Clinical trial NCT01720225
Conditions: Leukemia
Keywords: Leukemia Myelodysplastic syndromes MDS Low and Intermediate-1 Risk Disease Decitabine DAC Dacogen Azacitidine AZA 5-azacytidine 5-aza Vidaza 5-AZC AZA-CR Ladakamycin NSC-102816
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-11-06; Completion date: 2020-01-08
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to compare how two different drugs, decitabine and azacitidine, when given on a shorter than standard dosing schedule can help to control MDS. The safety of the drugs will also be studied.

Decitabine is designed to damage the DNA (the genetic material) of cells, which may cause cancer cells to die.

Azacitidine is designed to block certain proteins in cancer cells whose job is to stop the function of the tumor-fighting proteins. By blocking the "bad" proteins, the tumor-fighting genes may be able to work better. This could cause the cancer cells to die.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups:

* If you are in Group 1, you will receive decitabine by vein over about 1 hour.
* If you are in Group 2, you will receive azacitidine either as an injection under your skin or through a vein. If by vein, the infusion will take about an hour.

At first, there will be an equal chance of being assigned to either group. However, as the study goes on and more information becomes available, the chance of being assigned to the group that has shown the most effectiveness will increase. However, once you are already enrolled and assigned to a group, you will not be eligible to change groups.

Study Drug Administration:

Each cycle is 28 days.

You will receive the study drug on Days 1-3 of every cycle and you will receive at least 2 cycles of study drug.

Study Visits:

Every 7-14 days, blood (about 2 tablespoons) will be drawn for routine tests.

At the end of Cycle 2, you will have a bone marrow biopsy and/or aspirate to check the status of the disease. This will then be repeated every 2-4 cycles until any point that the disease appears to have responded to the study drug, then as often as the study doctor thinks is necessary. To collect a bone marrow biopsy/aspirate, an area of the hip bone is numbed with anesthetic, and a small amount of bone and/or bone marrow is withdrawn through a large needle.

After Cycle 3:

If the study doctor decides it is acceptable, you may be allowed to receive treatment from your local cancer doctor. However, you have to return to Houston at least every 3 months for your study visits.

The frequency of the visits will depend on what the doctor thinks is in your best interest.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Follow-Up Visits:

One (1) time every 3 months after your last dose of study drug, you will return to the clinic for a bone marrow aspiration to check the status of the disease.

Other Information:

You may be given other drugs to help prevent side effects. The study staff will tell you about these drugs, how they will be given, and the possible risks.

This is an investigational study. Decitabine and Azacitidine are both FDA approved and commercially available for use in patients with MDS.

Up to 120 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Patients randomized to receive Decitabine 20 mg/m2 by vein daily for 3 days (days 1-3) every 28 days. arm 2: Patients randomized to receive Azacitidine 75 mg/m2 subcutaneously or by vein daily for 3 days (days 1-3) every 28 days.
Interventions: intervention 1: Decitabine intervention 2: Azacitidine
Intervention descriptions: intervention 1: 20 mg/m2 by vein daily for 3 days (days 1-3) every 28 days. intervention 2: 75 mg/m2 subcutaneously or by vein daily for 3 days (days 1-3) every 28 days.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Phase II Randomized Study of Lower Doses of Decitabine (DAC; 20 mg/m2 IV 
daily for 3 days every month) versus Azacitidine (AZA; 75 mg/m2 SC/IV daily for 3 
days every month) in MDS Patients with Low and Intermediate-1 Risk Disease
2012-0507
Core Protocol Information
Short Title 
DAC vs AZA in MDS Patients with Low and Intermediate-1 
Risk
Study Chair: 
Elias Jabbour
Additional Contact:
Darla K. Miller
Sheri L. Rivera
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
OHSP DSMB
PDOL OPR DMC Addl Cont
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-7305
Unit:
0428
Full Title: 
Phase II Randomized Study of Lower Doses of Decitabine 
(DAC; 20 mg/m2 IV daily for 3 days every month) versus 
Azacitidine (AZA; 75 mg/m2 SC/IV daily for 3 days every 
month) in MDS Patients with Low and Intermediate-1 Risk 
Disease
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 03/02/2016
Version:
11
Document Status:
Saved as "Final"
Submitted by:
Sheri L. Rivera--2/12/2016 12:50:55 PM
OPR Action:
Accepted by:  Julie Arevalo -- 2/22/2016 8:53:25 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


