A Phase II Trial of Eltrombopag for Patients With Chronic Lymphocytic Leukemia (CLL) and Thrombocytopenia
Phase: PHASE2
Conditions: CLL, Leukemia
Sponsor: M.D. Anderson Cancer Center

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A Phase II Trial of Eltrombopag for  
Patients with Chronic Lymphocytic Leukemia (CLL) 
and Thrombocytopenia 
 
 
Version 3 
 
December 10, 2010 
 
William G. Wierda, M.D., Ph.D. 
Associate Professor of Medicine 
Department of Leukemia 
Division of Cancer Medicine 
UT MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX  77030 
(713) 745-0428 (ph) 
(713) 794-1602 (fax) 
 
 
 
 
Short Title: 
Phase II Eltrombopag in CLL 
 

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1.0 
OBJECTIVES 
Primary objective: 
a. 
Determine the overall response rate of eltrombopag in patients with CLL and 
thrombocytopenia. 
 
Secondary objectives: 
a. 
Determine the time-to-response and duration of response. 
b. 
Determine time to CLL progression requiring leukemia treatment. 
c. 
Assess tolerability and toxicities of eltrombopag in patients with CLL. 
d. 
Assess pharmacokinetics of eltrombopag and thrombopoietin levels in patients 
with CLL. 
 
2.0 
BACKGROUND 
Rationale: 
Eltrombopag (Promacta) is a thrombopoietin (TPO)-receptor agonist that triggers a 
cascade that induces proliferation and differentiation of megakaryocytes from bone 
marrow progenitor cells1,2.  It received FDA accelerated approval for the treatment of 
chronic immune thrombocytopenic purpura in November, 2008 based on the results of 
the pivotal phase II and III studies 3,4. Patients with CLL frequently have 
thrombocytopenia, which may be the result of reduced numbers of megakaryocytes 
resulting from infiltration of the bone marrow by leukemia or from prior treatment; 
reduced function of megakaryocytes resulting from prior chemotherapy; or from 
Idiopathic Thombocytopenic Purpura (ITP). Among 2300 treatment-naive patients with 
CLL who presented to MD Anderson Cancer Center (MDACC) as new patients between 
2000 and 11/2009, 102 had platelet (PLT) count 51-100K/µL, 21 had PLT count 21-
50K/L, and 6 had PLT count 20K/L.  The incidence of thrombocytopenia is higher for 
previously treated patients.  Indeed, among 1370 previously treated patients with CLL 
who presented to MDACC as new patients during the same time period, 236 had PLT 
count 51-100K/µL, 120 had PLT count 21-50K/L and 66 had PLT count 20K/L.  
These numbers do not include patients on routine follow-up with the Leukemia Service 
who develop thrombocytopenia at some point during their follow-up. 
 
Thrombocytopenia in patients with CLL is associated with morbidity and mortality from 
bleeding complications and significant limitation in administering chemotherapy for 
active, progressive CLL. Identifying an active agent to treat thrombocytopenia in 
patients with CLL would be a significant advance in managing these patients. 
Eltrombopag is an ideal candidate to evaluate as treatment for thrombocytopenia in 
patients with CLL, owing to the previously mentioned mechanism of action and the 
demonstrated activity in treating patients with chronic ITP. This trial will evaluate the 
activity of eltrombopag in treating thrombocytopenia in patients with CLL and PLT 
50K/L. 
 
In this study, patients will be stratified into 2 groups according to physician-assessed 
etiology of thrombocytopenia, those due to prior treatment or disease and those due to 
ITP.  Physicians will use available data to make this determination including, CLL 

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treatment history, history of thrombocytopenia, complete blood count, and bone marrow 
aspiration and biopsy results to evaluate for extent of CLL and presence of 
megakaryocytes.  This determination and stratification will be declared at the time of 
initiation of eltrombopag. 
 
