Eltrombopag for the Management of Thrombocytopenia Associated With Tyrosine Kinase Therapy in Patients With Chronic Myeloid Leukemia (CML) and Myelofibrosis (MF)
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Primary Myelofibrosis, Thrombocytopenia
Sponsor: M.D. Anderson Cancer Center

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
1 
 
Title: 
Eltrombopag for the Management of Thrombocytopenia 
Associated with Tyrosine Kinase Therapy in Patients with 
Chronic Myeloid Leukemia (CML) and Myelofibrosis 
 
Principal Investigator:   
 
Gautam Borthakur, MD 
 
Co-Principal Investigators:  
Jorge Cortes, MD 
 
Sponsor: 
 
 
 
 
Novartis Pharmaceuticals Corporation 
 
Statistician:  
 
 
 
Xuemei Wang 
 
 
 
 
 
Protocol No.: 
 
 
 
2011-0319  
 
 
 
 
 
Date of Protocol:  
 
 
05-20-2011 
 
Amendment 1: 
 
 
 
02-08-2012 
Amendment 2: 
 
 
 
09-20-2012 
Amendment 3: 
 
 
 
08-15-2013 
Amendment 4: 
 
 
 
10-17-2013 
Amendment 5: 
 
 
 
03-28-2016 
Amendment 6: 
 
 
 
06-15-2016 
Amendment 7: 
 
 
 
08-23-2017 
Amendment 8: 
 
 
 
08-14-2018 
 
 
 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
2 
 
Table of Contents 
 
Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
3 
 
I. 
Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
10 
 
II. 
Rationale  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
10 
 
III. 
Proposed Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
12 
 
IV. 
Background Drug Information . . . . . . . . . . . . . . . . . . . . . . . . 
12 
 
V. 
Study Design 
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
13 
 
VI. 
Outside Physician Participation During Treatment . . . . . . . . 
14 
 
VII. 
Dose Delay/Modifications (Guidelines) . . . . . . . . . . . . . . . .  
14 
 
VIII. 
Supportive Care Guidelines 
. . . . . . . . . . . . . . . . . . . . . . . 
15 
 
IX. 
Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
15 
 
X. 
Evaluations  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
16 
 
XI. 
Criteria for Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
18 
 
XII. 
Criteria for Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
20 
 
XIII. 
Reporting Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
20 
 
XIV. 
Adverse Drug Reaction Reporting 
. . . . . . . . . . . . . . . . . . 
23 
 
XV. 
Drug Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
23 
 
XVI. 
Statistical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . .  
23 
 
XVII. Study Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
26 
 
XVIII. Reference List . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
27 
 
 
 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
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Synopsis 
 
Title of study 
Eltrombopag for the Management of Thrombocytopenia Associated with Tyrosine 
Kinase Therapy in Patients with Chronic Myeloid Leukemia (CML) or Myelofibrosis 
(MF) 
Investigator/study 
center location 
University of Texas MD Anderson Cancer Center 
Phase of 
development 
Phase 2 
Study objectives 
Primary:  
To determine the efficacy of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with tyrosine kinase 
inhibitors (TKI) as measured by recovery of platelet count 
Secondary: 
1. To determine the safety of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with TKI 
2. To determine the dose intensity of TKI after start of therapy with eltrombopag 
3. To determine response to TKI after start of therapy with eltrombopag 
 
Study design 
This is a non-randomized, Phase II, single arm study of individualized dosing of 
eltrombopag.   A maximum of 29 subjects with CML and 10 subjects with MF will be 
evaluated. 
Subjects will continue receiving their TKI at the doses prescribed at the time of 
registration and eltrombopag therapy will be initiated. Dose escalations of TKI are 
allowed once improvement in platelet count (≥ 50 x 109/L for CML and ≥ 100 x 109/L 
for MF) is demonstrated for at least 2 consecutive weeks. 
Study criteria 
Inclusion: 
1. CML patients in chronic phase receiving treatment with any FDA approved TKI; 
or CML patients in accelerated or blastic phase who are considered to be in 
this phase because of thrombocytopenia or because of clonal evolution and 
with no other criteria for accelerated/blastic phase or patients with 
myelofibrosis receiving treatment with FDA approved TKI and with peripheral 
blood and/or bone marrow blast ≤ 10% 
2. Grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) after the first 3 months of 
therapy with the TKI for patients with CML and platelets <100 x 109/L for 
patients with MF after first 3 months therapy. Thrombocytopenia must be either 
recurrent (i.e., second or greater episode of  thrombocytopenia) or having 
required dose reductions of the TKI; 
3. Subject is anticipated to have therapy with TKI continued for ≥3 months; 
4. Adequate organ function: 
• 
Total bilirubin (except for Gilbert’s Syndrome) ≤ 1.5xULN 
• 
ALT and AST < 3xULN 
• 
Creatinine ≤ 2xULN 
Exclusion: 
1. CML patients in accelerated or blastic phase except for those who are 
considered to be in this phase because of thrombocytopenia or because of 
clonal evolution and with no other criteria for accelerated/blastic phase; 
or myelofibrosis patients who have transformed in to acute leukemia or has ≥ 
10% blast in peripheral blood and/or in bone marrow. 
2. Thrombocytopenia that is considered to be unrelated to treatment with TKI or 
accelerated phase as defined above; 
3. Age < 18 years; 
4. Stem cell transplantation within preceding 60 days prior to registration; 
5. Patients with documented active hepatitis B or C infection; 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
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6. Patients with known bone marrow reticulin fibrosis (≥ grade 2) (only applicable 
to patients with CML); 
7. Patients with palpable splenomegaly ≥ 16cm below coastal margin (only 
applicable to patients with CML); 
8. Female subjects who are pregnant or breastfeeding. Women of childbearing 
potential are required to have a βHCG serum or urine pregnancy test 
performed within 7 days prior to first study drug dose. 
9. Patients with known risk factors for thromboembolism (e.g. Factor V Leiden 
mutation, ATIII deficiency, Protein C and S deficiency, antiphospholipid 
syndrome, portal hypertension, etc.) 
Expected number 
of patients 
Maximum of 39 patients   
 
Dosage and 
administration 
Eltrombopag (PROMACTA) is a thrombopoietin (TPO) receptor agonist indicated for 
the treatment of thrombocytopenia in patients with chronic immune (idiopathic) 
thrombocytopenic purpura (ITP) who have had an insufficient response to 
corticosteroids, immunoglobulins, or splenectomy. Patients will receive eltrombopag 
at a starting dose of 50 mg daily, except for patients of East Asian ancestry who will 
receive a starting dose of 25 mg daily. Treatment will be continued for as long as 
patients are deriving benefit from therapy with eltrombopag.  Treatment cycle is 
defined as daily continuous dosing. 
 
Eltrombopag will be administered on an empty stomach (1 hour before or 2 hours 
after a meal). There should be at least 2 hours before or 4 hours 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, aluminium, magnesium, selenium, and zinc. Eltrombopag will be 
commenced at 50 mg with dose escalation allowed every 2 weeks to 100 mg, 150 
mg, 200 mg and 300 mg according to platelet response. For patients of East Asian 
ancestry, eltrombopag will be commenced at 25 mg daily with dose escalation 
allowed every two weeks to 50 mg.  Subsequent dose escalations will follow the 
schema described above.  Failure to achieve a platelet count ≥ 50 x 109 /L after 8 
weeks of eltrombopag will constitute lack of response.  
 
Monitoring and  
dose adjustment 
Patients will be followed with regular CBC and platelet counts. Guidelines for dose 
adjustment for eltrombopag will be as recommended for ITP[1].  
After initiating eltrombopag, the dose should be adjusted to achieve and maintain a 
platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding.  
 