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Phase II Randomized Study of Lower Doses of Decitabine (DAC; 20 mg/m2 IV daily 
for 3 days every month) versus Azacitidine (AZA; 75 mg/m2 SC/IV daily for 3 days 
every month) in MDS Patients with Low and Intermediate-1 Risk Disease 
 
 
I. OBJECTIVES 
Primary: 
Compare the response rates of two different drugs DAC versus AZA on an abbreviated 
schedule 
Secondary: 
Evaluate the durability of response, the overall and event-free survival rates, and the 
safety profile of 2 different drugs. 
 
II. RATIONALE 
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem-cell disorders 
characterized by ineffective hematopoiesis, peripheral-blood cytopenias, and increased 
tendency to progress to acute myeloid leukemia (AML).1 Median age of patients with 
MDS is approximately 70 years.2 This patient population is frequently affected by other 
comorbid conditions, a factor that often influences treatment decisions.  
 
Treatment of MDS is based on prognostic factors that predict survival and progression 
to AML. The most widely used prognostic system for therapeutic decision making is still 
the International Prognostic Scoring System.3 This system stratifies patients into the 


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following four groups: low, intermediate-1, intermediate-2, and high risk. Risk is based 
on number of cytopenias, percentage of bone marrow blasts, and karyotype. Low risk 
and intermediate-1 risk are usually grouped together as lower-risk disease, whereas 
intermediate-2 risk and high risk are grouped together as higher-risk disease. Several 
other factors have recently been shown to have prognostic value. These include, among 
others, the need for RBC transfusions4 and the presence of reticulin marrow fibrosis.5 
Analysis of recently identified genetic and immunophenotypic alterations has not yet 
been introduced in the therapeutic decision making of MDS.1 
 
The survival of patients with higher-risk MDS is significantly different than that of 
patients with lower-risk disease. Without intervention, median survival of higher-risk 
patients is close to 12 months.3 Survival of patients with lower-risk disease is more 
diverse and ranges from a few months (poor-prognosis, lower-risk disease) to more 
than a decade (Fig 1 and Tables 1 and 2).3,6 Risk of transformation to AML in lower-risk 
MDS is less than 30%.6 A recent analysis has indicated that most patients with lower-
risk MDS die from causes directly related to complications of MDS.7  
Therefore, the objectives of therapy are different in lower- versus higher-risk disease. In 
higher-risk MDS, treatment options should impact survival as a primary end point. In 
lower-risk MDS, therapies should be adapted to specific patient situation, including 
severity and type of cytopenias and expected survival.6 Therefore, in lower-risk MDS, 
therapies should have the capacity to improve transfusion needs and potentially 
survival.  
 


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Until recently, treatment approaches in patients with lower-risk MDS have focused on 
improving transfusion needs. It should be noted that we consider transfusions as part of 
supportive care in MDS. In general, patients with lower-risk MDS do not receive therapy 
until they become transfusion dependent. This notion could be challenged by the recent 
report that the prognosis of patients with lower-risk MDS is heterogeneous, ranging from 
9 months to more than a decade.6 This model may allow the identification of patients 
with lower-risk disease and poor prognosis (Fig 1). The question is whether the more 
aggressive treatment of these patients, can favorably change the natural history of this 
group of patients with poor prognosis and lower-risk disease.  
 
In MDS, tumor suppressor genes are silenced by the effects of irregular DNA 
hypermethylation.8-9 Two hypomethylating agents (HMA), decitabine at 20 mg/m2 IV 
daily for 5 days every months, and azacitidine at 75 mg/m2 IV/SC daily for 7 days every 
month, are approved for treatment of patients with higher-risk MDS.8-9 The use of the 
hypomethylating agent azacitidine, has been formally shown in a randomized clinical 
trial to improve survival of patients with higher-risk MDS.8  
 
We assessed the use of decitabine in patients with lower risk MDS. In a phase II trial, 
decitabine given at lower dose, 20 mg/m2  IV daily for 3 days every month induced an 
objective response rate of 23% in 43 patients with low and intermediate-1 risk disease. 
The median overall survival (OS) was not reached; about 70% of patients were alive at 
500 days. The safety profile was adequate.10  


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Results from a study investigating alternative SC azacitidine dosing schedules in lower-
risk patients with MDS suggested that a lower dose schedule (375 mg/m2 total dose) 
was beneficial.11   Furthermore, clinical responses were reported in patients who 
received oral azacitidine, a formulation proven to have lower drug exposure and DNA 
hypomethylation relative to SC azacitidine.  
 
