Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic Myeloid Leukemia Who Have Minimal Residual Disease While Receiving Therapy With Tyrosine Kinase Inhibitors (VZ-CML-PI-0236)
Phase: PHASE1
Conditions: Leukemia
Sponsor: M.D. Anderson Cancer Center

2011-0254
April 24, 2014
Page 1
Protocol Page
Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic 
Myeloid Leukemia who Have Minimal Residual Disease While Receiving Therapy 
with Tyrosine Kinase Inhibitors (VZ-CML-PI-0236)
2011-0254
Core Protocol Information
Short Title 
AZA in MRD CML
Study Chair: 
Jorge Cortes
Additional Contact:
Rachel R. Abramowicz
Yolanda D. Brown
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-5783
Unit:
428
Full Title: 
Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic Myeloid Leukemia 
who Have Minimal Residual Disease While Receiving Therapy with Tyrosine Kinase Inhibitors 
(VZ-CML-PI-0236)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 10/11/2017
Version:
12
Submitted by:
Rachel R. Abramowicz--10/11/2017 7:05:13 AM
OPR Action:
Accepted by:  Julie Arevalo -- 10/11/2017 8:45:24 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2011-0254
April 24, 2014
Page 2
Protocol Body
 
Principal Investigator
Jorge Cortes, MD
Department of Leukemia
MD Anderson Cancer Center
1515 Holcombe Blvd., Unit 428
Houston, TX 77030
(713)792-7305
Study Product:
Azacitidine
Protocol Number:
2011-0254
Coordinating Center:
MD Anderson Cancer Center
1515 Holcombe Blvd.
Houston, TX 77030

2011-0254 
April 24, 2014 
Page 1 of 28 
Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic Myeloid 
Leukemia who Have Minimal Residual Disease While Receiving Therapy with Tyrosine 
Kinase Inhibitors (VZ-CML-PI-0236) 
 
 
 
 
 
 
Principal Investigator 
Jorge Cortes, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Study Product: 
Azacitidine 
Protocol Number: 
2011-0254  (VZ-CML-PI-0236) 
Coordinating Center: 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 

2011-0254 
April 24, 2014 
Page 2 of 28 
1. OBJECTIVES 
 
1.1.Primary Objective:  
1.1.1. 
Phase I: To determine the DLT and MTD of the combination of azacitidine 
(AZA) and a tyrosine kinase inhibitor (TKI) in patients with chronic myeloid 
leukemia (CML).  
 
1.1.2. 
Phase II: To determine the clinical activity of the combination of AZA and a 
TKI in patients with CML in complete cytogenetic remission (CCyR) with 
minimal residual disease. 
 
1.2. Secondary Objectives:  
1.2.1. 
Phase I 
1.2.1.1. 
To determine the clinical activity of the combination of AZA and a 
TKI in patients with CML 
1.2.2. 
Phase II 
1.2.2.1. 
To determine the safety of the combination of AZA and a TKI in 
patients with CML in CCyR with minimal residual disease. 
1.2.3. 
Both phases 
1.2.3.1. 
Determine the effect of therapy over DNA methylation 
 
1.2.3.2. 
Investigate the correlation of DNA methylation and response to 
therapy 
 
2. BACKGROUND 
 
2.1. Chronic Myeloid Leukemia 
 
Chronic myeloid leukemia (CML) is a pluripotent stem cell disorder characterized by 
the presence of the Philadelphia (Ph) chromosome in the leukemic cells. The Ph 
chromosome results from a (9;22) translocation in which the c-ABL oncogene has 
moved from chromosome 9 into the BCR (breakpoint cluster region) gene on 
chromosome 22, resulting in a chimeric BCR-ABL gene 1-3. This is the causative 
abnormality in CML. The fused gene encodes an 8.5 kb chimeric mRNA 4,5, which is 
translated into a 210-kDa protein 6. This p210 BCR-ABL protein functions as a 
constitutively activated tyrosine kinase and is uniquely present in the leukemic cells of 
CML patients 7. The breakpoint in the BCR gene occurs either between BCR exon b2 
and b3 or between BCR exons b3 and b4. Therefore, in the mature BCR-ABL mRNA, 
either b2 or b3 is spliced to ABL exon a2, which results in two alternative chimeric 
p210 BCR-ABL proteins, with either a B2A2 or B3A2 junction 8.  
 
2.2. Tyrosine Kinase Inhibitor (TKI) Therapy 
 
Imatinib is a low molecular weight phenylaminopyrimidine designed to selectively 
inhibit BCR-ABL tyrosine kinase activity 9, and is now the standard therapy for newly 
diagnosed patients with CML who do not undergo allogeneic stem cell transplant 10. 

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Results of the pivotal IRIS trial have shown that over 80% of patients achieve a CCyR, 
with most of these responses being durable. After 7 years of follow-up, the event-free 
survival rate is 81% and the survival free from transformation to accelerated or blast  
phase is 92%.11 For patients who develop resistance or intolerance to imatinib, effective 
therapy with second generation tyrosine kinase inhibitors has been developed. Two of 
these agents (dasatinib and niloitinib) are currently available, and others are under 
development (e.g, bosutinib). Approximately 50% of patients treated with these agents 
after imatinib failure achieve a CCyR, and these responses are also durable in most 
patients. 
 
Several reports have shown that, among patients who achieve a CCyR with imatinib or 
other TKI, those who achieve a MMR (ie, at 18 months from the start of therapy) have 
an improved EFS and survival free from transformation to accelerated or blast phase 
compared to those with CCyR but no MMR (7-year EFS 95% vs 86%, respectively).12 
In this same analysis, none of the patients who had achieved a MMR transformed to 
accelerated or blast phase. Recently, it has been suggested that achieving a complete 
molecular response (CMR) further improves the long-term outcome of patents after 
treatment with imatinib. In one series, patients who had an MMR had a shorter relapse-
free survival (median 44 months) compared to those that achieved CMR (median not 
reached, with a hazard ratio for relapse 11%.13 Similar results were reported from our 
institution, where patients with sustained complete molecular response have an estimate 
EFS at 7-years of 95%, compared to 85% for those with sustained MMR but no CMR, 
and 50% for those with CCyR but no MMR.14 Thus, improving the molecular response 
of patients who have already achieved a CCyR with TKI has become an important goal 
of therapy. It has been suggested that patients who achieve CMR may discontinue 
therapy with imatinib, an important goal for patients. However, discontinuation of 
imatinib among patient who achieve CMR results in relapse in over 50% of patients.15 
Thus additional measures are needed to make treatment discontinuation a safer 
proposition. 
 
