Conditions: Leukemia
Keywords: Leukemia Advanced Myelodysplastic Syndrome MDS Intermediate-2 Myelodysplastic Syndrome High-Risk Myelodysplastic Syndrome Chronic myelomonocytic leukemia CMML Eltrombopag Promacta Decitabine Dacogen
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if eltrombopag given in combination with decitabine can help to control advanced MDS. The safety of this study drug combination will also be studied.

Detailed description:
Study Drug Administration:

Each cycle is 28 days.

If you are found to be eligible to take part in this study, you will receive decitabine by vein over 1 hour on Days 1-5 of each cycle.

You will also take eltrombopag capsules by mouth 1 time every day of each cycle. You should take it on an empty stomach (1 hour before a meal or 2 hours after a meal) with 8 ounces (1 cup) of water.

Do not eat calcium-rich foods (such as dairy products and juices with added calcium), or take other drugs (such as antacids) or supplements containing iron, calcium, aluminum, magnesium, selenium, and/or zinc for 4 hours before or 4 hours after taking eltrombopag.

If a dose of eltrombopag is vomited, you should not make it up or re-take it on the same day. If the morning dose is missed, it may be taken up until 5:00 PM on the same day.

Study Visits:

On Day 1 of each cycle:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

On Days 8, 15, and 22 of Cycle 1 only, blood (about 2-3 teaspoons) will be drawn for routine tests.

If the doctor thinks it is needed, on Day 1 of Cycles 2-4, then every 3 cycles (Cycles 7, 10, 13, and so on), you will also have a bone marrow aspirate/biopsy to check the status of the disease and for cytogenetic testing.

If the doctor thinks it is needed, once each week blood (about 2-3 teaspoons) will be drawn for routine tests.

End-of-Treatment Visit:

Within 5 days of your last dose of study drug, you will come to the clinic for an end-of-treatment visit. The following procedures will be performed:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.
* You will have a bone marrow aspirate/biopsy to check the status of the disease and for cytogenetic testing.

Length of Study:

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

Your participation on the study will be over after the follow-up visits.

Follow-up Visit:

About 28 days after your last dose of study drugs, you will come to the clinic for a follow-up visit. The following procedures will be performed:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

This is an investigational study. Eltrombopag is FDA approved and commercially available for the treatment of low platelet counts in patients with idiopathic thrombocytopenic purpura (ITP -- a severe bleeding disease). Decitabine is FDA approved for the treatment of MDS and is commercially available. The combination of eltrombopag and decitabine to treat MDS is investigational.

Up to 50 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Starting dose of Eltrombopag is 100 mg by mouth daily for each 28 day cycle. East Asians will start at 50 mg by mouth daily for each 28 day cycle.

Starting dose of Decitabine is 20 mg/m2 by vein on Days 1-5 for each 28 day cycle.

Interventions: intervention 1: Eltrombopag intervention 2: Decitabine
Intervention descriptions: intervention 1: Starting dose of Eltrombopag is 100 mg by mouth daily for each 28 day cycle. East Asians will start at 50 mg by mouth daily for each 28 day cycle. intervention 2: Starting dose of Decitabine is 20 mg/m2 by vein on Days 1-5 for each 28 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
2013-0590
December 13, 2013
Page 1
Protocol Page
Phase II Study of Eltrombopag in Combination with Decitabine in Subjects with 
Advanced Myelodysplastic Syndrome
2013-0590
Core Protocol Information
Short Title 
Eltrombopag with decitabine in advanced MDS
Study Chair: 
Courtney DiNardo
Additional Contact:
Tawana Heiskell
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-1141
Unit:
428
Full Title: 
Phase II Study of Eltrombopag in Combination with Decitabine in Subjects with Advanced 
Myelodysplastic Syndrome
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/03/2019
Version:
11
Submitted by:
Tawana Heiskell--11/11/2015 4:03:01 PM
OPR Action:
Accepted by:  Debbie D. Stroughter -- 12/1/2015 3:05:44 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2013-0590
December 13, 2013
Page 2
Protocol Body
 


Protocol 2013-0590 
December 13, 2013 
Page 1 of 38 
 
 
Phase II study of eltrombopag in combination with decitabine in subjects with 
advanced myelodysplastic syndrome 
 
 
MDACC Protocol #: 
 
2013-0590 
 
 
Principal Investigator:  
 
Courtney DiNardo, M.D., M.S.C.E. 
 
 
Address: 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
Houston, TX 77030 
 
 
Phone: 
 
 
 
713) 794-1141 
 
 
Fax:  
 
 
 
713) 792-0319 
 
 
Email: 
 
 
 
cdinardo@mdanderson.org 
 
 


Protocol 2013-0590 
December 13, 2013 
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  TABLE OF CONTENTS 
 
 
Page 
1.  Objectives ............................................................................................................................. 3 
2.  Background .......................................................................................................................... 4 
3.  Subject Eligibility ................................................................................................................. 8 
4.  Treatment Plan ................................................................................................................... 10 
5.  Study Procedures .............................................................................................................. 17 
6.  Response Definitions ........................................................................................................ 19 
7.  Regulatory and Reporting Requirements ......................................................................... 26 
8.  Statistical Considerations ................................................................................................. 29 
References .............................................................................................................................. 34 
 
 
 
 
 


Protocol 2013-0590 
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1. OBJECTIVES 
 
1.1 Primary Objective 
 
The primary objective of this study is to evaluate the efficacy of eltrombopag in 
combination with decitabine for the front-line treatment of Intermediate-2 or High-Risk 
Myelodysplastic Syndrome (MDS).  The primary endpoint is the overall response rate 
(ORR) based on the IWG-2006 criteria, which includes complete remission (CR), partial 
remission (PR), and hematologic improvement (HI).   
 
 
1.2 Secondary Objectives 
 
The secondary objectives of the study are: 
 
- 
To evaluate the safety and tolerability of the combination of eltrombopag and 
decitabine.  Safety will be assessed by the overall incidence and severity of all 
study-treatment related adverse events per CTCAE v 4.0 
 
- 
To evaluate the incidence of dose reductions and delays of decitabine therapy 
 
- 
To evaluate the effect of eltrombopag on medically significant hemorrhagic 
events (defined as Grade 3 or 4 hemorrhagic events on CTCAE v 4.0) 
 
- 
To evaluate the effect of eltrombopag on platelet and RBC transfusion 
independence per IWG-2006 criteria 
 
- 
Incidence of transformation to AML per FAB criteria (>30% blasts) during 
treatment period and follow-up 
 
- 
Incidence and severity of bone marrow fibrosis during treatment period and 
follow-up 
 
- 
To examine the relationship between clinical response with ferritin level and other 
markers of iron burden at study start 
 
1.3 Exploratory Objectives 
 
- 
Correlative laboratory studies of subjects including gene expression profiling and 
molecular analysis to determine the in vivo mechanism of action and the 
molecular and biological effects of the combination of decitabine and 
eltrombopag will be performed. 
 
 
2. BACKGROUND AND SCIENTIFIC RATIONALE 
 
2.1  Background 


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Myelodysplastic syndromes (MDS) are malignant clonal disorders characterized by 
ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias including 
thrombocytopenia, and a propensity to transform into acute myeloid leukemia (AML).1,2  
Classically, MDS is associated with apoptosis and excessive proliferation, resulting in a 
paradoxical combination of a hyper-cellular marrow and peripheral cytopenias.3  The 
incidence of MDS in the United States is rising, with approximately 20,000 to 30,000 
new cases of MDS diagnosed annually, and a median age at diagnosis of 70 years.3-6 
 
Over the past decade, clinical use of the hypomethylating agent decitabine has been 
shown to improve patient quality of life, decrease transfusion requirements, and improve 
outcome parameters in MDS patients, and is now a standard of care for MDS patients 
requiring therapy.  However, myelosuppression including severe thrombocytopenia is 
commonly seen in decitabine-treated patients, and is the most frequent cause of dose 
reduction, delay and discontinuation of the HMA agents ( including both decitabine and 
5-azacitidine) in up to 80% of patients.7  With current HMA regimens, achievement of an 
ORR is estimated at 28-70%, with a CR rate of only 6-34% in patients treated with front-
line HMA therapy, and with a median length of response in the HMA-responders of only 
8 to 10 months.6,8-11   
 
As alluded to above, the platelet count in MDS patients is critically important, and 
impacts both treatment decisions and overall survival in the majority of MDS patients.  
Among 2410 patients with MDS referred to the MD Anderson Cancer Center, 67% had 
a platelet count <100 x 10^9/L at the time of their initial consultation, with over 10% of 
patients presenting with life-threatening thrombocytopenia (<20x10^9/L). The frequency 
of hemorrhagic deaths within this population ranged from 14 to 24%.12  
 
Thrombocytopenia has been identified as an independent and adverse prognostic factor 
for overall survival in MDS at all stages.13  An analysis of 892 primary MDS subjects 
identified a median survival in patients with platelet counts < 100 x 10^9/L of 27 months, 
compared to 60 months for patients with platelet counts > 100 x 10^9/L.14  Furthermore, 
the mainstay of treatment for thrombocytopenia in MDS patients, transfusions, are 
short-lived, and associated with transfusion reactions, allo-immunization, transmission 
of bacterial and viral infections, and have no impact on the underlying disease biology. 
 