The overall objective of this phase II study will be to determine the PLT response rate 
with eltrombopag in patients with CLL and thrombocytopenia (PLT 50K/L). 
 
3.0 
BACKGROUND DRUG INFORMATION  
Eltrombopag (Promacta) is a thrombopoietin receptor agonist indicated for the treatment 
of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic 
purpura who have had an insufficient response to corticosteroids, immunoglobulins, or 
splenectomy.  Eltrombopag is available in 75mg, 50mg and 25mg tablets.  Also, 12.5mg 
tablets are available for clinical trial only. For this study, eltrombopag will be supplied by 
GlaxoSmithKline (GSK), Collegeville, PA, 19426. 
 
Eltrombopag is being evaluated both in several GSK-sponsored trials and in 
investigator-initiated studies supported by GSK.  Eltrombopag has been evaluated in 
healthy volunteers at a dose of up to 200 mg daily for 5 days and for treatment of 
thrombocytopenia related to immune thrombocytopenia, hepatitis C virus infection, 
myelodysplastic syndrome (MDS), and chemotherapy-induced thrombocytopenia in 
cancer patients.  Eltrombopag is currently being evaluated in multiple trials with the 
following dose escalation schema:  the starting dose is 75 mg/day and dose may be 
escalated as follows: 150 mg, 225 mg, 300 mg given daily for 10 days after completion 
of chemotherapy; continuous dosing is used in the MDS/AML trials.  The maximum 
dose that is currently being considered for all eltrombopag studies is also 300 mg 
continuous dose.  Currently 300 mg is the highest tested safe dose of eltrombopag, 
either in interrupted dosing (with chemotherapy) or continuous dosing.  Therefore, the 
dose escalation schema in this protocol is consistent with GSK-sponsored trials with 
eltrombopag and dose-modification parameters are consistent with those recommended 
by  GSK for all eltrombopag trials. 
 
In ITP, the recommended starting dose of eltrombopag is 50 mg once daily except in 
patients who are of East Asian ancestry or who have moderate to severe hepatic 
impairment.  For ITP patients of East Asian ancestry such as Chinese, Japanese, 
Taiwanese, or Korean, it is recommended to initiate eltrombopag at a reduced dose of 
25 mg once daily.  For all ITP patients with moderate or severe hepatic impairment, 
initiate eltrombopag at a reduced dose of 25 mg once daily. 
 
Eltrombopag should be taken on an empty stomach (1 hour before or 2 hours after a 
meal).  At least a 4-hour interval between eltrombopag and other medications (e.g., 
antacids) should be allotted, 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. 
 

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In patients with ITP, after initiating eltrombopag, the dose should be adjusted to achieve 
and maintain a platelet count ≥50 K/µL x 10K/L as necessary to reduce the risk for 
bleeding.  
 
Clinical hematology and liver tests should be monitored regularly throughout therapy 
with eltrombopag and modified based on platelet counts as outlined in the package 
insert for Promacta.  Recommendations for monitoring are as follows:  during 
eltrombopag therapy assess CBC, including platelet count and peripheral blood smears, 
weekly until a stable platelet count has been achieved. Obtain CBC, including platelet 
counts and peripheral blood smears, monthly thereafter. 
 
Safety Considerations: 
Summary 
Common side effects (occurring in 3-20% of patients): 
 Dermatologic: skin rash 
 Gastrointestinal: nausea, vomiting 
 Hematologic: bleeding including heavy menstrual bleeding, low platelets 
requiring transfusion 
 Hepatic: abnormal liver function  tests (possible liver damage) 
 Musculoskeletal: pain in arms and or legs 
 Neurologic: peripheral neuropathy 
 
Potentially serious side effects (occurring in fewer than 3% of patients): 
 Hematologic:  bruising, epistaxis, conjunctival hemorrhage, bone marrow 
reticulin formation, worsening thrombocytopenia, 
thrombotic/thromboembolic complications (such as in the liver or other 
symptoms) 
 Neurologic: peripheral neuropathy 
 Ophthalmologic: cataracts or worsening of existing cataracts 
 Other:  hematological malignancies, progression of malignancies and non-
Hodgkin’s lymphoma 
 
Liver toxicity 
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. No patients in the placebo group experienced Grade 4 liver test abnormalities. In 
controlled studies, elevations of alanine aminotransferase (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 

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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, aspartate aminotransferase (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 (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 of hepatic impairment. 
 