2.3. Methylation and Hypomethylating Agents in CML 
 
Increased methylation has been documented in CML and it plays a role in disease 
progression. The Pa promoter of Abl and several other key genes are hypermethylated 
in a significant percentage of patients. Methylation of this promoter increases with 
disease progression.  Some studies have suggested an association of hypermethylation 
with worse prognosis, although this is still controversial.16-19 The p15 gene is also 
hypermethylated as CML progresses, with differential patterns of hypermethylation for 
myeloid and lymphoid blastic phases.16  Hypermethylation of Caderin-13 may be 
associated with high-risk features in CML and with a lower probability of response to 
IFN-.20  
 
Hypomethylating agents have been investigated in CML showing clinical efficacy, 
although their use has been mostly limited to advanced stages of the disease. 5-
azacitidine (AZA) was used in combination with chemotherapy (e.g., etoposide, 
mitoxantrone) for patients with CML in transformation, with 25% to 60% responding 

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(i.e., back to chronic phase –BCP-).  A pilot study of AZA alone in 14 patients with 
CML resulted in 2 responses (MDACC internal data). Decitabine has been more 
extensively studied in CML. It was first used for patients with CML in transformation 
as a single agent at a dose of 50 to 100 mg/m2 over 6 hours every 12 hours for 5 days 
every 4-8 weeks21. Twenty-eight of 51 (55%) patients treated in accelerated phase and 
18 of 64 (28%) in myeloid blast phase had a hematologic responses (CHR in 12 and 6, 
respectively). Cytogenetic responses were achieved in 14% and 8%, respectively. 
Therapy was almost universally myelosuppressive with infections occurring in 34% of 
patients, with 4 (3%) treatment-related deaths. Subsequently, lower doses have been 
used based the optimized demethylating effect with this schedule. In one study, 
decitabine was used at lower doses until the minimal effective dose was reached. A 
dose of 15 mg/m2 daily for 10 days (i.e., 15% to 30% of the dose previously used) was 
well tolerated and provided the best response in a variety of myeloid malignancies.22 
This schedule has been investigated in 35 patients with CML who have failed imatinib 
therapy (12 chronic, 17 accelerated, 6 blastic). A hematologic response was reported in 
23 (66%) patients (CHR 12, PHR 7, HI 4). Sixteen patients (46%) had a cytogenetic 
response (major 6, minor 10).23 Preclinical studies have shown synergy between 
imatinib and decitabine.24 25 This combination was used in a phase II trial in patients 
with advanced phase CML, most of them previously treated with imatinib. Patients 
received decitabine 15 mg/m2 intravenously daily, 5 days a week for 2 weeks, and 
imatinib 600 mg orally daily. A hematologic response was achieved in 50% and 30% of 
patients in accelerated and blast phase, respectively, with major  cytogenetic responses 
in 33% and 20%, respectively. 
 
We hypothesize that adding AZA to a TKI may improve the molecular response of 
patients with CML with CCyR but no MMR. If a significant number of patients convert 
to a CMR, we will explore whether TKI can be safely discontinued with minimal risk 
of relapse. Throughout the study we will measure the effect of therapy on DNA 
methylation in the peripheral blood and bone marrow, both global and gene-specific. 
 
2.4. 5-azacitidine 
 
Azacitidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and 
metabolism.26 Since the early 1970s, azacitidine has been investigated primarily in the 
US for the treatment of acute leukemia. Clinical studies have focused mainly on 
patients with disease refractory to conventional chemotherapy. Results of these 
investigations demonstrated activity of azacitidine in the treatment of AML. Clinical 
studies subsequently evaluated the effects of azacitidine in a variety of other malignant 
and hematologic disorders, including solid tumors, hemoglobinopathies (eg, 
thalassemia and sickle cell anemia), and MDS. In 1984, the Cancer and Leukemia 
Group B (CALGB) began a series of clinical studies with azacitidine in patients with 
MDS. These studies, in addition to other supportive data, led to the approval of 
Vidaza® (azacitidine) in May 2004 for the treatment of MDS.26  
 

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Azacitidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT).27-29 Increased methylation of DNA (hypermethylation) 
may result in the silencing of critical genes responsible for cell growth control and 
differentiation. Hypermethylation of CpG islands spanning the promoter regions of 
tumor suppressor genes is commonly associated with cancers.30 It is now widely 
recognized 
that 
hypermethylation 
of 
DNA 
is 
frequently 
associated 
with 
myelodysplastic syndromes and other cancers,31-33 such as renal,34 melanoma,35 
breast,36 colorectal,37 non-small cell lung38 and hematologic malignancies.39 Azacitidine 
is believed to exert its antineoplastic effects through hypomethylation and cytotoxicity 
on abnormal hematopoietic cells in the bone marrow.40-44 Hypomethylation may restore 
normal function to genes that are critical for differentiation and proliferation.30,45,46 The 
cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including 
cancer cells that are no longer responsive to normal growth control mechanisms.40,47-49  
 
The cytotoxicity of azacitidine is proportional to dose and exposure time.40,41 Although 
the mechanisms of cytotoxicity are complex and multifaceted, there is general 
agreement that incorporation of azacitidine into DNA and ribonucleic acid (RNA), and 
inhibition of protein synthesis, are critically important.50 Cytotoxicity is greatest in cells 
that are proliferating (S phase) and metabolically active.40 Cytotoxic effects may also 
be mediated through induction of the DNA damage response pathways.49 
Nonproliferating cells are relatively insensitive to azacitidine.40  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys.51 
Most of the studies were performed during the 1970s and early 1980s according to 
existing guidelines and standards in place during that period. The preclinical studies 
identified the bone marrow, liver, kidneys, and lymphoid tissues (spleen, lymph nodes, 
and thymus) as the main target organs of toxicity for azacitidine.51  In single-dose 
studies, the lethal dose of azacitidine after intravenous (IV) administration in mice, rats, 
and dogs was approximately 250 mg/m2. Repeated daily dosing appears to increase the 
toxicity of azacitidine.51 The genotoxicity of azacitidine is consistent with that of other 
nucleoside analogs that interact with nucleic acids.51 Likewise, similar to other agents 
with cytostatic properties, azacitidine was embryotoxic and reduced the reproductive 
performance in mice and rats.51 
 