Given our previous experience and considering the above data in support of lower 
doses regimen we propose to evaluate in a phase II Bayesian design the efficacy of 
DAC versus AZA in patients with low and intermediate-1 risk MDS. 
 
III. BACKGROUND DRUG INFORMATION 
A. Decitabine: 
Decitabine (Dacogen™, 5-aza-2’-deoxycytidine) is an analogue of the natural 
nucleoside 2’- deoxycytidine. It is believed to exert its antineoplastic effects after 
phosphorylation and direct incorporation into DNA and inhibition of DNA 
methyltransferase, causing hypomethylation of DNA and cellular differentiation or 
apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at 
concentrations that do not cause major suppression of DNA synthesis. In rapidly 
dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of 
covalent adducts between DNA methyltransferase and decitabine incorporated into 
DNA. Non-proliferating cells are relatively insensitive to decitabine. 
 


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In solid tumor patients who received 72-hour infusion of decitabine at 20 to 30 
mg/m2/day, decitabine pharmacokinetics were characterized by a biphasic disposition. 
The total body clearance (mean ± SD) was 124 ± 19 L/hr/m2, and the terminal phase 
elimination half-life was 0.51 ± 0.31 hr. The exact route of elimination and metabolic fate 
of decitabine is not known in humans. One of the pathways of elimination of decitabine 
appears to be deamination by cytidine deaminase found principally in the liver but also 
in granulocytes, intestinal epithelium and whole blood. In vitro studies in human liver 
microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 
enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate 
for the human liver cytochrome P450 enzymes. As plasma protein binding of decitabine 
is negligible (<1%), interactions due to displacement of more highly protein bound drugs 
from plasma proteins are not expected. 
 
Decitabine has been approved by the Food and Drug Administration (FDA) in the United 
States for treatment of patients with MDS including previously treated and untreated, de 
novo and secondary MDS of all French-American-British subtypes (refractory anemia, 
refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, 
refractory anemia with excess blasts in transformation, and chronic myelomonocytic 
leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic 
Scoring System (IPSS) groups. 
 


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The major toxicity is myelosuppression. Decitabine may also cause fever, cough, 
constipation, diarrhea, nausea, vomiting, edema, headache, insomnia and 
hyperglycemia. Rarely, decitabine can cause allergic reactions.4 
 
B. Azacitidine (AZA) 
Azacitidine, a ring analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and DNA synthesis and metabolism. Since the early 
1970s, azacitidine has been investigated in the US for the treatment of acute leukemia. 
Clinical trials have focused primarily on patients with disease refractory to conventional 
chemotherapy. These investigations indicated azacitidine has activity in the treatment of 
acute myelogenous leukemia (AML). Clinical trials subsequently have been conducted 
to evaluate the effects of azacitidine in a variety of other malignant and hematologic 
disorders, including solid tumors, hemoglobinopathies (thalassemia and sickle cell 
anemia), and myelodysplastic syndromes (MDS). 
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys. 
Most of the studies were performed during the 1970s and early 1980s according to 
existing guidelines and standards in place during that period. The nonclinical studies 
identified the bone marrow, liver, kidneys, and lymphoid tissues (spleen, lymph nodes) 
as the main target organs of toxicity. 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. The genotoxicity of azacitidine is consistent with that of other nucleoside 


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analogs that interact with nucleic acids. Likewise, similar to other agents with cytostatic 
properties, azacitidine was embryotoxic and reduced the reproductive performance in 
mice and rats. It is important to note that animal study data is superseded in many 
respects by the extensive clinical safety data collected in the last two decades. 
 
Limited azacitidine pharmacokinetic data are currently available. Based on plasma 
concentrations of total radioactivity (which represent 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. Azacitidine and/or 
its by-products are rapidly cleared by the kidneys. The half-lives and percent 
radioactivity recovered in urine are similar for the IV and SC routes of administration. 
The effects of renal or hepatic impairment, gender, age, and race on the 
pharmacokinetics of azacitidine have not been studied. 
 
