Conditions: Leukemia
Keywords: Leukemia Myelodysplastic syndrome MDS Low or intermediate-1 risk Transfusion-dependent Transfusion-independent Best supportive care BSC Azacitidine 5-Azacytidine 5-AZA Vidaza 5-AZC AZA-CR Ladakamycin NSC-102816 Azacytidine Decitabine Dacogen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 185
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to compare how 2 different drugs, decitabine and azacitidine, when given on a shorter than standard dosing schedule, may help to control MDS. The safety of each study drug given on these schedules will also be studied.

This is an investigational study. Decitabine and azacitidine are both FDA approved and commercially available for use in patients with MDS. Giving these drugs on a different schedule than is standard is considered investigational.

The study doctor can tell you how the study drugs are designed to work.

Detailed description:
Study Groups and Study Drug Administration:

Each cycle is approximately 28 days.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to 1 of 4 groups:

* If you are in Group 1, you will receive decitabine by vein over about 1 hour on Days 1-3 of every cycle.
* If you are in Group 2, you will receive azacitidine either as an injection under your skin or by vein on Days 1-3 of every cycle.
* If you are in Group 3, you will receive azacitidine either as an injection under your skin or by vein on Days 1-5 of every cycle.
* If you are in Group 4, you will receive the standard of care. The study doctor can explain the treatment you will receive and the risks involved.

Transfusion-dependent participants will be randomly assigned to 1 of 3 groups

This is done because no one knows if one study group is better, the same, or worse than the other group. If you are among the first 20 participants, you will have an equal chance of being in any of the groups. If you enroll after that, you will have a higher chance of being assigned to the group that has had better results.

However, once you are assigned to a group, you will not be allowed to change groups.

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.

Study Visits:

One (1) time each month, blood (about 2 tablespoons) will be drawn for routine tests.

At the end of Cycle 2, then every 3 cycles for the first year, then every 6 cycles, you will have a bone marrow biopsy and/or aspirate to check the status of the disease and for cytogenetic testing.

After Cycle 1, if the study doctor decides it is acceptable, you may be allowed to receive treatment from your local cancer doctor. However, you must return to Houston at least every 3 cycles for study visits. How often these visits will occur will depend on what the doctor thinks is in your best interest.

Length of Study:

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

Follow-Up:

When you are off-treatment, every 6 -12 months for up to 5 years, you will be called by a member of the study staff. You will be asked about any side effects you may be having. The phone calls will take about 5-10 minutes.

Arms:
arm 1: Azacitidine (AZA) Azacitidine 75 mg/m2 by vein or subcutaneously daily for 3 days (days 1-3) approximately every 28 days. arm 2: Azacitidine (AZA) 75 mg/m2 by vein or subcutaneously daily for 5 days (days 1-5) approximately every 28 days. arm 3: Decitabine 20 mg/m2 by vein for 3 days (days 1-3) approximately every 28 days. arm 4: Participants receive standard of care as chosen by study doctor. Best supportive care for transfusion-independent participants only.

Interventions: intervention 1: Azacitidine (AZA) Days 1 - 3 intervention 2: Decitabine (DAC) intervention 3: Best Supportive Care (BSC) intervention 4: Azacitidine (AZA) Days 1 - 5
Intervention descriptions: intervention 1: Azacitidine 75 mg/m2 by vein or subcutaneously daily for 3 days (days 1-3) approximately every 28 days. intervention 2: Decitabine 20 mg/m2 by vein for 3 days (days 1-3) approximately every 28 days. intervention 3: Participants receive standard of care as chosen by study doctor. Best supportive care for transfusion-independent participants only. intervention 4: Azacitidine 75 mg/m2 by vein or subcutaneously daily for 5 days (days 1-5) approximately every 28 days.

Protocol document:
Prot_SAP_000.pdf: 
 
 
2014-0112 
October 19, 2016 
1 
 
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) versus Azacitidine (AZA; 75 mg/m2 SC/IV daily for 5 days every 
month) in MDS Patients with Low and Intermediate-1 Risk Disease Transfusion-
Dependent versus Best Supportive Care (BSC) in MDS Patients with Low and 
Intermediate-1 Risk Disease Transfusion-Independent  
 
 
 
 
 
 
Study Chair 
Guillermo Garcia-Manero, MD 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 428 
Houston, TX 77030-4009 
713.745.3428 
ggarciam@mdanderson.org 
 
 
Co-Chair 
Elias Jabbour 
The University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 428 
Houston, TX 77030-4009 
713-792-4764 
713-563-7746 
ejabbour@mdanderson.org 
 
I. OBJECTIVES 
Primary: 
Compare the event-free survival rates of two different drugs: DAC versus AZA on an 
abbreviated schedule to a standard arm of AZA given over 5 days in patients with low-
risk MDS transfusion-dependent and to BSC in patients with low-risk MDS transfusion-
independent.  
 


 
 
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Secondary: 
Compare the response rates for the transfusion independent and the transfusion 
dependent patients. For example the response rate of two different drugs DAC versus 
AZA on abbreviated schedule to a standard arm of AZA given over 5 days.  
 
Evaluate the durability of response, the overall and transformation-free survival rates, 
and the safety profile of 2 different drugs. 
 