Limited azacitidine pharmacokinetic data are currently available. Based on human 
plasma concentrations of total radioactivity (which represents parent drug plus 
circulating metabolites), azacitidine is rapidly absorbed when given subcutaneously 
(SC), with maximum plasma concentrations found 0.5 to 2 hours after dosing.51 
Azacitidine and/or its by-products are then rapidly cleared by the kidneys. The half-
lives and percent radioactivity recovered in urine are similar following IV and SC 
routes of administration. The effects of renal or hepatic impairment, gender, age, or 
race on the pharmacokinetics of azacitidine have not been studied.51 A single dose (75 
mg/m2) SC versus IV crossover study in 6 MDS subjects52 revealed an approximate 
bioavailability of 89% for the SC dose (range 52% to 128%) with mean half-lives of 
0.69 hour and 0.36 hour after SC and IV administration, respectively. These results 
demonstrated that azacitidine is rapidly and nearly completely absorbed after SC 

2011-0254 
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administration and that elimination is also rapid. The apparent SC clearance (167 L/h or 
2791 mL/min) and systemic IV clearance (147 L/h) of azacitidine exceeded the 
glomerular filtration rate (approximately 125 mL/min) and total renal blood flow (1200 
mL/min) in healthy subjects. This indicates that non-renal elimination (eg, metabolism, 
hydrolysis, and/or degradation) plays a role in the elimination of parent azacitidine. In 
addition, azacitidine 75 mg/m2 was generally well-tolerated after single SC injection or 
IV infusion over 10 minutes.52  
 
A number of studies have looked at different parenteral doses and schedules of 
azacitidine, finding maximum tolerated doses of up to 500 mg/m2 when administered 
weekly.53 
 
During the two decades between the start of the CALGB studies and the approval of 
azacitidine, a new understanding of MDS has developed, such as the World Health 
Organization (WHO) diagnostic criteria, the International Prognostic Scoring System 
(IPSS), and the International Working Group (IWG) response criteria. Silverman et al. 
reevaluated the combined data (N = 309) from 3 of the CALGB studies using the WHO 
classification system for MDS and AML and the IWG response criteria.54 Using the 
IWG response criteria in MDS patients, response rates were between 40% and 70% in 
azacitidine treated patients. Ten to 17% of patients achieved a complete remission; 
partial remission was rare; and 23% to 36% of patients had a hematologic 
improvement. In patients with AML (N = 103), 35% to 48% had hematologic 
improvement or better responses. The median survival time for 27 patients assigned to 
azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to 
observation.54 
 
A randomized international Phase III trial (Study AZA PH GL 2003 CL 001) for 
higher-risk MDS patients, classified by FAB as RAEB, RAEB-T, or CMML with 0-
29% marrow blasts, with an IPSS of Intermediate -2 or High by central 
pathology/cytogenetic review was recently reported.55 Patients were randomized to 
azacitidine (75 mg/m2/day x 7days in 28 day cycles) or conventional care regimens 
(CCR) , where CCR was pre-selected by the Investigator as best supportive care 
(transfusions, antibiotics, and G-CSF for neutropenic infection), low-dose cytarabine 
(20 mg/m2/day x 14 days in 28 day cycles); or standard chemotherapy (conventional 
induction/consolidation). Patients were stratified by FAB/IPSS and randomized 1:1 to 
azacitidine or CCR. This trial did not allow erythropoietin. Three-hundred fifty eight 
patients (70% male) were randomized at 79 centers to azacitidine (N=179) or CCR 
(N=179): best supportive care only (N=105, 59%), low-dose cytarabine (N=49, 27%), 
or standard chemotherapy (N=25, 14%). Median age was 69 years (range 38-88 years). 
The azacitidine and CCR groups were comparable for baseline patient characteristics. 
At baseline, 95% of patients were higher risk: RAEB (58%), RAEB-T/WHO AML 
(34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: Intermediate -2 
(40%), High (47%), and 13% Indeterminate/other. Azacitidine was administered for a 
median of 9 cycles; low-dose cytarabine for 4 cycles. Median follow-up for the survival 
analysis was 21.1 months. Azacitidine demonstrated statistically superior overall 
survival compared to CCR, with a median overall survival of 24.4 months vs. 15 

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months for CCR (stratified log-rank p=0.0001, hazard ration 0.58). Two-year survival 
approximately doubled in the azacitidine arm compared to CCR: 51% vs. 26% 
(p<0.0001). Azacitidine was well tolerated with safety data consistent with previous 
reports.  
 
Further details can be found in the azacitidine Investigator’s Brochure, which contains 
comprehensive pharmacology, toxicology, pharmacokinetics, pharmacodynamics, 
metabolism, preclinical, and clinical efficacy and safety data information.51  
 
3. Criteria for Patient Eligibility 
 
3.1. Inclusion Criteria 
 
3.1.1. Patients 16 years or older with Philadelphia chromosome (Ph)- or BCR/ABL-
positive CML (as determined by cytogenetics, FISH, or PCR).   
 
3.1.2. Patients must have received FDA-approved TKI therapy for at least 18 months 
and not have increased their dose of FDA-approved TKI in the last 6 months.  
Patients participating on frontline protocols 2005-0048 (nilotinib) and 2005-
0422 (dasatinib) are eligible for enrollment on this study. 
 