 
Exercise caution when administering eltrombopag to patients with hepatic disease. Use 
a lower starting dose of eltrombopag in patients with moderate to severe hepatic 
disease and monitor closely  
 
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, examine the peripheral blood smear closely to 
establish a baseline level of cellular morphologic abnormalities. Following identification 
of a stable dose of eltrombopag, examine peripheral blood smears and CBC 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 morphological abnormalities or cytopenia(s), discontinue treatment with 
eltrombopag and consider a bone marrow biopsy, including staining for fibrosis.  
 
Worsening thrombocytopenia following discontinuation 
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 

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the patient is on anticoagulants or antiplatelet agents. In the 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 3 severely thrombocytopenic patients within one 
month following the discontinuation of eltrombopag; none were reported among the 
placebo group.  
 
 
Following discontinuation of eltrombopag, obtain weekly CBC, 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 
groups. Thrombotic/thromboembolic complications have also been reported in the ITP 
extension study.  
 
In a placebo-controlled double-blind study (ELEVATE) of 261 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 one 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. 
 
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).  
 
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 

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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. 
 
4.0 
PATIENT ELIGIBILITY 
4.1 
Inclusion criteria: 
1. 
Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic 
lymphoma (SLL) 
2. 
Age  18 years 
3. 
PLT transfusion-dependent, defined as need for transfusion to maintain 
PLT count ≥ 20K/µL, or the average of two (non-transfused) PLT counts 
taken within 2 weeks of the screening period ≤50K/µL, with no individual 
count >55K/µL 
4. 
Patients with ITP must have failed at least 1 prior treatment for ITP 
including one of the following:  corticosteroids, rituximab, splenectomy, 
cyclosporine 
5. 
At least 3 weeks must have elapsed since the last chemotherapy 
treatment for CLL 
6. 
ECOG performance status (PS) ≤ 2 
7. 
Adequate liver function (total bilirubin  ≤2X upper limit normal (ULN); ALT 
≤2.5X ULN) 
8. 
Adequate renal function (serum creatinine Cr ≤2.2 mg/dL) 
9. 
For patients with ITP on corticosteroids or cyclosporine, dose of 
corticosteroids or cyclosporine must be stable for 2 weeks prior to 
enrollment and planned to be tapered in patients responding to 
eltrombopag 
10. 
Able to provide informed consent 
 
4.2 
Exclusion Criteria: 
1. 
Concurrent chemotherapy for CLL 
2. 
Diagnosis of Richter’s transformation 
3. 
Uncontrolled autoimmune hemolytic anemia, i.e. patients with AIHA that is 
not controlled with treatment such as corticosteroids or cyclosporine.  This 
would include patients who require PBRC transfusions or who do not have 
a stable hemoglobin (HGB) due to ongoing hemolysis. 
4. 
Concurrent treatment for ITP (except corticosteroids and cyclosporine) 
5. 
Diagnosis of myelodysplastic syndrome or acute myeloid leukemia 
6. 
Active infection or significant medical illness as determined by the treating 
physician 
7. 
Treatment with thrombomimetic agents in the past 3 months (rTPO, PEG-
rHuMGDF, Nplate or Promacta) 
8. 
Pregnant or breast feeding subjects and subjects not willing to use 
adequate contraceptive precautions 
 

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5.0 
TREATMENT PLAN 
Once patients have signed their informed consent form, all pretreatment evaluations 
have been completed and eligibility confirmed, patients will begin treatment with 
eltrombopag. 
 