The quality of life protocol (2014-0636) titled “Interventional Validation of an MDS-
Specific Measure of Quality of Life:  Assessing the Responsiveness of the QUALMS-1 
to Different Hypomethylating Agent Regimens for Low and Intermediate Risk Disease” 
was written specifically as a companion study to protocol 2014-0112 and may be 
offered as an optional assessment to patients enrolled onto this protocol. 
 
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 


 
 
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the International Prognostic Scoring System.3 This system stratifies patients into the 
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, 


 
 
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therapies should have the capacity to improve transfusion needs and potentially 
survival.  
 
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 Furthermore, azacitidine given 
over 5 days was found to be equivalent to a regimen given over 7 days in a phase II 
randomized trial.11  
 


 
 
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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  
 
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.  
 
We have recently initiated a phase II randomized trial comparing decitabine to 
azacitidine given in an abbreviated way of 3 days in patients with low-risk MDS. So far, 
34 patients were enrolled (19 treated with azacitidine and 15 with decitabine). 24 
patients are evaluable for response. The response rates were 31% and 36% for patients 
treated with azacitidine and decitabine respectively with no significant toxicity.     
 
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 versus standard AZA (5 days) in patients with low and intermediate-1 
risk MDS transfusion-dependent versus BSC in patients with low and intermediate-1 risk 
MDS transfusion-independent . 


 
 
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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. 
 
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 


 
 
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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. 
 
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 


 
 
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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 
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. 


 
 
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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 
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 


 
 
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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.  
 
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. 
 IPSS low- or intermediate-1–risk MDS, including CMML-1 
 ECOG performance status of ≤ 3 at study entry. 
 Organ function as defined below: 
o Serum creatinine ≤ 2 mg/dL  
o Total bilirubin ≤ 2 x ULN 
o ALT (SGPT) ≤ 2 x ULN  
o AST (SGOT) </= 2 x ULN 


 
 
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 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  
Transfusion-dependent subjects will be randomized to AZA 75 mg/m2 IV/SC for 5 days, 
AZA 75 mg/m2 IV/SC for 3 days, or DAC 20 mg/m2 IV for 3 days on an even basis at the 
beginning, then, based on efficacy and following a Bayesian design, patients will be 
assigned to the superior arm.  
 
Transfusion-independent subjects will be randomized to either BSC or one of the 3 
arms mentioned above on an even basis at the beginning, then, based on efficacy and 
following a Bayesian design, patients will be assigned to the superior arm. 
 
Transfusion-independent subjects assigned to BSC will be assigned to one of the 3 
above arms once they start requiring blood transfusion. That would be considered an 
event.  
 


 
 
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Transfusion-dependent group will be defined as patients requiring blood transfusion for 
MDS or CMML-1 at any time.  
 
2. Treatment plan 
Patients will be randomized to receive: 
Decitabine 20 mg/m2 IV daily for 3 days (days 1-3) approximately every 28 days 
or 
Azacitidine 75 mg/m2 SC or IV daily for 3 days (days 1-3) approximately every 28 days 
or 
Azacitidine 75 mg/m2 SC or IV daily for 5 days  (days 1-5) approximately every 28 days 
or 
BSC (for transfusion-independent subjects only) 
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  37 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 


 
 
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AZA.  Granulocyte-colony stimulating factor for fever of unknown origin, infection, and/or 
ANC <0.75 x 109/L can be administered. 
 
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: 
 
Table 1: Dose levels adjustment 
Dose level 
AZA (mg/m2) 
DAC (mg/m2) 
 
 
-1 
56 
15 
 
 
-2 
37 
10 
 
 
-3 
18 
5 
 
 
 
VI. BASELINE AND PER-TREATMENT EVALUATION 
Baseline 
1.   A complete history and physical examination within 14 days prior to study entry.  
2. CBC, differential platelet count.  
3. Creatinine, bilirubin, ALT or AST,  
4. Bone marrow aspirate and/or biopsy with cytogenetics (if bone marrow not done 
within 6 weeks and cytogenetics (if previously abnormal) within 3 months prior to 
study entry. 


 
 
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5. Serum or urine pregnancy test within 7 days of treatment start for women of 
childbearing potential  
6. Documentation of frequency of transfusions (PRBC and Platelets) prior to start of 
each cycle 
7. Documentation of any prior administration of growth factors and ESA 
Prestudy laboratory tests must be obtained within 14 days of registration. 
 
 
During therapy 
1. CBC, differential, and platelet count once monthly prior to start of each cycle 
(the differential may be omitted when the WBC is < 0.5 x 109/L) 
2. Creatinine, bilirubin, ALT or AST once monthly prior to start of each cycle.  
3. Bone marrow aspirate and/or biopsy to confirm response, to be performed 
after cycle 2 then every 3 cycles for the first year, then every 6 cycles thereafter. 
All bone marrows will be performed by the registering center, not in the local MD 
office. 
4. Conventional cytogenetics to be performed after cycle 2 then every 3 cycles 
for the first year, then every 6 cycles thereafter 
5. Documentation of frequency of transfusions (PRBC and Platelets) prior to start 
of each cycle.  
6. Documentation in the medical record of any grade 3 or higher possibly, 
probably, definitely related adverse events that have occurred prior to start of 
each cycle. For guidelines on SAE Reporting and AE entry for Case Report 


 
 
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Forms (CRF), please refer to Appendix A (for MD Anderson) and Appendix G (for 
Participating Institutions). 
 