In 1985, the Cancer and Leukemia Group B (CALGB) study investigators began clinical 
trials with azacitidine in MDS patients under the auspices of the National Cancer 
Institute (NCI). Results from the three studies conducted by the CALGB (Protocols 
8421, 8921, and 9221) have been published. The first two CALGB studies (Protocol 
8421 and Protocol 8921) were uncontrolled Phase 2 investigations. The most recent 
CALGB study (Protocol 9221) was a Phase 3 investigation that compared azacitidine to 
supportive care alone. The azacitidine dose investigated in the CALGB studies was 75 
mg/m2/day for 7 days, repeated on a 28-day cycle. Azacitidine was administered by 
continuous IV infusion in the first study (Protocol 8421), and by SC injection in the two 


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studies that followed. The dose was adjusted based on toxicity and clinical response. In 
the Phase 3 investigation (Protocol 9221), azacitidine produced higher response rates 
than supportive care alone. In addition, azacitidine prolonged the time to transformation 
to AML or death. 
 
The efficacy of azacitidine to treat MDS also was evaluated in 7 open-label studies 
conducted outside the CALGB protocols. The dosage regimen used in 6 of these 
studies was 75 mg/m2 given daily for 7 days every 3-4 weeks by SC injection in 4 
studies, SC or IV in 1 study, and the route was not specified in the last study. The 
dosage regimen used in the seventh study was 5-35 mg/m2/day given by continuous IV 
infusion for 14 days. The lowest response rate was found in this seventh study, which 
suggests the mechanism of 5-azacitidine’s activity requires repeated administration of a 
minimally effective dose to achieve improvement in hematologic parameters. 
 
As with other antimetabolites, bone marrow suppression (leukopenia, 
thrombocytopenia) is a common adverse event associated with azacitidine. However, 
myelosuppression generally occurs more often and with greater severity at doses higher 
than those used to treat MDS. Gastrointestinal toxicity (ie, nausea, vomiting, and 
diarrhea) can limit the dose of azacitidine in any patient population. Infrequent adverse 
effects include neuromuscular aches, generalized weakness, renal tubular acidosis, and 
liver enzyme abnormalities. Erythema and burning at the injection site can occur 
following SC administration, which usually resolves within 24-72 hours.  
 


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Azacitidine is approved for all patients with MDS using FAB criteria (up to 30% blasts). 
 
IV. Eligibility criteria 
Inclusion criteria: 
 Sign an IRB-approved informed consent document. 
 Age ≥18 years. 
 de novo or secondary IPSS low- or intermediate-1–risk MDS, including CMML 
 ECOG performance status of ≤ 3 at study entry. 
 Organ function as defined below: 
o Serum creatinine ≤ 3 x ULN 
o Total bilirubin ≤ 2 x ULN 
o ALT (SGPT) ≤ 2 x ULN  
 Women of childbearing potential must have a negative serum or urine pregnancy 
test within 7 days and will also need to use contraceptives. Men must agree not to 
father a child and agree to use a condom if his partner is of child bearing potential. 
 
Exclusion Criteria: 
 Breast feeding females 
 Prior therapy with decitabine or azacitidine 
 
V. Treatment plan 
1. Study design  


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Patients will be randomized to either arm on an even basis at the beginning, then, 
based on efficacy and following a Bayesian design, patients will be assigned to the 
superior arm.  
 
2. Treatment plan 
Patients will randomized to receive 
Decitabine 20 mg/m2  IV daily for 3 days (days 1-3) every 28 days 
or 
Azacitidine 75 mg/m2 SC or IV daily for 3 days (days 1-3) every 28 days 
 
Patients may receive their second course of therapy without interruption, regardless of 
their degree of myelosuppression. After the first course of therapy, the interval between 
subsequent cycles of therapy could be shortened or prolonged at the discretion of the 
investigator. Subsequent cycles can be given prior to peripheral blood count recovery if 
considered to be in the best interest for the patient and after discussion with the 
principal investigator and the discussion documented in the patient’s medical record. If 
study drug related prolonged myelosuppression (≥42 days of absolute neutrophil count 
[ANC] <1 x 109/L and platelet count <30 x 109/L) is observed after cycle 2, subsequent 
cycles may be given at the next lower dose (DAC, 15 mg/m2/day, then 10 mg/m2/day, 
then 5 mg/m2/day; AZA, 56 mg/m2/day, then 32 mg/m2/day, then 18 mg/m2/day) after 
recovery (ANC ≥1 x 109/L and platelet count >50 x 109/L) and subsequent cycles of 
AZA.  All patients may receive erythropoietin for hemoglobin <10 g/dL, and granulocyte-