3.1.3. Phase II patients must be in complete cytogenetic remission.  
 
3.1.3.1. For the phase I portion of the study, patients may be included without 
a complete cytogenetic remission provided they are in chronic phase 
 
3.1.4. Phase II patients must have detectable BCR-ABL transcript levels meeting at 
least one of the following criteria: 
 
3.1.4.1. Patient has never achieved a major molecular response, and transcript 
levels have shown in at least two consecutive measures separated by at 
least 1 month to have increased by any value, or 
 
3.1.4.2. Achieved a major molecular response that has been lost with an 
increase in transcript levels by at least 1-log, confirmed in two 
consecutive analyses separated by at least 1 month, or 
 
3.1.4.3. The patient has received therapy for at least 2 years and does not have 
a sustained major molecular response, or 
 
3.1.4.4. The patient has received therapy for at least 5 years and does not have 
a sustained complete molecular response. 
 
3.1.4.5. Patients included in the phase I portion of the study are eligible 
regardless of their level of BCR-ABL transcripts.  
 

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3.1.5. Patients must not have had a known continuous interruption of imatinib therapy 
of greater than 14 days or for a total of 6 weeks in the 6 months prior to 
enrollment.  
 
3.1.6. Patients must sign an informed consent indicating that they are aware of the 
investigational nature of this study in keeping with the policies of the hospital.  
 
3.1.7. ECOG performance status <2. 
 
3.1.8. Adequate organ function defined as: bilirubin <2x upper limit of normal (ULN) 
(unless associated with Gilbert’s syndrome), and ALT or AST <2.5x ULN. 
 
3.1.9. ANC ≥1 x109/L and platelets ≥50 x109/L. 
 
3.1.10. Serum creatinine < 1.8 mg/dL or creatinine clearance greater or equal than 40 
cc/min as defined by the Cockcroft-Gault Equation*.  Males(mL/min):(140-
age)*ABW(kg) / 72*(serum creatinine(mg/dl)); Females (mL/min):0.85*(140-
age)*ABW(kg) / 72*(serum creatinine (mg/dl)) 
 
3.1.11. Women of childbearing potential should be advised to avoid becoming pregnant 
and practice effective methods of contraception.  Men should be advised not to 
father a child while receiving treatment with azacitidine.   Azacitidine is 
classified as Pregnancy Category D. Females of childbearing potential: 
Recommendation is for 2 effective contraceptive methods during the study. 
Adequate forms of contraception are double-barrier methods (condoms with 
spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, 
depo provera, or injectable contraceptives, intrauterine devices, and tubal 
ligation. Male patients with female partners who are of childbearing potential: 
Recommendation is for male and partner to use at least 2 effective contraceptive 
methods, as described above, during the study. 
 
3.1.12. Women of childbearing potential should have a pregnancy test within 7 days 
before initiation of study drug. 
 
3.2. Exclusion Criteria 
 
3.2.1. Patients receiving any other investigational agents 
 
3.2.2. Patients who are pregnant or breast-feeding 
 
3.2.3. Patients with clinically significant heart disease (NYHA Class III or IV) 
 
3.2.4. Known or suspected hypersensitivity to azacitidine or mannitol. 
 
3.2.5. Patients with advanced malignant hepatic tumors. 
 

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4. Treatment Plan 
 
4.1. TKI: Patients will continue receiving TKI at the dose they had been receiving during 
the last 6 months.  
 
4.2.AZA:  
Phase I: patients will be treated in cohorts of 3. The starting dose will be dose level 0 
(50 mg/m2/d x 3 days subcutaneous or intravenous; Table 1). 
4.2.1. At least 3 patients will be entered at each level. All patients treated at any one 
dose level must have been observed for at least four weeks before escalating to 
the next dose level.  Patients who come off study prior to the first four weeks 
and have not experienced a DLT will be replaced. 
Table 1: Dose escalation levels 
Dose level 
AZA (mg/m2/d x 3 days) 
-3 
25 (1 day only) 
-2 
25 (2 days only) 
-1 
25 
0 
50 
1 (Target dose) 
75 
2 
75 (for 5 days) 
3 
75 (for 7 days) 
 
4.2.2. Dose escalation will be done as follows: 
Dose-limiting toxicity in  
Result  
 
 
 
0/3  
 
 
 
Escalate to next level 
 
1/3  
 
 
 
Enter 3 more patients 
 
2/3 or > 2/6 
MTD exceeded. This dose level will be 
declared the maximally administered dose. 
Expand previous level to include a total of 6 
patients if not already accrued to this 
number.  
 
4.2.3. Definition of Dose-Limiting Toxicity (DLT) 
 
4.2.3.1. 
DLT will be defined by events that are clinically significant and 
possibly related to study drug occurring during the first 4 weeks (1 
cycle) of therapy. 
 
4.2.3.2. 
Non-hematologic DLT is defined as grade 3 or 4 toxicity (NCI 
common criteria, version 4.0) that is clinically significant and 

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considered to be at least possibly related to the study drug. Grade 3 
or 4 nausea, vomiting and diarrhea will be considered DLT only if 
not controlled by optimal therapy. 
 
4.2.3.3. 
Grade 3 biochemical abnormalities (e.g., lipase or bilirubin 
elevation) will only be considered DLT if accompanied by clinical 
consequences.  Grade 3 or 4 electrolyte abnormalities will only be 
considered DLT if possibly related to study drug and not corrected 
by optimal replacement therapy. 
 
4.2.3.4. 
Hematologic DLT is defined as grade 3 neutropenia and/or 
thrombocytopenia with a hypocellular bone marrow lasting for 6 
weeks or more after the start of a course. (In case of a normocellular 
bone marrow, 8 weeks with pancytopenia will be considered DLT). 
Anemia will not be considered for the definition of DLT. 
 
4.2.4. If dose-level 0 exceeds MTD, subsequent patients will be treated at dose level -
1. Additional cohorts at lower doses (down to dose level -4) may be included if 
higher doses exceed MTD. If dose level -4 exceeds MTD, the study will be 
terminated.   
 
4.3. Phase II: The dose to be used for the phase II portion of the study is 75mg/m2 daily for 
3 days, unless MTD is defined at a lower dose level in the phase I portion of the study 
in which case that would become the dose to be used for the phase II portion. Other 
dose levels shown in Table 1 will be used for dose adjustments for toxicity or lack of 
improvement (as described in section 4.5.5) during therapy. For phase II portion of the 
study, if at any time patients need to be escalated to dose level +2 or +3, if at any time 
33% or more of patients experience DLT at this dose level during the first cycle they 
receive at this dose, this would be considered to have exceeded MTD and that dose 
level should not be used any further.   
 