7. Documentation of any prior administration of growth factors and ESA prior to 
start of each cycle 
 
Table 2: Evaluation 
Test 
Pre-treatment 
During treatment 
CBC, differential platelet count 
within 14 days of 
treatment start 
Monthly prior to start of each cycle (+/- 7 days) 
Creatinine, bilirubin, ALT or AST 
within 14 days of 
treatment start 
Monthly prior to start of each cycle (+/- 7 days) 
Bone marrow aspirate 
 
Within 6 weeks 
prior to study 
entry 
after cycle 2 then prior to every 3 cycles for the 
first year, then prior to every 6 cycles thereafter 
Cytogenetics 
Within 3 months 
prior to study 
entry 
after cycle 2 then prior to every 3 cycles for the 
first year, then prior to every 6 cycles thereafter 
Serum or urine pregnancy test for 
woman of childbearing potential 
within 7 days of 
treatment start  
 
Transfusion history documented 
Prior to study 
entry 
Prior to start of each cycle 
Growth factors and ESA 
documentation 
Prior to study 
entry 
Prior to start of each cycle 
 
 
Follow-Up 
Following completion of active treatment and while still on study, patients will be 
followed for survival approximately every 6 to 12 months for up to 5 years. This follow 
up can either be done as a visit to the study doctor’s clinic or via telephone call to the 
patient. 
 
 


 
 
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Chemotherapy administration 
If the study doctor decides it is acceptable, enrolled subjects may be allowed to receive 
treatment from their local cancer doctor following cycle 1 (appendix B). However, 
enrolled subjects will have to return to the study doctor’s clinic at least every 3 cycles for 
study visits. 
 
Supportive care 
Supportive measures such as prophylaxis for tumor lysis syndrome, analgesics, blood 
transfusions, antimicrobials and G-CSF for fever/infection are permitted as clinically 
indicated. Growth factor and ESA administration while on study will be documented. 
 
VII. STUDY END POINTS 
Primary: 
1. Event-free survival rates of two different drugs DAC versus AZA on an 
abbreviated schedule and a standard arm of AZA given over 5 days in patients 
with low-risk MDS transfusion-dependent and to BSC in patients with low-risk 
MDS transfusion-independent. Events are defined as no response, loss of 
response, progression to higher risk category MDS, transformation to AML, 
discontinuation of therapy due to side effects, or death.  
Secondary: 
1. Overall improvement rate (OIR), defined as complete remission (CR), partial 
remission (PR), marrow CR (mCR), or hematologic improvement (HI), measured 
using each patient’s best response with the 2 different agents. Response will be 


 
 
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assessed using the modified MDS International Working Group 2006 criteria. 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. 
2. Transfusion independence (defined as being transfusion-free for ≥8 consecutive 
weeks between the first dose and study treatment discontinuation)  
3. Cytogenetic response, if applicable 
4. Clinical benefit 
5. Duration of response 
6. Time to transformation into AML 
7. Overall survival 
8. Safety profile 
 
VII. CRITERIA FOR WITHDRAWAL 
Reasons for withdrawal include: 
• 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 


 
 
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record. A bone marrow biopsy and/or aspirate is required to confirm that the patient has 
not achieved a response. 
• 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 2006. 
Responses must be verified, documented, and signed in the local medical record by the 
local PI.  (Patients are considered non evaluable if they have received less than 2 
courses of treatment, unless there is clear disease progression.) 
Definitions: 
Complete Response (CR): 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines; persistent 
dysplasia will be noted  
 Peripheral blood:  
     Hgb ≥ 11 g/dL   
     Platelets ≥ 100 × 109/L   
     Neutrophils ≥ 1.0 × 109/L 
     Blasts 0%   
Partial response (PR): 
All CR criteria if abnormal before treatment except:  bone marrow blasts decreased by ≥ 
50% over pretreatment but still > 5% 


 
 
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Marrow CR: 
Blasts ≤ 5% and decrease by ≥ 50% from baseline (baseline blasts should be above 5% 
to be eligible for marrow CR) 
Hematologic Improvement (HI): (responses must last at least 8 weeks) 
Erythroid response [HI-E; (if pretreatment Hgb < 11 g/dL)]; Hgb increase by ≥ 1.5 
g/dL; Relevant reduction of units of RBC transfusions by an absolute number of at least 
4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the 
previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will 
count in the RBC transfusion response evaluation. 
Platelet response [HI-P; ((if pretreatment Platelet count < 100 x 109 /L)]: Absolute 
increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L platelets, or  increase 
from < 20 × 109/L to > 20 × 109/L and by at least 100%. 
Neutrophil response [HI-N; (pretreatment, ANC < 1.0 × 109/L)]: At least 100% increase 
and an absolute increase > 0.5 × 109/L 
Progression/Relapse after hematological improvement:  ≥1 of the following:  ≥50% 
decrement from maximum response levels in granulocytes or platelets; ↓ in Hgb by ≥1.5 
g/dL; transfusion dependence 
Stable Disease: Not satisfying criteria for Complete Remission, Partial Response, 
Marrow CR, Hematologic Improvement or Progression/Relapse.  
 
IX. REPORTING REQUIREMENTS 
All adverse and serious adverse events will be recorded and reported according to the 
Leukemia-Specific Adverse Events (appendix A).  The MD Anderson Leukemia 


 
 
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20 
 
Department will report SAEs in accordance with MD Anderson IRB policies and 
procedures and Appendix A of the protocol. 
Participating Multicenter Institutions SAE requirements will be followed as written in the 
Data Quality Management Plan. 
 