5.1 
Patients will take eltrombopag 75 mg PO daily as the starting dose. 
 
5.2 
Dose adjustments may occur every 2 weeks: 
 Dose reduction may occur for toxicity or PLT count over 400K/L. 
 Dose may be increased according to the following guidelines after the first 
2 weeks on eltrombopag. 
 
5.3 
Dose levels: 
-2 = 25 mg PO daily 
-1 = 50 mg PO daily 
0 = 75 mg PO daily 
+1 = 150 mg PO daily 
+2 = 225 mg PO daily 
+3 = 300 mg PO daily 
 
5.4 
Dose modification schema: 
PLT count x 10K/L Dose 
< 100 
Increase by 1 dose level 
101 - 200 
No change 
 201- 400 
decrease by 1 dose level 
> 400 at any time 
hold drug and resume when PLT reaches < 400K/L 
at next lower dose level. Additional dose adjustment will be necessary for 
platelets remaining > 400. 
 
5.5 
Eltrombopag treatment will continue until loss of PLT response (i.e. a return to 
PLT count as at enrollment into the study) or until treatment (chemotherapy) for 
CLL is necessary.  
 
6.0 
PRETREATMENT EVALUATION 
6.1 
Pretreatment evaluation will consist of history, physical examination, CBC with 
differential and PLT count, blood chemistries (SMA 12), serum 2 microglobulin, 
pregnancy test for women of childbearing potential, bone marrow aspirate and 
biopsy with qualitative and semi-quantitative evaluation of megakaryocytes.  
Fractionated bilirubin should be obtained for individuals with total bilirubin greater 
than the upper limit of normal.   
 
6.2 
CLL prognostic factors will be characterized including chromosome abnormalities 
by FISH, CD38 expression, ZAP-70 expression, and IGHV gene mutation status.  
FISH and CD38 must be repeated if not done within 4 months; ZAP-70 and IGHV 
mutation status do not need to be repeated if previously done.  If there is 

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inadequate amount of CLL present to obtain prognostic factor results for patients 
with ITP, then these will not be obtained. 
 
6.3 
Assessment of bruising and bleeding using the World Health Organization 
(WHO) Bleeding Scale (Appendix C) will be performed prior to treatment.  The 
investigator or designee should ask questions such as “have you experienced 
any bruising or bleeding within the last 7 days?”  The bruising or bleeding grade 
(0-4), using the WHO Bleeding Scale, will be collected and recorded. 
 
7.0 
EVALUATION DURING STUDY 
7.1 
Monitoring of patients while on treatment will consist of weekly physical exam, 
including vital signs, interval history, CBC with differential and PLT count, and 
blood chemistries (SMA12), including liver function tests (3 days) for the first 
month, then every two weeks (3 days) for the second and third months on 
treatment, then monthly (1 week) thereafter.  Additional evaluations may be 
ordered as clinically indicated by the healthcare provider.  The patients’ referring 
physician may perform monitoring labs and clinic visits; results will be obtained 
and monitored by the MDACC treating physician. 
 
7.2 
Assessment of bruising and bleeding using the World Health Organization 
(WHO) Bleeding Scale (Appendix A) will be performed at each visit.  Any sign or 
symptom of thrombocytopenia observed during the Bleeding Assessments that 
fulfils the definition of an AE or SAE, as described, should be documented. The 
investigator or designee should ask questions such as “have you experienced 
any bruising or bleeding within the last 7 days or since your last visit?”  The 
bruising or bleeding grade (0-4), using the WHO Bleeding Scale, will be collected 
and recorded. 
 
7.3 
A physician will see patients at least monthly (1 week). A mid-level provider will 
evaluate patients and review counts weekly or biweekly (3 days) when not seen 
by the physician, for the first 3 months. 
 
7.4 
Review of response and toxicity will be done with weekly counts (3 days) for the 
first month, then every other week for months 2 and 3 on treatment, then monthly 
thereafter; formal response evaluation will occur monthly and will include review 
of PLT transfusion history and blood counts. 
 