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colony stimulating factor for fever of unknown origin, infection, and/or ANC <0.75 x 
109/L 
  
Dose reductions can also be made in other clinical situations where this step is 
considered to be in the best interest for the patient and after discussion with the 
principal investigator and the discussion documented in the patient’s medical record. 
The following table is a suggestion for dose modifications in subsequent treatment 
courses: 
Dose level 
AZA (mg/m2) 
DAC (mg/m2) 
 
 
-1 
56 
15 
 
 
-2 
37 
10 
 
 
-3 
18 
5 
 
 
 
VI. PRETREATMENT AND PER-TREATMENT EVALUATION 
Pre-treatment 
1. CBC, differential platelet count.  
Creatinine, bilirubin, ALT or AST, marrow aspirate with cytogenetics (if bone 
marrow not done within 1 month and cytogenetics (if previously abnormal) within 
3 months.  
2. Molecular Diagnostic MDS Panel 
3. MDS Flow Panel 
 
 


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During therapy 
1. CBC, differential, and platelet count once monthly (the differential may be 
omitted when the WBC is < 0.5 x 109/L.) 
2. Creatinine, bilirubin, ALT or AST once monthly.  
3. Marrow aspirate to confirm response, to be performed after cycle 2 then every 
2 to 4 cycles until response observed, then as clinically indicated  
4. Molecular Diagnostic MDS Panel, if previously abnormal, if possible. Not all 
samples will be collected at all times. 
5. Sequential MDS Flow Panel to be performed after cycle 2 then every 2 to 4 
cycles until response observed, then as clinically indicated. 
6. Conventional cytogenetics to be performed after cycle 2 then every 2 to 4 
cycles until response observed, then as clinically indicated. 
After Cycle 3 
If the study doctor decides it is acceptable, you may be allowed to receive treatment 
from your local cancer doctor. However, you have to return to Houston at least every 3 
months for one year, then every 6 months for your study visits for as long as the patient 
remains on study. 
 
Supportive care 
Supportive measures such as prophylaxis for tumor lysis syndrome, erythropoietin, 
analgesics, blood transfusions, antimicrobials and hematopoietic colony stimulating 
factors for treatment of cytopenias are permitted 
 


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VII. STUDY END POINTS 
Primary: 
1. Overall improvement rate (OIR), defined as complete remission (CR), partial 
remission (PR), marrow CR (mCR), or hematologic improvement (HI), measured 
at the end of each cycle using each patient’s best response with the 2 different 
agents. Response will be assessed using the modified International Working 
Group 2006 criteria.11 The best response within the first two cycles will be the 
OIR for each treatment arm that will be used in the adaptive randomization 
algorithm. 
 
Secondary: 
1. Transfusion independence (defined as being transfusion-free for ≥8 consecutive 
weeks between the first dose and study treatment discontinuation) 
2. Cytogenetic response 
3. Clinical benefit 
4. Duration of response 
5. Time to transformation into AML 
6. Overall survival 
7. Safety profile 
 
VII. CRITERIA FOR WITHDRAWAL 
Reasons for withdrawal include: 


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• Withdrawal of consent or the subject refuses to continue treatment and/or 
procedures/observations. 
• Relapse/progression unless the treating physician determines that the patient has 
achieved clinical benefit, at which time further therapy on protocol may be permitted 
with approval from the PI and the discussion documented in the patient’s medical 
record. 
• No response after at least 6 courses unless the treating physician determines that the 
patient has achieved clinical benefit, at which time further therapy on protocol may be 
permitted with approval from the PI and the discussion documented in the medical 
record.  
 Intercurrent illness preventing further administration of protocol treatment, 
 Unacceptable toxicity that in the opinion of the investigator makes continued 
therapy unsafe. 
VIII. CRITERIA FOR RESPONSE 
The response criteria recommended by the MDS International Working Group. 
Definitions: 
Complete Response (CR): 
Normalization of the peripheral blood and bone marrow with <5% bone marrow blasts, a 
peripheral blood granulocyte count > (1.0 x 109/ L, and a platelet count > 100 x 109/L). 
Partial response (PR): 
As above except for the presence of 6-15% marrow blasts, or 50% reduction if <15% at 
start of treatment. 
Marrow CR: 