X. Randomization 
The Department of Biostatistics at MD Anderson 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. 
 
XII. STATISTICAL CONSIDERATIONS 
General Description 
 


 
 
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21 
 
This is an adaptive randomized phase II trial for low-risk MDS patients. Regarding the 
patients transfusion status, patients can be categorized as transfusion dependent and 
transfusion independent patients. It is expected that there will be half of the transfusion-
dependent patients and half of transfusion-independent patients. For transfusion 
dependent patients, the goal is to compare three treatment arms: 1) DAC, 2) AZA3 
(treatment of 3 days), and 3) AZA5 (treatment of 5 days). For transfusion independent 
patients, the goal is to compare four treatment arms: 1) best supportive care (BSC) 2) 
DAC, 3)AZA3 (treatment of 3 days), and 4) AZA5 (treatment of 5 days). The primary 
outcome is event free survival (EFS) defined as the time from beginning of treatment till 
an event occurs or last follow-up. For transfusion independent patients, the events 
includes lack of response, requirement of blood transfusion, progression to advanced 
stages of disease, transformation into AML, discontinuation of therapy due to side 
effects, and death. The patients who change from transfusion independence to 
transfusion dependence under BSC will be enrolled in transfusion-dependent group and 
adaptively assign to the three treatment arms, that is, DAC, AZA3, or AZA5. For 
transfusion dependent patients, the events includes lack of response, progression to 
advanced stages of disease, transformation into AML, discontinuation of therapy due to 
side effects, and death. 
 
Study design 
The maximum number of patients accrued will be 240. There will be two parallel 
adaptive randomization trials for transfusion dependent  (N=120) and transfusion 
independent (N=120) patients respectively. Since we are expecting patients under BSC 


 
 
2014-0112 
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22 
 
will eventually become the transfusion dependent, it is assumed that initially there will 
be 120 patients under transfusion-dependent group, and the total number increases to 
about 150 after enrolling the approximate 30 patients under BSC. 
 
 Part I Transfusion dependent patients (N=150) 
Design 
Patients will be randomized using a Bayesian adaptive algorithm. Patients will be 
randomized fairly among the three arms at the start of the trial (for the first 30 patients), 
that is, 10 patients per arm. Thereafter, as the trial progresses and data accrue, the 
randomization will become unbalanced in favor of the treatment that, on average, has 
better results in terms of event free survival. Therefore, each successive patient is more 
likely to receive the treatment with better results, on average. A minimum of 30 and a 
maximum of 150 patients will be accrued. There will be 12 months follow up after the 
last patient is accrued with an anticipated accrual rate of 5 patients per month. 
 
Denote the event free survival for the patients in the three arms (DAC; AZA3; AZA5) as 
Ti for i=1,2,3. Assume the Ti is independent exponential with median µi. And each µi 
independently follows an inverse gamma distribution with parameter α=2.05, β=7.34. 
The parameters were chosen to set the mean of the prior equal to 7 (the historical 
median EFS in months) and a variance of 1000. For each patient, the randomization 
probability for treatment arm i will be based on the posterior probability that it has the 
largest median EFS. For example, for arm 1, the posterior probability is π1=Pr(µ1> µi) for 
i=2,3. In order to avoid aggressively favoring one arm too early in a large trial, instead of 


 
 
2014-0112 
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23 
 
assigning patients with posterior probability, we use its square root transformation as in 
the following formula to assign patients: 
 
Aa=
3
2
1
1






,  where Aa is the probability of assigning patients to arm 1,  π1 is 
the posterior probability that arm 1 is superior, etc. 
 
If at any point during the trial Pr(µi>max{uj, for all j ≠i} |data) > 0.975, the trial will be 
terminated and treatment i will be selected as superior.  If at any point during the trial 
Pr(µi>max{uj, for all j ≠ i} |data)<0.025, then accrual to the arm i will be suspended, 
and will be reopen if in the future, the changes in other arms make this probability 
Pr(µi>max{uj, for all j ≠ i} |data) ≥ 0.025.  If the maximum accrual is reached and Pr 
(µi>max{uj, for all j ≠i }|data) > 0.8 (< 0.2), treatment i will be selected as superior 
(inferior).  A treatment arm will be dropped at any point during the trial if Pr(µi > 7 
|data) < 0.1, for i=1,2,3. Table 3 given below summarizes operating characteristics of 
the design. The historical median EFS is assumed to be  7 months with the accrual 
rate of 5 patients per month. The trial will be stopped early and a treatment selected 
as being “better” if the probability that one treatment’s median EFS is larger than the 
other’s EFS exceeds 0.975. If the trial does not stop early and the maximum 150 
patients are accrued, a treatment is selected as being “better” if the probability that 
one treatment’s median EFS is larger than the other’s EFS exceeds 0.8. A treatment 
arm will be dropped at any point during the trial if the probability that the treatment’s 
median EFS is larger than 7 months is less than 0.1. The “# of patients treated” row is 


 
 