4.4. Treatment with AZA (in both phase I and phase II) may be repeated every 28 days. The 
start of subsequent cycles may be delayed to allow for recovery of any adverse events 
to grade 1 or less. 
 
4.5. Dosing Delays/Dose Modifications 
 
4.5.1. Patients experiencing unacceptable toxicity directly attributable to the study drugs 
should temporarily stop treatment according to the guidelines in the dose 
adjustment schema.  
 
4.5.2. Toxicity grading will be according to the NCI CTCAE, v4. To prevent 
unnecessary morbidity, the following guidelines for dose adjustment for drug-
related toxicities are recommended.  
 

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4.5.3. TKI: dose modifications will be done according to institutional guidelines. The 
following guidelines may be used for dose adjustments: 
 
4.5.3.1. 
Non-Hematologic Toxicity 
 Grade 2: Patients with persistent grade 2 toxicity that is 
considered clinically significant, unresponsive to appropriate 
therapy, may have treatment held until the toxicity has resolved to 
grade <1.  TKI may then be resumed at the same dose the patient 
was receiving at the time treatment was interrupted. If the grade 2 
toxicity recurs, TKI may be held until the toxicity has resolved to 
grade 1. Treatment may then be resumed with a one dose level 
reduction. 
 Grade 3-4: If a patient experiences Grade 3-4 toxicity that is 
considered clinically significant and related to TKI, therapy may 
be withheld until the toxicity has resolved to Grade < 1. TKI may 
then be resumed with a one dose level reduction. 
4.5.3.2. 
Hematologic Toxicity 
If granulocytes are <0.5 x 109/L or platelets are <40 x 109/L, hold 
therapy until granulocytes are above 10
9/L and platelets are above 60 x 
109/L, then resume therapy. 
If recovery takes more than 2 weeks, resume TKI at 1 dose level 
reduction from the dose the patient was receiving at the time therapy 
was interrupted. 
If recovery takes less than 2 weeks, resume TKI at the same dose the 
patient was receiving at the time treatment was interrupted. If 
myelosuppression recurs, resume TKI at one dose level reduction from 
the dose the patient was receiving at the time the treatment was 
interrupted. 
If a similar degree of toxicity returns, a further dose reduction by one 
dose level can be performed, using the above procedures.  
 
4.5.3.3. 
The usual dose levels for dose adjustments are as follows: 
 
Imatinib (mg/d) 
Dasatinib (mg/d) 
Nilotinib (mg/d) 
800 
140 
800 
600 
100 
600 
400 
70 
400 
300 
50 
300 
200 
40 
200 
100 
20 
150 
 

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4.5.3.3.1. The maximum allowable daily doses of TKI are: dasatinib 
140 mg/d, nilotinib 800 mg (usually as 400 mg BID), and 
imatinib 800 mg. 
4.5.3.4. 
Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 Further dose reductions can be made to keep toxicity grade ≤2.  
 Dose adjustments by more than 1 dose level at a time can be 
considered when judged in the best interest of the patient (e.g., 
neutropenia with sepsis, bleeding requiring platelet transfusions) 
when toxicity has resolved.  
 A patient who has had a dose reduction because of any reason may 
have their dose re-escalated provided the patient has remained free 
of toxicity requiring dose adjustments as defined above for at least 
1 month. Escalation will be made by 1 dose-level increments only, 
and not more frequent than every month.  
 
4.5.4. AZA: dose modifications for toxicity will be done according to the following 
guidelines: 
 
4.5.4.1. 
Non-Hematologic Toxicity 
4.5.4.1.1. Persistent Grade 2: Patients with persistent grade 2 
toxicity 
that 
is 
considered 
clinically 
significant, 
unresponsive to appropriate therapy, may have treatment 
held until the toxicity has resolved to grade <1.  Therapy 
may then be resumed at the same dose the patient was 
receiving at the time treatment was interrupted. If the grade 
2 toxicity recurs, therapy may be held until the toxicity has 
resolved to grade 1. Treatment may then be resumed with a 
one dose level reduction. 
 
4.5.4.2. 
Grade 3-4: If a patient experiences Grade 3-4 toxicity that is 
considered clinically significant and possibly related to AZA, therapy 
must be withheld until the toxicity has resolved to Grade <1. 
Treatment may then be resumed with a one dose level reduction. If 
toxicity recurs, additional dose reductions may be implemented 
according following the same general guidelines. 
 
4.5.4.3. 
If unexplained reductions in serum bicarbonate <20mEq/L occur, the 
dosage should be reduced by 50% on the next course.  Similarly, if 
unexplained elevations of BUN or serum creatinine occur, the next 
cycle should be delayed until values return to normal or baseline and 
the dose should be reduced by 50% on the next treatment course. 
 

2011-0254 
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Page 13 of 28 
4.5.4.4. 
Hematologic Toxicity 
 
4.5.4.4.1. If neutrophils are <0.5 x 109/L and/or platelets are <40 x 
x109/L, hold therapy until granulocytes are above 1 x109/L 
and platelets are above 60 x109/L, then resume therapy. 
 
4.5.4.4.2. If recovery takes more than 2 weeks, resume therapy at 1 
dose level reduction from the dose the patient was 
receiving at the time therapy was interrupted. 
 
4.5.4.4.3. If recovery takes less than 2 weeks, resume therapy at the 
same dose the patient was receiving at the time treatment 
was interrupted. If myelosuppression recurs, resume 
therapy at one dose level reduction from the dose the 
patient was receiving at the time the treatment was 
interrupted. 
 
4.5.4.4.4. If a similar degree of toxicity returns, a further dose 
reduction by one dose level can be performed, using the 
above procedures.  
 
4.5.4.4.5. Patients in whom the toxicity occurs or persists beyond the 
planned completion of drug administration for the cycle 
will have the dose reductions implemented in subsequent 
cycles provided the toxicity has resolved as specified 
above.  
 
