Conditions: Leukemia
Keywords: Leukemia Myelodysplastic syndrome MDS Overall response rate ORR Eltrombopag Promacta Hypomethylating Agent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

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

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 arms.The selection of treatment arm will be made by you and your treating physician.

* If you are in Arm A, you will receive eltrombopag alone.
* If you are in Arm B, you will receive eltrombopag and will continue to receive the hypomethylating agent that you were receiving before you took part in this study.

Study Drug Administration:

You will take eltrombopag by mouth every day of each 28-day study cycle. If you are in Arm B, you will also continue to take the hypomethylating agent you took before joining the study at the same dosing schedule you were receiving before entering this study.

Eltrombopag should be taken on an empty stomach (1 hour before or 2 hours after a meal). Do not eat calcium-rich foods (such as dairy products and calcium fortified juices), or take other drugs (such as antacids) or supplements containing iron, calcium, aluminum, magnesium, selenium, and/or zinc for 2 hours before or 4 hours after taking eltrombopag. If a dose of eltrombopag is vomited, it should not be made up or re-taken 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 all Cycles:

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

On Days 8, 15, and 22 of Cycle 1:

* Your vital signs (blood pressure, heart rate, and temperature) will be measured.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

If the doctor thinks it is needed, on Day 1 of every 3 cycles (Cycles 3, 6, 9, and so on), you will also 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 drug(s) for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug(s) 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.

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 may have a bone marrow aspirate/biopsy collected to check the status of the disease and for cytogenetic testing.

Follow-up Visit:

About 28 days after your last dose of study drug, 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). Its use in this study is investigational. Azacitidine and decitabine are each FDA approved for the treatment of MDS and are commercially available. The study doctor can explain how the study drug(s) are designed to work.

Up to 46 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Eltrombopag 200 mg by mouth daily in a 28 day cycle. arm 2: Eltrombopag in combination with continuation of hypomethylating agent in 28-day cycles. Eltrombopag 200 mg by mouth daily in a 28 day cycle.

The choice of HMA agent (e.g. azacitidine or decitabine) will be the HMA the patient has received prior to enrollment on study. Eltrombopag should be initiated at the start of the next HMA cycle whenever possible so the start date of both agents is consistent.

Interventions: intervention 1: Eltrombopag intervention 2: Hypomethylating Agent (HMA)
Intervention descriptions: intervention 1: 200 mg by mouth daily in a 28 day cycle. intervention 2: The choice of HMA agent (e.g. azacitidine or decitabine) will be the HMA the patient has received prior to enrollment on study.

Protocol document:
Prot_SAP_000.pdf: 
2013-0225
September 23, 2015
Page 1
Protocol Page
Phase II Study of Eltrombopag With or Without Continuation of Hypomethylating 
Agent After Hypomethylating Agent Failure For Patients with MDS
2013-0225
Core Protocol Information
Short Title 
Eltrombopag With or Without Hypomethylating Agent After Hypomethylating Agent Failure For 
Patients with 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 With or Without Continuation of Hypomethylating Agent After 
Hypomethylating Agent Failure For Patients with MDS
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/17/2019
Version:
14
Submitted by:
Tawana Heiskell--10/26/2016 3:54:17 PM
OPR Action:
Accepted by:  Julie Arevalo -- 11/1/2016 8:45:27 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2013-0225
September 23, 2015
Page 2
Protocol Body
 


Protocol 2013-0225 
September 22, 2015 
Page 1 of 40 
 
 
Phase II Study of Eltrombopag With or Without Continuation of Hypomethylating 
Agent after Hypomethylating Agent Failure for Patients with MDS 
 
 
MDACC Protocol #: 
 
2013-0225 
 
 
Principal Investigator:  
 
Courtney DiNardo, M.D., M.S.C.E. 
 
 
Co-Principal Investigator:  
Guillermo Garcia-Manero, M.D. 
 
 
Address: 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
Houston, TX 77030 
 
 
Phone: 
 
 
 
713) 794-1141 
 
 
Fax:  
 
 
 
713) 792-0319 
 
 
Email: 
 
 
 
cdinardo@mdanderson.org 
 
 


Protocol 2013-0225 
September 22, 2015 
Page 2 of 40 
 
  TABLE OF CONTENTS 
 
 
Page 
1.  Objectives ............................................................................................................................. 3 
2.  Background .......................................................................................................................... 3 
3.  Subject Eligibility ............................................................................................................... 10 
4.  Treatment Plan ................................................................................................................... 12 
5.  Study Procedures .............................................................................................................. 20 
6.  Response Definitions ........................................................................................................ 23 
7.  Regulatory and Reporting Requirements ......................................................................... 30 
8.  Statistical Considerations ................................................................................................. 33 
References .............................................................................................................................. 38 
 
 
 
 
 


Protocol 2013-0225 
September 22, 2015 
Page 3 of 40 
 
1. OBJECTIVES 
 
1.1 Primary 
 
The primary objectives of this study are to evaluate the safety and efficacy of 
eltrombopag for the treatment of MDS patients after experiencing hypomethylating 
agent (HMA) failure.  The primary efficacy endpoint is the overall response rate (ORR) 
based on the IWG-2006 criteria, which includes complete remission (CR), partial 
remission (PR), and major hematologic improvement (HI).  Safety will be assessed by 
the overall incidence and severity of all study-treatment related adverse events and 
clinically thrombocytopenic events per CTC v 4 
 
1.2 Secondary 
 
The secondary objectives of the study are: 
 