2014-0112 
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24 
 
the average number of patients treated on a given arm under the given scenario. 
When the medians all equal to 7 months (scenario 1), the probability of selecting one 
of the three arms (i.e., a false positive result) is at most 9.8%. The probability of 
selecting the best treatment (i.e., a true positive result) for scenario 2, when the 
medians EFS are 7, 7, and 12 months for the arms, respectively, are 0.7%, 0.7%, 
and  88%. 
Table 3: simulation results (simulation=5000) for transfusion dependent patients  
with the minimum randomization probability set as 0.1 and tuning parameter as 0.5 
 
 
treatment 
 
 
 
 
DAC 
AZA3 
AZA5 
1 
True Median EFS 
7 
7 
7 
 
# of patients treated 
40.1 
40.6 
40.5 
 
Pr(selected) 
0.086 
0.095 
0.098 
 
Pr(selected early) 
0.003 
0.006 
0.005 
 
Pr (stopped early) 
0.321 
0.317 
0.316 
 
 
 
 
 
2 
True Median EFS 
7 
7 
12 
 
# of patients treated 
28.5 
28.6 
54.2 
 
Pr(selected) 
0.007 
0.007 
0.88 
 
Pr(selected early) 
0.0002 
0.001 
0.188 
 
Pr (stopped early) 
0.806 
0.814 
0.028 
 
 
 
 
 
3 
True Median EFS 
3 
3 
3 
 
# of patients treated 
10.5 
10.5 
10.5 
 
Pr(selected) 
0.046 
0.043 
0.045 
 
Pr(selected early) 
0.001 
0.001 
0.001 
 
Pr (stopped early) 
0.779 
0.779 
0.777 
 
 
 
 
 
4 
True Median EFS 
7 
9 
14 
 
# of patients treated 
23.6 
36.2 
57.4 
 
Pr(selected) 
0.003 
0.013 
0.882 
 
Pr(selected early) 
0.0002 
0.003 
0.217 
 
Pr (stopped early) 
0.921 
0.686 
0.0162 
 
 
 
 
 
5 
True Median EFS 
7 
12 
12 
 
# of patients treated 
23.1 
56.6 
55.6 
 
Pr(selected) 
0.001 
0.242 
0.235 
 
Pr(selected early) 
0.0002 
0.04 
0.036 
 
Pr (stopped early) 
0.877 
0.12 
0.13 


 
 
2014-0112 
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25 
 
 
 
 
 
 
6 
True Median EFS 
4 
7 
12 
 
# of patients treated 
13.3 
29.5 
45.3 
 
Pr(selected) 
0.001 
0.014 
0.883 
 
Pr(selected early) 
0 
0.002 
0.357 
 
Pr (stopped early) 
0.994 
0.866 
0.036 
 
 
 
 
 
7 
True Median EFS 
4 
7 
10 
 
# of patients treated 
13.9 
34.1 
48.1 
 
Pr(selected) 
0.001 
0.039 
0.757 
 
Pr(selected early) 
0 
0.004 
0.194 
 
Pr (stopped early) 
0.987 
0.661 
0.083 
 
 
Toxicity Monitoring 
 
Evidence of toxicity will be monitored closely for all patients. As expected, there will be 
150 transfusion-dependent patients enrolled which includes the 120 patients initially 
recruited and another 30 patients who have changed from transfusion independence to 
dependence. With 10 patients fairly randomized to each arm, there will be at most 120 
patients being adaptively assigned to any of the three arms. Taking the initial 10 
patients assigning to each arm, the maximum number of patient per treatment arm will 
be 130.  For each treatment, treatment will be terminated if Pr((E >0.2 | data)  >0.9, 
where E is the proportion of any grade 3 or higher treatment related non-hematologic 
toxicities. It is assumed to follow a non-informative prior of Beta (0.4, 1.6)   That is, the 
trial will be terminated if at any time during the study, there is a more than 90% chance 
that the average rate of grade 3 or greater treatment related non-hematologic toxicity is 
more than 20%. Patients will be monitored by a cohort size of 10 according to the 
following stopping boundaries for toxicity. The design software Multc Lean Desktop 
(version 2.1) developed by the Department of Biostatistics at M. D. Anderson Cancer 


 
 
2014-0112 
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26 
 
Center (MDACC) was used to generate the futility/toxicity stopping boundaries and the 
OC table. 
 
 
Table 4: stopping boundaries for toxicity 
 
Number of patients 
evaluated 
Stop the trial if there are 
this many treatment 
related toxicities 
10 
5-10 
20 
7-20 
30 
10-30 
40 
12-40 
50 
15-50 
60 
17-60 
70 
19-70 
80 
21-80 
90 
24-90 
100 
26-100 
110 
28-110 
120 
30-120 
  
 
 
 
Table 5: Operating characteristics of safety monitoring  
True Toxicity Rate 
Prob (stop the trial early) 
0.15 
0.04 
 0.2 
0.25 
0.25  
0.68 
 0.3 
0.94 
 
    
Part II: Transfusion independent patients (N=120) 


 
 
2014-0112 
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27 
 
 
Design 
 
Patients will be randomized using a Bayesian adaptive algorithm. Patients will be 
randomized fairly among the four arms at the start of the trial (for the first 40 patients), 
that is, 10 patients per arm. Thereafter, as the trial progresses and data accrue, the 
randomization will become unbalanced in favor of the treatment that, on average, has 
better results in terms of event free survival. Therefore, each successive patient is more 
likely to receive the treatment with better results, on average. A minimum of 40 and a 
maximum of 120 patients will be accrued. There will be 12 months follow up after the 
last patient is accrued with an anticipated accrual rate of 4 patients per month. 
 