Given the high rate of thrombocytopenia both prior to and during decitabine therapy, 
which can result in inadequate treatment due to dose reductions and therapy delay, as 
well as the risks of hemorrhagic complications, the addition of eltrombopag to improve 
thrombocytopenia in MDS patients is justified.  Furthermore, the anti-leukemia 
properties of eltrombopag seen both in vitro and in early clinical studies, identify 
eltrombopag as an excellent candidate agent for this purpose. 
 
2.2 Rationale for Use of Eltrombopag and Dose Selection 
 
Eltrombopag (Promacta), a second-generation thrombopoietin-receptor agonist (TPO-
RA), is a synthetic small-molecule oral thrombopoietin mimetic that binds to c-MPL, 


Protocol 2013-0590 
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promoting megakaryopoiesis and release of platelets from mature megakaryocytes.15  It 
is currently FDA-approved for the treatment of immune thrombocytopenic purpura (ITP) 
and hepatitis C (HCV) associated thrombocytopenia.16-18  Eltrombopag has a unique 
mechanism of action compared to the other TPO-RAs, and functions through binding to 
a transmembrane domain of the TPO-receptor, activating the JAK/STAT pathway but 
producing much less activation of the STAT family, and without activation of the Akt 
pathway.19  Intriguingly, in cell lines and in Phase I clinical studies, eltrombopag has 
shown anti-leukemia activity unrelated to the TPO-RA pathway, leading to a modest 
inhibition of leukemia or MDS cell growth, while continuing to simulate normal 
megakaryopoiesis in bone marrow samples,20-22 and has also been associated with 
multilineage clinical responses in patients with severe and refractory aplastic anemia.23  
 
This study will enroll patients with advanced MDS, defined as IPSS Int-2 or high-risk 
MDS, or IPSS-R high or very-high MDS and with thrombocytopenia with a platelet count 
< 100K.  The study will explore the supportive care and disease-modifying effects of 
eltrombopag in addition to decitabine standard of care treatment for advanced MDS.  In 
patients with advanced MDS receiving decitabine, the consequences of low platelet 
counts, namely platelet transfusions and hemorrhage, form the basis of clinical 
outcomes which provide clinically meaningful benefit.   
 
Optimal dosing of eltrombopag is adjusted, based upon platelet count response in 
individual patients.  The starting dose of eltrombopag selected for this study is 100mg 
(50mg for East Asian patients).  Dose modifications will be permitted, from a minimum 
dose of 25mg to a maximum dose of 300mg in order to maintain platelet counts at a 
safe and effective level.  This is based upon the observed efficacy, safety and 
pharmacokinetics of studies including PMA112509 (NCT009034) and TRC114968 
(NCT014403).  In both studies, the majority of subjects were escalated to the maximum 
dose of 300mg (150mg for East Asian patients).  The safety profile of eltrombopag at 
these doses was similar to prior studies at lower doses (i.e. 50mg in ITP registry 
studies).  No new safety signals were identified, and the frequency and intensity of AEs 
known to be associated with eltrombopag (e.g. elevation in liver enzymes) were not 
increased despite the higher doses.  Additional trials of lower-risk and higher-risk MDS 
patients with thrombocytopenia have shown daily eltrombopag, dosed from 50mg to up 
to 300mg daily, is safe and effective in the MDS population.24-26 
 
2.3. Eltrombopag Safety Profile: 
 
2.3.1 Hepatotoxicity 
Eltrombopag may cause hepatotoxicity. In the controlled clinical trials in chronic ITP, 
one patient experienced Grade 4 (NCI Common Terminology Criteria for Adverse 
Events [NCI CTCAE] toxicity scale) elevations in serum liver test values during therapy 
with eltrombopag, worsening of underlying cardiopulmonary disease, and death. One 
patient in the placebo group experienced a Grade 4 liver test abnormality. Overall, 
serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported 


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in 11% and 7% of the eltrombopag and placebo groups, respectively. In the 3 controlled 
chronic ITP trials, four patients (1%) treated with eltrombopag and three patients in the 
placebo group (2%) discontinued treatment due to hepatobiliary laboratory 
abnormalities. Seven of the patients treated with eltrombopag in the controlled trials with 
hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the extension 
trial. Six of these patients again experienced liver test abnormalities (predominantly 
Grade 1) resulting in discontinuation of eltrombopag in one patient. In the extension 
study chronic ITP trial, one additional patient had eltrombopag discontinued due to liver 
test abnormalities (<Grade 3). 
In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 
ALT or AST ≥3X ULN was reported in 34% and 38% of the eltrombopag and placebo 
groups, respectively. Most patients receiving eltrombopag in combination with 
peginterferon/ribavirin therapy will experience indirect hyperbilirubinemia. Overall, total 
bilirubin ≥1.5 X ULN was reported in 76% and 50% of patients receiving eltrombopag 
and placebo, respectively. 
Measure serum ALT, AST, and bilirubin prior to initiation of eltrombopag, every 2 weeks 
during the dose adjustment phase, and monthly following establishment of a stable 
dose. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests 
with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum 
liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels. 
Discontinue eltrombopag if ALT levels increase to >3X (ULN) in patients with normal 
liver function or ≥3X baseline in patients with pre-treatment elevations in transaminases 
and are: 
x progressive, or 
x persistent for >4 weeks, or 
x accompanied by increased direct bilirubin, or 
x accompanied by clinical symptoms of liver injury or evidence for hepatic 
decompensation.  
 
Reinitiating treatment with eltrombopag is not recommended. If the potential benefit for 
reinitiating treatment with eltrombopag is considered to outweigh the risk for 
hepatotoxicity, then cautiously reintroduce eltrombopag and measure serum liver tests 
weekly during the dose adjustment phase. If liver tests abnormalities persist, worsen or 
recur, then permanently discontinue eltrombopag. 
2.3.2. Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis 
 


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Eltrombopag may increase the risk for development or progression of reticulin fiber 
deposition within the bone marrow. In the extension trial in chronic ITP, 151 patients 
have had bone marrow biopsies evaluated for increased reticulin and collagen fiber 
deposition. Bone marrow biopsies taken after 1 year of therapy showed predominantly 
myelofibrosis (MF) Grade 1 or less in 140/151 (93%) of patients. There were 11/151 
(7%) of patients with MF Grade 2. Four patients had collagen deposition reported. One 
patient with a pre-existing MF Grade 1 developed a MF Grade 2 and subsequently 
discontinued treatment with eltrombopag. Clinical trials have not excluded a risk of bone 
marrow fibrosis with demonstrated clinical consequences to date. If new or worsening 
blood morphological abnormalities or cytopenias occur, consider a bone marrow biopsy 
including staining for fibrosis. 
2.3.3. Thrombotic/Thromboembolic Complications 
In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 
(31/955) treated with eltrombopag experienced a thrombotic event compared to 1% 
(5/484) on placebo. The majority of events were of the portal venous system (1% in 
patients treated with eltrombopag versus <1% for placebo). 
Thrombotic/thromboembolic complications may result from increases in platelet counts 
with eltrombopag. Reported thrombotic/thromboembolic complications included both 
venous and arterial events and were observed at low and at normal platelet counts. 
Consider the potential for an increased risk of thromboembolism when administering 
eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V 
Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize 
the risk for thrombotic/thromboembolic complications, do not use eltrombopag in an 
attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve 
and maintain a target platelet count. 


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In a controlled trial in non-ITP thrombocytopenic patients with chronic liver disease 
undergoing elective invasive procedures (N = 292), the risk of thrombotic events was 
increased in patients treated with 75 mg eltrombopag once daily. Seven thrombotic 
complications (six patients) were reported in the group that received eltrombopag and 
three thrombotic complications were reported in the placebo group (two patients). All of 
the thrombotic complications reported in the group that received eltrombopag were 
portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, 
vomiting, and diarrhea. Five of the six patients in the group that received eltrombopag 
experienced a thrombotic complication within 30 days of completing treatment with 
eltrombopag and at a platelet count above 200 x 109/L. The risk of portal venous 
thrombosis was increased in thrombocytopenic patients with chronic liver disease 
treated with 75 mg eltrombopag once daily for 2 weeks in preparation for invasive 
procedures. 
 
2.3.4 Cataracts 
In the 3 controlled clinical trials in chronic ITP, cataracts developed or worsened in 15 
(7%) patients who received 50 mg eltrombopag daily and 8 (7%) placebo-group 
patients. In the extension trial, cataracts developed or worsened in 4% of patients who 
underwent ocular examination prior to therapy with eltrombopag. In the 2 controlled 
clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts 
developed or worsened in 8% patients treated with eltrombopag and 5% patients 
treated with placebo.  Patients treated with eltrombopag who experience visual 
difficulties should have an appropriate ophthalmologic examination including evaluation 
for cataract formation.   
 
2.4. Decitabine 
 
Decitabine is supplied as a lyophilized white to almost white, finely crystalline, odorless 
powder for injection in 20 mL glass vials, containing 50 mg of decitabine, monobasic 
potassium phosphate, and sodium hydroxide. When reconstituted with 10 mL of sterile 
water for injection each mL will contain 5 mg of decitabine, 6.8mg of KH2PO4, and 
approximately 1.1 mg NaOH. The pH of teh resulting solution is 6.5-7.5. The 
reconstituted solution can be further diluted to a concentration of 1 mg/mL or 0.1 mg/mL 
in cold infusion fluids (0.9% Sodium Chloride Injection USP, 5% Dextrose in Water 
Injection, USP, or Lactated Ringer's Injection USP). 
 