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Blasts ≤ 5% and decrease by ≥ 50% from baseline (baseline blasts should be above 5% 
to be eligible for marrow CR) 
Hematologic Improvement (HI):  
Platelets increase by 50% and to above 30 x 109/L untransfused (if lower than that 
pretherapy); or granulocytes increase by 100% and to above 109/L (if lower than that 
pretherapy); or hemoglobin increase by 2 g/dl; or transfusion independent; or 
splenomegaly reduction by > 50%; or monocytosis reduction by > 50% if pretreatment > 
5 x 109/L. 
 
IX. REPORTING REQUIREMENTS 
All adverse and serious adverse events will be recorded and reported according to the 
Department of Leukemia guidelines (appendix C) 
X. Randomization 
The Department of Biostatistics will provide and maintain a website (“Clinical Trial 
Conduct”:  https://biostatistics.mdanderson.org/ClinicalTrialConduct/) for patients 
enrolled on this study. The Clinical Trial Conduct website resides on a secure server, 
and access is gained through usernames and passwords provided to personnel 
responsible for enrolling patients and updating patient data.  The website is 
accessed through a browser using secure socket layer (SSL) technology. Personnel 
responsible for enrolling patients on trials, which includes the principal 
investigator(s), research nurse(s), and data coordinator(s), will be trained by 
members of the Department of Biostatistics in the use of the trial website; the 
importance of timely updating of follow-up times and recording of events will be 
emphasized in training. 
 
XI. Data Safety Monitoring 
A data safety monitoring board (DSMB) at MD Anderson will monitor the 
trial for the safety. 
 


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XII. STATISTICAL CONSIDERATIONS 
General Description 
 
This is a Phase II open-label, efficacy and toxicity study of two treatment arms (lower 
doses of Decitabine versus Azacitidine) in subjects with low risk or intermediate-1 
myelodysplastic syndrome.  Patients will be enrolled to evaluate the 2 agents. In arm A, 
Decitabine (DAC) will be administrated 20mg/m2 IV daily for 3 days every 28 days and 
in treatment B Azacitidine (AZA) will be administrated 75mg/m2 SC or IV daily for 3 days 
every 28 days. For both arms, one course will be considered of 4 weeks. An adaptive 
randomization design will be employed to compare the efficacy between the two arms. 
The primary efficacy outcome is the overall improvement rate (OIR), defined as 
complete remission (CR), partial remission (PR), marrow CR (mCR), or hematologic 
improvement (HI), assessed after maximum of 2 cycles. At the end of the trial, we will 
estimate the probability that one arm is superior to the other. We will also evaluate 
toxicity on each arm. A maximum of 120 patients will be accrued, at an expected 
accrual rate of 3 patients per month. 
 
Study design 
 
Patients will be assigned to receive Decitabine or Azacitidine, using an adaptive 
procedure that bases assignment probabilities on observed results in preceding 
patients. At first, 20 patients will be assigned to each arm with equal probability. As 
efficacy data accrues, patient assignment to the two arms will become unbalanced in 
favor of the one that has the higher overall improvement rate (OIR). The OIR for both 
arms will be estimated with a 95% CI (similar to Bayesian highest posterior density 
interval). 
 
Based on previous studies, we expect an OIR of about 23% in both arms. Therefore, we 
assume OIR has a prior Beta distribution (0.46, 1.54) with mean 0.23. Let OIRa and 
OIRb denote the overall improvement rates for arm A and arm B, respectively. 
Beginning with the 21st patient in each arm and for each subsequent patient, we will 
compare OIRa with OIRb, incorporating data from all patients with evaluable response. 
In order to avoid favoring one arm earlier in a large trial, instead of assigning patients 
with posterior probability (Pa=Pr(OIRa>OIRb|data) and Pb=1-Pa), we use the following 
formula to assign patients: 
 
Aa=
Pb
Pa
Pa

,  Ab=1-Aa, where Aa is the probability of assigning patients to arm A,  
Ab is the probability of assigning patients to arm B, Pa is the posterior probability that 
arm A is superior to arm B and Pb is the posterior probability that arm B is superior to 
arm A. 
 
