability, and 
disposition of study drug are provided below. 
 
Drug Ordering:  Sapacitabine should be requested by the Principal Investigator 
(or his/her authorized designees) at each participating institution.  Sapacitabine 
may not be used outside the scope of this protocol, nor can it be transferred or 
licensed to any party not participating in the clinical study.  Cyclacel policy 
requires that Sapacitabine be shipped directly to the institution where the patient 
is to be treated.  Cyclacel does not permit the transfer of Sapacitabine between 
institutions. 


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3.1.5 Drug Accountability 
A capsule count of the drug will be maintained on the Drug Accountability Record 
(DAR).  All drug received, dispensed, and returned by the patient must be 
recorded on the DAR.  Patients will be instructed to return the dispensed capsule 
bottle on Day 1 of each cycle.  Capsule count will occur at each visit to assess 
patient compliance with study drug. 
 
3.1.6 Disposition of Unused Drug 
All unused drug, including drug returned by patients, must be retained by study 
site staff until verified by MDCC Investigational Pharmacy.  After the drug 
accountability has been verified, unused drug will be destroyed according to 
Institutional guidelines and applicable laws and regulations. 
 
The clinical supplies of cyclophosphamide and rituximab will be commercial drug supply. 
 
3.2 Cyclophosphamide (Cytoxan) 
Cyclophosphamide is commercially available and has activity in treating a variety of 
malignancies.  Cyclophosphamide is an alkylating agent that prevents cell division by 
cross-linking DNA strands and decreasing DNA synthesis.  It is a cell cycle phase non-
specific agent.  Cyclophosphamide is a prodrug that must be metabolized to active 
metabolites in the liver. 
 
Expected toxicities include myelosuppression.  Cystitis can be caused by 
cyclophosphamide and can be dose limiting.   
 
3.2.1 How Supplied: Supplied in quantities of 100 mg, 200 mg, 500 mg, 1 gm, an 2 gm 
for intravenous use.  Maximum concentration is 20 mg/ml.:  
 
3.2.2 Solution Preparation: This is per standard pharmacy practice. 
 
3.2.3 Stability: Room temperature stability is 48 hrs.  Refrigeration stability is 28 days. 
 
3.2.4 Route of Administration: Intravenous 
 
3.2.5 Toxicities: 
• 
COMMON: The most common effects observed include alopecia (40% to 
60%), which usually starts 3 to 6 weeks after therapy, effects on fertility (ie, 
irreversible sterility, amenorrhea), gastrointestinal effects (ie, nausea, 
vomiting, diarrhea, anorexia, mucositis, stomatitis), a potentially fatal acute 
hemorrhagic cystitis (in up to 40% of patients), and thrombocytopenia, 
anemia, and leukopenia, which generally starts 7 days after exposure with a 
nadir at 10 to 14 days and recovery at 3 weeks. Less common effects (1% to 
10%) in patients include facial flushing, headache, skin rashes, SIADH, renal 
tubular necrosis, and after rapid intravenous infusion, nasal congestion, runny 
eyes, rhinorrhea, sinus congestion, and sneezing. 
 
• 
RARE: Rare but life-threatening side effects include cardiac effects (ie, 
congestive heart failure, cardiac necrosis, and hemorrhagic myocarditis), 
pulmonary effects (ie, interstitial pneumonitis and pulmonary fibrosis), 


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anaphylactic reactions, hepatotoxicity, electrolyte imbalances, renal injury, 
secondary malignancy, and toxic epidermal necrolysis. Cyclophosphamide is 
teratogenic (FDA pregnancy category D) and long-term use is associated 
with an increased risk of a variety of malignancies. 
 
3.3 
Rituximab: 
 
3.3.1 Drug Nomenclature 
 
• 
IDEC Pharmaceuticals code designation Rituxan® 
• 
Generic Name: rituximab 
 
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. 
 