Clinical hematology and liver tests will be monitored regularly throughout therapy 
with eltrombopag and modified based on platelet counts. 
  
During eltrombopag therapy, CBCs, including platelet count, will be assessed 
weekly until a stable platelet count has been achieved. CBCs including platelet 
counts will be obtained monthly thereafter. 
 
The following guidelines will be used to adjust dosing of eltrombopag 
• 
Platelet count >200 x109/L (at any time): Reduce daily dose by 25 mg; 
reassess in 2 weeks. 
• 
Platelet count >400 x109/L: Withhold assessing platelet count twice weekly 
until platelet count <150 x109/L, resume with daily dose at a reduced dose by 
25 mg.  
• 
Platelet count >400 x109/L after 2 weeks at the lowest dose: Permanently 
discontinue. 
Laboratory 
Complete Blood Counts (CBCs): Monitor CBCs, including platelet counts prior to 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
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monitoring 
 
initiation, throughout, and following discontinuation of therapy with eltrombopag. 
Obtain CBCs, including platelet counts, weekly during the dose adjustment phase 
of therapy with eltrombopag and then monthly following establishment of a stable 
dose of eltrombopag. Obtain CBCs, including platelet counts, weekly for at least 
4 weeks following discontinuation of eltrombopag.  
 
 
Liver tests: Monitor serum liver tests (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. If abnormal levels are detected, repeat the tests 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 clinically significant liver test abnormalities develop. 
 
Renal Tests: Monitor creatinine prior to initiation of eltrombopag, every 2 weeks 
during the dose adjustment phase and monthly following establishment of a stable 
dose. 
 
The dose adjustment for TKIs will be carried out according to institutional 
guidelines. 
Study Endpoints/ 
Objectives 
1. To determine the efficacy of eltrombopag for patients with CML or MF who 
have developed thrombocytopenia during the course of therapy with TKIs as 
measured by recovery of platelet count. 
2. To determine the safety of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with TKI. 
3. To determine the dose intensity of TKI after start of therapy with eltrombopag. 
4. To determine response to TKI after start of therapy with eltrombopag. 
Additional safety 
wording 
Increased Liver Chemistries 
Eltrombopag administration may cause hepatotoxicity. In the ITP controlled clinical 
studies, 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 Grade 4 liver 
test abnormalities. In controlled studies, elevations of ALT and indirect bilirubin 
were observed more frequently on the eltrombopag arm than placebo.  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 controlled studies, four patients (1%) treated with eltrombopag and three 
patients in the placebo group (2%) discontinued treatment due to hepatobiliary 
laboratory abnormalities. Eighteen of the patients treated with eltrombopag in the 
controlled studies with hepatobiliary laboratory abnormalities were re-exposed to 
eltrombopag in the ITP extension study. Seven of these patients again experienced 
liver test abnormalities (predominantly Grade 1) resulting in discontinuation of 
eltrombopag in one patient. In the ITP extension study, one additional patient had 
eltrombopag discontinued due to liver test abnormalities (all Grade 3). 
 
Serum ALT, AST, and bilirubin should be measured 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. Permanently 
discontinue eltrombopag if ALT levels increase to  3X the upper limit of normal 

Protocol No. 2011-0319, Amendment 8 
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(ULN) and are: 
• 
progressive, or 
• 
persistent for  4 weeks, or 
• 
accompanied by increased direct bilirubin, or 
• 
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 (consider a lower dose e.g. 
25 mg) and measure serum liver tests weekly during the dose adjustment phase.  If 
liver tests abnormalities persist, worsen or recur, then permanently discontinue 
eltrombopag. 
 
 
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis  
Eltrombopag is a 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, examine the peripheral blood smear closely to 
establish a baseline level of cellular morphologic abnormalities. Following 
identification of a stable dose of eltrombopag, examine CBCs monthly for new or 
worsening morphological abnormalities (e.g., teardrop and nucleated red blood 
cells, immature white blood cells) or cytopenia(s). If the patient develops new or 
worsening clinically significant morphological abnormalities or cytopenia(s), 
discontinue treatment with eltrombopag and consider a bone marrow aspirate and 
biopsy, including staining for fibrosis.  
 
Worsened Thrombocytopenia After Cessation of Eltrombopag 
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, obtain weekly CBCs, including platelet 
counts for at least 4 weeks and consider alternative treatments for worsening 
thrombocytopenia, according to current treatment guidelines. 
 
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 

Protocol No. 2011-0319, Amendment 8 
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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 75 mg 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. Four of the 6 
subjects receiving eltrombopag also had a tumor (2 hepatocellular carcinoma; 1 
lymphoma and 1 brain tumor).  Tumors are known to increase the risk for 
developing a thrombotic/thromboembolic event.  The ELEVATE study has been 
terminated and remains blinded.  Eltrombopag is not indicated for the treatment of 
thrombocytopenia in patients with chronic liver disease. 
Malignancies and Progression of Malignancies 
Stimulation of the TPO receptor on the surface of hematopoietic cells by 
eltrombopag may increase the risk for hematologic malignancies. Across the ITP 
clinical program, hematologic malignancies were reported in one eltrombopag 
patient and one in placebo patient.  
 
Cataracts  
Cataracts were observed in toxicology studies of eltrombopag in rodents (see Non-
clinical Information). To date, there is however, no evidence that eltrombopag 
increases 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.   
 
Routine monitoring of patients for cataracts is recommended. Patients treated with 
eltrombopag who experience visual difficulties should have an appropriate 
ophthalmologic evaluation. 
Study Variables 
(Clinical 
procedures, 
laboratory tests, 
safety 
assessments) 
To determine the efficacy of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with TKIs as measured 
by recovery of platelet count. 
 
In addition, we will measure CML disease status by cytogenetic and PCR analysis 
and response coded based on European Leukemia Network (ELN) guidelines[2, 
3]. This is summarized in Section X. For responses in patients with MF, consensus 
criteria from International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT)[4] will be used and are summarized in section X.  
 
Safety and efficacy will also be monitored by serial evaluations of blood counts, 
liver enzymes as summarized in Section IX.  
 
Treatment discontinuations and interruptions for both eltrombopag and TKI will be 
recorded. 
Outcome 
Parameters and  
Analytical 
Endpoints 
The primary endpoint is complete (platelet) response (yes/no).  A complete 
(platelet) response will be defined as a sustained (3 months) platelet count of ≥ 50 
x 109/L for patients with CML and ≥ 100 x 109/L for patients with MF and at least a 
20% increase in platelet count from baseline with no more than 3 counts in that 
period being < 50 x 109/L for patients with CML and < 100 x 109/L for patients with 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
8 
 
MF, while continuing TKI therapy. Successful re-escalation following dose 
reduction of TKI will be considered as continuing TKI. 
 
In patients who required dose reduction of TKI because of thrombocytopenia, 
complete (platelet) response can also be defined as successful re-escalation of the 
dose of TKI sustained for at least 3 months without recurrence of 
thrombocytopenia i.e. platelet count ≤ 50 x 109/L for patients with CML and < 100 x 
109/L for patients with MF. 
 