The intact vials should be stored under refrigeration (2-8°C; 36-46°F) in the original 
package. Shelf life surveillance of the intact vials is on-going. The intact vials are stable 
for at least 1 year at room temperature (22-25°C), 2 years at 2-8°C or 6 months at 40°C. 
Reconstiution and dilution of the powder for injection (with 10 mL of sterile water for 
injection) results in a rapidly decomposing solution. The concentration of decitabine in 
the reconstituted and diluted solution decreases about 10% after 4 hours at 25°C or 


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about 10% after 24 hours at 4°C. Since 10% is the maximum allowable decomposition, 
and the solution will also decompose during administration (infusion), the solution 
should be prepared just prior to administration. If this is not possible the solution should 
be prepared at least twice a day and be kept in a refrigerator (2-8°C) until  
administration. Furthermore, the solution should be prepared only with cold infusion 
fluids at a temperature of 2-8°C (36-45°F). The solution can be infused over a maximum 
period of 3 hours. 
 
Drug handling precautions will be strictly followed. Skin contact with the solution should 
be avoided and protective gloves should be worn. Spilt drug can be inactivated by 2 M 
sodium hydroxide solution. 
 
 
3. STUDY ELIGIBILITY 
 
3.1 Inclusion Criteria 
 
1. Signed, informed consent must be obtained prior to any study specific procedures. 
 
2.  Subjects with a histologically confirmed diagnosis of MDS by FAB criteria, including 
both MDS and RAEB-T (AML with 20-30% blasts and multilineage dysplasia) and 
chronic myelomonocytic leukemia (CMML) with at least 10% bone marrow blasts by 
World Health Organization (WHO) classification are eligible.   
 
3.  Advanced MDS by virtue of intermediate-2 or high-risk MDS by IPSS score, or high 
or very-high risk by IPSS-R. 
 
4.  Platelet count ≤ 100 x 10^9/L at baseline 
 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
 
6.  Adequate liver function, as evidenced by a serum bilirubin <2x the ULN (except for 
patients with a confirmed diagnosis of Gilbert’s Disease) and an ALT or AST <3x the 
laboratory ULN. 
 
7.  Serum creatinine < 2.5x upper limit of normal 
 
8.  Subjects must be > 18 years of age at the time of informed consent 
 
9.  Subject is practicing an acceptable method of contraception (documented in chart).  
Female subjects (or female partners of male subject) must either be of non-childbearing 
potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-
menopausal > 1 year), or of childbearing potential and use one of the following highly 
effective methods of contraception (i.e. Pearl index < 1.0%) from 2 weeks prior to 
administration of study medication, throughout the study, and 28 days after completion 
or premature discontinuation from the study: 


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- 
Complete abstinence from intercourse; 
- 
Intrauterine device (IUD); 
- 
Two forms of barrier contraception (diaphragm plus spermicide, and for males 
condom plus spermicide); 
- 
Male partner is sterile prior to entry into the study and is the only partner of the 
female; 
- 
Systemic contraceptives (combined or progesterone only). 
 
 
3.2 Exclusion Criteria 
 
1.  Subjects with any prior exposure to a thrombopoietin-receptor agonist 
 
2.  Prior hypomethylating agent treatment for MDS 
 
3.  Any prior or co-existing medical condition that in the investigator’s judgment will 
substantially increase the risk associated with the subject’s participation in the study 
 
4.  Psychiatric disorders or altered mental status precluding understanding of the 
informed consent process and/or completion of the necessary study procedures 
 
5.  Active uncontrolled serious infection or sepsis at study enrollment 
 
6.  Clinically significant gastrointestinal disorders that may interfere with absorption of 
drug. 
 
7.  History of arterial thrombosis (i.e. stroke) in the past year 
 
8.  History of venous thrombosis currently requiring anti-coagulation therapy  
 
9.  Unstable angina, congestive heart failure (New York Heart Association (NYHA) > 
Class II), uncontrolled hypertension (diastolic blood pressure > 100mmHg), or recent 
(within 1 year) myocardial infarction 
 
10.  Subjects with a QTc > 480 msec (QTc > 510 msec for subjects with Bundle Branch 
Block) at baseline 
 
11.  Pregnant or breast-feeding 
 
12.  Subjects with known history of human immunodeficiency virus (HIV) or active 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), because eltrombopag is 
hepatically cleared, and underlying hepatic impairment may lead to an increased risk of 
hepatotoxicity.  Eltrombopag has not been evaluated with combination antiretroviral 
regimens. 
 
13.  Subjects with liver cirrhosis (as determined by the investigator) 


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14.  Subjects with hypersensitivity to study drugs or their excipients. 
 
 
4. TREATMENT PLAN 
 
4.1 Study Design 
 
This is a single arm phase II study of eltrombopag in combination with decitabine in 
subjects with thrombocytopenia and higher risk (advanced) myelodysplastic syndromes 
(MDS).  The purpose of this study is to explore the supportive care and disease-
modifying effects of eltrombopag in combination with decitabine standard of care for 
patients with advanced MDS.  The primary objective will be the overall response rate 
(ORR) based on the IWG-2006 criteria, which includes complete remission (CR), partial 
remission (PR), and hematologic improvement (HI).   
 
The primary endpoint will be evaluated for each 28-day cycle of decitabine treatment 
during the first four cycles, and these 4 cycles will be used for the primary analysis.  
Four cycles of the primary endpoint was chosen since the median duration to decitabine 
response is 3.3 cycles, and the occurrence or worsening of thrombocytopenia in 
patients treated with hypomethylating agents is most commonly observed in the initial 
cycles of treatment.  Adverse events, bleeding events, and concomitant medications will 
be assessed continually throughout the study; specific information will be requested at 
every study visit.   
 
A total of 40 patients will be accrued from M. D. Anderson Cancer Center (MDACC). 
4.1.1. Study Replacement:  
 
All patients who receive at least one dose of the study drug will be included in the 
efficacy and safety analysis.  For efficacy analysis, patients who drop out of the study 
early (i.e. before the end of cycle 1) due to treatment-related toxicities will be counted as 
treatment failures (i.e. non-responders).  Patients will be replaced if they drop out of the 
study before receiving any dose of the study drug. 
 
4.2. Study Duration 
 
4.2.1. All subjects must complete a screening visit, day 1 visits for each new cycle, an 
end of treatment visit and whenever possible, an end of study safety visit 28 days after 
the last dose of eltrombopag.   
 
4.2.2. Treatment will continue until discontinuation due to relapse, unacceptable toxicity, 
or disease progression as defined by the IWG 2006 criteria for MDS. This includes: 
 
- 
clinically significant progressive disease at any time, or 
 


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- 
a lack of clinical benefit after 4 cycles of treatment at the highest dose of study 
medication, or 
 
- 
Possibility of undergoing allogeneic stem cell transplantation 
 
- 
discontinuation of study drug for more than 6 weeks, or 
 
- 
intercurrent illness that prevents further administration of treatment, or 
 
- 
unacceptable adverse event(s), or 
 
- 
patient decision for study withdrawal, or 
 
- 
general or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgement of the investigator 
  
4.2.3. Study cycles will be administered every 28 days + 5 days or upon resolution of 
any clinically significant study drug related AE to grade 0-1, whichever occurs first.  If a 
subsequent cycle is delayed due to adverse events related to decitabine, or if it is 
considered in the best interest of the patient to delay administration of decitabine (e.g. 
because of concern for an infection), administration of the eltrombopag may continue as 
planned. 
 
4.2.4. Administration of subsequent cycles should be administered when neutrophils 
recover to > 1 x 10^9/L and platelets to >30 x 10^9/L or to baseline levels prior to the 
start of the last cycle of therapy.  Patients with residual disease may start the next cycle 
with neutrophil and/or platelet counts lower than these if judged to be in the best interest 
of the patient to start the next cycle.  The decision to treat should be documented in the 
patient’s medical record. 
 
4.2.5. Patients may remain on study for up to 12 cycles if the patient demonstrates 
clinical benefit and no excessive toxicity (i.e. no clinically significant study-drug related 
grade > 3 toxicity).  Patients who are experiencing clinical benefit and have not 
experienced excessive toxicity may be eligible to continue therapy after discussion with 
the PI and the discussion documented in the patient’s medical record. 
 
4.3. Decitabine Administration  
 
Decitabine may be administered by local doctor or at MD Anderson, inclusive of the 
Regional Cancer Centers (RCC).  Commercial supplies of decitabine and will be used 
and records will be obtained from the local physician as indicated in the Dear Doctor 
Letter (Appendix E).   
 
4.4 Eltrombopag Administration 


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4.4.1. Eltrombopag should be taken on an empty stomach (1 hour before or 2 hours 
after a meal) or with food containing little (<50 mg) or preferably no calcium or dairy 
products.  Allow at least a 4 hour interval between eltrombopag and other medications 
or products containing polyvalent cations (e.g. calcium, magnesium, aluminum, zinc, 
selenium or iron) such as antacids, dairy products, and mineral supplements to avoid 
significant reduction in eltrombopag absorption due to chelation. 
4.4.2. Eltrombopag will be self-administered primarily on an outpatient basis; but may 
be administered as an inpatient.  Vomited doses will not be made up on the same day.  
If the patient misses the dose of eltrombopag in the morning they can take the daily 
dose no later than 5pm on the same day.  Destruction of unused study drug will be in 
accordance with the institution’s drug destruction policy. 
 