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 


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• 
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 
• 
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 had FISH evaluation of leukemia cells within 3 months without 
intervening treatment demonstrating deletion 11q22-23 
3. Patients must have an indication for treatment by 2008 IWCLL Criteria 
4. Age ≥ 18 years 
5. ECOG/Zubrod performance status ≤ 2 
6. 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; 
c. total bilirubin ≤ 2.5 times upper limit of normal 


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7. Patients must have an ANC ≥500/μL, HGB ≥8 gm/dL, PLT count ≥20K/μL, unless attributed 
to marrow infiltration with CLL  
8. Patients must give written informed consent 
9. Patients of childbearing potential (females who have not been postmenopausal for at least 
12 consecutive months or who have not undergone previous surgical sterilization or males 
who have not been surgically sterilized) 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 infection, uncontrolled with intravenous antibiotics 
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 3 weeks prior to enrollment or concurrent with this trial 
 
5.0 
TREATMENT PLAN 
After patients provide informed consent, complete screening, complete all pretreatment 
evaluations, and eligibility is confirmed, they may begin treatment.  Treatment will 
consist of combined Sapacitabine, cyclophosphamide, and rituximab. 
 
Sapacitabine will be given at 350 mg oral flat dose, preferably 1 hour prior or 2 hours 
after a meal on Days 1,2, and 3 of each course. Cyclophosphamide 250 mg/m2 will be 
administered IV 2 hrs following the dose of Sapacitabine on Days 1,2, and 3 of each 
course.  Rituximab 375 mg/m2 IV will be administered on Day 3 of Course 1, after 
cyclophosphamide, then at 500 mg/m2 on Day 1, after cyclophosphamide for subsequent 
courses.  Courses will be every 4 weeks as permitted by recovery of blood counts.  The 
total number of courses given will be 2 courses beyond best response.  Patients will be 
monitored closely for myelopsuppression.  The next course of treatment may begin 4 
weeks after start of last course and when absolute neutrophil count (ANC) and platelet 
(PLT) count have recovered to within 20% of pretreatment levels or ANC ≥ 1,000/μL and 
PLT ≥ 75,000/μL. 
 
Patients who experience delayed recovery of neutrophils or platelets will have dose 
reduction. Delayed recovery will be defined as failure to recover counts to within 20% of 
pretreatment level by Day 42 or later for patients who begin treatment with baseline 
cytopenias and for patients who begin treatment with normal neutrophil and platelet 
counts, they must have < grade 2 cytopenia (IWCLL Criteria).  Dose reduction may 
occur at the treating physicians’ discretion for treatment-related, non-hematologic toxicity 
≥ grade 2 that occurs at any time during a treatment course.  Dose reduction will be 
according to Table 1. 
 


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Table 1.  Dose Reduction Schema for Course ≥ 2 
Dose 
Level 
Sapacitabine 
(PO dose, D=days) 
Cyclophosphamide
(IV dose, D=days)
Rituximab 
(IV dose, D=day, course > 1)
0 
350 mg, D1-3 
250 mg/m2, D1-3
500 mg/m2, D1 
-1 
300 mg, D1-3 
200 mg/m2, D1-3
500 mg/m2, D1 
-2 
250 mg, D1-3 
175 mg/m2, D1-3
500 mg/m2, D1 
-3 
200 mg, D1-3 
150 mg/m2, D1-3
500 mg/m2, D1 
 
Patients will be evaluated for response by 2008 IWCLL/NCI criteria before course 4, 
then after every 2 courses, and at end of treatment (2 months after last course) 
according to the schedule of events.  Response assessment will include CT scan and 
bone marrow evaluations for patients considered in clinical CR.  Non-hematologic 
toxicity will be evaluated using the National Cancer Institute Version 4.0 criteria.  
Patients will continue study treatment until 2 courses beyond best response; they will 
stop treatment early for disease progression, unacceptable toxicity, patient choice, or 
death. 
 
5.1 
Suggested premedications:  Antiemetic (ondansetron 8 mg IV or equivalent) 
premedication will be given 30 min prior to cyclophosphamide.  Premedication for 
rituximab will consist of 325-650 mg acetaminophen orally and 25-50 mg 
diphenhydramine hydrochloride oral or intravenous.  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 14 
days of course 1 for tumor lysis prophylaxis.  Valacyclovir (or equivalent) is 
recommended for herpes virus prophylaxis and Bactrim DS (or equivalent) for PCP 
prophylaxis throughout treatment and for at least 3 months following completion of 
treatment.  For patients who were previously exposed to hepatitis B and are 
seropositive, consideration should be given for lamivudine prophylaxis. 
 