Secondary endpoints will include: 
• 
The frequency of adverse events;  
• 
Average dose intensity of TKI; 
• 
Failure to therapy with TKI as defined by the ELN recommmendations[2](for 
patients with CML). For patients with myelofibrosis, IWG-MRT criteria[4] will be 
used.  
Exploratory endpoints: 
• 
Platelet function (platelet aggregation studies) 
Statistical 
Analysis Plan 
Design Considerations and Sample Size Justification 
This is a phase II, open-label single-arm study of individualized dosing of 
eltrombopag.  The primary objective is to investigate whether eltrombopag will 
increase platelet count, thus reducing the occurrence of thrombocytopenia in 
subjects with CML or MF receiving therapy with TKI. All patients will be enrolled 
from MDACC, with 1-2 patients per month.  The objective is to demonstrate that at 
least 30% of subjects have a complete (platelet) response, where complete 
(platelet) response is achieved if a patient meets all of the following criteria: (1) 
reach platelet count ≥ 50 x 109/L for patients with CML and ≥ 100 x 109/L for 
patients with MF within 8 weeks of treatment initiation;  (2) the platelet count is 
sustained at ≥ 50 x 109/L for patients with CML and ≥ 100 x 109/L for patients with 
MF for 3 months, where “sustained” means having no more than 3 platelet counts 
in the 3-month period being < 50 x 109/L for patients with CML and < 100 x 109/L 
for patients with MF; and (3) at least a 20% increase in platelet count from baseline 
at the end of 3 months while continuing TKI therapy. Successful re-escalation 
following a dose reduction of TKI will be considered as continuing TKI. In patients 
who required dose reduction of TKI because of thrombocytopenia, complete 
(platelet) response can also be defined as successful re-escalation of the dose of 
TKI sustained for at least 3 months without recurrence of thrombocytopenia to < ≤ 
50 x 109/L for patients with CML and < 100 x 109/L for patients with MF. 
 
For the cohort of patients with CML: Simon’s optimal two-stage design [Simon, 
1989] will be used to test the null hypothesis that the proportion of subjects with 
complete response is <=0.10 versus the alternative that it is >=0.30 (i.e., Po<=0.10 
vs Pa>=0.30) at alpha=0.05 with 80% power.  The design will result in an expected 
sample size of 15 and a probability of early termination of 0.736.  After testing the 
drug on 10 subjects in the first stage, the trial will be terminated if 1 or fewer 
achieve complete (platelet) response. Otherwise, if the trial goes on to the second 
stage, a total of 29 subjects will be studied. If the total number of patients with 
complete (platelet) response is less than or equal to 5, the drug will be deemed as 
ineffective. The trial will suspend accrual if not at least 2 patients have achieved 
complete response in the first 10 patients.  To be evaluable for response 
(improvement in platelet count and durability of improvement in platelet count) 
patient will need to be followed for 12-20 weeks from start of eltrombopag therapy. 
 
For safety monitoring, we will continuously monitor the occurrence of any grade 3 

Protocol No. 2011-0319, Amendment 8 
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9 
 
or greater non-hematologic adverse events as well as leukemia failure, which is 
defined as failure to achieve optimal response as defined by European Leukemia 
Network or as progression to accelerated/blastic phase (not clonal evolution).  
Safety monitoring will be based on a beta-binomial distribution. The trial will be 
terminated early if Pr[0.15 < toxicity rate | data] > 0.90, where the prior is assumed 
to be beta(1, 1).  Applying this stopping rule and starting from the 7th subjects, the 
trial will stop early if [#subjects with leukemia failure or grade 3 or greater non-
hematolgic AEs]/[#subjects evaluated] >= 3/7, 4/12, 5/17, 6/22, 7/27. 
 
For MF cohort: As the group with MF is an exploratory group of 10 patients to 
study the safety and activity of eltrombopag in patients with MF treated with 
Ruxolitinib and thrombocytopenia, we will consider the activity promising if 3 or 
more patients out of 10 achieve complete (platelet) response. For safety monitoring 
in the cohort with MF, accrual will stop if at any time 4 out of 10 patients encounter 
grade 3 or more non-hematological toxicity or progression to acute leukemia. As an 
additional safety procedure, we will observe the first 3 MF patients on trial for at 
least 3 months before additional patients are accrued.  
 
Analytic Methods 
 
The statistical analyses as detailed below will be performed in each disease cohort 
(i.e., CML and MF) separately.  
 
The proportions of subjects with complete (platelet) response will be reported 
together with exact 95% confidence intervals. The denominator will include all 
subjects who received eltrombopag.  The proportion of subjects with leukemia, and 
the proportion failing to TKI will be summarized similarly. 
 
Platelet counts over time and in relationship to exposure to eltrombopag and TKI 
will be summarized using descriptive statistics.  
 
Kaplan-Meier methods will be used to estimate the risk of leukemia (i.e., 
suboptimal response and progression to accelerated or blastic phase) over time. 
 
Descriptive statistics will be used to summarize the extent of exposure to 
eltrombopag, and to TKI (duration of TKI therapy and dose intensity of TKI 
therapy).  
 
The number (%) of subjects with adverse events, serious adverse events, and 
adverse events leading to discontinuation will be reported.  Adverse events will be 
reported by type, severity and frequency.  Laboratory parameters will also be 
summarized using descriptive statistics; laboratory toxicity will be summarized 
using frequency counts. 
 

Protocol No. 2011-0319, Amendment 8 
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10 
 
OBJECTIVES 
Primary  
To determine the efficacy of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with tyrosine kinase 
inhibitors (TKI) as measured by recovery of platelet count 
 
Secondary 
1. To determine the safety of eltrombopag for patients with CML or MF who have 
developed thrombocytopenia during the course of therapy with TKI; 
2. To determine the dose intensity of TKI after start of therapy with eltrombopag; 
3. To determine response to TKI after start of therapy with eltrombopag. 
 
II. RATIONALE 
TKI have become standard therapy for patients with CML. Imatinib mesylate 
(Gleevec) was the first agent approved for this indication and induces complete 
cytogenetic responses in 40 to 50% of patients with CML after failure to interferon 
alpha [5, 6] and in 75 to 90% of those previously untreated[7, 8].  High-dose imatinib 
has resulted in improved outcome[9] and is currently being evaluated in a 
randomized study for a possible change in standard dose recommendation. 
Dasatinib (Sprycel) received regulatory approval for the treatment of patients who 
have failed imatinib in 2006 and over 50% of patients have demonstrated a major 
cytogenetic response.[10] In October 2010 dasatinib received accelerated approval 
for treatment of patients with newly diagnosed CML in chronic phase. Nilotinib 
(Tasigna) was approved by the FDA in 2007, also for the treatment of patients after 
imatinib failure.[11] In June 2010, Nilotinib has been approved by the FDA for 
treatment of patients with newly diagnosed CML in chronic phase.  Although these 
agents are overall well tolerated, some patients may develop adverse events, with 
myelosuppression being the most prominent. Cytopenias, particularly neutropenia 
and thrombocytopenia, have been consistently reported in studies of imatinib, 
dasatinib and nilotinib in CML[7, 8, 10-15]. For most patients, myelosuppression is 
grade 1 or 2 requiring no intervention. However, grade  3 thrombocytopenia (i.e., 
platelets ≤ 50 x109/L) and neutropenia (i.e., absolute neutrophil count [ANC ≤ 1 x 
109/L]) have been reported in a significant proportion of patients as shown in Table 
1. 
 
Table 1. Incidence of grade 3-4 neutropenia and thrombocytopenia (values in 
percentage) in CML chronic phase treated with TKIs. 
 
Study  
Neutropenia (%) 
Thrombocytopenia (%) 
Imatinib post IFN failure[8] 
35 
20 
Imatinib frontline[7] 
17 
9 
High-dose imatinib frontline[16] 
32 
25 
Dasatinib after imatinib failure[10] 
48 
48 
Nilotinib after imatinib failure[14] 
28 
29 

Protocol No. 2011-0319, Amendment 8 
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11 
 
Patients who develop myelosuppression have a decreased probability of achieving a 
major or complete cytogenetic response [17]. In one report, among 31 patients who 
developed grade 3 thrombocytopenia, 11 (35%) achieved a complete cytogenetic 
response, compared to 66 (59%) of 112 who never developed thrombocytopenia 
(p=0.02). Similarly, patients who developed grade 3 neutropenia had a lower rate 
(44%) of complete cytogenetic response compared to those who never developed 
neutropenia grade 3 (62%; p=0.03). This difference in prognosis was particularly 
noticeable for those who had myelosuppression lasting > 2 weeks[17]. In a 
multivariate analysis, myelosuppression was an independent adverse prognostic 
factor for response [17].  
 