- 
Incidence of transformation from MDS to AML during treatment period and 
follow-up 
- 
Incidence and severity of bone marrow fibrosis during treatment period and 
follow-up 
- 
Proportion of patients achieving a platelet response during treatment per IWG-
2006 criteria 
- 
Proportion of patients achieving a durable platelet response during treatment per 
IWG-2006 criteria 
 
1.3 Exploratory 
 
The exploratory objectives of the study are: 
 
- 
Correlative laboratory studies of subjects including detailed mutation analysis of 
53-genes known to be affected in myelodysplastic syndromes and acute 
leukemias will be performed 
- 
Proportion of subjects achieving a major or minor cytogenetic response will be 
obtained per IWG-2006 criteria 
- 
To evaluate efficacy of eltrombopag based on IPSS risk classification at 
diagnosis 
- 
The number and frequency of platelet transfusions during the treatment period 
will be assessed. 
- 
To examine the relationship between clinical response with ferritin level and other 
markers of iron burden at study start. 
 
 
2. BACKGROUND AND SCIENTIFIC RATIONALE 
 
2.1 Background 
 


Protocol 2013-0225 
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Page 4 of 40 
 
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 
 
The therapeutic options for MDS remain limited. A small percentage of patients are 
candidates for curative therapies such as allogeneic stem cell transplant. For the vast 
majority of patients the lack of acceptable donors, advanced age, and/or serious co-
morbid medical conditions and organ dysfunction prevent access to this option. For 
essentially the same reasons, AML-like chemotherapy regimens represent an 
unacceptable benefit/risk ratio for many of these patients. In fact, the standard of care in 
MDS has generally been accepted as supportive in nature. 
 
Over the past decade, clinical use of the hypomethylating agents (HMA) azacitidine and 
decitabine have been shown to improve patient quality of life, decrease transfusion 
requirements, and improve outcome parameters in MDS patients, and are now the 
standard of care for MDS patients requiring therapy.  However, not all patients respond 
to HMAs, and unfortunately most patients initially responding to HMAs will ultimately 
progress on therapy.  Current evidence suggests ORRs of 28-48% and CR rates of 6-
34% in all patients treated with HMAs, with a median length of response in HMA-
responders of only 8 to 10 months.6,7  Myelosuppression, including severe 
thrombocytopenia, is commonly seen in HMA-treated patients, and is the most frequent 
cause of dose reduction, delay and discontinuation of HMA agents in up to 80% of 
patients.8  Currently there are no thrombopoietic agents indicated for use in MDS.   
 
Prognosis in HMA-failure patients is extremely poor.  Jabbour et al9 report a median 
survival of merely 4 months in MDS patients with progressive disease after decitabine 
(Figure 1), and Prebet et al7 identified a similar median survival of 5.6 months in MDS 
patients with progressive disease after 5-azacytadine.  There are no currently approved 
agents in the setting of HMA-failure MDS patients, and there are limited therapeutic 
options, particularly given the increased age and frequent comorbidities of this 
population.   
 


Protocol 2013-0225 
September 22, 2015 
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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, and even within the 
lower-risk MDS categories, over 10% of patients experience life-threatening 
thrombocytopenia (<20x10^9/L) at presentation.10 Thrombocytopenia has been 
identified as an independent and adverse prognostic factor for overall survival in MDS at 
all stages.11  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.12  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. 
 
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, 
promoting megakaryopoiesis and release of platelets from mature megakaryocytes.13  It 
is currently FDA-approved for the treatment of immune thrombocytopenic purpura (ITP) 
and hepatitis C (HCV) associated thrombocytopenia.14-16  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.17  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,18-20 and has also been associated with 
multilineage clinical responses in patients with severe and refractory aplastic anemia.21  
 
 


Protocol 2013-0225 
September 22, 2015 
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The dose of eltrombopag selected is 200mg (100mg for East Asian patients).  This is 
based on the encouraging results of a recent Phase I clinical study of eltrombopag 
monotherapy for elderly patients with relapsed or refractory AML.22  Eltrombopag 
monotherapy revealed no platelet responses in the 50mg or 100mg eltrombopag 
cohorts (n=7).  Two of the seven patients treated at the 200mg dose level and two of the 
nine patients treated at the 300mg dose level achieved platelet response and platelet 
transfusion independence.  Interestingly, one patient with primary refractory AML 
associated with monosomy 7 obtained a CR with a complete cytogenetic response with 
eltrombopag monotherapy.  Overall eltrombopag was well tolerated at all doses studied 
and a maximally tolerated dose (MTD) was not reached.  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.23,24  
 
Furthermore, the combination of eltrombopag in addition to a hypomethylating agent is 
currently being evaluated in two ongoing studies (NCT02488565 and NCT01481220) of 
MDS patients with thrombocytopenia with eltrombopag doses ranging from 50-300mg in 
both studies, with promising efficacy results, and without new identified safety signals.   
 
Interim results from the first clinical trial (NCT02488565) are available in abstract form 
from the EHA 2013 meeting.  In this trial, n=17 patients have been started on 50mg of 
eltrombopag and dose-escalated every 2 weeks up to 300mg daily.  One patient 
developed reversible grade III LFT abnormalities, and 4 patients developed 
thrombocytosis requiring eltrombopag cessation.  Activity was seen in 76% (4 CR, 3 
marrow CR, 3 HI-P, 1 HI-E, 2 with >50% bone marrow blast reduction) and platelet 
improvement was seen in 8/15 (53%) patients with baseline platelets <100K.  One 
patient had an improvement in platelet count during the lead-in 2-week 50mg 
eltrombopag phase.  Treatment with the combination of eltrombopag and azacitidine at 
doses up to 300mg were well-tolerated, with encouraging response and AE events. 
 