4.4.3. Patient compliance will be documented using the MDACC Research Medication 
Diary and will be assessed at each study visit. 
 
 
4.4.4 Subjects will be permitted to use HMG-CoA reductase inhibitors (statins) during 
the study, but these drugs should be used with caution and a 50% dose reduction of the 
HMG-CoA reductase inhibitor is recommended, with close monitoring for safety, such 
as liver chemistry and signs and symptoms of myolysis as well as efficacy.  Preclinical 
data showed that eltrombopag is an inhibitor of the organic anion transporters 
OATP1B1 and BCRP.  A clinical drug interaction study to evaluate the impact of 
eltrombopag on the PK of rosuvastatin, an OATP1B1 and BCRP substrate, was 
conducted in healthy subjects and identified increased plasma rosuvastatin Cmax and 
AUC.27,28 
 
4.4.5. Subjects of East Asian ancestry exhibit higher eltrombopag drug exposure and 
will be initiated at a 50% reduced initial dose.  
 
4.5. Non-MDACC Physician Participation 
4.5.1. Outside physician participation during treatment is acceptable.  Documentation of 
MDACC physician communication with the outside physician will be required.  Protocol 
required evaluations outside MDACC will be documented by telephone, fax or email.  
Fax and/or email will be dated and signed by the MDACC physician.  For protocol 
required labs that are completed outside MDACC, the PI or treating physician must 
review results for clinical significance and sign and date results.  The screening visit, 
start of treatment visit (Cycle 1 Day 1), and the end of treatment assessment must be 
performed at MDACC.  MDACC visits must occur at least every 3 months on study, and 
all study bone marrow assessments should be performed at MDACC.   
4.5.2. Changes in decitabine drug dose and/or schedule must be discussed with and 
approved by the MDACC PI, or their representative prior to initiation, and will be 


Protocol 2013-0590 
December 13, 2013 
Page 14 of 38 
 
documented in the patient record.  All decisions for dose adjustments of eltrombopag 
will be made by the MD Anderson treating physician.  
 
4.5.3. All serious adverse events (SAEs) that occur will be reported to the research 
nurse and will be evaluated by the PI within 48 hours of observing or learning of the 
event for reportability to the FDA (Appendix E).  Fax and/or email will be dated and 
signed by the MDACC physician. 
 
4.6. Identity of Investigational Product 
 
International Non-proprietary name 
eltrombopag 
Manufacturer  
 
 
 
Novartis Oncology 
Dose  
 
 
 
 
100mg daily 
Route of Administration 
 
 
oral 
Formulation 
12.5mg, 50mg, 75mg and 100mg capsules; in 
bottle 
 
Eltrombopag will be provided by  Novartis Oncology. 
 
For oral administration only 
Bottle containing 60 capsules of 100mg eltrombopag. 
Store below 300C (860 F). Do not refrigerate or freeze. Keep bottle tightly 
closed.   
The Expiry date will provided via Certificate of Analysis prepared by  
Novartis Oncology 
 
 
4.7. Supportive Care Guidelines 
 
4.7.1. Supportive measures including blood and platelet transfusions, antimicrobials, 
and analgesics are permitted. 
 
4.7.2. The administration of anticancer therapies, other investigational cytotoxic agents, 
or prophylactic use of hematopoietic colony stimulating factors are not permitted. 
 
4.7.3. Erythropoietin or hematopoietic colony stimulating factors for treatment of 
cytopenias are discouraged.  If administered, the subject will not be eligible for a HI 
response assessment within one week of the receipt of Procrit or Neupogen, or for one 
month after receipt of Neulasta or Darbopoetin. 
 
4.7.4. Platelet Transfusions: Platelet transfusion data must be captured on the case 
report form during the screening, treatment and extension periods.  A unit of platelets is 


Protocol 2013-0590 
December 13, 2013 
Page 15 of 38 
 
defined as a single unit of platelet-rich plasma or buffy-coat concentrate or 1 apheresis 
(single donor) concentrate.  The number of units transfused must be recorded. 
 
ASCO guidelines suggest platelet transfusion criteria of: 
 
- 
Platelet count < 10 x 10^9/L (i.e. severe thrombocytopenia) 
 
- 
Signs of hemorrhage 
 
- 
Subject with a high fever and platelet count < 20 x 10^9/L 
 
- 
Subject has a hyperleukocytosis 
 
- 
There has been a rapid fall in platelet count and transfusions will not be readily 
available in case of emergencies 
 
4.8 Dosing Delays and Dose Modifications 
 
4.8.1. Dose Adjustments for Toxicity: 
The doses of eltrombopag and decitabine will be adjusted according to the guidelines 
shown in the following tables for study drug-related clinically significant toxicity.  If 
toxicity is not covered in the table, doses may be reduced or held at the discretion of the 
investigator for the patient’s safety.  See section 4.8.4 for liver chemistry stopping and 
follow-up criteria. 
 
Patients will be withdrawn from the study if they fail to recover to CTCAE grade 0 to 1 
(or within 1 grade of starting values for pre-existing laboratory abnormalities) from a 
clinically significant non-hematologic treatment-related toxicity within 6 weeks (leading 
to treatment delay of > 4 weeks) unless the investigator feels that the patient should 
remain in the study because of evidence that the patient is/may continue deriving 
benefit from continuing study treatment. Such instances will be discussed with the 
principal investigator on a case by case basis and the discussion documented in the 
medical record. 
 
Patients with study-drug related toxicities that are manageable with supportive therapy 
may not require dose reductions. For patients with other drug-related toxicities, the 
following dose adjustment rules apply: 
 
NCI  CTCAE Grade 
Action 
Grade 0-2 non-hematological 
toxicity 
No dose reduction. 
For grade 2 toxicities that are 
persistent and/or intolerable (e.g. 
stomatitis) patients may have a 
treatment interruption or dose 


Protocol 2013-0590 
December 13, 2013 
Page 16 of 38 
 
 
 
 
 
 
 
† see 4.8.4 for additional liver chemistry stopping and follow-up criteria 
4.8.2 Decitabine Dosing, Delays and Dose Modifications 
 
4.8.2.1. Decitabine 20mg/m2 IV on Days 1-5 will be administered for each 28-day cycle.  
 
 
4.8.2.2. Standard dose reductions for decitabine are described in the following table.  
Patients with drug-related toxicities that are manageable with supportive therapy may 
not require dose reductions.   
 
Dose level 
Decitabine (in mg/m2 for 5 
days) 
0 
20 
-1 
15 
-2 
10 
-3 
10 for 4 days 
 
 
 
4.8.2.3. Administration of subsequent cycles should be administered when neutrophils 
recover to > 1 x 10^9/L and platelets to >30 x 10^9/L, or to baseline levels prior to the 
start of the last cycle of therapy.  Patients with residual disease may start the next cycle 
with neutrophil and/or platelet counts lower than these if judged to be in the best interest 
of the patient to start the next cycle.  The decision to treat should be documented in the 
patient’s medical record.  Patients with delayed recovery of neutrophils to 1x10^9/L 
and/or platelets to 75x10^9/L in the absence of residual disease may have dose 
reductions by 1 dose level in subsequent cycles. 
 
4.8.2.4. Patients with serious infectious complications in prior cycles may have the 
subsequent cycles administered at one dose level reduction in subsequent cycles. 
 
4.8.2.5. Dose reductions and delays of decitabine different than those described above 
are acceptable after discussion with the investigator, and will require documentation of 
the rationale for such action. 
reductions to the next lower dose 
level. 
Grade 3-4 clinically significant non-
hematological toxicity† 
Hold until recover to NCI CTC AE 
grade 0-1 
If recovery occurs within 2 weeks 
after treatment has been held, 
dose should be reduced to –1 
dose level, if applicable.   


Protocol 2013-0590 
December 13, 2013 
Page 17 of 38 
 
 
4.8.3 Eltrombopag Dosing Delays and Dose Modifications 
 
Dose modifications for eltrombopag: 
Dose level 
eltrombopag (mg/day) 
+2 
300 
+1 
200 
0 
100 
-1 
 
50 
 
-2 
25 
 
4.8.3.1. Starting Dose 
The starting dose for all study patients (with the exception of East Asians, see 4.8.3.2.) 
will be 100mg orally daily.  East Asians will start at 50mg orally daily. 
 
4.8.3.2. Dose Adjustments for Platelet Count:   
The dose of eltrombopag can be increased every 2 weeks by 100mg until a maximum 
of 300mg per day has been attained.  Dose adjustments will be dependent on each 
subject’s platelet counts; adjusted to maintain an un-transfused platelet count >100 x 
10^9/L.  Laboratory work including a CBC with differential and blood chemistries must 
be evaluated weekly for 4 weeks after any change in eltrombopag dosing. 
 
All decisions for dose adjustments of eltrombopag will be made by the MD Anderson 
treating physician.  If needed, additional supplies of eltrombopag may be mailed by the 
MD Anderson research pharmacy to the patient.   
 
Eltrombopag will be held if platelet counts exceed 400 x 10^9/L, and will be resumed the 
next scheduled day that platelet counts have decreased to ≤100 x 10^9/L.  Dose should 
be reduced to the next lower dose level, if appropriate.  
 