The reason for this decreased probability of response is not clear, but one possible 
explanation is that myelosuppression results in interruption of imatinib therapy and 
dose reductions. Thus, patients who develop myelosuppression may have prolonged 
periods when effective therapy is withheld. In fact, myelosuppression is the leading 
cause of dose reductions and treatment interruptions. The guidelines for 
management of myelosuppression occurring while on therapy with imatinib for CML 
include holding therapy when there is grade 3 neutropenia (i.e., neutrophils ≤ 1 
x109/L) or thrombocytopenia (i.e., platelets ≤ 50 x109/L)[18]. Thus, it is important for 
patients that develop myelosuppression to have a rapid recovery and, if possible, to 
prevent recurrence of myelosuppression. With this intent, hematopoietic growth 
factors have been used to manage patients with persistent or recurrent 
myelosuppression. Filgrastim has been successfully used to manage neutropenia, 
resulting not only in the recovery of neutrophils which allows for continuation of 
therapy with imatinib, but it has also led to an improved response to imatinib.[19] 
Erythropoietin and darbepoetin have been effective in managing anemia in this 
setting.[20, 21]  Options for the management of thrombocytopenia have been more 
limited. Low-dose interleukin-11 (oprelvekin) was first used to treat 3 patients with 
thromobocytopenia associated with imatinib therapy and demonstrated not only a 
good platelet response, but also allowed for uninterrupted imatinib therapy which 
resulted in improved response to therapy.[22] This observation was subsequently 
expanded to 14 patients with thrombocytopenia associated with imatinib, dasatinib 
or nilotinib.[23] These patients received IL-11 10 mcg/kg 3 times weekly. Eight of the 
14 (57%) patients responded. Use of IL-11 allowed patients to maintain the dose 
intensity of their TKI with only one of the eight responders requiring any further dose 
reductions in the TKI therapy after initiation of IL-11. Overall 11 patients had a 
decrease in the number of days of TKI therapy interruption secondary to 
thrombocytopenia after initiation of IL-11 (6% of the total treatment time versus 34% 
before IL-11)[23]. 
 
The pivotal study of Ruxolitinib excluded patients with platelet count <100 x 
109/L[24]. Among these patients, the discontinuation rate of Ruxolitinib due to low 
platelet counts was quite low. However thrombocytopenia was encountered in 
approximately 70% of patients and approximately 17% of these were grade 3/4 
events. At the time of approval of Ruxolitinib, the FDA did not impose any platelet 
count. The package insert of Ruxolitinib advises reduction of dose by 50% for 

Protocol No. 2011-0319, Amendment 8 
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12 
 
platelet counts <100 x 109/L and interruption of dosing at <50 x 109/L[25]. In the 
pivotal study, MF related symptoms returned to baseline after interruption of 
Ruxolitinib dose for a median of one week[24], highlighting the need for continued 
dosing. The possibility of interruptions is expected to be much higher than reported 
in the pivotal study among patients whose platelet count is <100 x 109/L and the 
concomitant use of eltrombopag is expected to allow patients to stay at prescribed 
dose of Ruxilitinib.      
 
Study Drug: Eltrombopag 
Eltrombopag is a nonpeptide agonist of thrombopoietin (TPO) which increases 
platelet counts by binding to and activating the human TPO receptor. Eltrombopag 
has been found to be effective and well tolerated among patients with chronic 
idiopathic thrombocytopenic purpura (ITP) who had failed prior therapy with standard 
therapy. Among patients receiving a dose of 50 or 75mg daily, 70% and 80% of 
patients treated, respectively, improved their platelet count to greater than 50 x109/L 
after 43 days.[26-28] Responses occurred early, with 80% of patients receiving 
these doses having an increased platelet count by day 14. We propose to 
investigate whether eltrombopag may correct and/or prevent the development of 
recurrent thrombocytopenia (≤ 50 x 109/L) in patients with CML or (100 x 109/L) in 
patients with MF who are receiving therapy with TKIs. 
III. PROPOSED STUDY 
This will be a non-randomized, Phase II, single arm study of individualized dosing of 
eltrombopag. CML patients in chronic phase receiving treatment with any FDA 
approved TKI and experiencing Grade ≥ 3 thrombocytopenia (platelets ≤ 50 x 109/L) 
for patients with CML and patients with MF and platelets <100 x 109/L after the first 3 
months of therapy with the TKI are eligible. Thrombocytopenia must be either 
recurrent (i.e., be at least the second episode of thrombocytopenia) or have 
necessitated dose reductions of the TKI. A maximum of 39 subjects will be 
evaluated. 
 
Subjects will continue receiving their TKI at the doses prescribed at the time of 
enrollment into the study and eltrombopag therapy will be initiated. Dose escalations 
of TKI are allowed once improvement in platelet count (≥ 50 x 109/L for CML and ≥ 
100 x 109/L for patients with MF) is demonstrated for at least 2 consecutive weeks. 
 
IV. BACKGROUND DRUG INFORMATION 
 
Eltrombopag 
 
Mode of Action: 
Eltrombopag is a Thrombopoietin (TPO) nonpeptide agonist which increases platelet 
counts by binding to and activating the human TPO receptor. It activates intracellular 
signal transduction pathways to increase proliferation and differentiation of marrow 
progenitor cells. It does not induce platelet aggregation n activation. 
 
Approved Use: 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
13 
 
Treatment of thrombocytopenia in patients with chronic immune (idiopathic) 
thrombocytopenic purpura (ITP) at risk for bleeding who have had insufficient 
response to corticosteroids, immunoglobulin, or splenectomy. 
 
Route of Administration: 
Oral 
 
Contraindications: 
None. 
 
Reported Adverse Events and Potential Risks 
1% to 10%:  
Dermatologic: Rash (≤ 7%), bruising (2%) 
Endocrine and metabolic: Menorrhagia (4%) 
Gastrointestinal: Nausea (6%), vomiting (4%), dyspepsia (2%) 
Hematologic: Rebound thrombocytopenia (10%), thrombocytopenia (2%) 
Hepatic: Liver function tests abnormal (10%), ALT increased (2%), AST increased 
(2%) 
Neuromuscular and skeletal: Limb pain (≤ 7%), myalgia (3%), paresthesia (3%) 
Ocular: Cataract (3%), conjunctival hemorrhage (2%) 
 
< 1%, postmarketing, and/or case reports:  
Bone marrow collagen fiber deposits, bone marrow reticulin fiber deposits, cataract 
worsening, epistaxis, headache, hemorrhage (due to thrombocytopenia or rebound 
thrombocytopenia), non-Hodgkin’s lymphoma, portal vein thrombosis, 
thrombotic/thromboembolic complications. 
V. STUDY DESIGN 
This will be a non-randomized, Phase II, single arm study of individualized dosing of 
eltrombopag.   A maximum of 39 subjects will be evaluated. 
 
Subjects will continue receiving their TKI at the doses prescribed at the time of 
enrollment into the study when eltrombopag therapy will be initiated. Dose 
escalations of TKI are permitted within the study. 
Study Drug 
Eltrombopag will be commenced at 50 mg (except for patients of East Asian ancestry 
who will receive a starting dose of 25 mg daily) with dose escalation allowed every 2 
weeks to 100 mg, 150 mg, 200 mg and 300 mg according to platelet response. For 
patients of East Asian ancestry, dose escalation will be allowed every two weeks to 
50 mg.  Subsequent dose escalations will follow the schema described above. 
Eltrombopag will be continued for as long as patients continue to benefit clinically.  
Treatment cycle is defined as daily continuous dosing. 
 