Interim results from the second trial (NCT01481220) are also available from the EHA 
meeting.  This pilot study explores eltrombopag with increasing doses of eltrombopag 
(from 50mg to 300mg in a 3+3 dose-escalation fashion) in conjunction with standard 
azacitidine dosing, and reports on n=11 patients.  Reported SAEs were one case of 
fatal pneumonia with E. coli septicemia, erysipelas (occurring twice in n=1 patient), and 
bronchitis (n=1).  One patient developed DLT with an extremity DVT, elevated liver 
enzymes and progressive disease at the n=300mg dose.  The combination of 
eltrombopag with azacitidine was summarized as feasible and well-tolerated. 
 
Additionally, in a Phase II study of 25 patients with refractory aplastic anemia21, 
eltrombopag monotherapy was administered to all patients at a dose of 50mg, with dose 
escalation to a maximum dose of 150mg daily possible.  All but one patient in this study 
received the maximum dose of 150mg per day, and 11 of 25 patients obtained a platelet 
response.  Serious adverse events in this cohort included abdominal pain and 
orthostatic hypotension in a patient with diabetic gastroparesis, a severe rash that was 
temporally related to the initiation of cephalosporin, severe gingival bleeding associated 
with thrombocytopenia, and episodes of fever with neutropenia.  One patient acquired 


Protocol 2013-0225 
September 22, 2015 
Page 7 of 40 
 
Hepatitis B virus infection during the study and eltrombopag was discontinued.  
Diagnosis of a cataract in one patient at week 9, during examination for a “floater”, 
prompted the discontinuation of eltrombopag, although the patient met hematologic 
response criteria.  The cataract could not be confirmed on subsequent examinations. 
 
Given this scientific rationale, we propose to evaluate the safety and efficacy of 
eltrombopag in MDS patients with HMA-failure (as defined by persistent cytopenias or 
rising blast percentage on HMAs).  The use of a parallel two-arm Phase II design will 
allow the evaluation of disease response with the addition of single-agent eltrombopag 
after HMA failure, as well as to the addition of eltrombopag with continuation of the 
hypomethylating agent to evaluate for additive or synergistic responses, as have been 
reported with lenalidomide in combination with azacitidine in MDS-azacitidine failures.25  
As thrombocytopenia <100,000 x 10^9/L is an independent and adverse prognostic 
factor for overall survival in MDS at all stages and given the primary eltrombopag 
mechanism of augmented megakaryopoiesis, this study will evaluate HMA-failure 
patients with a platelet count of <100 x 10^9/L. 
 
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 
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. 


Protocol 2013-0225 
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Current guidelines include measurement of 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: 
Eltrombopag is a thrombopoietin (TPO) receptor agonist and TPO-receptor agonists 
may increase the risk for the development or progression of reticulin fiber deposition 
within the bone marrow.  
In the ITP extension study, seven patients had reticulin fiber deposition reported in bone 
marrow biopsies, including two patients who also had collagen fiber deposition. The 
fiber deposition was not associated with cytopenias and did not necessitate 
discontinuation of eltrombopag. However, clinical studies have not yet excluded a risk of 
bone marrow fibrosis with cytopenias. 
Prior to initiation of eltrombopag, the screening bone marrow biopsy should be 
examined closely to establish a baseline level of fibrosis.  The presence and degree of 
reticulin fiber fibrosis should be evaluated on all bone marrow biopsies performed on 
study.  
2.3.3. Worsened Thrombocytopenia After Cessation of Eltrombopag  
 


Protocol 2013-0225 
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Discontinuation of eltrombopag may result in thrombocytopenia of greater severity than 
was present prior to therapy with eltrombopag. This worsened thrombocytopenia may 
increase the patient's risk of bleeding, particularly if eltrombopag is discontinued while 
the patient is on anticoagulants or antiplatelet agents. In the 3 controlled ITP clinical 
studies, transient decreases in platelet counts to levels lower than baseline were 
observed following discontinuation of treatment in 8% and 8% of the eltrombopag and 
placebo groups, respectively.  Serious hemorrhagic events requiring the use of 
supportive ITP medications occurred in 4 severely thrombocytopenic patients within one 
month following the discontinuation of eltrombopag; none were reported among the 
placebo group.  
 
Following discontinuation of eltrombopag, weekly CBCs including platelet counts for at 
least 4 weeks should be obtained and alternative treatments for worsening 
thrombocytopenia, according to current treatment guidelines, considered. 
2.3.4. Thrombotic/thromboembolic complications 
Eltrombopag may increase the risk of thrombotic/thromboembolic events. In the 
controlled ITP clinical studies, four thrombotic/thromboembolic complications were 
reported within the groups that received eltrombopag and none within the placebo 
groups. Thrombotic/thromboembolic complications have also been reported in the ITP 
extension study.  
In a placebo-controlled double-blind study (ELEVATE) of 292 patients with chronic liver 
disease who were undergoing an elective surgical procedure, the risk of thrombotic 
events was increased in patients treated with 75mg eltrombopag. Six thrombotic 
complications were reported within the group that received eltrombopag and two within 
the placebo group. All of the thrombotic complications reported within the eltrombopag 
group were of the portal venous system. Malignancy is known to increase the risk for 
developing a thrombotic event.  Four of the 6 subjects receiving eltrombopag either had 
a diagnosis or suspicion of malignancy (2 hepatocellular carcinoma; 1 possible 
lymphoma and 1 brain tumor).  The ELEVATE study was terminated in November 2009 
and a Dear Health Care Professional Letter (DHCPL) was sent to all physicians enrolled 
in Promacta Cares in May 2010.  Eltrombopag is not indicated for the treatment of 
thrombocytopenia in patients with chronic liver disease.  Caution should be used when 
administering eltrombopag to patients with known risk factors for thromboembolism 
(e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome and portal 
hypertension).  
2.3.5. Cataracts 
Cataracts were observed in toxicology studies of eltrombopag in rodents (see Non-
clinical Information). To date, however, there is no evidence that eltrombopag increases 