Denote the event free survival for the patients in the four arms (BSC; DAC; AZA3; 
AZA5) as Ti for i=1,2,3,4. Assume the Ti is independent exponential with median µi. And 
each µi independently follows an inverse gamma distribution with parameter α=2.14, 
β=13.73. The parameters were chosen to set the mean of the prior equal to 12 (the 
historical median EFS in months) and a variance of 1000. For each patient, the 
randomization probability for treatment arm i will be based on the posterior probability 
that it has the largest median EFS. For example, for arm 1, the posterior probability is 
π1=Pr(µ1> µi) for i=2,3,4. In order to avoid favoring one arm earlier in a large trial, 
instead of assigning patients with posterior probability, we use the following formula to 
assign patients: 
 
Aa=
4
3
2
1
1








, where Aa is the probability of assigning patients to arm 1,  
π1 is the posterior probability that arm 1 is superior, etc. 
 


 
 
2014-0112 
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28 
 
If at any point during the trial Pr(µi>max(uj for all j ≠i )|data) > 0.975 (< 0.025), the trial 
will be terminated and treatment i will be selected as superior (inferior).  If the 
maximum accrual is reached and Pr (µi>max{uj for all j ≠i}|data) > 0.8 (< 0.2), 
treatment i will be selected as superior (inferior).  A treatment arm will be dropped at 
any point during the trial if Pr(µi > 12 |data) < 0.1, for i=1,2,3,4. Table 6 given below 
summarizes operating characteristics of the design. The historical median EFS  is 12 
months. The tables below assume an accrual rate of 4 patients per month. The trial 
will be stopped early and a treatment selected as being “better” if the probability that 
one treatment’s median EFS is larger than the other’s EFS exceeds 0.975. If the trial 
does not stop early and the maximum 120 patients are accrued, a treatment is 
selected as being “better” if the probability that one treatment’s median EFS is larger 
than the other’s EFS exceeds 0.8. A treatment arm will be dropped at any point 
during the trial if the probability that the treatment’s median EFS is larger than 12 
months is less than 0.1. The “# of patients treated” row is the average number of 
patients treated on a given arm under the given scenario. When the medians all 
equal to 12 months (scenario 1), the probability of selecting one of the three arms 
(i.e., a false positive result) is at most 3.7 %. The probability of selecting the best 
treatment (i.e., a true positive result) for scenario 5, when the medians TTP are 12, 
12, and 24 months for the arms, respectively, are 0.1%, 0.04%, 0.2%, and  79.7%. 
 
 
Table 6: simulation results (simulation=5000) for transfusion dependent patients 
with the minimum randomization probability set as 0.1 and tuning parameter as 0.5 
 
 
 
treatment 
 
 
 
 
BSC 
DAC 
AZA3 
AZA5 
1 
True Median EFS 
12 
12 
12 
12 
 
# of patients treated 
29 
28.9 
28.8 
28.6 


 
 
2014-0112 
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29 
 
 
Pr(selected) 
0.037 
0.036 
0.034 
0.029 
 
Pr(selected early) 
0.001 
0.001 
0.001 
0.0004 
 
Pr (stopped early) 
0.235 
0.233 
0.253 
0.244 
 
 
 
 
 
 
2 
True Median EFS 
7 
7 
7 
7 
 
# of patients treated 
14.2 
14.3 
14.3 
14.4 
 
Pr(selected) 
0.029 
0.024 
0.027 
0.027 
 
Pr(selected early) 
0.0002 
0 
0.0002 
0.0002 
 
Pr (stopped early) 
0.764 
0.774 
0.773 
0.755 
 
 
 
 
 
 
3 
True Median EFS 
7 
12 
15 
20 
 
# of patients treated 
13.2 
24.2 
32.3 
42 
 
Pr(selected) 
0 
0.003 
0.035 
0.496 
 
Pr(selected early) 
0 
0.0004 
0.003 
0.036 
 
Pr (stopped early) 
0.971 
0.58 
0.296 
0.032 
 
 
 
 
 
 
4 
True Median EFS 
12 
12 
12 
20 
 
# of patients treated 
24 
24.3 
23.8 
40.7 
 
Pr(selected) 
0.003 
0.004 
0.006 
0.572 
 
Pr(selected early) 
0 
0.0002 
0.0002 
0.027 
 
Pr (stopped early) 
0.538 
0.533 
0.544 
0.014 
 
 
 
 
 
 
5 
True Median EFS 
12 
12 
12 
24 
 
# of patients treated 
22.3 
22.3 
22 
42.5 
 
Pr(selected) 
0.001 
0.0004 
0.002 
0.797 
 
Pr(selected early) 
0 
0.0002 
0 
0.059 
 
Pr (stopped early) 
0.713 
0.719 
0.721 
0.006 
 
 
 
 
 
 
 
The design software adaptive Randomization  version 4.1.1.  developed by the 
Department of Biostatistics at M. D. Anderson Cancer Center (MDACC) was used to 
generate the OC table. 
 