Eltrombopag will be administered on an empty stomach (1 hour before or 2 hours 
after a meal). There should be at least a 4-hour interval between 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, 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
14 
 
calcium, aluminum, magnesium, selenium, and zinc that can interfere with its 
absorption.  
 
Patient Registration 
All patients and study-specific data will be registered through the Protocol Data 
Management System (PDMS)/CORe.  
 
VI.  Outside Physician Participation During Treatment 
• MDACC Physician communication with the outside physician is required prior to 
the patient returning to the local physician.  This will be documented in the 
patient record. 
• A letter to the local physician outlining the patient's participation in a clinical trial 
will request local physician agreement to supervise the patient's care (Appendix 
F). 
• Protocol required evaluations outside MDACC will be documented by telephone, 
fax or e-mail.  Fax and/or e-mail will be dated and signed by the MDACC 
physician, indicating that they have reviewed it. 
• Changes in drug dose and/or schedule must be discussed with and approved by 
the MDACC physician investigator, or their representative prior to initiation, and 
will be documented in the patient record. 
• A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
• Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required laboratory 
and diagnostic studies and documentation of any hospitalizations. 
• The home physician will be requested to report to the MDACC physician 
investigator all life threatening events within 24 hours of documented occurrence. 
• Patients will return to MDACC every 3-4 months for evaluation. 
• The patient will be contacted by telephone approximately every 4 weeks by a 
member of the research team. 
 
VII. 
DOSE DELAY/MODIFICATIONS (Guidelines) FOR ELTROMBOPAG 
Dose modifications for platelet response: 
The following guidelines will be used to adjust dosing of Eltrombopag: 
1. Platelet count > 200 x109/L (at any time): Reduce daily dose by 25 mg; reassess 
in 2 weeks. 
2. Platelet count > 400 x109/L: Withhold dose; assess platelet count twice weekly; 
when platelet count < 150 x109/L, resume with the daily dose reduced by 25 mg. 
3. Platelet count > 400 x109/L after 2 weeks at the lowest dose: Permanently 
discontinue. 
 
Dosage adjustment for toxicity:  
 
Hepatotoxicity: 
• ALT/AST levels ≥ 3 times the upper limit of normal (ULN): Hold treatment.  

Protocol No. 2011-0319, Amendment 8 
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15 
 
• Obtain fractionation for elevated bilirubin levels grade 3.  
• Repeat abnormal liver function tests within 3-5 days; if confirmed abnormal, 
monitor weekly until resolves, stabilizes, or returns to baseline. Discontinue 
treatment for ALT/AST levels ≥ 3 times the ULN and which are progressive, or 
persistent (≥ 4 weeks), or accompanied by increased direct bilirubin, or 
accompanied by clinical signs of liver injury or evidence of hepatic 
decompensation. Reinitiation of eltrombopag after discontinuation for these 
reasons will not be allowed. 
 
Dose adjustments for other grade 3-4 toxicity:  
Patients experiencing clinically significant grade 3 or greater toxicity possibly related 
to eltrombopag may have their treatment interrupted until toxicity resolved to grade 1 
or less. Treatment can then be resumed at the immediate lower dose level. Greater 
dose reductions can be allowed if judged in the best interest of the patient after 
discussion with the principal investigator.  
 
Dose modifications for TKIs 
Appropriate dose modifications will be done according to institutional guidelines. For 
dasatinib and nilotinib, approved dosing will be used. Highest dose for imatinib will 
be 800 mg/day, for nilotinib 400 mg twice daily and for dasatinib 140 mg/day. For 
Ruxolitinib the highest dose will be 20 mg twice daily. Dose escalations of TKIs are 
allowed once improvement in platelet count (>/= 50 x 109/L for CML and (>/= 100 x 
109/L for MF) is demonstrated for at least 2 consecutive weeks.   
 
VIII. SUPPORTIVE CARE GUIDELINES 
Use of growth factors (G-CSF, GM-CSF and erythropoietic growth factors) will be 
permitted if considered to be in the best interest of the patient.  Use of 
prophylactic/therapeutic antiemetics, antibiotics, antivirals and antifungals are 
permitted as per the decision of the treating physician. The use of oprevelkin is not 
allowed while patients are on study.  
 
IX. 
ELIGIBILITY CRITERIA 
Inclusion: 
 
1. CML patients in chronic phase receiving treatment with any FDA approved TKI; 
or CML patients in accelerated or blastic phase who are considered to be in this 
phase because of thrombocytopenia or because of clonal evolution and with no 
other criteria for accelerated/blastic phase; or patients with myelofibrosis 
receiving treatment with FDA approved TKI and with peripheral blood and/or 
bone marrow blast ≤ 10% 
 
2. Grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) after the first 3 months of 
therapy with the TKI for patients with CML and platelets <100 x 109/L for patients 
with MF after first 3 months therapy. Thrombocytopenia must be either recurrent 

Protocol No. 2011-0319, Amendment 8 
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16 
 
(i.e., second or greater episode of thrombocytopenia) or having required dose 
reductions of the TKI; 
 
3. Subject is anticipated to have therapy with TKI continued for ≥3 months; 
 
4. Adequate organ function: 
• Total bilirubin (except for Gilbert’s Syndrome) ≤ 1.5xULN 
• ALT and AST < 3xULN 
• Creatinine ≤ 2xULN 
 
Exclusion: 
 
1. 
CML patients in accelerated or blastic phase except for those who are 
considered to be in this phase because of thrombocytopenia or because of clonal 
evolution and with no other criteria for accelerated/blastic phase; or MF patients 
who have transformed in to acute leukemia or has ≥ 10% blast in peripheral 
blood and/or in bone marrow. 
 
2. 
Thrombocytopenia that is considered to be unrelated to treatment with TKI or 
accelerated phase as defined above; 
 
3. 
Age < 18 years; 
 
4. 
Stem cell transplantation within preceding 60 days prior to registration; 
 
5. 
Patients with documented active hepatitis B or C infection; 
 
6. 
Patients with known bone marrow reticulin fibrosis (≥ grade 2) (only applicable to 
patients with CML); 
 
7. 
Patients with palpable splenomegaly ≥ 16cm below coastal margin (only 
applicable to patients with CML); 
 
8. 
Female subjects who are pregnant or breastfeeding. Women of childbearing 
potential are required to have a βHCG serum or urine pregnancy test performed 
within 7 days prior to first study drug dose. 
 
9. 
Patients with known risk factors for thromboembolism (e.g. Factor V Leiden 
mutation, ATIII deficiency, Protein C and S deficiency, antiphospholipid 
syndrome, portal hypertension, etc.) 
X. 
EVALUATIONS 
Pretreatment evaluation (within 7 days of start of study drug except where noted) 
• 
History and physical exam. 
• 
CBC, platelet count, differential, peripheral blood smear. 
• 
Serum chemistry to include bilirubin, AST, ALT, BUN, creatinine. 

Protocol No. 2011-0319, Amendment 8 
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17 
 
• 
Hepatitis panel (within 6 weeks).  
• 
Bone marrow aspirate and biopsy (including reticulin stain) and cytogenetics 
(within 6 weeks). 
• 
Record all concomitant medications and baseline adverse events.  
• 
Q-PCR for BCR-ABL for assessment of response to TKIs (peripheral blood or 
bone marrow) (within 6 weeks). 
• 
Pregnancy test (if applicable).  βHCG serum or urine pregnancy test for 
women of childbearing potential.  A female of childbearing potential is a sexually 
mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the preceding 12 
consecutive months). Women of child-bearing potential and men must agree to 
use contraception prior to study entry and for the duration of study participation. 
 