Neutrophil growth factor and erythrocyte growth factor may be used at the discretion of 
the treatment physician and according to appropriate standard of care guidelines. 
 
5.3 
Administration of rituximab: See institutional standard of care and package insert 
guidelines. 
 
 
5.4 
Patients achieving a stable disease, partial response or demonstrating continued 
response after 3 courses will continue on treatment.  Responses will be evaluated every 
2 courses beyond course 3 and patients will receive 2 additional courses beyond best 
response to complete treatment.  
 
5.5 
Patients demonstrating progressive disease after receiving 3 courses of treatment will 
come off study. 
 
5.6 
Dose adjustment to the next lower level may be made for pneumonia, sepsis, or other 
life-threatening infection or any grade ≥ 3 non-hematologic toxicity. 
 
5.7 
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. 


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6.0 
PRETREATMENT EVALUATION 
Patients will undergo screening to evaluate and confirm eligibility.  Upon confirming 
eligibility, patients will proceed with treatment.  Screening evaluation, including 
laboratory tests will be done within 3 weeks of starting treatment. 
 
6.1 
Screening will consist of medical history and physical examination and pertinent 
laboratories, including SMA12 (sodium, potassium, chloride, CO2, BUN, creatinine, 
glucose, albumin, alkaline phosphatase, ALT, total protein, calcium, phosphorus, uric 
acid, total bilirubin, lactate dehydrogenase) and CBC with differential, as well as a 
pregnancy test (blood) 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 have bone marrow aspirate and biopsy with samples sent for differential 
and morphology within 3 months of screening if no intervening treatment.  Patients will 
be screened for hepatitis exposure and infection by serum HBcAb, HBsAb and 
AHBSAG. 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 β-2 microglobulin.  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. 
 
6.3 
Any appropriate radiological and radioisotopic examinations should be performed as 
clinically indicated. 
 
6.4 
Optional blood (20 mL purple-top tube) and bone marrow (5 mL purple-top tube) will be 
taken to isolate and store pretreatment mononuclear cells, DNA, RNA, and plasma.  For 
patients with WBC ≥10,000/μL, 10 mL will be taken for pharmacodynamic studies as 
specified in Section 11.0. Not all samples will be collected on all patients at all time 
points. 
 
7.0 
EVALUATION DURING STUDY (TABLE 3) 
 


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Table 3.  Schedule of Events 
Tests and 
Evaluations 
Screening 
Visit 
Day ≤ -21 
C1 
D1 
C1
D2
C1
D3
C1
D4
C1*
D8
C1*
D15
C1*
D22
C2-Σ*
D1 
C2-Σ
D2
C2-Σ 
D3 
C2-Σ* 
D15 
Prior 
to 
C4 
End of 
Tx 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval history 
 
 
 
 
 
 
 
 
X* 
 
 
 
 
 
PE including VS 
X 
 
 
 
 
 
 
 
X* 
 
 
 
 
X 
HBcAb, HBsAb, 
AHBSAG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prognostic factors 
and sample for 
ATM function 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(blood) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening BM 
aspiration and 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sapacitabine 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Cyclophos. 
 
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 
X 
X 
SMA12 
X 
X 
 
 
 
X
X 
X 
X* 
 
 
 
X 
X 
Optional blood 
and BM samples 
(including PD 
samples) 
X 
X 
X 
X 
X
 
 
 
X 
 
 
 
 
X 
Response 
assessment 
(IWCLL criteria***) 
 
 
 
 
 
 
 
 
 
 
 
 
X** 
2 mos 
after 
last 
course, 
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; *indicates ± 3 days; **indicates response assessments after each 2nd course 
beyond course 3 and 2 months after last course; ***IWCLL criteria requires history and physical 
examination, blood count with differential, and for patients in clinical complete remission, confirmatory 
bone marrow aspirate, biopsy, evaluation for MRD, and CT scan of chest, abdomen, and pelvis to confirm 
CR; ****Beyond 24 months after last course, patients will be followed annually with history, physical 
examination, and blood counts; bone marrow examination and CT scans will be done as clinically 
indicated; Σ=last course 
 
7.1 
Patients will be followed with CBC, platelet count and differential weekly (±3 days) for 
the first course and q2 weeks (±3 days) during therapy thereafter.  An SMA12 will be 
done weekly (±3 days) for the first course.  For course 2 and beyond, SMA12 will be 


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done before each course and as clinically indicated.  For labs done outside of MDACC 
phos, uric acid and LDH may be eliminated if normal on C1D8. 
 