Toxicity Monitoring 
Evidence of Toxicity will be monitored closely for all patients except for the patients 
under the BSC. With 10 patients fairly randomized to each arm of the four arms, there 
will be at most 80 patients being adaptively assigned to any arm. Taking the initial 10 
patients assigning to each arm, the maximum number of patient per treatment arm will 
be 90.  For each treatment, treatment will be terminated if Pr((E >0.2 | data)  >0.88.  
where E is the proportion of any grade 3 or greater treatment related non-hematologic 
toxicities attributed to study drug and is assumed to follow a non-informative prior of 
Beta (0.4, 1.6)   That is, the trial will be terminated if at any time during the study, there 
is a more than 88% chance that the average rate of grade 3 or greater treatment related 


 
 
2014-0112 
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30 
 
non-hematologic toxicity is more than 20%. Patients will be monitored by a cohort size 
of 10 according to the following stopping boundaries for toxicity. The design software 
Multc Lean Desktop (version 2.1) developed by the Department of Biostatistics at M. D. 
Anderson Cancer Center (MDACC) was used to generate the futility/toxicity stopping 
boundaries and the OC table. 
 
 
 
 
Table 7: stopping boundaries for toxicity 
 
Number of patients 
evaluated 
Stop the trial if there are 
this many treatment 
related toxicities 
10 
4-10 
20 
7-20 
30 
9-30 
40 
12-40 
50 
14-50 
60 
17-60 
70 
19-70 
80 
21-80 
  
 
Table 8: Operating characteristics of safety monitoring  
True Toxicity Rate 
Prob (stop the trial early) 
0.15 
0.08 
 0.2 
0.28 
0.25  
0.62 
 0.3 
0.88 
 
 
Analysis Plan 


 
 
2014-0112 
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31 
 
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 EFS under 
different treatment will be estimated by Kaplan-Merier method, along with the 95% 
credible intervals, and logrank test will be used to assess the EFS differences under 
different treatments. The Cox proportional hazards model will be used to analyze the 
effects of treatments and other covariates.  
 
Figure 1. Survival of Patients with Low Risk MDS According to the Lower Risk 
Prognostic Model 


 
 
2014-0112 
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32 
 
 
 
 
 
 
 
Table 9. 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 


 
 
2014-0112 
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33 
 
Adverse Factor 
P 
Assigned Score
Hgb < 10 g/dL 
< .001 1 
Plt, ×109/L  
 
 
    < 50 
< .001 2 
    50-200 
< .001 1 
BM blasts ≥ 4% 
< .001 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10. 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 


 
 
2014-0112 
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34 
 
Score No. of PatientsMedian Survival (months)4-Year Survival Rate (%) 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
XI. References: 
1. Nimer SD (2008) Myelodysplastic syndromes. Blood 111:4841–4851. 


 
 
2014-0112 
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35 
 
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 
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 


 
 
2014-0112 
October 19, 2016 
36 
 
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. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006;108:419-425  
13. Peter F. Thall, Leiko H. Wooten, and Nizar M. Tannir (2005). Monitoring Event 
Times in Early Phase Clinical Trials: Some Practical Issues, Clinical Trials 2, 
467-478. 
14. Thall, PF, Simon, R, Estey, EH: New statistical strategy for monitoring safety and 
efficacy in single-arm clinical trials. J. Clinical Oncology 14:296-303, 1996 
 
 
 
 
 
Appendix A 
 
Appendix Subtitle: 
 


 
 
2014-0112 
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37 
 
 
 
Leukemia-specific Adverse Event Recording and 
Reporting Guidelines 
 
These guidelines serve to bring the Department of Leukemia in compliance with the 
institutional policy on Reporting of Serious Adverse Events-definition of expected AE-" 
All clinical protocols should include a list of the expected and anticipated events or 
hospitalizations relating to the study treatment" and Guideline for Good Clinical 
Practice 4.11.1 "All serious adverse events (SAEs) should be reported immediately to 
the sponsor except for those SAEs that the protocol or other document  (e.g., 
Investigator’s Brochure) identifies as not needing immediate reporting". 
 
 
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. 
 
Adverse Events (AEs) will be evaluated according to current CTC version in each 
protocol. Only unexpected AEs will be recorded in the Case Report Form (CRF).  
Expected events during leukemia therapy are: 
1. Myelosuppression related events (due to disease or leukemia therapy) 
a. febrile or infection episodes not requiring management in the intensive 
care unit 
b. epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
c. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, 
leukocytosis 
2. Disease related events 
a. symptoms associated with anemia 
i. 
fatigue 
ii. weakness 
iii. shortness of breath 
b. electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
c. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, 
albumin, uric acid, alkaline phosphatase, glucose) 
d. coagulation abnormalities 
e. disease specific therapy (induction, maintenance, salvage, or stem cell 
therapy) 


 
 
2014-0112 
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38 
 
f. 
alopecia 
g. bone,  joint, or muscle pain 
h. liver function test abnormalities associated with infection or disease 
progression 
i. 
disease progression 
3.  General therapy related events 
a. catheter related events 
b. renal failure related to tumor lysis syndrome or antibiotic/antifungal therapy 
c. rash related to antibiotic use 
4. Hospitalization for the management of any of the above expected events 
 
Abnormal hematologic values will not be recorded on the CRF. For abnormal 
chemical values grade 3 or 4, the apogee will be reported per course in the CRF. 
 
Serious Adverse Event Reporting (SAE) 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence 
that at any dose  
Results in death 
Is life-threatening 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Results in persistent or significant disability/incapacity  
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). 
 