Evaluation During Study 
• Physical examination every 3-4 months. After the first year physical examinations 
can be every 12 months (+/- 2 months). 
• CBCs, including platelet count, weekly at beginning or at any time dose 
adjustments are made for eltrombopag or TKI until a stable platelet count has 
been achieved. Obtain CBCs including platelet counts, monthly thereafter; every 
12 months (+/-2 months) after the first year. 
• Monitor serum liver tests (ALT, AST, and bilirubin) every 2 weeks during the dose 
adjustment phase and monthly following establishment of a stable dose. If 
bilirubin is elevated, perform fractionation. If abnormal levels are detected, repeat 
the tests within 3 to 5 days. If the abnormalities are confirmed, monitor liver tests 
weekly until the abnormality (ies) resolve, stabilize, or return to baseline levels. 
• Bone marrow aspiration and/or biopsy including cytogenetics studies every 3-4 
months in the first year; not required after the first year  
• Q-PCR studies for BCR-ABL as indicated for assessment of response to TKIs 
(peripheral blood and/or bone marrow), every 3-4 months in the first year; every 
12 months (+/- 2 months) after the first year. 
• Record all concomitant medications and adverse events every 3-4 months; every 
12 months (+/- 2 months) after the first year.  
 
CBCs and serum chemistry tests can be performed by the patient’s local physician 
following baseline exams.  Results will be faxed to the appropriate research nurse at 
MD Anderson Cancer Center.  All other testing will be performed at MD Anderson 
Cancer Center. 
 
End of Treatment Evaluation (30 days [± 5 days] after the last dose of study drug) 
• 
Physical examination 
• 
CBC, platelet count, differential 
• 
Serum chemistry to include bilirubin, AST, ALT, BUN, creatinine. 
• 
Record adverse events. 

Protocol No. 2011-0319, Amendment 8 
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18 
 
XI. 
CRITERIA FOR RESPONSE 
 
Criteria of Response to Eltrombopag 
1. A complete (platelet) response will be defined as a sustained (3 months) platelet 
count of ≥ 50 x 109/L and at least a 20% increase in platelet count from baseline 
with no more than 3 counts in that period being ≤ 50 x 109/L , while continuing 
imatinib or other TKI therapy. Successful re-escalation following dose reduction 
of TKI will be considered as continuing TKI. 
2. In patients who required dose reduction of imatinib or other TKI because of 
thrombocytopenia, complete (platelet) response can also be defined as 
successful re-escalation of the dose of imatinib or other TKI sustained for at least 
3 months without recurrence of thrombocytopenia to ≤ 50 x 109/L. 
 
 
Criteria of Response to TKIs in CML (adapted from ELN guidelines[2, 3]) 
• Complete Hematologic Remission (CHR): 
▪ Normalization for at least 4 weeks of the bone marrow (less than 5% blasts) 
and peripheral blood with WBC within normal institutional limits with no 
peripheral blasts, promyelocytes or myelocytes, and basophils <5%. 
▪ This is in addition to disappearance of all signs and symptoms of the disease 
 
• Partial Hematologic Response (PHR): 
▪ CHR except for persistence of immature cells (myelocytes, metamyelocytes), 
or splenomegaly < 50% of pretreatment, or thrombocytosis > 450x109/L but < 
50% of pretreatment. 
 
• Complete Hematologic Remission:  
Will further be classified according to suppression of the Philadelphia 
chromosome (Ph) by cytogenetics (FISH if cytogenetic analysis not informative, 
e.g., insufficient metaphases) 
▪ No cytogenetic response: Ph positive 100% of pretreatment value 
▪ Minor cytogenetic response: Ph positive 36-90% of pretreatment value 
▪ Partial cytogenetic response: Ph positive 1-35% of pretreatment value 
▪ Complete cytogenetic response: Ph positive 0% 
*Major cytogenetic response = complete + partial (Ph positive < 35%) 
 
• Molecular response 
▪ Major (MMR): BCR-ABL/ABL ratio < 0.1% in the International Scale 
▪ Complete: Undetectable BCR-ABL, confirmed by nested PCR 
▪ 
Optimal, suboptimal responses and failure to TKI will be based on 
European Leukemia Network recommendations. 
 
Criteria for response in Myelofibrosis[4] 
 
Criteria for response for MF: 
Best overall response will be categorized according to the International Working 
Group (IWG) Criteria: 

Protocol No. 2011-0319, Amendment 8 
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19 
 
Complete remission (CR): Requires all of the following in the absence of both 
transfusion and growth factor support:  
• Complete resolution of disease-related symptoms and signs including 
palpable hepatosplenomegaly. 
• Peripheral blood count remission defined as hemoglobin > 11 g/dL, 
platelet count ≥ 100 x 109/L, and absolute neutrophil count ≥ 1.0 x 109/L. 
• Normal leukocyte differential including disappearance of nucleated red 
blood cells and immature myeloid cells in the peripheral smear, in the 
absence of splenectomy. * 
• Bone marrow histological remission defined as the presence of age-
adjusted normocellularity, < 5% myeloblasts, and an osteomyelofibrosis 
grade of ≤ 1. **  
 
 
Partial remission (PR): Requires all of the above criteria for CR except the 
requirement for bone marrow histological remission. However, a repeat bone 
marrow biopsy is required in the assessment of PR and may or may not show 
favorable changes that do not however fulfill criteria for CR. 
 
Clinical improvement (CI): Requires one of the following in the absence of both 
disease progression (as outlined below) and CR/PR assignment (CI response is 
validated only if it lasts for ≥ 8 weeks). 
• A ≥ 2 g/dL increase in hemoglobin level or becoming transfusion 
independent (applicable only for patients with baseline hemoglobin level 
of < 10 g/dL).  
• Either a ≥ 50% reduction in palpable splenomegaly of a spleen that is ≥ 
10 cm at baseline or a spleen that is palpable at > 5 cm at baseline 
becomes not palpable.  
• A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 
50,000 x 109/L. (applicable only for patients with baseline platelet count of 
< 50 x 109/L). 
• A ≥ 100% increase in ANC and an ANC of ≥ 0.5 x 109/L (applicable only 
for patients with baseline absolute neutrophil count of < 1 x 109/L). 
 
Progressive disease: Requires one of the following:  
• Progressive splenomegaly that is defined by the appearance of a 
previously absent splenomegaly that is palpable at > 5 cm below the 
left costal margin or a ≥ 100% increase in palpable distance for 
baseline splenomegaly of 5-10 cm or a ≥ 50% increase in palpable 
distance for baseline splenomegaly of > 10 cm. 
• Leukemic transformation confirmed by a bone marrow blast count of ≥ 
20%.  
• An increase in peripheral blood blast percentage of ≥ 20% that lasts for 
≥ 8 weeks. 
 
Stable disease: None of the above. 
 

Protocol No. 2011-0319, Amendment 8 
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20 
 
Relapse: Loss CR, PR, and CI. In other words, a patient with CR or PR is 
considered to have undergone relapse when he or she no longer fulfills the 
criteria for CI. 
*Because of subjectivity in peripheral blood smear interpretation; CR does not require absence of 
morphological abnormalities of red cells, platelets, and neutrophils.  
** In patients with CR, a complete cytogenetic response is defined as failure to detect a cytogenetic 
abnormality in cases with a pre-existing abnormality. A partial cytogenetic response is defined as 50% or 
greater reduction in abnormal metaphases. In both cases, at least 20-bone marrow- or peripheral blood-
derived metaphases should be analyzed. A major molecular response is defined as the absence of a specific 
disease-associated mutation in peripheral blood granulocytes of previously positive cases. In the absence 
of a cytogenetic/molecular marker, monitoring for treatment-induced inhibition of endogenous myeloid 
colony formation is encouraged. 
 