Protocol 2013-0225 
September 22, 2015 
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the incidence nor progression of cataracts in patients who have received eltrombopag.  
In the three placebo-controlled ITP studies, 7% of patients in both the placebo and 
eltrombopag treatment groups had a report of cataract.  A significant proportion of 
patients in the ITP clinical studies were also exposed to chronic corticosteroid 
administration.  Patients treated with eltrombopag who experience visual difficulties 
should have an appropriate ophthalmologic evaluation including evaluation for cataract 
formation. 
 
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) by World 
Health Organization (WHO) classification are eligible.   
 
3.  Patients must have completed at least 4 cycles of hypomethylating agent therapy 
(e.g azacitidine or decitabine) with failure to achieve at least a partial response, or with 
the presence of ongoing cytopenias per IWG (platelet count < 100x10^9/L, hemoglobin 
<11g/L or ANC <1x10^9/L).  Patients with progressive disease on HMA-therapy prior to 
this time point are also eligible at the time of documented progression.  Therapy with 
decitabine analogs (i.e. SGI-110) will be considered as decitabine for the purposes of 
this study. 
 
4.  Platelet count <100x10^9/L  
 
5.  Low, intermediate-1, intermediate-2 or High-risk category by IPSS 
 
6.  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
 
7.  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. 
 
8.  Serum creatinine <2x upper limit of normal 
 
9.  Subjects must be > 18 years of age at the time of informed consent, because no 
dosing or adverse event data are currently available on the use of eltrombopag in 
children. 
 


Protocol 2013-0225 
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10.  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: 
- 
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). 
 
11. Patients must have recovered from acute toxicity (to grade 1 or less) of all previous 
therapy prior to enrollment.  Treatment may start earlier if necessitated by the patient’s 
medical condition (e.g. progressive disease) following discussion with the Investigator. 
 
3.2 Exclusion Criteria 
 
1.  Subjects with any prior exposure to a thrombopoietin-receptor agonist 
 
2.  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 
 
3.  Psychiatric disorders or altered mental status precluding understanding of the 
informed consent process and/or completion of the necessary study procedures 
 
4.  Active uncontrolled serious infection or sepsis at study enrollment 
 
5.  Clinically significant gastrointestinal disorders that may interfere with absorption of 
drug. 
 
6.  History of arterial thrombosis (i.e. stroke) in the past year 
 
7.  History of venous thrombosis currently requiring anti-coagulation therapy 
 
8.  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 
 
9.  Subjects with a QTc > 480 msec (QTc > 510 msec for subjects with Bundle Branch 
Block) at baseline 
 


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10.  Pregnant or breast-feeding, because there are no adequate and well-controlled 
studies of eltrombopag use in pregnancy and it is unknown whether eltrombopag is 
excreted in human milk. 
 
11.  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. 
 
4. TREATMENT PLAN 
 
4.1 Study Design 
 
This is a  two arm phase II study to evaluate the safety and efficacy of high dose 
eltrombopag for the treatment of MDS patients with thrombocytopenia after 
experiencing hypomethylating agent (HMA) failure.  The primary efficacy endpoint is the 
overall response rate (ORR) based on the IWG-2006 criteria, which includes complete 
remission (CR), partial remission (PR), and major hematologic improvement (HI). 
Patients’ overall response will be assessed after at least 2 cycles of treatment and no 
more than after 6 cycles of treatment and each cycle is 28 days.  A total of 46 patients 
will be enrolled into two arms: (A) eltrombopag only or (B) eltrombopag with 
continuation of the hypomethylating agent. All patients will be accrued from M. D. 
Anderson Cancer Center (MDACC). 
 
4.1.1  Arm A:  Eltrombopag monotherapy in 28-day cycles. 
 
4.1.2. Arm B: Eltrombopag in combination with continuation of hypomethylating agent 
in 28-day cycles.  The choice of HMA agent (e.g. azacitidine or decitabine) will be the 
HMA the patient has received prior to enrollment on study.  Eltrombopag should be 
initiated at the start of the next HMA cycle whenever possible so the start date of both 
agents is consistent. Subsequent cycles will begin on the first day of Decitabine or 
Azacitidine therapy, and in the absence of toxicity,  Eltrombopag  administration will not 
be interrupted.  HMA dosing and dosing adjustments should be performed according to 
the approved package insert, or alternatively at a dose of decitabine 20mg/m2 IV over 1 
hour for 5 days every 4 weeks and/or according to the institution’s standard of care (see 
Section 4.7.2 for rules of dose reduction or delay). 
 
4.1.2.1. For patients on Arm B, discontinuation of the hypomethylating agent and 
continued therapy with eltrombopag monotherapy after cycle 2 of combination therapy 
may be considered at the discretion of the investigator. 
 