 


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If at any point during the trial Pr(OIRa>OIRb|data)>0.95(or <0.05) the schedule A(or B) 
will be selected as superior. If accruing information gives strong evidence that an OIR of 
23% or greater is unlikely to be true for any one of the treatment arms (Pr(OIRa or 
OIRb>0.23|data)<0.05), assignment to that arm will be stopped. If the maximum of 120 
patients is enrolled and evaluated and Pr(OIRa>OIRb|data)>0.9 (or <0.1), we will 
declare that arm A(or B) has a higher OIR rate than arm B (or A). Otherwise, the trial 
will be inconclusive. We used simulation (5,000 simulations per scenario) to evaluate 
the performance of the adaptive randomization procedure under several different 
scenarios (Table 2). There was an 86% power to select a superior arm (arm B) if the 
OIR rates are 20% and 40%, respectively. 
 
Toxicity Monitoring 
 
Evidence of Toxicity will be monitored closely in all patients. For each arm, treatment 
will be terminated if Pr( non hematological grade 3 or higher Toxicity >0.2 | data)  >0.95, 
and the toxicity rate is assumed to follow a non-informative prior of Beta(0.4,1.6).  Table 
1 shows the simulation of the trial.  The treatment will be stopped if the number of 
patients with study drug related toxicities equal to or greater than indicated (i.e., #pts 
with tox) among the number of patients accrued (i.e., #pts): 4/5, 5/10, 7/15, 8/20, 9/25, 
11/30, 12/35, 13/40, 15/45, 16/50, 17/55, 18/60, 19/65, 21/70, 22/75, 23/80, 24/85, 
26/90, 27/95, 28/100, 29/105, 30/110, 31/115, 33/120.  
 
Table 1: Operating characteristics 
of Safety Monitoring (based on 
10000 simulations) 
True 
probability 
Stop 
probability 
Average 
sample 
size 
0.15 
0.02 
117.7 
0.2 
0.15 
108.1 
0.25 
0.51 
83.3 
0.3 
0.87 
53 
 
 
 
Table 2: Operating characteristics of adaptive randomization design to compare DAC with 
AZA. Randomly assign 20 patients to each arm with equal probability before adapting the 
randomization, tuning parameter of 0.5, and accrual rate of 3 patients/month. 
 
 
 
Arm A 
Arm B 
OIR Rate 
0.05 
0.1 
Expected # of 
Patients 
20.8 
20.9 
Pr(Select) 
0.03 
0.23 


2012-0507 
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18 
 
Pr(Select Early) 
0.01 
0.11 
Pr(Stop Early) 
0.85 
0.51 
 
 
 
OIR Rate 
0.1 
0.23 
Expected # of 
Patients 
25.5 
28.7 
Pr(Select) 
0.02 
0.52 
Pr(Select Early) 
0.01 
0.38 
Pr(Stop Early) 
0.86 
0.13 
 
 
 
OIR Rate 
0.2 
0.4 
Expected # of 
Patients 
28.9 
35.9 
Pr(Select) 
0.01 
0.86 
Pr(Select Early) 
0.01 
0.81 
Pr(Stop Early) 
0.85 
0.01 
 
 
 
OIR Rate 
0.23 
0.23 
Expected # of 
Patients 
44.3 
44 
Pr(Select) 
0.17 
0.18 
Pr(Select Early) 
0.13 
0.13 
Pr(Stop Early) 
0.26 
0.24 
 
 
 
OIR Rate 
0.3 
0.5 
Expected # of 
Patients 
30.7 
38.6 
Pr(Select) 
0.01 
0.85 
Pr(Select Early) 
0.01 
0.81 
Pr(Stop Early) 
0.81 
0.01 
 
 
 
 
Analysis Plan 
Data analysis will be performed using SAS or S-plus, as appropriate. All patients will be 
included in the intent-to-treat analysis for efficacy.  Demographic and disease 
characteristics of the patients at registration will be summarized using descriptive 
statistics such as mean, standard deviation (SD), median and range. The OIR for both 
arms will be estimated by Bayesian posterior estimates, along with the 95% credible 
intervals. The posterior probability that one treatment is better than the other will be 
computed, and the 95% credible interval of the posterior probability will also be 
estimated. Time to event end points, such as response duration, overall survival and 


2012-0507 
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19 
 
event-free survival, will be analyzed by the Kaplan-Meier method, the log-rank tests and 
the Cox proportional hazards models. 
 