XII. 
CRITERIA FOR REMOVAL 
• Patients who develop accelerated/blastic disease features (except when clonal 
evolution is the only criterion for accelerated phase). 
• Hematologic resistance while on optimal therapy. 
• Unacceptable severe (grade 3-4) toxicity possibly related to eltrombopag despite 
dose optimization. 
• Patient request. 
• Development of ≥ 2 reticulin fibrosis in marrow (only applicable to CML patients). 
• Pattern of non-compliance. 
 
XIII. 
REPORTING REQUIREMENTS 
Reporting requirements will be as per institutional guidelines.  
 
Adverse events (AE) related to study conditions  
The serious adverse event (SAE) reporting period will begin with the signing of the 
informed consent. 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to patients experiencing AEs that cause 
interruption or discontinuation of investigational product, or those experiencing AEs 
that are present at the end of their participation in the study. Such patients should 
receive post-treatment follow-up as appropriate. 
 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND 
Protocols 
 
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 

Protocol No. 2011-0319, Amendment 8 
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21 
 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.  
 
• 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 the informed consent is 
signed, 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. 

Protocol No. 2011-0319, Amendment 8 
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22 
 
 
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. 
 
The principal investigator has the obligation to report all serious adverse events to 
the IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
 
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. 
 
Investigator Communication with Supporting Companies: 
 
Prompt Reporting of Serious Adverse Events and Other Events to Novartis 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment must be reported by the investigator and 
documented in PDMS/CORe and to Novartis within 24 hours of learning of its 
occurrence. Information about all SAEs is collected and recorded on a Serious 
Adverse Event Report Form.  The investigator must assess and record the 
relationship of each SAE to each specific study treatment (if there is more than one 
study treatment), complete the SAE Report Form in English, and send the 
completed, signed form along with the Novartis provided fax cover sheet to 
the Novartis Oncology Drug Safety and Epidemiology (DS&E) department by 
fax (fax: 877-778-9739) within 24 hours. 
Any additional information for the SAE including complications, progression of the 
initial SAE, and recurrent episodes must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An 
SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new 
event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period (or 5 half-
lives, if half-life is established, whichever is longer) should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.   
Follow-up information is submitted in the same way as the original SAE Report.  
Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how 
it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation. 

Protocol No. 2011-0319, Amendment 8 
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23 
 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate 
may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees 
in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be reported by the investigator to the Novartis Oncology Drug 
Safety and Epidemiology Department (DS&E) by fax (fax: 877-778-9739). 
Pregnancy follow-up should include an assessment of the possible relationship to 
the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who 
took study treatment in this study. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
 
XIV. 
  
ADVERSE DRUG REACTION REPORTING 
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting according to the MDACC guidelines (Appendix C).  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  
All appropriate treatment areas have access to a copy of the CTCAE Version 4.0. 
Only clinically significant drug-related toxicities will be recorded. Known grade 1 or 2 
toxicities of the drugs will not be recorded or reported. Grade 3, 4 and 5 toxicities, 
whether related or not, will be recorded.  Lower grade toxicities not known to be 
related to drug may be recorded if considered clinically significant by the 
investigator.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
 
XV. 
     DRUG ACCOUNTABILITY 
The Investigator and study staff will be responsible for the accountability of all 
clinical supplies (dispensing, inventory, and record keeping) and adhere to Good 
Clinical Practice guidelines 
Under no circumstances will the Investigator allow the study drug to be used other 
than as directed by this protocol. Clinical supplies will not be administered to any 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
24 
 
individual who is not enrolled in the study.  
 
XVI. 
 
STATISTICAL CONSIDERATIONS 
 Design considerations and Sample Size Justification 
This is a phase II, open-label single-arm study of individualized dosing of 
eltrombopag in patients with CML or MF.  The primary objective is to investigate 
whether eltrombopag will increase platelet count, thus reducing the occurrence of 
thrombocytopenia in subjects with CML and MF receiving therapy with TKI.  The 
objective is to demonstrate that at least 30% of subjects have a complete (platelet) 
response, where complete (platelet) response is achieved if a patient meets all of 
the following criteria:  
(1) reach platelet count ≥ 50 x 109/L within 8 weeks of treatment initiation for 
patients with CML and ≥ 100 x 109/L for patients with MF;   
(2) the platelet count is sustained at ≥ 50 x 109/L for CML and  ≥ 100 x 109/L for 
patients with MF for 3 months, where “sustained” means having no more than 
3 platelet counts in the 3-month period being < 50 x 109/L in CML and < 100 x 
109/L for patients with MF; and  
(3) at least a 20% increase in platelet count from baseline at the end of 3 months 
while continuing TKI therapy.  
 
Successful re-escalation following a dose reduction of TKI will be considered as 
continuing TKI.  In patients who required dose reduction of TKI because of 
thrombocytopenia, complete (platelet) response can also be defined as successful 
re-escalation of the dose of TKI sustained for at least 3 months without recurrence of 
thrombocytopenia to ≤ 50 x 109/L for patients with CML and <100 x 109/L for patients 
with MF. All patients will be enrolled from MDACC, with 1-2 patients per month. 
 
For the cohort  of CML patients: 
Simon’s optimal two-stage design [Simon, 1989] will be used to test the null 
hypothesis that the proportion of subjects with complete response is <=0.10 versus 
the alternative that it is >=0.30 (i.e., Po<=0.10 vs Pa>=0.30) at alpha=0.05 with 80% 
power.  The design will result in an expected sample size of 15 and a probability of 
early termination of 0.736.  After testing the drug on 10 subjects in the first stage, the 
trial will be terminated if 1 or fewer achieve complete (platelet) response. Otherwise, 
if the trial goes on to the second stage, a total of 29 subjects will be studied. If the 
total number of patients with complete (platelet) response is less than or equal to 5, 
the drug will be deemed as ineffective. The trial will suspend accrual if not at least 2 
patients have achieved complete response in the first 10 patients. To be evaluable 
for response (improvement in platelet count and durability of improvement in platelet 
count) patient will need to be followed for 12-20 weeks from start of eltrombopag 
therapy. 
 
For safety monitoring, we will continuously monitor the occurrence of any grade 3 or 
greater non-hematologic adverse events as well as leukemia failure, which is 
defined as failure to achieve optimal response as defined by European Leukemia 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
25 
 
Network or as progression to accelerated/blastic phase (not clonal evolution).     
Safety monitoring will be based on a beta-binomial distribution. The trial will be 
terminated early if Pr[0.15 < toxicity rate | data] > 0.90, where the prior is assumed to 
be beta(1, 1).  Applying this stopping rule and starting from the 7th subjects, the trial 
will stop early if [#subjects with leukemia failure or grade 3 or greater non-hematolgic 
AEs]/[#subjects evaluated] >= 3/7, 4/12, 5/17, 6/22, 7/27. 
  
The operating characteristics are summarized in the following table: 
 
True 
toxicity rate 
 
True complete 
(platelet) response 
rate 
 
Prob(stop the 
trial early) 
0.05 
0.30 
0.166 
 
0.20 
0.388 
 
0.10 
0.741 
 
0.05 
0.916 
0.15 
0.30 
0.433 
 
0.20 
0.584 
 
0.10 
0.824 
 
0.05 
0.943 
0.30 
0.30 
0.916 
 
0.20 
0.938 
 
0.10 
0.974 
 
0.05 
0.991 
 
For the cohort of MF patients: 
 
As the group with MF is an exploratory group of 10 patients to study the safety and 
activity of eltrombopag in patients with MF and thrombocytopenia, we will consider 
the activity promising if 3 or more patients out of 10 achieve complete response. 
 