Protocol 2013-0225 
September 22, 2015 
Page 13 of 40 
 
4.1.3. Study Replacement: Study patients that discontinue during cycle 1 of the study 
for reasons other than toxicity or progressive disease will be replaced.   
 
4.1.4. Treatment Extension:  After 12 cycles, subjects experiencing continued clinical 
benefit and no clinically significant study-drug related grade > 3 toxicity may be eligible 
to continue therapy after discussion with the PI, and the discussion documented in the 
patient’s medical record. 
 
4.1.5 General 
 
Adverse events, bleeding events, and concomitant medications will be assessed 
continually throughout the study; specific information will be requested at every study 
visit.   
 
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. 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. Administration of eltrombopag, +/- decitabine and azacitidine 
 
4.3.1. Decitabine and azacitidine may be administered by local doctor or at MD 
Anderson, inclusive of the Regional Cancer Centers (RCC).  Commercial supplies of 
decitabine and azacitidine will be used and records will be obtained from the local 
physician as indicated in the Dear Doctor letter (Appendix F).  Eltrombopag is self-
administered.   
 
4.3.2. Eltrombopag should be taken on an empty stomach (1 hour before or 2 hours 
after a meal).  Allow a 2-hour interval before or a 4 hour interval after eltrombopag and 
other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium 
fortified juices), or supplements containing polyvalent cations such as iron, calcium, 
aluminum, magnesium, selenium, and zinc. 
4.3.3. 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.  All 
serious adverse events (SAEs) that occur will be reported to the research nurse and will 
be evaluated by the Principle Investigator within 48 hours of observing or learning of the 


Protocol 2013-0225 
September 22, 2015 
Page 14 of 40 
 
event for reportability to the FDA (Appendix F).  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.   
4.3.4. Changes in drug dose and/or schedule must be discussed with and approved by 
the MDACC PI, or their representative prior to initiation, and will be documented in the 
patient record.  
 
4.3.5. Eltrombopag will be 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. 
 
4.3.6. Patient compliance will be documented using the MDACC Research Medication 
Diary and will be assessed at each study visit. 
 
4.3.7. Study cycles will be administered every 28 days  +/-7 days or upon resolution of 
any clinically significant study drug related AE to grade 0-1, whichever occurs first. 
Subsequent cycles will begin on the first day of Decitabine or Azacitidine therapy, and in 
the absence of toxicity, Eltrombopag administration will not be interrupted.   If a 
subsequent cycle is delayed due to adverse events related to HMA-agent in Arm B, or if 
it is considered in the best interest of the patient to delay administration of HMA (e.g. 
because of concern for an infection), administration of the eltrombopag may continue as 
planned. 
 
4.3.8. Administration of subsequent cycles may 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. 
 
4.3.9. Variations from the described doses and sequence may be considered on an 
individual basis after discussion with the PI and sponsor on a case-by-case basis. 
 
 
4.4. Identity of Investigational Product 
 
International Non-proprietary name 
eltrombopag 
Manufacturer  
 
 
 
GlaxoSmithKline (GSK) 


Protocol 2013-0225 
September 22, 2015 
Page 15 of 40 
 
Dose  
 
 
 
 
200mg daily 
Route of Administration 
 
 
oral 
Formulation  
 
 
 
50mg and 100mg tablets; in bottle 
 
Eltrombopag will be provided by   GSK 
For oral administration only 
Bottle containing 60 tablets 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  GSK 
 
4.5. Supportive Care Guidelines 
 
4.5.1. Supportive measures including blood and platelet transfusions, antimicrobials, 
and analgesics are permitted. 
 
4.5.2. The administration of anticancer therapies, other investigational cytotoxic agents, 
or prophylactic use of hematopoietic colony stimulating factors are not permitted. 
 
4.5.3.  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 epoetin alfa, filgrastim, or 
sargramostim, or for one month after receipt of pegfilgrastim or darbopoetin. 
 
4.5.4. 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 
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 
 
- 
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 
 


Protocol 2013-0225 
September 22, 2015 
Page 16 of 40 
 
4.6. Duration of Therapy 
 
Treatment is expected to continue until one of the following criteria applies: 
- 
Lack of objective response after 2 cycles of therapy unless eltrombopag is 
considered to be of clinical benefit to the patient, or 
 
- 
Clinically significant progressive disease, or 
 
- 
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 render the patient 
unacceptable for further treatment in the judgment of the investigator 
Continuation of therapy beyond 12 months will be considered on a case-by-case basis 
for patients deriving clinical benefit after discussion with the PI and the discussion 
documented in the patient’s medical record. 
4.7 Dosing Delays/Dose Modifications 
 
4.7.1 Dose adjustments for eltrombopag  
 
The dose of eltrombopag 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 4.7.1.1. for additional 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. 
 


Protocol 2013-0225 
September 22, 2015 
Page 17 of 40 
 
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: 
 
 
 
 
 
 
 
† see 4.7.1.1. for additional liver chemistry stopping and follow-up criteria 
 
Dose modifications for eltrombopag: 
Dose level 
eltrombopag (mg/day) 
+1 
300 
0 
200 
-1 
 
100 
 
-2 
50 
 
4.7.1.1. Additional Liver Chemistry Stopping and Follow-Up Criteria: 
If ALT >3x ULN and/or bilirubin >2x ULN, systematic evaluation for possible causes of 
hepatotoxicity must be initiated, with discontinuation of any potentially offending 
concomitant medications (in particular statins, antifungal agents, herbal supplements) 
and consideration of hepatobiliary imaging as appropriate.  Subjects should return to 
clinic for repeat liver chemistries within 24-72 hours, and then at least weekly until liver 
chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve or stabilize.    
 