7.2 
Before course 4, after every 2nd course and 2 months after last course a full evaluation 
for response assessment will be performed including history, physical examination, CBC 
with differential and platelet count to assess for clinical remission. Patients in clinical CR 
will have confirmatory bone marrow aspiration and biopsy with samples sent for 
differential, flow cytometry (4-color flow for MRD), and morphologic analysis and 
restaging CT scan of chest, abdomen, and pelvis.  Last course of treatment will be 2 
courses beyond best response. 
 
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 adverse drug 
reactions (ADRs), but will be summarized in the annual safety 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, and CT scan to confirm CR 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 MDACC.  Follow-up will be annually thereafter with history, physical 
examination, blood counts, bone marrow examinations and CT scans will be done at the 
discretion of the treating physician for those visits.  Patients will be followed until disease 
progression requiring alternative treatment or death. 
 
7.5 
Optional blood (10 ml purple- or yellow-top tube) will be taken to determine rituximab 
levels prior to rituximab dose with each course. Not all samples will be collected on all 
patients at all time points. 
 
Samples will be delivered 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 purple- or yellow-top tube) will 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.  Not all samples will be collected on all patients at all time 
points. 
7.7 
 


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Information regarding concomitant medication will not be collected separately for 
patients treated on this study.  Concomitant medication information is routinely collected 
and stored in Clinic Station (MDACC electronic medical record) and is routinely updated 
each patient visit to the MDACC out-patient clinic and during in-patient stays. Therefore, 
there is no need to collect this information separately. 
 
8.0 
RESPONSE CRITERIA, TOXICITY EVALUATION, AND EVENT REPORTING 
Responses will be evaluated by the updated 2008 IWCLL Response Criteria (Table 5), 
including staging with CT scan of chest abdomen and pelvis, and bone marrow 
evaluation for MRD for patients in CR4.  Bone marrow will be evaluated for MRD by 4-
color flow cytometry.  Lymph nodes 1.5 cm in diameter or smaller on CT scan will be 
considered normal and consistent with CR. 
 
Table 5.  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 
 
Non-hematologic toxicity will be described and graded by the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.  Hematologic toxicity will be graded 
according to the 2008 IWCLL criteria for grading (Table 4)4. Adverse events will be 
documented in the medical record and entered into the case report form according to the 
Leukemia-Specific Adverse Event Recording and Reporting Guidelines (Appendix D). 
PDMS/CORe will be used as the electronic case report form for this protocol.  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. The investigator will sign and date the PDMS CRF toxicity 
pages for each patient at the completion of each course. Following signature, the CRF 
will be used as source documentation for the adverse event attribution. 
 


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Table 4. – 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. 
 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND 
Protocols 
 
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 


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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 reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND 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 “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on 
Reporting Unanticipated Adverse Events for Drugs and 
Devices”. 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.  
 
• Unless otherwise noted, the electronic SAE application 
(eSAE) will be utilized for safety reporting to the IND Office 
and MDACC IRB.  
 
• Serious adverse events will be captured from the time of 
the first protocol-specific intervention, until 30 days after the 
last dose of drug, unless the participant withdraws consent. 
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.  
ionally, 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: 
 


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• 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 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
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 
10.1 
Primary Endpoint and sample size 
The primary endpoint is overall response rate (ORR).  A maximum of 40 patients with 
deletion 11q22-23 will be enrolled into this study.  A sample size of 40 ensures that, if 
the trial continues to completion, a posterior 90% credible interval (CI) of response rate 
will be (0.49, 0.74), assuming a response rate of 0.625 (25/40 in these 40 patients). 
 