7.5 
Patients will have a bone marrow evaluation upon achieving a complete 
response or after 3 months on eltrombopag (whichever comes first), then 
subsequently as clinically indicated. Bone marrow samples will be evaluated for 
changes in megakaryocyte number and characteristics.  This visit, including bone 
marrow evaluation, history and physical examination, and laboratory evaluation 
must occur at MDACC. Overall response will be the best response achieved 
according to Section 8.1 over the first 3 months of treatment. 
 

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Table 1.  Schedule of Events 
Test and Evaluations 
Screening Visit
Day  -14 
M1 
D1 
M1 
D8 
M1 
D15 
M1 
D22 
M2&
3 
D1
M2&
3 
D15
M ≥4 
D1 
End 
of 
Tx
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Interval history & WHO 
Bleeding Assessment 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X2,8 
 
PE including vital signs 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X2,8 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Eltrombopag 
 
X 
 
 
 
 
 
 
 
CBC with diff, PLT 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X2,8 
X1,3 
SMA 126 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X2,8 
 
CLL prognostic factors 
X 
 
 
 
 
 
 
 
 
Bone Marrow aspirate  
and core biopsy 
X 
 
 
 
 
 
 
X2,5,8 
 
PK & PD, optional  
samples 
 
X1 
X1 
X1 
X1 
X1 
X1,7 
X2,8 
 
Formal PLT response  
assessment 
 
X1 
 
 
 
X1,4 
 
X2,8 
 
D=day; M=month; PE=physical examination; VS=vital signs; CBC=complete blood count; 
PK=pharmacokinetic; PD=pharmacodynamic; Tx=treatment;  
1 indicates ± 3 days 
2 indicates ± 1 week 
3 indicates to be done weekly after discontinuation of eltrombopag for at least 4 weeks 
4 begins M2 
5 BM to be done after 3 months on eltrombopag or at complete response, which ever is first. 
6 If bilirubin is elevated at any time, 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 for the 
development of liver test abnormalities 
7 indicates additional sampling done pre-dose, 2, 4 and 6 hour at M2D15 only 
8 indicates visits and evaluations that must occur at MDACC starting on Month 4 and continuing every 3 
months thereafter while on treatment 
 
7.6 
Concurrent chemotherapy, including investigational treatment for CLL or 
Richter’s transformation is not permitted.  Growth factor support including G-
CSF, GM-CSF and erythropoietin and prophylactic antibiotics are permitted. 
 
8.0 
TOXICITY EVALUATION AND RESPONSE CRITERIA 
8.1 
Formal PLT response criteria reflect clinically meaningful improvement in PLT 
counts and are based on International Working Group (IWG) response criteria for 
myelodysplasia5.  Formal PLT response criteria as follows: 
 
 Complete Response (CR): Increase in PLT count to ≥100K/µL for at least 4 
weeks 
 
 Major Response (MR): 
Increase in PLT count from <20K/µL to ≥20K/µL and 
by at least 100% for at least 8 weeks; or for patients 
starting with >20K/µL platelets, absolute increase in 

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PLT count of ≥30K/µL for at least 4 weeks: or PLT 
transfusion independence (no PLT transfusion) for at 
least 4 weeks).  
 
 Minor Response (MNR): 
Increase of PLT counts by ≥50% and by an absolute 
count of ≥10K/µL (non-transfused) for at least 4 
weeks. 
 
 Sustained Response (SR): Includes CR, MR, and MNR.  Platelets response of at 
least MR lasting for ≥8 weeks on therapy. 
 
 Treatment failure: 
Failure to respond by the above criteria after at least 2 
weeks treatment at the highest tolerated dose level or 
300 mg/day, which ever is higher. 
 
8.2 
The primary efficacy endpoint is overall response (OR), which is defined as the 
composite of complete response (CR) and major response (MR).  Individual 
response criteria (CR, MR, MNR, SR) will be summarized as secondary 
endpoints. 
 