Treatment should be held for any of the following liver chemistry criteria (all of which 
confer Grade III non-hematologic toxicity per NCI CTCAE): 
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 
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 2013-0225 
September 22, 2015 
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1. ALT > 5x ULN and bilirubin > 2.7x ULN (>35% direct bilirubin) 
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 Oncologywithin 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 trials26, 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). 


Protocol 2013-0225 
September 22, 2015 
Page 19 of 40 
 
- 
Obtain complete blood count with differential to assess eosinophilia 
- 
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. 
 
4.7.1.2. Dose Adjustments Related to Platelet Count:   
The starting dose for all study patients (with the exception of East Asians, see 4.7.1.3) 
will be 200mg orally daily.  East Asians will start at 100mg orally daily.  The eltrombopag 
dose can be increased by 100mg (to maximum of 300mg  daily) after 2 weeks if the un-
transfused platelet count has not increased to > 100 x 10^9/L and the patient has not 
experienced any grade > 3 study drug related toxicity.  Laboratory work including a CBC 
with differential and blood chemistries including ALT, AST and bilirubin must be 
evaluated bi-weekly for 4 weeks after any change in eltrombopag dosing. 
 
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.  
 
Dose reductions or delays 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. 
 
4.7.1.3. Dose Adjustments for Subjects of East Asian Ancestry: 
The starting dose for patients of East Asian ancestry will be 100mg orally daily.  East 
Asian (i.e. Japanese, Chinese, Taiwanese and Korean) subjects exhibited 50-55% 
higher eltrombopag concentrations compared to non-East Asian subjects.  Dose 
adjustments for platelet counts will proceed as per 4.7.1.2., regardless of ethnicity.  
 
4.7.2. Dosing for azacitidine and decitabine-related toxicities 
 
Patients with 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. 
 
Grade 2 toxicities that are persistent and 
intolerable (e.g. stomatitis) can result in 
dose delays or dose reductions to the 
next lower dose level in Cycle 2 or 
beyond. 


Protocol 2013-0225 
September 22, 2015 
Page 20 of 40 
 
 
Grade 3-4 clinically significant 
non-hematological toxicity 
Hold until recover to NCI CTCAE grade 
0-1 
 
If recovery occurs within 2 weeks after 
treatment has been held, dose should be 
reduced to –1 dose level, if applicable.   
 
Standard dose reductions for azacitidine and decitabine are described in the following 
table (please note patients should start at the dose level they were receiving prior to 
study enrollment): 
 
Dose level Decitabine (in mg/m2 for 5 
days) 
Azacitidine (in mg/m2 for 
7 days) 
0 
20 
75 
-1 
15 
50 
-2 
10 
25 
-3 
10 for 4 days 
25 for 5 days 
 
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. 
 
Patients with serious infectious complications in prior cycles may have the subsequent 
cycles administered at one dose level reduction in subsequent cycles. 
 
Dose reductions or delays different than those described above are acceptable after 
discussion with the sponsor and the PI, and will require documentation of the rationale 
for such action. 
 
4.7.3. For patients with adverse events that are due to one of the two agents, dose 
adjustments to only one of the study drugs may be adjusted as per the guidelines 
mentioned above. 
 
4.7.4. For patients on Arm B, discontinuation of the hypomethylating agent and 
continued therapy with eltrombopag monotherapy after cycle 2 may be considered at 
the discretion of the investigator.   
 
 
5. STUDY PROCEDURES 
 
5.1 Screening (Visit 1) 
 


Protocol 2013-0225 
September 22, 2015 
Page 21 of 40 
 
The following procedures are performed during screening, staging and workup (see also 
Table 5.3).  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 biopsy or aspirate 
within 4 weeks prior to first dose of drug in 
all patients. Cytogenetics and 
immunohistochemistries performed as 
indicated. 
Staging with bone marrow biopsy and/or 
aspirates for disease assessment.  
 
Serum chemistries (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, and uric acid. 
 
Note that serum iron, transferrin, transferrin 
saturation, total iron binding capacity and 
ferritin only need to be performed once and 
do not need to be repeated.  
CBC with differential (repeat if screening 
test completed greater than 72 hours prior 
Differential may be omitted if WBC ≤0.5 
x109/L 


Protocol 2013-0225 
September 22, 2015 
Page 22 of 40 
 
to the first dose) 
 
5.2 Treatment Assignment 
 
This is a two arm, non randomized study. Selection of treatment arm will be peformed by the 
patient and the treating physician in the best interest of the patient, based upon available space in 
either Arm. 
 
5.3 On-Study Procedures  
 
Table 5.3: Study Calendar 
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 
(+/- 7 
days) 
End of 
Treatment 
Visit (+/- 7 
days) 
Safety 
Visit  
28 days 
after last 
dose (+/- 
28 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Medical History 
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 
CBC with differential 
 
X* 
X 
X 
X 
X 
X¹ 
X 
X² 
Blood Chemistries 
(AST, ALT, bilirubin) 
X*^ 
X 
X 
X 
X 
X¹ 
X 
X 
Bone marrow aspiration 
and/or biopsy  
X 
 
 
 
 
X³ 
X 
 
IPSS score & WHO 
disease classification 
X 
 
 
 
 
 
X 
 
Pregnancy Test 
X† 
 
 
 
 
 
 
 
Investigational Drug 
Dispensement 
 
X 
 
 
 
X 
 
 
AE and SAE 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Optional: Correlative 
Studies 
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, , total iron binding capacity and ferritiin) must be 
performed within 72 hours of Cycle 1 Day 1  
^Serum iron, transferrin, total iron binding capacity and ferritin are required only on Cycle 1 Day 1 and do not need to be repeated 
†Within 7 days of Day 1 in females of child-bearing potential 
¹Weekly CBC with differential and blood chemistries required until stable counts, and bi-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 biopsy with cytogenetics required for study entry, at completion of cycle 2, and then every 3 cycles as clinically 
indicated.  Cytogenetics do not need to be repeated if normal at study start. 