4.5.4.4.6. There will be no making up for missed doses. 
 
4.5.4.5. 
Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 
4.5.4.5.1. Further dose reductions can be made to keep clinically 
significant, AZA-related toxicity grade ≤2. However, the 
lowest acceptable dose level is -4.  
 
4.5.4.5.2. Dose adjustments by more than 1 dose level at a time can 
be considered when judged in the best interest of the patient 
(e.g., neutropenia with sepsis, bleeding requiring platelet 
transfusions) when toxicity has resolved. The reason for 
this reduction will be discussed with the PI and the drug 
supplier and documented in the medical record. 
 
4.5.4.5.3. A patient who has had a dose reduction because of any of 
the reasons mentioned above may have their dose re-
escalated provided the patient has remained free of toxicity 

2011-0254 
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Page 14 of 28 
requiring dose adjustments as defined above for at least 1 
month. Escalation will be made by 1 dose-level increments 
only, and not more frequent than every month.  
 
4.5.5. Dose Escalation: Patients that do not achieve an improvement in molecular 
response after 3 months (eg., from major to complete or from non-major to major) 
and have experienced no grade ≥3 toxicity may have the dose of AZA escalated 
by one dose level. Patients who have had a prior dose reduction of AZA and who 
have no toxicity for at least 1 month of therapy may increase the dose of AZA 
following the guidelines mentioned above. Dose escalation of the TKI is also 
allowed according to institutional guidelines. However, concomitant dose 
escalation of the two agents is not allowed. Patients who have had dose escalation 
of TKI cannot have dose escalation of AZA within 2 months of this escalation. 
 
4.5.6. Occasional missed doses of TKI will not be considered a deviation.  Missed dosed 
of ≥ 2 weeks without adequate justification will be considered a protocol 
deviation. 
 
4.5.7. Duration of Therapy: Patients may receive therapy for six cycles. After 
completion of the 6th cycle, patients may continue therapy if in the opinion of the 
investigator there is clinical benefit provided there has been no grade 3 or higher 
non-hematologic toxicity attributable to AZA at the doses being administered.  
 
4.5.7.1. 
Patients who achieve a major or complete molecular remission can 
hold therapy with AZA and/or TKI and be monitored with PCR. If 
there is reappearance of transcripts detectable by PCR, therapy with 
one or both agents can be resumed at the doses being administered at 
the time treatment was interrupted.  
 
4.5.8. Concomitant Medications 
 
4.5.8.1. 
Patients may not receive any other treatment for CML while on study. 
This includes the use of hydroxyurea and anagrelide. 
4.5.8.2. 
The use of other medications for management of comorbidities or 
adverse events is allowed as clinically indicated.  
 
5. Evaluation During Study 
 
5.1. Pretreatment Evaluation (within 7 days from treatment start, unless otherwise 
specified)   
 
5.1.1. A complete history and physical examination including performance status. 
 
5.1.2. CBC, platelet count and differential (differential not required if WBC < 0.5 
x109/L), total bilirubin, SGPT (or SGOT), and creatinine within 1 week. 
 

2011-0254 
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Page 15 of 28 
5.1.3. Bone marrow aspirate for morphology and cytogenetics or FISH (if not done 
within 3 months). 
 
5.1.4. Pregnancy test (blood or urine) for female patients of childbearing potential 
within 7 days before initiation of study drug dosing. 
 
5.1.5. Peripheral blood and/or bone marrow for quantitative PCR (QPCR) (if not done 
within 3 months).  
 
5.1.6. Peripheral blood and/or bone marrow for correlative studies (optional – 
Appendix A, B & C).  Not all optional samples may be collected.  
 
5.2. Evaluation During Study  
 
5.2.1. Physical exam and evaluation of toxicity (clinic visit or telephone interview): 
 
5.2.1.1. Phase I portion: every 2 weeks for the first month, then every month 
for the first 3 months, then every 3 months (±1 month) until month 6, 
then every 6 to 12 months.   
 
5.2.1.2. Phase 2 portion: every 3 months (±1 month) until month 6, then every 
6 to 12 months. 
 
5.2.2. CBC, platelet, differential every 1-2 weeks for 8 weeks, then at the start of 
every cycle. Differential not required if WBC ≤0.5 x109/L.  
 
5.2.3. Bone marrow aspirate with cytogenetics or FISH every 3-6 months in year 1, 
then as clinically indicated. 
 
5.2.4. Total bilirubin, SGPT or SGOT, and creatinine every 1-2 weeks for 8 weeks, 
then before each cycle. 
 
5.2.5. Quantitative PCR (peripheral blood and/or bone marrow) before each cycle for 
3 cycles, then every 3-6 cycles until one year, then every 6-12 cycles. 
 
5.2.6. Peripheral blood and bone marrow for correlative studies every 3-6 months in 
year 1, then every 6-12 months. Methylation studies will also be done on days 5, 
10 and 28 (all ± 3 days) of the first cycle. Not all optional samples may be 
collected. (Optional – Appendix A, B & C).   
 
6. Criteria for Response 
 
6.1. A favorable response for the primary endpoint is defined as a greater than a one-log 
reduction of BCR-ABL transcript levels from the baseline level at the time vaccination 
was initiated, or a disappearance of BCR-ABL transcripts (i.e., complete molecular 
response). 

2011-0254 
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7. Criteria for Removal from Study 
 
7.1. The patient receives CML-directed therapy other than TKI and AZA. 
 
7.2. The patient develops disease progression defined as confirmed loss of CCyR, 
confirmed loss of CHR or transformation to accelerated or blast phase. 
 
7.3. The dose of TKI is increased or new therapies for their leukemia are added.  
 
7.4. The patient has a continuous interruption of imatinib therapy for greater than 6 weeks. 
 
7.5. The patient withdraws consent. 
 
7.6. The treating physician considers it in the best interest of the patient. 
 
7.7. Pregnancy or suspected pregnancy 
 
8. Adverse Event Reporting 
 
8.1. Adverse event is any untoward medical occurrence that may present during treatment 
with a pharmaceutical product but which does not necessarily have a causal relationship 
with this treatment.  
 