8.3 
Secondary Endpoints: 
1. 
Time-to-response (start of eltrombopag to response) and duration of response 
(initial response to loss of PLT response). 
2. 
Time to CLL progression requiring chemotherapy (start of eltrombopag to 
chemotherapy for CLL). 
3. 
Assess tolerability and toxicities of eltrombopag. 
4. 
Pharmacokinetics (PK) of eltrombopag and thrombopoietin levels in patients with 
CLL. 
 
9.0 
REMOVAL FROM STUDY 
9.1 
Progressive CLL Disease 
 
Progressive CLL disease (PD) will be characterized by at least one of the 
following: 
 
a. > 50% increase in the sum of the products of at least two nodes on two 
consecutive examinations two weeks apart (at least one node must be > 2 
cm). 
 
b. > 50% increase in the size of liver and/or spleen as determined by 
measurement below the respective costal margin. 
 
c. > 50% increase in absolute number of circulating lymphocytes and at least 
10L/l. 
 

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9.2 
Patient request. 
 
9.3 
Active HBV infection or hepatitis. 
 
9.4 
Eltrombopag failure as defined in Section 5.5 for initial responders and Section 
8.1 for non-responders. 
 
10.0 STATISTICAL CONSIDERATIONS 
This is a phase II, open label study. The primary efficacy endpoint is overall 
response rate (OR), which is defined as the composite of complete response 
(CR) and major response (MR).  CR is defined as an increase in PLT count to 
≥100K/µL for at least 4 weeks.  MR is defined as an increase in PLT count from 
<20K/µL to ≥20K/µL and by at least 100% for at least 8 weeks; or for patients 
starting with >20K/µL platelets, absolute increase in PLT count of ≥30K/µL for at 
least 4 weeks: or PLT transfusion independence (no PLT transfusion) for at least 
4 weeks). Overall response will be the best response achieved according to 
Section 8.1 over the first 3 months of treatment. 
 
The objective is to demonstrate a 30% Overall Response Rate (ORR) for the 
cohort of patients with CLL and ITP and 30% ORR for the cohort of patients with 
disease-related thrombocytopenia.  There will be a total of 36 patients enrolled in 
this study and with an average enrollment of 1-2 monthly, total enrollment is 
anticipated to take 15-20 months.  Simon’s two-stage optimal design will be used 
in this study for the 2 different cohorts, separately.  
 
In each of these cohorts, a total sample size of 18 is chosen to differentiate 
between a desirable ORR of 30% and a poor response rate of 10% at the 
significance level of 0.10 with 80% power. Specifically, 7 patients will be enrolled 
in the first stage. If there are no responders, the trial will be terminated due to 
lack of efficacy; otherwise an additional 11 patients will be treated resulting in a 
total of 18 patients. If there are 3 or fewer responses among 18 patients, the 
treatment will be concluded ineffective. The probability of early termination due to 
futility is 0.48.  
 
Safety monitoring will be based on a beta-binomial distribution.  The probability of 
toxicity will be monitored based on a beta-binomial model, assuming a priori that 
p = Prob(toxicity) ~ beta(1, 1).  The trial will be terminated if Prob(p > .15 | data) > 
.9. This rule will stop the trial if [# patients with toxicity]/[# patients evaluated] > 
3/7, 4/12, 5/17, 6/22, 7/27, 8/32. Toxicity events, for purposes of safety 
monitoring, will be defined as eltrombopag-related, grade ≥ 4 toxicity by CTCAE 
V 4.0, that persist longer than 1 week despite holding drug and/or dose 
reduction. The operating characteristics for toxicity are summarized in Table 2. 
 