Protocol 2013-0225 
September 22, 2015 
Page 23 of 40 
 
4Optional correlative studies will be performed on bone marrow sample taken at screening.  The studies will include an analysis of mutational 
status of 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. 
 
 
5.4. End of Study Visit:  
 
Subjects will undergo an End of Treatment Visit at the time of discontinuation of 
investigational product.  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 normal at study start. 
 
5.5. 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.   
 
5.6. Criteria for Removal from Study: 
 
Treatment is expected to continue until one of the following criteria applies: 
 
- 
Lack of objective response after 2 cycles of therapy unless eltrombopag is 
considered to be of clinical benefit to the patient 
 
- 
Unacceptable adverse event(s)  
 
- 
Discontinuation of study drug for more than 6 weeks 
 
- 
Clinically significant progressive disease 
 
- 
Possibility of undergoing allogeneic stem cell transplantation 
 
- 
Intercurrent illness that prevents further administration of treatment 
 
- 
Patient request 
 
- 
General or specific changes in the patient’s condition that renders the patient 
unacceptable for further treatment in the judgment of the investigator 
 
Continuation of therapy beyond 12 months will be considered on a case-by-case basis 
for patients deriving clinical benefit after discussion with the PI and sponsor. 
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. 
 


Protocol 2013-0225 
September 22, 2015 
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6.2. Study Endpoints 
 
6.2.1. Primary Efficacy Endpoint:  The overall response rate (CR + PR + HI) based on 
the IWG-2006 criteria.  Responses must last at least 4 weeks. 
 
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 
 
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 


Protocol 2013-0225 
September 22, 2015 
Page 25 of 40 
 
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‡: 
 
- 
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: 
 


Protocol 2013-0225 
September 22, 2015 
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- 
Complete: Disappearance of the known chromosomal abnormality without 
appearance of new abnormalities 
 
- 
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: 
 
- 
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 


Protocol 2013-0225 
September 22, 2015 
Page 27 of 40 
 
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. 
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. 
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 congential 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 


Protocol 2013-0225 
September 22, 2015 
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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 
Device. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug,unless  the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event. 
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 
 


Protocol 2013-0225 
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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. 
 
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 (GSK/Novartis  
 
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 


Protocol 2013-0225 
September 22, 2015 
Page 30 of 40 
 
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: 
 
- 
The incidence of transformation to AML by FAB during treatment period and 
follow-up 
 
- 
The incidence and severity of bone marrow fibrosis during treatment period and 
follow-up 
 
- 
Proportion of patients achieving a platelet response during treatment; and 
proportion of patients achieving a durable platelet response. 
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. 
 
6.2.4. Exploratory Endpoints 
 
The following exploratory endpoints will be examined by descriptive statistics: 
 
- 
Correlative laboratory studies of subjects including an analysis of mutational 
status of at least 53 genes known to be affected in acute leukemias will be 
performed, and evaluation of any potential relationship with the presence or 
absence of mutations and response will be assessed.  This panel has been 
validated using a next generation sequencing (NGS) platform for the detection of 
frequently reported mutations in our CLIA-certified molecular diagnostics 
laboratory. 
 
- 
Proportion of subjects achieving a major or minor cytogenetics response during 
study bone marrow assessments per IWG-2006 criteria. 
 
o Major: Disappearance of cytogenetic abnormality 
 
o Minor: > 50% reduction in abnormal metaphases out of 20 analyzable 
metaphases 
 
- 
Evaluation of the efficacy of eltrombopag (as determined by IWG-2006 criteria) 
based on IPSS risk classification system at diagnosis 
 


Protocol 2013-0225 
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- 
The number and frequency of platelet transfusions received during the treatment 
period will also be assessed 
 
- 
To examine the relationship between clinical response with ferritin level and other 
markers of iron burden at study start, given recent data that the antileukemic 
effects of eltrombopag may be mediated through modulation of intracellular iron 
content. 
 
 
6.3 Subsets 
 
6.3.1. Full Analysis Set 
 
The full analysis set will consist of all enrolled  subjects.  Subjects will be analyzed 
according to their treatment group.  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 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  enrolled 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 


Protocol 2013-0225 
September 22, 2015 
Page 32 of 40 
 
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 Oncology before recruitment of subjects into the 
study and shipment of investigational product. 
 