Adverse drug reaction is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
disease or for the modification of physiologic function.  
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the 
event would not have happened at all, 2) the event would have occurred later than it 
actually did, or 3) the event would have been less severe. 
 
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. 
 
8.2. Adverse Events (AEs) will be evaluated according to the latest CTC version and 
documented in medical record.  Only unexpected AEs will be recorded in the Case 
Report Form (CRF).  Expected events during leukemia therapy are: 
 
8.2.1. 
Myelosuppression Related Events (due to disease or leukemia therapy) 
 
8.2.1.1. febrile or infection episodes not requiring management in the intensive 
care unit 

2011-0254 
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Page 17 of 28 
 
8.2.1.2. epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
 
8.2.1.3. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia 
 
8.2.2. 
Disease Related Events 
 
8.2.2.1. symptoms associated with anemia 
 
8.2.2.2. fatigue 
 
8.2.2.2.1. weakness 
 
8.2.2.2.2. shortness of breath 
 
8.2.2.3. electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
 
8.2.2.4. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, 
albumin, uric acid, alkaline phosphatase, glucose) 
 
8.2.2.5. coagulation abnormalities 
 
8.2.2.6. disease specific therapy (induction, maintenance, salvage, or stem cell 
therapy) 
 
8.2.2.7. alopecia 
 
8.2.2.8. bone,  joint, or muscle pain 
 
8.2.2.9. liver function test abnormalities associated with infection or disease 
progression 
 
8.2.2.10. disease progression 
 
8.2.2.11. abnormal hematologic values  
 
8.2.3. General Therapy Related Events 
 
8.2.3.1. catheter related events 
 
8.2.3.2. renal failure related to tumor lysis syndrome or antibiotic/ antifungal 
therapy 
 
8.2.3.3. rash related to antibiotic use 

2011-0254 
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8.2.3.4. Hospitalization for the management of any of the above expected 
events 
 
8.3. Abnormal hematologic values will not be recorded on the case report form.  For 
abnormal chemical values, the apogee or nadir (whichever is appropriate) will be 
reported per course on the case report form. 
 
8.4. Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
 
 
Death 
 A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be 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.  

2011-0254 
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 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.  
 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
8.5. Annual Reports 
 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows. 
Celgene Corporation 
Attn: Medical Development 
86 Morris Avenue 
Summit, NJ  07901 
Tel: (908) 673-9000 
 
8.6. Pregnancies: 
 
Pregnancy of a female subject or the female partner of a male subject  occurring while 
the subject is on azacitidine or within 28 days after the subject’s last dose of 
Azacitidine are considered expedited reportable events.  If the subject is on Azacitidine, 
it is to be discontinued immediately.  The pregnancy must be reported to Celgene Drug 
Safety within 24 hours of the Investigator’s knowledge of the pregnancy by facsimile 
using the SAE Form. 

2011-0254 
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The Investigator will follow the pregnant female until completion of the pregnancy, and 
must notify Celgene Drug Safety of the outcome as specified below.  The Investigator 
will provide this information as a follow-up to the initial SAE. 
If the outcome of the pregnancy meets the criteria for immediate classification as a 
SAE (i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is 
to be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator 
should follow the procedures for Expedited Reporting of SAEs to Celgene (i.e., report 
the event to Celgene Drug Safety by facsimile within 24 hours of the Investigator’s 
knowledge of the event). 
Any suspected fetal exposure to Azacitidine must be reported to Celgene within 24 
hours of being made aware of the event.  The pregnant female should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation 
and counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to Azacitidine should also be 
reported. 
In the case of a live “normal” birth, Celgene Drug Safety should be advised as soon as 
the information is available. 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
 
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
9. Statistical Considerations 
 
9.1. This is a single arm, open label, phase I-II trial to evaluate the toxicity and efficacy of 
the combination of AZA and a TKI in CML patients in complete cytogenetic remission 
with minimal residual disease. A total of 48 patients will be accrued at a rate of 1 to 2 
patients per month.  
 
9.2. Phase I 

2011-0254 
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The primary objective of phase I part is to determine the maximum tolerated dose 
(MTD) of AZA; and the primary endpoint is the occurrence of dose-limiting toxicity 
(DLT: section 4.3.3) within the first course of treatment. Standard 3+3 design will be 
used. The starting dose is 50 mg/m2/d x 3 days (Table 1).  
Table 1: Dose escalation levels 
Dose level 
AZA (mg/m2/d x 3 days) 
-1 
25  
0 
50 
1 
75 
 
9.2.1. 
The 3+3 algorithm is described below: 
9.2.1.1. 
Three patients will be enrolled at the starting dose level 
 
9.2.1.2. 
If 0/3 patient experiences DLT at a given level, enroll three 
patients to the next higher dose level 
 
9.2.1.3. 
If 1/3 patient experiences DLT at a given level, enroll additional 
three patients to the same dose level 
 
9.2.1.4. 
If 2/3 or 2/6 patients experience DLT at a given level, the MTD 
has been exceeded and dose escalation will be stopped. Up to three 
additional patients will be enrolled at the next lower dose level if 
only 3 patients were treated at that level. 
 
9.2.2. 
MTD is defined as the highest dose level in which 6 patients have been treated 
and one or fewer patient experiences DLT. 
 
The MTD identified in phase I part will be recommended for phase II. If MTD 
is not determined, the highest AZA level of 75 mg/m2/d x 3 days will be used 
as the recommended phase II dose. 
 
A maximum of 18 patients will be accrued for phase I part. The data from the 
6 patients treated at the recommended phase II dose level (MTD or 75 
mg/m2/d x 3 days if MTD is not determined) will be used in phase II part. 
 
9.3. Phase II 
The primary endpoint for phase II portion is the decrease of transcript levels by at least 
one log (or undetectable transcript level) within 12 months. Including the 6 patients 
treated at the recommended phase II dose level in the phase I part, a total of 36 patients 
will be accrued.  