10.2 
Safety lead-in 
Sapacitabine was previously studied in 2 phase I trials for patients with solid tumors and 
in 1 phase I trial for patients with AML/MDS; all 3 trials evaluated different schedules and 
doses.  In the solid tumor trials, myelosuppression was the DLT and in the AML/MDS 
trial, GI toxicity was DLT that defined the MTD.  There are no trials yet combining 
Sapacitabine with other agents, therefore, there will be a safety lead-in to this trial.  The 
schedule of Sapacitabine in this trial is daily for 3 days of each 4-week course, which is 
significantly less frequent administration compared to all phase I trials.  The chosen 
Sapacitabine dose in this combination is 350 mg flat dose, which less than half the MTD 
dose identified in the AML/MDS trial (where the drug was administered on a more 
frequent schedule). This trial combines Sapacitabine with cyclophosphamide and 
rituximab, which may contribute to toxicity or have unforeseen associated toxicity.  
Therefore, there will be a lead-in phase to this trial, where 3 patients will be enrolled, 
treated, and monitored for toxicity for at least 4 weeks during course 1.  If there are no 
unforeseen toxicities and no “excessive myelosuppression”, defined as Grade ≥3 
myelosuppression with delayed recovery beyond day 42 of course 1, then enrollment will 


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proceed without further pause.  If 1 of 3 patient experiences excessive 
myelosuppression, then an additional 3 patients will be enrolled at dose level 0 and 
evaluated for at least 4 weeks during course 1.  If >2 of the 6 patients enrolled at dose 
level 0 experience excessive myelosuppression, then enrollment will be held pending 
review of all cases and discussion of rational strategy for dose reduction.  If exactly 2 of 
6 patients experience excessive myelosuppression during course 1, then the next 3 
patients will be enrolled at dose level -1. If any of these 3 patients experiences excessive 
myelosuppression, then enrollment will be suspended pending review of all cases and 
discussion of rational strategy for dose reduction.  Patients who experience excessive 
myelosuppression during the lead-in phase may proceed to their next course of 
treatment with -1 level dose reduction (Table 1), when their counts have recovered to 
acceptable levels as defined elsewhere in this protocol. 
 
10.3 
Interim analysis on efficacy  
This trial will follow a Bayesian sequential monitoring design54 with a recommendation to 
stop the trial if the new treatment is unfavorable in comparison with historical data.  In 
particular, the following decision criterion will be applied. Let P(exp) and P(hist) be 
probability of response in the experimental regimen and historical data, respectively, 
stop the trial for lack of efficacy if: 
 
Prob{P(exp) > P(hist) + 0.15 | data} < 0.01 
 
In a historical data set, the overall response rate is 50% in 103 patients. Thus, the prior 
distribution is beta(51, 52) based on 103 patients for the historical data, and beta(1, 1) 
for the new experimental regimen.  Following this rule, the trial will be terminated due to 
futility if [# responses]/[# patients evaluated] =< 2/10, 7/20, 12/30. For purposes of 
futility, patients will be considered evaluable if they have received at least 6 courses of 
treatment. If they were removed from treatment prior to 6 courses for treatment failure or 
toxicity, they will also be evaluable for futility. The operating characteristics for the 
efficacy are summarized in Table 6, based on a 1000 simulations study.  For example, 
the probability of early stopping will be 0.93 when true response rate is 0.3; this 
probability will be only 0.04 if the true response rate is 0.6. 
 
Table 6.  Simulation study with maximum 40 patients: 
Scenario 
Prob. of early stop
Total Samples (25%, 75%)
True overall response rate
0.30 
0.93
20 (10, 20) 
0.40 
0.63
30 (20, 40) 
0.50 
0.23
40 (40, 40) 
0.55 
0.10
40 (40, 40) 
0.60 
0.04
40 (40, 40) 
0.65 
0.01
40 (40, 40) 
 
10.4 
Interim analysis for toxicity  
The probability of toxicity (non-hematologic Grade 3 or 4) will be monitored based on a 
beta-binomial distribution by assuming a priori probability of toxicity following beta(1,1). 
Accrual to the trial will be suspended if Prob(toxicity > 0.25 | data) > 0.8. Following this 
rule, accrual to the trial will be suspended if [# patients with toxicity]/[# patients 
evaluated] >=  4/10, 5/15, 7/20, 8/25, 10/30, or 11/35. All cases will be reviewed and the 


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PI will make a determination if the trial will be terminated or may resume accrual at 
reduced dose of study drugs. The operating characteristics for toxicity are summarized 
in Table 7. 
 