XI. References: 
1. Nimer SD (2008) Myelodysplastic syndromes. Blood 111:4841–4851. 
2. Rollison DE, Howlader N, Smith MT, et al. (2008) Epidemiology of 
myelodysplastic syndromes and chronic myeloproliferative disorders in the 
United States, 2001-2004, using data from the NAACCR and SEER programs. 
Blood 112:45–52. 
3. Greenberg P, Cox C, LeBeau MM, et al. (1997) International scoring system for 
evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088. 
4. Malcovati L, Porta MG, Pascutto C, et al. (2005) Prognostic factors and life 
expectancy in myelodysplastic syndromes classified according to WHO criteria: A 
basis for clinical decision making. J Clin Oncol 23:7594–7603. 
5. Della Porta MG, Malcovati L, Boveri E, et al. (2009) Clinical relevance of bone 
marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic 
syndromes. J Clin Oncol 27:754–762. 
6. Garcia-Manero G, Shan J, Faderl S, et al. (2008) A prognostic score for patients 
with lower risk myelodysplastic syndrome. Leukemia 22:538–543. 
7.  Dayyani F, Conley AP, Strom SS, et al. (2010) Cause of death in patients with 
lower-risk myelodysplastic syndrome. Cancer 116:2174–2179. 
8. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. (2009) Efficacy of azacitidine 
compared with that of conventional care regimens in the treatment of higher-risk 


2012-0507 
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20 
 
myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet 
Oncol 10:223–232. 
9. Kantarjian HM, O'Brien S, Huang X,  et al. (2007) Survival advantage with 
decitabine versus intensive chemotherapy in patients with higher risk 
myelodysplastic syndrome: Comparison with historical experience. Cancer 
109:1133–1137 
10. Garcia-Manero G, Couriel D, Tambaro F, et al. (2009) A phase II randomized 
bayesian study of very low dose subcutaneous decitabine administered daily or 
weekly times three in patients with lower risk myelodysplastic syndrome (MDS) 
Blood 114:119, (abstr). 
11. Lyons RM, Cosgriff TM, Modi SS, et al. (2009) Hematologic response to three 
alternative dosing schedules of azacitidine in patients with myelodysplastic 
syndromes. J Clin Oncol 27:1850–1856. 
12. 1.  J. Kyle Wathen and John D. Cook. Power and bias in adaptively randomized clinical 
trials (2006). Technical Report UTMDABTR-002-06. 
 
13. 2.  Peter F. Thall and Jay K. Wathen, Practical Bayesian Adaptive Randomization in 
Clinical Trials (December 2006). UT MD Anderson Cancer Center Department of 
Biostatistics Working Paper Series. Working Paper 31.  
 
 
 
 
Figure 1.  


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2012-0507 
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22 
 
Table 1. Prognostic Model of Lower-Risk Myelodysplastic Syndrome: Multivariate 
Analysis Poor-Prognosis Parameters and Assigned Score 
Adverse Factor 
P 
Assigned Score
Unfavorable cytogenetics < .001 1 
Age ≥ 60 years 
< .001 2 
Hgb < 10 g/dL 
< .001 1 
Plt, ×109/L  
 
 
    < 50 
< .001 2 
    50-200 
< .001 1 
BM blasts ≥ 4% 
< .001 1 
 
 
 
 
 
 
 
 
 
 
 
 
 


2012-0507 
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23 
 
Table 2. Prognostic Model of Lower-Risk Myelodysplastic Syndrome: Estimated 
Survival Outcome Within Each Score Range 
Score No. of PatientsMedian Survival (months)4-Year Survival Rate (%) 
0 
11 
NR 
78 
1 
58 
83 
82 
2 
113 
51 
51 
3 
185 
36 
40 
4 
223 
22 
27 
5 
166 
14 
9 
6 
86 
16 
7 
7 
13 
9 
NA