2011-0254 
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9.3.1. 
Efficacy Monitoring 
Since the efficacy of the drug will be assessed over a long period of time (12 
months) and the accrual rate is relatively fast (1-2 patients per month), no 
formal futility monitoring rule will be applied. However, the PI and the study 
committee will meet regularly, and the study will be stopped early if 
consensus has been reached on any clear indications of poor efficacy of the 
drug. 
9.3.2. 
Toxicity Monitoring 
The method of Thall, Simon, and Estey will be used to perform interim safety 
monitoring [1].  The safety monitoring of the trial will be initiated after the 
first 6 patients have been evaluated, and then monitored continuously. The 
monitoring rule for toxicity is P(E>0.20|data)>0.90, where E is the 
proportion of any DLT (as defined in section 4.3.3), and is assumed to follow 
a non-informative prior of Beta (0.4, 1.6). Namely, the trial will be terminated 
if at any time during the study there is a more than 90% chance that the 
average rate of DLT is more than 20%.  The stopping boundaries of the trial 
are 3out of 6, 4 out of 7, 5 out of 10, 6 out of 14, 7 out of 18, 8 out of 
22, 9 out of 26,  10 out of 30,  11 out of 34 patients experienced DLT. 
Table 2: Operating characteristics of Safety Monitoring (based on 
10000 simulations) 
True  
Probability 
Stop  
Probability 
Trial Sample Size Percentile 
25% 
50% 
75% 
0.10 
 0.02 
36 
36 
36 
0.20 
0.25 
36 
36 
36 
0.30 
0.69 
6 
17 
36 
0.40 
0.96 
6 
8 
16 
All calculations were performed using Multc99. 
9.4. Statistical Methods 
Data analysis will be performed using SAS or S-plus, whichever is appropriate. All 
patients who receive at least one dose of therapy will be included in the primary 
efficacy and toxicity analysis. Patients who do not have molecular response and 

2011-0254 
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withdraw within 12-months after initiation of treatment will be counted as failure in the 
primary efficacy analysis.  
The rate of molecular response will be estimated with 95% confidence interval. The 
null hypothesis is that the response rate is 5%, and alternative hypothesis is that the 
response rate is 20%. If a 20% response is reached, the study would be considered 
positive. Under this setting, 36 patients can provide a power of 87% for a one-sided test 
of the above hypothesis at significance level alpha=5%. 
10. Protocol Amendments, Deviations and Regulatory  
 
Any amendment to this protocol must be agreed to by the Principal Investigator and by MD 
Anderson Cancer Center and by Celgene.  Amendments should only be submitted to IRB 
after consideration of M. D. Anderson Cancer Center, Celgene review.  Written verification 
of IRB approval will be obtained before any amendment is implemented.   
 
10.1. Protocol Deviations 
 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as 
possible to determine whether or not the subject (for whom the deviation from 
protocol was effected) is to continue in the study.  The subject’s medical records will 
completely describe the deviation from the protocol and state the reasons for such 
deviation.  In addition, the Investigator will notify the IRB in writing of such 
deviation from protocol. 
10.2. Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical 
Practice (GCP) and in the US Code of Federal Regulations. 
 
Investigators must enter study data into MDACC’s PDMS.  The Investigator will 
permit study-related monitoring visits and audits by Celgene or its representatives, 
IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing 
direct access to the facilities where the study took place, to source documents, to 
CRFs, and to all other study documents. 
 
The Investigator, or a designated member of the Investigator’s staff, must be available 
at some time during monitoring visits to review data and resolve any queries and to 
allow direct access to the subject’s records (e.g., medical records, office charts, 
hospital charts, and study related charts) for source data verification.  The data 
collection must be completed prior to each visit and be made available to the Celgene 
representative so that the accuracy and completeness may be checked. 
 
10.3. Institutional Review Board/Ethics Committee Approval 
 

2011-0254 
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The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used 
for obtaining informed consent, must also be in accordance with principles enunciated 
in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal 
Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional 
Review Boards. 
 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted 
by the Investigator to the IRB/EC for approval.  The Investigator is also responsible 
for notifying the IRB/EC of any serious deviations from the protocol, or anything else 
that may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and 
approved by the IRB/EC prior to use. 
 
10.4. Informed Consent 
 
The Investigator must obtain informed consent of a subject or his/her designee prior 
to any study related procedures as per GCPs as set forth in the CFR and ICH 
guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the 
study and the informed consent process should be recorded in the subject’s source 
documents.   
 
10.5. Study Records Requirements 
 
The Investigator must ensure that the records and documents pertaining to the 
conduct of the study  and the distribution of the study drug, that is copies of CRFs and 
source documents (original documents, data, and records [e.g., hospital records; 
clinical and office charts; laboratory notes; memoranda; subject’s diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate 
copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; 
subject files; and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be 

2011-0254 
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retained by the Investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  The Investigator agrees to adhere to the 
document/records retention procedures by signing the protocol. 
 
10.6. Premature Discontinuation of Study 
The responsible local clinical Investigator as well as Celgene has the right to 
discontinue this study at any time for reasonable medical or administrative reasons in 
any single center.  Possible reasons for termination of the study could be but are not 
limited to: 
10.6.1. Unsatisfactory enrollment with respect to quantity or quality. 
 
10.6.2. Inaccurate or incomplete data collection. 
 
10.6.3. Falsification of records. 
 
10.6.4. Failure to adhere to the study protocol 
 
References 
 
1. de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the 
Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300:765-767. 
2. Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-ab1 oncogene 
adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 
1983;306:239-242. 
3. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous 
leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 
1973;243:290-293. 
4. Grosveld G, Verwoerd T, van Agthoven T, et al. The chronic myelocytic cell line K562 
contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript. Mol Cell Biol. 
1986;6:607-616. 
5. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in 
chronic myelogenous leukaemia. Nature. 1985;315:550-554. 
6. Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D. The chronic 
myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. 
Science. 1986;233:212-214. 
7. Kloetzer W, Kurzrock R, Smith L, et al. The human cellular abl gene product in the 
chronic myelogenous leukemia cell line K562 has an associated tyrosine protein kinase 
activity. Virology. 1985;140:230-238. 
8. Shtivelman E, Lifshitz B, Gale RP, Roe BA, Canaani E. Alternative splicing of RNAs 
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9. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl 
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10. Peggs K, Mackinnon S. Imatinib mesylate--the new gold standard for treatment of 
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