4.8.3.3. Dose Adjustments for Subjects of East Asian Ancestry: 
The starting dose for patients of East Asian ancestry will be 50mg orally daily.  East 
Asian (i.e. Japanese, Chinese, Taiwanese and Korean) subjects exhibited 50-55% 
higher eltrombopag plasma concentrations compared to non-East Asian subjects.  Dose 
adjustments for platelet counts will proceed as per 4.8.3.1. regardless of ethnicity. 
 
Dose reductions different than the dose described above are acceptable after 
discussion with the sponsor and the PI, and will require documentation of the rationale 
for such action. 
 
4.8.4. Liver Chemistry Stopping and Follow-Up Criteria: 
Treatment should be held for any of the following liver chemistry criteria: 
1. ALT > 5x ULN and bilirubin > 2.7x ULN (>35% direct bilirubin) 


Protocol 2013-0590 
December 13, 2013 
Page 18 of 38 
 
2. ALT > 8x ULN 
3. ALT > 5x ULN but < 8x ULN and persists for > 2 weeks 
4. ALT > 5x ULN if associated with the appearance or worsening of symptoms of 
hepatitis such as nausea, vomiting, right upper quadrant pain or tenderness. 
5. ALT > 5x ULN but < 8x ULN and cannot be monitored weekly for > 2 weeks. 
 
When any of the above criteria is met, do the following: 
- 
Immediately withdraw investigational product 
Report the event to Novartis Oncology 
- 
 within 24 hours of learning of its occurrence 
- 
Complete the SAE data collection tool if the event also meets the criteria for an 
SAE.  All events of ALT > 5x ULN and bilirubin > 2.7x ULN (>35% direct 
bilirubin), modified Hy’s Law for oncology clinical trials29, must be reported as an 
SAE. 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should 
be discontinued if ALT > 5x ULN and bilirubin > 2.7x ULN.  Serum bilirubin 
fractionation should be performed if testing is available.  If testing is unavailable, 
record the presence of detectable urinary bilirubin on dipstick, indicating bilirubin 
elevation and suggesting liver injury. 
- 
Hold eltrombopag until recovery to NCI CTC AE grade 0-1 and restart at next 
lower dose level regardless of recovery time.  
 
In addition, for #1: 
- 
Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow-up assessments (see below) and 
close monitoring. 
- 
A specialist or hepatology consultation is recommended. 
- 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 
For #2, 3, 4, 5: 
- 
Make every reasonable attempt to have subjects return to clinic within 24-72 
hours for repeat liver chemistries and liver event follow-up assessments (see 
below) 
- 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values. 
 
For all Criteria 1-5, make every attempt to carry out the liver event follow-up 
assessments described below as clinically appropriate: 
- 
Viral hepatitis serology (Hepatitis A IgM antibody; Hepatitis B surface antigen and 
Hepatitis B core antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; 
Epstein-Barr viral capsid antigen IgM antibody; Hepatitis E IgM antibody if 
subject resides outside the USA or Canada or has travelled outside the USA or 
Canada in the past 3 months). 
- 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
- 
Obtain complete blood count with differential to assess eosinophilia 


Protocol 2013-0590 
December 13, 2013 
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- 
Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins. 
- 
Record alcohol use  
- 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
 
 
5. STUDY PROCEDURES 
 
5.1 Screening (Visit 1) 
 
The following procedures are performed during screening, staging and workup.  These 
procedures are to be performed within 4 weeks prior to study drug administration, 
except where indicated. 
 
A signed and dated IEC/IRB approved informed consent form must be obtained before 
any study specific procedures are performed.  Procedures that are part of routine care 
are not considered study specific procedures.  All subjects will be screened for eligibility 
before enrollment.  Once the subject has met all inclusion criteria, they will be enrolled 
onto the study. 
 
Table 5.1: Procedures during Screening, Staging and Workup 
 
Procedures 
Specifics 
Informed consent 
 
Full History and Physical Examination 
History – present illness, prior surgeries, 
other medical illnesses, review of systems, 
allergies, prior therapy for cancer and 
concurrent meds;  
 
Physical exam – record weight, and note 
abnormalities in any major organ system 
(including but not limited to neurologic, 
head and neck, lymph nodes, 
cardiovascular, pulmonary, abdomen, 
extremities), note and measure sites of 
disease 
Concomitant Medications 
 
Vital signs (including temperature, pulse, 
and blood pressure)  
 
ECOG performance status 
 
Urine or blood pregnancy test (females of 
child-bearing potential only) 
Within 7 days prior to first dose 
Disease status  (IPSS classification and 
WHO disease classification) 
 
Note: Bone marrow aspirate and/or biopsy 
within 4 weeks prior to first dose of drug in 
all patients. Cytogenetics and 
Staging with bone marrow aspiration and/or 
biopsy for disease assessment.  
 


Protocol 2013-0590 
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immunohistochemistries performed as 
indicated. 
Serum chemistries and iron studies (repeat 
if screening chemistries completed greater 
than 72 hours prior to the first dose) 
Sodium, potassium, blood urea nitrogen, 
creatinine, glucose, calcium, phosphate, 
magnesium, AST and/or ALT, total bilirubin, 
alkaline phosphatase, uric acid, serum iron, 
transferrin, transferrin saturation, total iron 
binding capacity and ferritin. 
CBC with differential (repeat if screening 
test completed greater than 72 hours prior 
to the first dose) 
Differential may be omitted if WBC ≤0.5 
x109/L 
 
 
5.2 On-Study Procedures  
PROCEDURES 
Pre-Study 
Screenº 
Cycle 1 
Day 1 
Cycle 1  
Day 8 
(+/- 2 
days) 
Cycle 1 
Day 15 
(+/- 2 
days) 
Cycle 1 
Day 22 
(+/- 2 
days) 
Day 1 
Cycle 2 
onwards 
(+/- 5 
days) 
End of 
Treatment 
Visit (+/- 5 
days) 
Safety 
Visit  
28 days 
after last 
dose (+/- 
28 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
Patient Weight 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam and 
Performance Status 
X 
X 
 
 
 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion and 
Supportive Care 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
 
X* 
X 
X 
X 
X 
X¹ 
X 
X² 
Blood Chemistries 
(AST, ALT, bilirubin) 
X*^ 
X 
X 
X 
X 
X¹ 
X 
X 
12-lead EKG 
Xª 
 
 
 
 
 
 
 
Bone marrow aspiration 
and/or biopsy  
X 
 
 
 
 
X³ 
X 
 
IPSS score & WHO 
disease classification 
X 
 
 
 
 
X³ 
X 
 
Pregnancy Test 
X† 
 
 
 
 
 
 
 
Investigational Drug 
Dispensement 
 
X 
 
 
 
X 
 
 
AE and SAE 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Optional:  Correlative 
studies4 
X 
 
 
 
 
 
 
 
ºScreening must be performed within 4 weeks prior to study drug initiation / study start unless otherwise indicated 
*CBC with differential and blood chemistries including iron studies (sodium, potassium, BUN, creatinine, glucose, calcium, phosphate, 
magnesium, AST, ALT, total bilirubin, alkaline phosphate, uric acid, serum iron, transferrin, transferrin saturation, total iron binding capacity and 
ferritiin) must be performed within 72 hours of Cycle 1 Day 1  


Protocol 2013-0590 
December 13, 2013 
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^Serum iron, transferrin, transferrin saturation, total iron binding capacity and ferritin are required only on Cycle 1 Day 1 and do not need to be 
repeated 
ªEKG, including QTc intervals, at screening or baseline.  A follow-up EKG will be performed if a subject experiences a clinically relevant 
abnormality. 
†Within 7 days of Day 1 in females of child-bearing potential 
¹Weekly CBC with differential and blood chemistries required until stable counts, and weekly x4 weeks after any change in eltrombopag dosing 
²Weely CBC with differential should be performed weekly for the 4 weeks after discontinuation of eltrombopag 
³Bone marrow aspiration and/or biopsy with cytogenetics required for study entry, and every cycle for the first 4 cycles for primary outcome, 
and then every 3 cycles as clinically indicated.  Cytogenetics do not need to be repeated if normal at study start. 
4Optional correlative studies will be performed on bone marrow sample taken at screening.  The studies will include an analysis of mutational 
status of up to 53 genes known to be affected in acute leukemias as well as gene expression profiling, and evaluation of any potential 
relationship with the presence or absence of mutations and response will be assessed. 
 
5.3. End of Study Visit:  
 
Subjects will undergo an End of Treatment Visit at the time of discontinuation of 
eltrombopag.  A bone marrow biopsy and/or aspirate with cytogenetics for IPSS and 
WHO classification will be performed at this visit.  Cytogenetics can be omitted if diploid 
at study start. 
 
5.4. Safety Visit:   
 
Whenever possible, subjects will undergo an End of Study Safety Visit 4 weeks after 
his/her last dose of investigational product in the treatment period.   
 
 
6. RESPONSE DEFINITIONS 
 
6.1. Patients’ overall response will be assessed after at least 2 cycles of treatment but 
no more than after 6 cycles, and each cycle is 28 days. 
 
6.2. Study Endpoints 
 
6.2.1. Primary Efficacy Endpoint:  The overall response rate (CR + PR + HI) based on 
the IWG-2006 criteria detailed below.  Responses must last at least 4 weeks per 
definition. 
 