Table 7.  Operating characteristics based on 1000 simulation study 
true Prob(tox) Pr(stop)  Median # Pts (25%, 75%) 
0.05 
0.0
40 (40, 40)
0.15 
0.09
40 (40, 40)
0.25 
0.43
40 (15, 40)
0.35 
0.80
15 (10, 25)
0.45 
0.97
10 (10, 10)
 
10.5 
Statistical Analyses 
The primary endpoint is overall response rate and the secondary endpoints include CR 
rate, time-to-treatment failure, time-to-progression, and overall survival.  We will also 
compare the outcomes between two sub-groups (with or without ATM function).  
Demographic and baseline laboratory results will be summarized using descriptive 
statistics, including means with standard deviations, or medians with ranges, histograms 
and box-plot. Fisher’s exact test and Wilcoxon rank test will be used in the data analyses 
of categorical and continuous variables, respectively. Survival or times-to-failure and 
time-to-progression functions will be estimated using the Kaplan-Meier method. The two-
sided log-rank test will be used to assess the differences of time to events between 
groups. Toxicity will be reported by type, frequency and severity. Worst toxicity grades 
per patient will be tabulated for selected adverse events and laboratory measurements. 
 
11.0 
PHARMACODYNAMIC ENDPOINTS 
These investigations will be performed in Dr. Plunkett’s laboratory.  Patients with more 
than 5,000 WBC/µl in peripheral blood who agree to participate in pharmacodynamic 
investigations will be evaluated. Not all samples will be collected on all patients at all 
time-points. 
Please page Yuling Chen (713-404-2550) or Min Fu (713-606-2212) or call 713-792-
3336 to inform of registration and treatment date and to coordinate blood sample pickup. 
Blood samples (10 ml) will be collected at the following times if there are circulating 
leukemia cells (≥5,000 WBC/µl) for correlative studies. If there are no circulating 
leukemia cells, then the sample will not be taken. 
• 
Screening and Course 1, Day 1 before treatment begins 
• 
Course 1, Day 2 
• 
Course 1, Day 3 
• 
Course 1, Day 4 
These samples will be processed to collect plasma and cells.  Plasma will be stored.  
Cells will be processed for the following endpoints: 
1. Pretreatment (screening) cell samples will be used to evaluate for ATM function.  
This will be evaluated by determining the phosphorylation response of Nbs1 and 
Smc1 to radiation in CLL cells isolated from these samples will be determined by 
comparison of the ratios of immunoblot band intensities of the phosphorylated 


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protein divided by band intensity of the total protein before and after irradiation.  The 
results will be averaged to generate standard values for the phosphorylation 
response to irradiation in samples with two ATM alleles (normal FISH and function).  
These values will be used as a denominator for assessing the ATM function of 
patients with deletion 11q22-23 entered on the clinical trial. 
 
2. Development of double-strand breaks after Sapacitabine and cyclophosphamide 
therapy requires a cycle of DNA replication.  To evaluate proliferation and the actions 
of Sapacitabine, the proliferative compartment will be determined in circulating CLL 
cells by changes in the CD38+, CD5+, and low expression of CRCX4 by multicolor 
flow cytometry55.  Evidence for double strand break formation will be assessed by the 
formation of Rad51 foci, visualized by confocal microscopy56.  We expect that 
cytoreductive therapy will trigger a homeostatic proliferation in surviving CLL cells 
that will be associated with greater strand break action in CLL that lacks ATM 
function. 
 
3. Changes in apoptosis will be evaluated in circulating leukemia cells before and 
during treatment by measuring binding of Annexin V and by mitochondrial 
permeability changes in freshly obtained patient samples.  For comparative 
analyses, each patient serves as his or her own control.  Correlations will be sought 
between these laboratory endpoints and cytoreduction and/or clinical response to 
therapy. 
 
12.0 
DATA CONFIDENTIALITY PLAN 
All laboratory and clinical data gathered on this protocol will be stored in a 
password-protected database. All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing 
a password-protected database. Access to the database is only available to 
individuals directly involved in the study. 
 
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed. 
 
13.0 
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