 
 
 

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Table 2. Operating characteristics based on 10000 simulation study 
true 
Prob(tox)
Pr(stop)
 Median # Pts (25%, 75%) 
0.05 
0.02 
36 (36, 36) 
0.10 
0.13 
36 (36, 36) 
0.15 
0.36 
36 (15, 36) 
0.20 
0.63 
20 (9, 36) 
0.30 
0.94 
9 (7, 15) 
 
Efficacy will be analyzed separately for each cohort.  The proportions of subjects 
with overall response (CR+MR) will reported together with exact confidence 
intervals.  All other response categories (minor, response, sustained response, 
failure) will be summarized using frequency counts and percentage.  The 
denominator will include all subjects who received eltrombopag. 
 
Continuous data including eltrombopag and thrombopoietin levels will be 
summarized using descriptive statistics (n, mean, sd, median, range).  Graphical, 
histograms, or box-plots will be used where appropriate.   Descriptive statistical 
analysis will be used to explore the data, including histograms or box-plots, 
proportions, means, standard deviations. The Fisher’s exact test or Chi-square 
test will be used for the univariable analysis on categorical variables (response 
variable with Yes versus No, for example). The t-test or Wilcoxon test will be 
used for continuous variables. The Kaplan-Meier methods will be used to 
estimate overall and event-free survival over 36 months. 
 
Descriptive statistics will be used to summarize the extent of exposure to 
eltrombopag. The number (%) of subjects with adverse events, serious adverse 
events, and adverse events leading to discontinuation will be reported.  Adverse 
events toxicity will be reported by type, frequency and severity.  Laboratory 
parameters will also be summarized by visit using descriptive statistics; 
laboratory toxicity will be summarized using frequency counts. 
 
Sample size determination: 
Simon’s optimal two-stage design will be used to test the null hypothesis that the 
proportion of subjects with overall response is <=0.10 versus the alternative that 
it is >=0.30 (i.e., Po<=0.10 vs. Pa>=0.30) at alpha=0.10 with 80% power.  It has 
an expected sample size of 13 and a probability of early termination of 0.478. 
After testing the drug on 7 subjects in the first stage, the trial will be terminated if 
0 respond. If the trial goes on to the second stage, a total of 18 patients will be 
studied.  If the total number responding is less than or equal to 3, the null 
hypothesis is not rejected. 
 
11.0 PHARMACODYNAMIC AND PHARMACOKINETIC ENDPOINTS 
Biomarkers: 

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December 10, 2010 
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We will evaluate eltrombopag and thrombopoietin levels for patients on this trial. 
Bone marrow will be evaluated for changes in megakaryocyte number and 
characteristics. 
 
PD samples will be shipped to:  
 
 
 
Attn: Ruth LaPushin 
 
 
 
MD Anderson Cancer Center 
 
 
 
1515 Holcombe Blvd., T6-3849 
 
 
 
Houston, TX 77030 
 
 
 
Phone: 713-792-3690 
 
PK samples will be shipped to: 
 
 
 
GlaxoSmithKline 
 
 
 
Department of Drug Metabolism and PharmacoKinetics 
 
 
 
Mail Stop UW2710,  Swedeland Road 
 
 
 
King of Prussia, PA 19406 
 
 
 
Attn: Josh Albert/Michael Adamek 
 
 
 
Phone: 610-270-6549 
 
 
 
 
12.0 REFERENCES 
1. 
Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, 
Toomey JR. Comparative analyses of the small molecule thrombopoietin 
receptor agonist eltrombopag and thrombopoietin on in vitro platelet 
function. Exp Hematol. 2009;37:1030-1037. 
2. 
Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of 
eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor 
agonist. Stem Cells. 2009;27:424-430. 
3. 
Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of 
chronic idiopathic thrombocytopenic purpura. N Engl J Med. 
2007;357:2237-2247. 
4. 
Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet 
counts and bleeding during treatment of chronic idiopathic 
thrombocytopenic purpura: a randomised, double-blind, placebo-controlled 
trial. Lancet. 2009;373:641-648. 
5. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood. 2006;108:419-425.