Complete Remission: 
 
- 
Bone marrow: < 5% myeloblasts with normal maturation of all cell lines 
 
- 
Persistent dysplasia will be noted 
 
- 
Peripheral blood 
 
o Hemoglobin > 11g/dL 
 
o Platelets > 100x10^9/L 
 


Protocol 2013-0590 
December 13, 2013 
Page 22 of 38 
 
o Neutrophils > 1.0x10^9/L 
 
o Blasts 0% 
 
Partial Remission: 
 
- 
All CR criteria if abnormal before treatment except: 
 
o Bone marrow blasts decreased by > 50% over pretreatment but still > 5% 
 
Stable Disease: 
 
- 
Failure to achieve at least PR, but no evidence of progression for >8 weeks 
 
Failure: 
 
- 
Death during treatment or disease progression characterized by worsening of 
cytopenias or significant increase in percentage of bone marrow blasts 
 
Hematologic Improvement (HI) Response Criteria*: responses must last at least 8 
weeks 
 
- 
Erythroid response (if pretreatment hemoglobin < 11g/dL) 
 
o Hemoglobin increase by > 1.5g/dL 
 
o Relevant reduction of units of RBC transfusions by an absolute number of 
at least 4 RBC transfusions/8 wk compared with the pretreatment 
transfusion number in the previous 8 wks.  Only RBC transfusions given 
for a Hgb of < 9.0 g/dL pretreatment will count in the RBC transfusion 
response evaluation 
 
- 
Platelet response (if pretreatment platelets < 100x10^9/L) 
o Absolute increase of > 30x10^9/L for patients starting with > 20x10^9/L 
platelets 
 
o Increase from <20x10^9/L to >20x10^9/L and by at least 100% 
 
- 
Neutrophil response (if pretreatment <1.0 x 10^9/L) 
o At least 100% increase and an absolute increase of >0.5 x 10^9/L 
 
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) for at least one 
week 
Progression or relapse after HI‡: 
 


Protocol 2013-0590 
December 13, 2013 
Page 23 of 38 
 
- 
At least 1 of the following: 
 
o At least 50% decrement form maximum response levels in granulocytes or 
platelets 
 
o Reduction in hemoglobin by > 1.5g/dL 
 
o Transfusion dependence 
 
- 
‡In the absence of another explanation, such as acute infection, repeated courses of chemotherapy 
(modification), gastrointestinal bleeding, hemolysis, and so forth. It is recommended that the 2 kinds of 
erythroid and platelet responses be reported overall as well as by the individual response pattern. 
Relapse after CR or PR: 
 
- 
At least 1 of the following 
 
o Return to pretreatment bone marrow blast percentage 
 
o Decrement of > 50% from maximum remission/response levels in 
granulocytes or platelets 
 
o Reduction in hemoglobin concentration by > 1.5g/dL or transfusion 
dependence 
 
Cytogenetic Response: 
 
- 
Complete: Disappearance of the known chromosomal abnormality without 
appearance of new abnormalities in 20 metaphases 
 
- 
Partial: At least 50% reduction of the chromosomal abnormality in 20 
metaphases 
 
Disease Progression:  
 
For patients with: 
- 
Less than 5% blasts: > 50% increase in blasts to > 5% blasts 
 
- 
5-10% blasts: > 50% increase to > 10% blasts 
 
- 
10-20% blasts: > 50% increase to >20% blasts 
 
- 
20-30% blasts: > 50% increase to > 30% blasts 
 
Any of the following: 
 


Protocol 2013-0590 
December 13, 2013 
Page 24 of 38 
 
- 
At least 50% decrement from maximum remission/response in granulocytes or 
platelets 
 
- 
Reduction in hemoglobin by > 2 g/dL 
 
- 
Transfusion dependence 
 
Survival Endpoints: 
 
- 
Overall: death from any cause 
 
- 
Event free: failure or death from any cause 
 
- 
PFS: disease progression or death from MDS 
 
- 
DFS: time to relapse 
 
- 
Cause specific death: death related to MDS 
 
6.2.2. Primary Safety Endpoint and Safety Considerations 
 
Primary safety endpoint: The overall incidence and severity of all adverse events 
including clinically significant thrombocytopenic events using Common Toxicity Criteria 
v 4.0.   
 
An 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 events (AEs) will be collected using the 
Leukemia AE guidelines. 
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. 
All “suspected adverse reactions” (as defined in 21 CFR 312.32(a)) will be captured in 
the case report forms.  For abnormal chemical values grade 3 or 4, the apogee will be 
reported per course in the CRF. 
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. 


Protocol 2013-0590 
December 13, 2013 
Page 25 of 38 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial.  Protocol specific data and adverse events will be entered 
into PDMS/CORe, the electronic case report form for this protocol. 
6.2.2.1. Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
- 
Death 
- 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred.  It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
- 
Inpatient hospitalization or prolongation of existing hospitalization 
- 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
- 
A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
- 
Important medical events as defined above may also be considered serious 
adverse events.  Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
Only unexpected AEs will be recorded in the Case Report Form (CRF).  The Principal 
Investigator will sign and date the PDMS or CORE Case Report Form toxicity pages per each 
patient at the completion of each course.  Following signature, the Case Report Form will be 
used as source documentation for the adverse events for attribution. 
 


Protocol 2013-0590 
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All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. MDACC.  
Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event. 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
The following SAEs are not subject to expedited reporting, but would still be included in 
the annual report via the SAE log. 
a. Infection or cytopenias leading to hospitalization or prolongation of hospitalization 
Disease progression leading to death, life-threating AE, hospitalization or 
prolongation of hospitalization, or disability.  
Reporting to FDA: 
- 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32 
 
- 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
6.2.2.2. Procedure in Case of Pregnancy 
 
If a female subject or partner of a male subject becomes pregnant during the study 
dosing period or within 3 months from the discontinuation of dosing, the investigator 
should report the information to the study supporter as if it is an SAE. The expected 
date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated fertility date, pregnancy result and neonatal data etc., should be included in 
this information.  The investigator will follow the medical status of the mother, as well as 
the fetus, as if the pregnancy is an SAE. 
 


Protocol 2013-0590 
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When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous 
abortion, induced abortion, stillbirth, death of newborn, congenital anomaly (including 
anomaly in a miscarried fetus)], the investigator should respond in accordance with the 
report procedure for SAEs. Additional information regarding the outcome of a pregnancy 
(which is categorized as an SAE) is mentioned below. 
- 
"Spontaneous abortion" includes abortion and missed abortion. 
- 
Death of an infant within 1 month after birth should be reported as an SAE 
regardless of its relationship with the study drug. 
- 
If an infant dies more than 1 month after the birth, it should be reported if a 
relationship between the death and intrauterine exposure to the study drug is 
judged as "possible" by the investigator. 
- 
In the case of a delivery of a living newborn, the "normality" of the infant is 
evaluated at the birth. 
- 
"Normality" of the miscarried fetus is evaluated by visual examination unless test 
results which indicate a congenital anomaly are obtained prior to miscarriage. 
 
6.2.2.3. SAE Reporting to Study Supporter ( Novartis Oncology) 
 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, 
must be reported by the investigator.  In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be reported. 
 
All serious adverse events must be reported by facsimile within 24 hours to Novartis 
Oncology . MDC – Oncology Fax: 1 610 422 2527 (make sure you include the 1 prior to 
the 610 as this is a desktop fax) 
 
The SAE report should comprise a full written summary, detailing relevant aspects of 
the adverse events in question.  Where applicable, information from relevant hospital 
case records and autopsy reports should be included.  Follow-up information should be 
forwarded to Novartis Oncology within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of 
eltromboapg and considered by the investigator to be related or possibly related to 
eltrombopag must be reported to Novartis Oncology if and when they occur.  
Additionally, in order to fulfill international reporting obligations, SAEs that are related to 
study participation (e.g., procedures, invasive tests, change from existing therapy) or 
are related to a concurrent medication will be collected and recorded from the time the 
subject consents to participate in the study until he/she is discharged. 
 
6.2.3. Secondary Efficacy Endpoints 
 
The key secondary endpoints for this study are: 
 


Protocol 2013-0590 
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- 
To evaluate the safety and tolerability of the combination of eltrombopag and 
decitabine.  Safety will be assessed by the overall incidence and severity of all 
study-treatment related adverse events per CTCAE v 4.0 
 
- 
To evaluate the incidence of dose reductions and delays of decitabine therapy 
 
- 
To evaluate the effect of eltrombopag on medically significant hemorrhagic 
events (defined as Grade 3 or 4 hemorrhagic events on CTCAE v 4.0) 
 
- 
To evaluate the effect of eltrombopag on platelet and RBC transfusion 
independence per IWG-2006 criteria 
o Platelet IWG-2006:  A complete response is defined as a platelet count > 100 x 
10^9/L; and a major response defined as an increase of platelet count by higher 
than 30 x 10^9/L. 
o Durable platelet count: in which a hematologic improvement in platelets (HI-P) 
defined as either an increase >30 x 10^9/L from patients with a baseline platelet 
count >20 x 10^9/L, or an increase from <20 x 10^9/L to >20 x 10^9/L and by 
at least 100%, present for >8 weeks. 
 