For safety monitoring in the cohort with MF, accrual will stop if at any time 4 out of 
10 patients encounter grade 3 or more non-hematological toxicity or progression to 
acute leukemia. As an additional safety procedure, we will observe the first 3 
patients on trial for at least 3 months before additional patients are accrued. 
 
 
Analytic Methods 
 

Protocol No. 2011-0319, Amendment 8 
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26 
 
The statistical analyses as detailed below will be performed in each disease cohort 
(i.e., CML and MF) separately. 
 
The proportions of subjects with complete (platelet) response will be reported 
together with exact 95% confidence intervals. The denominator will include all 
subjects who received eltrombopag.  The proportion of subjects with leukemia, and 
the proportion failing to TKI will be summarized similarly 
 
Platelet counts over time and in relationship to exposure to eltrombopag and TKI will 
be summarized using descriptive statistics.  
 
Kaplan-Meier methods will be used to estimate the risk of leukemia (i.e., suboptimal 
response and progression to accelerated or blastic phase) over time. 
 
Descriptive statistics will be used to summarize the extent of exposure to 
eltrombopag, and to TKI.  
 
The number (%) of subjects with adverse events, serious adverse events, and 
adverse events leading to discontinuation will be reported.  Adverse events will be 
reported by type, severity and frequency.  Laboratory parameters will also be 
summarized using descriptive statistics; laboratory toxicity will be summarized using 
frequency counts. 
 
XVII. STUDY SCHEDULE*: 
 
 
 
Screening/ 
Baseline 
 
During 
adjustment phase 
of eltrombopag or 
TKI dose 
Every 3-4 
months 
in first 
year 
Yearly 
after 
first 
year 
 
End of 
Treatment8 
History and 
physical 
examination 
Within 7 days 
 
X 
X 
X 
CBC, platelet 
count, 
differential and 
peripheral 
blood smear1 
Within 7 days 
Weekly 
(Monthly on stable 
dose) 
 
X 
X 
Serum 
Chemistry2 
Within 7 days 
Every 2 weeks3 
(Monthly on stable 
dose) 
 
 
X 
Hepatitis panel 
Within 6 
weeks 
 
 
 
 
Bone marrow 
aspirate and 
biopsy4 
Within 6 
weeks 
 
X 
 
 
Cytogenetics 
Within 6 
weeks 
 
X 
 
 
BCR-ABL 
QPCR6 
Within 6 
weeks 
 
X 
X 
 

Protocol No. 2011-0319, Amendment 8 
August 14, 2018 
27 
 
(CML only) 
Concomitant 
Medications 
Within 7 days 
 
X 
X 
 
Adverse 
Events 
Within 7 days 
 
X 
X 
X 
β-hCG or urine 
pregnancy 
test7 
Within 7 days 
 
 
 
 
 
1Peripheral blood smear at baseline only 
2Includes bilirubin, AST, ALT, BUN, creatinine 
3If bilirubin is elevated, perform fractionation.  If abnormal levels are detected, repeat the tests within 3 to 
5 days.  If the abnormalities are confirmed, monitor liver tests weekly (± 3 days) until the abnormality(ies) 
resolve, stabilize or return to baseline level. 
4Includes reticulin staining.  
5Aspiration and/or biopsy. 
6Peripheral blood or bone marrow 
7Women of childbearing potential only:  Serum β-hCG or urine pregnancy test.  830 days (± 5 days) after 
the last dose of study drug.   
*Weekly schedule is ±3 days; bi-weekly is ±5 days; monthly is ±7 days; every 3 months is ± 1 month; 
every 12 months is ±2 months. 
 
XVIII. 
REFERENCE LIST 
 
1. 
Prescribing Information Promacta. 
2. 
Baccarani, M., et al., Chronic myeloid leukemia: an update of concepts and management 
recommendations of European LeukemiaNet. J Clin Oncol, 2009. 27(35): p. 6041-51. 
3. 
Baccarani, M., et al., Evolving concepts in the management of chronic myeloid leukemia: 
recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 2006. 
108(6): p. 1809-20. 
4. 
Tefferi, A., et al., International Working Group (IWG) consensus criteria for treatment response in 
myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment 
(IWG-MRT). Blood, 2006. 108(5): p. 1497-503. 
5. 
Kantarjian, H., et al., Hematologic and cytogenetic responses to imatinib mesylate in chronic 
myelogenous leukemia. New England Journal of Medicine, 2002. 346(9): p. 645-652. 
6. 
Kantarjian, H.M., et al., Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase 
myeloid leukemia after failure of interferon-alpha: follow-up results. Clin Cancer Res, 2002. 8(7): 
p. 2177-87. 
7. 
Kantarjian, H.M., et al., Imatinib mesylate therapy in newly diagnosed patients with Philadelphia 
chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major 
cytogenetic responses. Blood, 2003. 101(1): p. 97-100. 
8. 
O'Brien, S.G., et al., Imatinib compared with interferon and low-dose cytarabine for newly 
diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 2003. 348(11): p. 994-1004. 
9. 
Aoki, E., et al., High-dose imatinib mesylate treatment in patients with untreated early chronic 
phase chronic myeloid leukemia. Journal of Clinical Oncology, 2006. 24(18s): p. 345s (Abs# 
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10. 
Hochhaus, A., et al., Dasatinib induces notable hematologic and cytogenetic responses in 
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11. 
Kantarjian, H., et al., Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive 
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12. 
Cortes, J.E., et al., Nilotinib as front-line treatment for patients with chronic myeloid leukemia in 
early chronic phase. J Clin Oncol. 28(3): p. 392-7. 
13. 
Kantarjian, H., et al., Hematologic and cytogenetic responses to imatinib mesylate in chronic 
myelogenous leukemia. N Engl J Med, 2002. 346(9): p. 645-52. 
14. 
Kantarjian, H.M., et al., Nilotinib is effective in patients with chronic myeloid leukemia in chronic 
phase following imatinib resistance or intolerance: 24-month follow-up results. Blood. 
15. 
Saglio, G., et al., Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J 
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16. 
Kantarjian, H., et al., High-dose imatinib mesylate therapy in newly diagnosed Philadelphia 
chromosome-positive chronic phase chronic myeloid leukemia. Blood, 2004. 103(8): p. 2873-8. 
17. 
Sneed, T.B., et al., Significance of myelosuppression during the course of therapy with imatinib in 
patients with chronic myelogenous leukemia in chronic phase. Blood, 2002. 100(11): p. 787a 
(Abstract #3110). 
18. 
Deininger, M.W., et al., Practical management of patients with chronic myeloid leukemia receiving 
imatinib. J Clin Oncol, 2003. 21(8): p. 1637-47. 
19. 
Quintas-Cardama, A., et al., Granulocyte-colony-stimulating factor (filgrastim) may overcome 
imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. 
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20. 
Cortes, J., et al., Erythropoietin is effective in improving the anemia induced by imatinib mesylate 
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21. 
Ault, P., et al., Use of darbepoietin alfa for the treatment of anemia occuring during imatinib 
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613 (Abstract #2467). 
22. 
Ault, P., et al., Interleukin 11 May improve thrombocytopenia associated with imatinib mesylate 
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23. 
Aribi, A.M., et al., The Effect of Interleukin-11 (Oprelvekin, Neumega(R)) on Thrombocytopenia 
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26. 
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