(Sections relating to ORERM are for MDACC held IND studies only.)  
 
Important medical events as defined above may also be considered serious 
adverse events. Any important medical event can and should be reported to 
the IRB as an SAE if deemed appropriate by the Principal Investigator, the 
IND Sponsor, or the Office of Research Education and Regulatory 
Management (ORERM). 
 
All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy on Reporting Serious Adverse Events”.   
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to ORERM, regardless of attribution (within 5 working days 
of knowledge of the event). Hospitalizations for the management of any 
expected adverse events (previously described) will not have an 


 
 
2014-0112 
October 19, 2016 
39 
 
expedited report but it will be included in the annual report via the SAE 
log. 
 
All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution 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 ORERM.   
 
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to ORERM.  
 
Serious adverse events will be captured from the time the patient signs 
consent until 30 days after the last dose of drug. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event. 
 
Additionally, any serious adverse event that occur after the 30 day time period 
that is related to the study treatment must be reported to IRB and ORERM. 
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 ORERM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research teams 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. 
 
 
Reporting of external SAEs 
The MDACC institutional policy for reporting of external SAEs will be followed. 
 
 
Version 1.0/ Sept 09 
IRB Approval Date:  September 23, 2009 
 
 
 
 
 
Appendix B 
 
 


 
 
2014-0112 
October 19, 2016 
40 
 
 
 
 mm/dd/yyyy 
 
Dear Doctor, 
 
_(Name)___  is a mutual patient of ours who has been enrolled on Protocol 2014-0112: 
Phase II Randomized Study of Lower Doses of Decitabine versus Azacitidine (3 day 
schedule) versus Azacitidine (5 day schedule) in MDS Patients with Low and Intermediate-1 
Risk Disease Transfusion-Dependent versus Best Supportive Care (BSC) in MDS Patients 
with Low and Intermediate-1 Risk Disease Transfusion-Independent  at M.D. Anderson 
Cancer Center in Houston, TX from _________ to present.  
 
 
The patient was randomized to treatment arm with ______________. The patient’s current 
treatment course is course ___ of this regimen. Following one cycle performed here at MD 
Anderson Cancer Center, this study requires enrolled patients to return to be seen in our clinic 
at least every three months for study visits. 
 
__(Name)__ would like to come home for the _______________treatment and interim tests, 
however, in order for us to support follow up at home we will need the following:  
1. A confirmation of your center feasibility to perform required testing of CBC with 
differential and platelets at least monthly and serum bilirubin, creatinine, SGPT or 
SGOT once per month. More frequent testing may be performed at your discretion. 
2. A faxed copy of the documented dictated or handwritten findings of visits as soon as 
they became available including the above monthly laboratory results, weekly 
progress notes/clinic notes, physician order for __________ administration, 
___________ medication administration records, hospital admission summary, 
hospital discharge summary. 
3. A copy of your lab’s certification. 
If the above protocol requirements are not feasible to be performed at your center, please let us 
know so that we may arrange for other plans.  
If you agree, we would ask you to sign and return this letter as confirmation that we will receive 
by fax, a copy of all labs, medication administration records, and a copy of the dictated or 
handwritten clinic visit notes regarding assessments. 
The study requires enrolled patients to return to be seen in our clinic at least every three months 
for study visits. 
A follow up visit at MDACC, for evaluation of response and additional testing is scheduled for: 
_________ 
We have included a copy of the abstract for your convenience.  
By signing below, I agree to perform all tests and evaluations as noted above, and fax all 
documentation to 713-745-2232. 
Please fax all the above protocol documents as soon as possible to 713-745-2232. 
For any questions please call the PI Guillermo Garcia-Manero, MD at 713-745-3428 
 


 
 
2014-0112 
October 19, 2016 
41 
 
Thank you for your assistance. 
 
 
____________________ 
Guillermo Garcia-Manero, M. D. 
(PI of the study) 
 
 
 
 
 
 
 


 
 
2014-0112 
October 19, 2016 
42 
 
Appendix – C 
 
 
MDS Clinical Research Consortium 
 
Information to be included in all MDS CRC protocols 
 
 
MDS CRC PI information 
 
 
Amy E. DeZern, MD, MHS 
Assistant Professor and Principal Investigator  
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
1650 Orleans Street, k CRB1, 3M87  
Baltimore, MD 21287  
410.502.7208  
Adezern1@jhmi.edu 
 
 
Rami Komrokji, MD 
H. Lee Moffitt Cancer Center and Research Institute, Inc. 
12902 Magnolia Drive  
Tampa, FL 33612-9497 
813.745.4294  
Rami.Komrokji@moffitt.org 
  
 
David Steensma, M.D.  
Dana-Farber Cancer Institute, Inc.  
450 Brookline Avenue, DA1B30  
Boston, MA 02215  
617.632.5202  
David_Steensma@DFCI.Harvard.edu 
 
 
Mikkael Sekeres, MD 
The Cleveland Clinic Foundation 
9500 Euclid Avenue, R35 
Cleveland, OH 44195 
Phone:  216-445-9353 
Fax:  216-444-9464 
SKEREM@ccf.org 
 
 
Gail Roboz, MD 
Weill Medical College of Cornell University 
1300 York Avenue, Box 305 
New York, NY 10065 
Phone:  646-962-8215 
Gar2001@med.cornell.edu