- 
Incidence of transformation to AML per FAB criteria (>30% blasts) during 
treatment period and follow-up 
 
- 
Incidence and severity of bone marrow fibrosis during treatment period and 
follow-up 
 
 
- 
To examine the relationship between clinical response with ferritin level and other 
markers of iron burden at study start 
 
6.2.4. Exploratory Endpoints 
 
The following exploratory endpoints and correlative laboratory studies will be examined 
to determine the in vivo mechanism of action of the therapeutic combination, the 
biological effects of the combination of decitabine and eltrombopag, as well as to detect 
whether certain molecular or other genetic patterns can predict response to this 
combination: 
 
- 
Genetic analysis of the mutational status of up to 53 genes known to be affected 
in myelodysplastic syndromes and acute leukemias prior to study start, 
performed through the molecular diagnostics laboratory of MD Anderson.  Any 
remaining sample may be banked for additional future scientific research. 
 
- 
Gene expression profiling and gene-specific DNA methylation may be performed 
in the pretreatment samples.  DNA methylation is assessed using bisulfite PCR 
assays (i.e. COBRA or pyrosequencing analysis) and gene expression profiling 
by real-time PCR analysis. 
 


Protocol 2013-0590 
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6.3 Subsets 
 
6.3.1. Full Analysis Set 
 
The full analysis set will consist of all enrolled subjects.  Analyses for demographics and 
baseline characteristics will utilize this analysis set. 
 
6.3.2. Efficacy Analysis Set 
 
The efficacy analysis set will consist of all enrolled subjects who have received at least 
one 28-day cycle of investigational product.  Analysis for efficacy endpoints will utilize 
this analysis set.6.3.3. Safety Analysis Set 
 
The safety analysis set will consist of all subjects who received at least 1 dose of 
investigational product.  Subjects will be analyzed according to the treatment actually 
received.  Analysis for safety endpoints will utilize this analysis set. 
 
 
 
7. Regulatory and Reporting Requirements 
 
7.1. Informed Consent 
 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational products are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
 
The acquisition of informed consent should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject or legally acceptable representative. 
 
7.2. Independent Ethics Committee/Institutional Review Board 
 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB 
for written approval. A copy of the written approval of the protocol and informed consent 
form must be received by Novartis Oncologybefore recruitment of subjects into the 
study and shipment of investigational product. 
 


Protocol 2013-0590 
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The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent form. 
The investigator should notify the IEC/IRB of deviations from the protocol or serious 
adverse events occurring at the site and other adverse event reports received from 
Novartis Oncology , in accordance with local procedures. 
 
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study. Copies of the investigator’s reports and the 
IEC/IRB’s continuance of approval must be sent to. Novartis Oncology 
 
 
7.3 Subject Confidentiality 
 
The investigator must ensure that the subject’s confidentiality is maintained. On 
documents submitted to Novartis Oncology, subjects should be identified by their study 
number only. Documents that are not for submission to Novartis Oncology 
 (eg, signed informed consent forms) should be kept in strict confidence by the 
investigator. 
 
In compliance with ICH GCP Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the subject’s original medical 
records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study. The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records without violating the confidentiality of the subject. 
 
7.4. Protocol Amendments and Study Termination 
 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Novartis Oncology. Agreement 
from the investigator must be obtained for all protocol amendments and amendments to 
the informed consent form. The IEC/IRB must be informed of all amendments and give 
approval. The investigator must send a copy of the approval letter from the IEC/IRB to 
Novartis Oncology. 
 
Both Novartis Oncology and the investigator reserve the right to terminate the study 
according to the study contract. The investigator should notify the IEC/IRB in writing of 
the study’s completion or early termination and send a copy of the notification to 
Novartis Oncology. 
 
Subjects may be eligible for continued treatment with investigational product by 
extension protocol or as provided for by the local country’s regulatory mechanism. 
However, Novartis Oncology reserves the unilateral right, at its sole discretion, to 


Protocol 2013-0590 
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determine whether to supply the investigational product, and by what mechanism, after 
termination of the trial and before it is available commercially. 
 
7.5. Study Documentation and Archival 
 
The investigator should maintain a list of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on case report forms will be included on the Delegation of Authority Form. 
 
Source documents are original documents, data, and records from which the subject’s 
case report form data are obtained. These include but are not limited to hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, and correspondence. Case report form entries may be 
considered source data if the CRF is the site of the original recording (ie, there is no 
other written or electronic record of data). In this study, case report forms calculating 
IPSS may be used as source documents for IPSS risk category assignment. 
 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Novartis Oncology and/or applicable 
regulatory authorities. Elements should include: 
 
- 
Subject files containing completed case report forms, informed consent forms, 
and subject identification list 
 
Study files containing the protocol with all amendments, investigator’s brochure, copies 
of prestudy documentation and all correspondence to and from the IEC/IRB and  
Novartis Oncology 
- 
 
- 
Proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement, and all drug-related correspondence 
 
 
In addition, all original source documents supporting entries in the case report forms 
must be maintained and be readily available.  No study document should be destroyed 
without prior written agreement between Novartis Oncology and the investigator. Should 
the investigator wish to assign the study records to another party or move them to 
another location, he/she must notify Novartis Oncology in writing of the new responsible 
person and/or the new location. 
 
7.6. Serious Adverse Event Reporting (SAE):  
 
See Section 6.2.2.1 for detailed information regarding SAE definitions. 
 
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 


Protocol 2013-0590 
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Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.   Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to , regardless of attribution (see Section 6.2.2.3).  SAE reporting will 
be done according to 21 CFR 312.32(c)(1)(iv) (“Sponsor must report any clinically 
important increase in the rate of a serious adverse reaction over that listed in the 
protocol or investigator brochure.”).  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html).   
 
8. Statistical Considerations 
 
This is an open label, phase II clinical trial to evaluate the efficacy of eltrombopag in 
combination with decitabine as a frontline therapy in patients with Intermediate-2 or 
High-Risk Myelodysplastic Syndrome (MDS). A total of 40 patients will be accrued from 
M.D. Anderson Cancer Center (MDACC), at a rate of 2-3 patients per month.  
The primary endpoint is the overall response rate (ORR) based on the IWG-2006 
criteria, which includes complete remission (CR), partial remission (PR), and 
hematologic improvement (HI).  Patients’ overall response will be assessed during the 
first four 28-day cycles of treatment. Patients who drop off the study early due to 
treatment-related toxicities will be counted as treatment failures (i.e., non-responders).    
The method of Thall, Simon and Estey [1995] will be used for futility and toxicity 
monitoring for this study. The target overall response rate is 60% and the following 
futility stopping rule will be applied in cohort size of 10, starting from the 10th patient: 
prob{p(ORR)< 0.6) > 0.95, where p(ORR) denotes the overall response rate. That is, 
the trial will be stopped early due to futility, if during the study we determine that there is 
more than 95% chance that the ORR is less than 60%.  Assuming that the prior 
distribution of p(ORR) is beta (1.2, 0.8), the stopping boundaries corresponding to this 
futility monitoring rule are shown below in Table 1. The operating characteristics (OCs) 
for this futility stopping rule are summarized in Table 2. The design software Multc Lean 
Desktop (version 1.2.0) developed by the Department of Biostatistics at M. D. Anderson 
Cancer Center (MDACC) was used to generate the futility stopping boundaries and the 


Protocol 2013-0590 
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OC table. In order to utilize the software for the design, a highly informative beta (600, 
400) prior was assumed to approximate the target 60% overall response rate.  
Table 1. Futility stopping boundaries in cohort size of 10.  
Number of patients  
Stop the trial if there are 
this many patients 
achieving overall response 
10 
0-3 
20 
0-8 
30 
0-13 
 
Table 2. Operating characteristics for futility monitoring in cohort size of 10 (max sample 
size = 40).  
True ORR 
Prob(stop the trial early 
due to futility) 
Average sample size 
0.3 
0.971 
14.8 
0.4 
0.775 
22.0 
0.5 
0.391 
31.3 
0.6 
0.105 
37.5 
0.7 
0.015 
39.6 
 
Toxicity monitoring will be conducted in cohort size of 5, starting from the 5th patient. 
Denote the probability of toxicity by p(T), where toxicity is defined as any grade 3-4 
clinically relevant non-hematologic toxicity or a serious adverse event that is felt to be 
drug related (Common Terminology Criteria for Adverse Events CTCAE version 4.0). 
We assume as a priori, p(T) ~ beta (0.6, 1.4).  The trial will be stopped if Pr(p(T)> 0.30 | 
data)  >0.90. That is, we will stop the trial for new patient enrollment if at any time during 
the study we determine that there is more than 90% chance that the toxicity rate is more 
than 30%. Stopping boundaries corresponding to this toxicity monitoring rule are shown 
in Table 3 below. The operating characteristics for toxicity monitoring are summarized in 
Table 4. Again, Multc Lean Desktop (version 1.2.0) was used to generate the toxicity 
stopping boundaries and the OC table and a highly informative beta (300,700) prior was 
assumed to approximate the fixed 30% toxicity rate.  
Table 3. Toxicity stopping boundaries in cohort size of 5.   