 
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 GSK 
or 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 all 
documents submitted to GSK or Novartis Oncology subjects should be identified by 
their initials and a subject 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 


Protocol 2013-0225 
September 22, 2015 
Page 33 of 40 
 
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 
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 


Protocol 2013-0225 
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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 
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 “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 Novartis Oncology, 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 
 
8.1. Design and Sample Size 
 
This is a  two arm phase II study to evaluate the safety and efficacy of high dose 
eltrombopag for the treatment of MDS patients after experiencing hypomethylating 
agent (HMA) failure.  The primary efficacy endpoint is the overall response rate (ORR) 
based on the IWG-2006 criteria, which include complete remission (CR), partial 
remission (PR), and major hematologic improvement (HI). 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. A total of 46 patients will be enrolled by patient and treating 
physician preference into two arms: (A) eltrombopag only or (B) eltrombopag with 
continuation of the hypomethylating agent. All patients will be accrued from M. D. 
Anderson Cancer Center (MDACC). 
Currently, there is no FDA approved agent for patients who have failed on 
hypomethylating agent, and therapeutic options are limited, particularly given the 


Protocol 2013-0225 
September 22, 2015 
Page 35 of 40 
 
increased age and frequent comorbidities of this population. In this proposed study, 
patients will be  enrolled into one of two treatment arms. Treatment arm will be 
determined by patient and treating physician, taking into account patient experience 
with prior hypomethylating  agent therapy.  Arm A (eltrombopag only) or Arm B 
(eltrombopag with continuation of HMA).We anticipate that patients treated in Arm A will 
achieve an ORR of 15-20%, while patients treated in Arm B will achieve an improved 
ORR of 25%. Given the expected small difference (5-10%) between the two arms, the 
sample size needed to detect such a difference with enough statistical power will be too 
large to be accommodated in this small phase II trial. Therefore, our focus for this study 
is to assess the ORR in each arm separately using Simon’s Minimax two-stage 
design27.   
8.2. Futility Monitoring 
 
8.2.1.  For patients treated in Arm A (eltrombopag alone), we assume a target ORR of 
18% and a response rate of 5% or lower will be considered not desirable. With a 1-
sided type I error rate of 10.3% and 80% power, we will enroll 15 patients in the first 
stage. If none of these patients achieve OR, the trial will be stopped. If 1 or more out of 
the first 15 patients have OR, accrual will continue until a total of 23 patients have been 
enrolled. At the end of the study, if 3 or more out of these 23 patients achieve OR, the 
treatment of eltrombopag alone will be considered efficacious and is worth further 
investigation. Under this Simon’s Minimax two-stage design, the probability of early 
termination is 46.3% if the true ORR is 5% and the expected sample size is 19 patients.  
For patients treated in Arm B (eltrombopag in combination with HMA), the target ORR is 
25%, and a response rate of 5% or lower will be considered not desirable. With a 1-
sided type I error rate of 3% and 85% power, we will enroll 12 patients in the first stage.  
If none of these 12 patients achieve OR, the trial will be stopped. If 1 or more out of the 
first 12 patients have OR, accrual will continue until a total of 23 patients have been 
enrolled. At the end of the study, if4 or more of these 23 patients achieve OR, the 
treatment of eltrombopag in combination with HMA will be considered efficacious and is 
worth further investigation. Under this Simon’s Minimax two-stage design, the 
probability of early termination is 54% if the true ORR is 5% and the expected sample 
size is 17 patients. 
Patient enrollment will be suspended if for an arm the first-stage patients have been 
enrolled and none of these first-stage patients has OR. Accrual will resume if at least 
one OR is observed within 2 cycles among the first-stage patients for that arm.  
8.2.2. The accumulating data will be summarized at regular intervals to provide an 
ongoing assessment of the safety and efficacy of eltrombopag in this population.  
Additional summaries of data may be provided for regulatory or publication activities. 


Protocol 2013-0225 
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8.3. Safety Monitoring 
 
8.3.1. The method of Thall, Simon, and Estey28 will be employed for interim safety 
monitoring.  We assume a Beta (0.6, 1.4) prior distribution for the toxicity rate which has 
mean of 30%. For the purpose of safety monitoring, toxicities are defined as any grade 
3 or greater clinically significant non-hematologic adverse events, attributed to the study 
drug.   
The following Bayesian monitoring rule will be applied in each arm separately, starting 
from the 3rd patient and up to the total of 23 patients per arm. Specifically, an arm will be 
stopped early if  
Pr[toxicity rate > 30%| data] > 0.9 
That is, if at any time during the study we determine that there is more than a 90% 
chance that the toxicity rate is more than 30% in a treatment arm, we will stop enrolling 
patients into that arm. If one arm is stopped due to severe toxicity, we will continue 
enroll patients into the other arm until the total accrual of 23 patients is reached or until 
the toxicity stopping boundary is crossed in that arm, whichever occurs first.  
Stopping boundaries corresponding to this toxicity monitoring rule are displayed in the 
following table: 
 
 
 
The operating characteristics of this toxicity monitoring rule are shown in the following 
table 
True 
toxicity 
rate 
Early stopping 
probability 
Sample size percentile 
25% 
50% 
75% 
0.2 
0.07 
23 
23 
23 
Number of patients evaluated 
Recommend stopping if ≥ toxicity observed 
3-4 
3 
5-7 
4 
8-9 
5 
10-12 
6 
13-14 
7 
15-17 
8 
18-20 
9 
21-22 
10 


Protocol 2013-0225 
September 22, 2015 
Page 37 of 40 
 
0.3 
0.25 
22 
23 
23 
0.35 
0.4 
9 
23 
23 
0.4 
0.57 
7 
17 
23 
 
 
8.4 Statistical Analysis Plan 
 
8.4.1. 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. 
 
8.4.2. Analysis of Key Study Endpoints 
 
The primary endpoint is overall response rate (ORR).   The ORR in each arm will be 
evaluated along with the exact 95% confidence interval.  Given the limited sample size, 
no formal comparison will be made between these two arms in terms of ORR. 
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 3 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. 
 


Protocol 2013-0225 
September 22, 2015 
Page 38 of 40 
 
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. 
 
8.4.2.1. Safety Endpoints 
 
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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