Protocol 2013-0590 
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Number of patients  
Stop the trial if there are this many patients 
having toxicities 
5 
4-5 
10 
6-10 
15 
8-15 
20 
9-20 
25 
11-25 
30 
13-30 
35 
15-35 
 
Table 4. Operating characteristics for toxicity monitoring in cohort size of 5 (max sample 
size = 40).  
True toxicity rate 
Prob(stop the trial early) 
Average sample size 
0.10 
0.0006 
40.0 
0.20 
0.020 
39.4 
0.30 
0.186 
35.8 
0.40 
0.583 
26.8 
0.50 
0.905 
17.3 
 
The PI and the study statistician will review the efficacy and toxicity data quarterly in 
order to determine whether the stopping boundaries have been crossed.  
 
8.1 Analysis Plan 
The primary endpoint is overall response rate (ORR).   The ORR will be estimated along 
with the exact 95% confidence interval.  Secondary endpoints include incidence of dose 
reductions and delays of decitabine therapy, hemorrhagic events (defined as Grade 3 or 
4 hemorrhagic events on CTCAE v 4.0), platelet and RBC transfusion independence 
per IWG-2006 criteria, transformation from MDS to AML, Incidence and severity of bone 
marrow fibrosis. Descriptive statistics will be used to summarize all secondary 
endpoints. The incidence rates of binary secondary endpoints will be estimated, along 
with the exact 95% confidence intervals. 
The probabilities of time-to-event outcomes (such as time to transformation from MDS 
to AML and time to developing BM fibrosis) will be estimated using the method of 


Protocol 2013-0590 
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Kaplan and Meier. Log-rank tests will be used to compare the time-to-event outcomes 
among subgroups of patients.  
 
8.2. General Approach/Considerations 
 
The final analysis will be performed when all data has been retrieved, entered, cleaned, 
locked and frozen.  Descriptive statistics for demographic and baseline characteristics 
will be summarized for all enrolled subjects.  For categorical variables, the number and 
percentage of subjects in each category will be summarized.  Continuous variables will 
be summarized by n, mean, standard deviation, median, Q1 (25% percentile), Q3 (75% 
percentile), minimum and maximum values. 
 
8.3. Analysis of Key Study Endpoints 
 
The primary endpoint is overall response rate (ORR).   The ORR will be evaluated along 
with the exact 95% confidence interval.  Secondary endpoints include platelet response, 
durable platelet response, transformation to AML, incidence of bone marrow fibrosis, 
and time-to-event outcomes such as progression-free survival (PFS) and overall 
survival (OS).  The probabilities of PFS and OS will be estimated using the method of 
Kaplan and Meier. The incidence rates of other binary secondary endpoints will be 
estimated, along with the exact 95% confidence intervals.  Subjects that discontinue the 
study prior to having achieved a clinical response will be considered to have not had an 
event.  
Patients receiving growth factors other than eltrombopag (erythropoietin, GM-
CSF or G-CSF) will not be considered in the HI analysis for the time periods 
specified in Section 4.5.3 Supportive Care Guidelines.  Hemoglobin levels and 
platelet counts collected from patients that have received a transfusion within the 
last 7 days will not be considered in the analysis.   
 
Survival or times to failure and time to progression functions will be estimated using the 
Kaplan-Meier method.  The two-sided log-rank test will be used to assess the 
differences of time to events between groups.   
 
The total number of dose administrations, the average dose (mg), and the cumulative 
dose administered will be summarized by eltrombopag treatment group. 
 
Blood chemistry and complete blood counts will be summarized by treatment group at 
each time point.   
 
Additional exploratory analyses of the key study endpoints will be performed as deemed 
appropriate. 
 
8.4. Safety Endpoints 


Protocol 2013-0590 
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The incidence of adverse events will be summarized by system organ class and by 
preferred term according to the MedDRA dictionary for each treatment group.  This 
summary includes all treatment-emergent adverse events recorded from the start of 
investigational product on this study, or any worsening of adverse events initially 
experienced before initiation of this study. 
 
Narratives of “on-study” deaths, serious and significant adverse events, including early 
withdrawals due to adverse events, may also be provided. 
 
 
 
 


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References: 
 
 
1. 
Doll DC, List AF: Myelodysplastic syndromes. West J Med 151:161-7, 1989 
 
2. 
Albitar M, Manshouri T, Shen Y, et al: Myelodysplastic syndrome is not merely 
"preleukemia". Blood 100:791-8, 2002 
 
3. 
Dansey R: Myelodysplasia. Curr Opin Oncol 12:13-21, 2000 
 
4. 
List AF: New agents in the treatment of MDS. Clin Adv Hematol Oncol 3:832-4, 2005 
 
5. 
Ma X, Does M, Raza A, et al: Myelodysplastic syndromes: incidence and survival in the 
United States. Cancer 109:1536-42, 2007 
 
6. 
Kadia TM, Jabbour E, Kantarjian H: Failure of hypomethylating agent-based therapy in 
myelodysplastic syndromes. Semin Oncol 38:682-92, 2011 
 
7. 
Garcia-Manero G, Gore SD: Future directions for the use of hypomethylating agents. 
Semin Hematol 42:S50-9, 2005 
 
8. 
Prebet T, Gore SD, Esterni B, et al: Outcome of high-risk myelodysplastic syndrome after 
azacitidine treatment failure. J Clin Oncol 29:3322-7, 2011 
 
9. 
Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of 3 schedules 
of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. 
Blood 109:52-7, 2007 
 
10. 
Steensma DP, Baer MR, Slack JL, et al: Multicenter study of decitabine administered 
daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for 
outpatient treatment (ADOPT) trial. J Clin Oncol 27:3842-8, 2009 
 
11. 
Lee JH, Jang JH, Park J, et al: A prospective multicenter observational study of decitabine 
treatment in Korean patients with myelodysplastic syndrome. Haematologica 96:1441-7, 2011 
 
12. 
Kantarjian H, Giles F, List A, et al: The incidence and impact of thrombocytopenia in 
myelodysplastic syndromes. Cancer 109:1705-14, 2007 
 
13. 
Kantarjian H, O'Brien S, Ravandi F, et al: Proposal for a new risk model in 
myelodysplastic syndrome that accounts for events not considered in the original International 
Prognostic Scoring System. Cancer 113:1351-61, 2008 
 
14. 
Germing U, Hildebrandt B, Pfeilstocker M, et al: Refinement of the international 
prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk 
assessment in patients with primary myelodysplastic syndromes (MDS). Leukemia 19:2223-31, 2005 
 
15. 
Kuter DJ: Thrombopoietin and thrombopoietin mimetics in the treatment of 
thrombocytopenia. Annu Rev Med 60:193-206, 2009 
 
16. 
Cheng G, Saleh MN, Marcher C, et al: Eltrombopag for management of chronic immune 
thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 377:393-402, 2011 
 
17. 
Saleh MN, Bussel JB, Cheng G, et al: Safety and efficacy of eltrombopag for treatment of 
chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood 121:537-
45, 2013 
 
18. 
McHutchison JG, Dusheiko G, Shiffman ML, et al: Eltrombopag for thrombocytopenia in 
patients with cirrhosis associated with hepatitis C. N Engl J Med 357:2227-36, 2007 
 
19. 
Kuter DJ: What is the potential for thrombopoietic agents in acute leukemia? Best Pract 
Res Clin Haematol 24:553-8, 2011 
 
20. 
Roth M, Will B, Simkin G, et al: Eltrombopag inhibits the proliferation of leukemia cells 
via reduction of intracellular iron and induction of differentiation. Blood 120:386-94, 2012 


Protocol 2013-0590 
December 13, 2013 
Page 38 of 38 
 
 
21. 
Mavroudi I, Pyrovolaki K, Pavlaki K, et al: Effect of the nonpeptide thrombopoietin 
receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic 
syndrome. Leuk Res 35:323-8, 2011 
 
22. 
Will B, Kawahara M, Luciano JP, et al: Effect of the nonpeptide thrombopoietin receptor 
agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and 
myelodysplastic syndrome. Blood 114:3899-908, 2009 
 
23. 
Olnes MJ, Scheinberg P, Calvo KR, et al: Eltrombopag and improved hematopoiesis in 
refractory aplastic anemia. N Engl J Med 367:11-9, 2012 
 
24. 
Mittelman M, Assouline S, Briasoulis E, et al: Eltrombopag Treatment of 
Thrombocytopenia in Advanced Myelodysplastic Syndromes and Acute Myeloid Leukemia: Results of the 
8-Week Open-Label Part of an Ongoing Study. ASH Annual Meeting Abstracts 120:3822-, 2012 
 
25. 
Oliva EN, Santini V, Zini G, et al: Efficacy and Safety of Eltrombopag for the Treatment of 
Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Interim Analysis of 
a Prospective, Randomized, Single-Blind, Placebo-Controlled Trial (EQoL-MDS). ASH Annual Meeting 
Abstracts 120:923-, 2012 
 
26. 
Frey NV, Hexner EO, Porter DL, et al: A Phase I Clinical Trial Using Eltrombopag in 
Patients with Acute Myelogenous Leukemia. ASH Annual Meeting Abstracts 120:3576-, 2012 
 
27. 
Allred AJ, Bowen CJ, Park JW, et al: Eltrombopag increases plasma rosuvastatin exposure 
in healthy volunteers. Br J Clin Pharmacol 72:321-9, 2011 
 
28. 
Eltrombopag Prescribing Information, 2013, pp Investigational Brochure 
 
29. 
Parks D, Lin X, Painter JL, et al: A proposed modification to Hy's law and Edish criteria in 
oncology clinical trials using aggregated historical data. Pharmacoepidemiol Drug Saf, 2013