Clinical trial NCT01772420
Conditions: Adult Myelodysplastic Syndrome Anemia Chronic Myelomonocytic Leukemia
Sponsor: Albert Einstein College of Medicine
Start date: 2012-10-01; Completion date: 2020-07-09
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well lenalidomide (LEN) and eltrombopag olamine (ELT) work in treating patients with symptomatic anemia in low or intermediate myelodysplastic syndrome (MDS). Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Eltrombopag olamine may increase the number of white blood cells and platelets found in bone marrow or peripheral blood. Giving lenalidomide and eltrombopag olamine may be an effective treatment for myelodysplastic syndrome.

Detailed description:
PRIMARY OBJECTIVES (not Outcome Measures):

I. To evaluate the rate of hematologic improvement of the eltrombopag (eltrombopag olamine)/lenalidomide combination (as per Modified International Working Group \[IWG\] criteria).

II. To evaluate the safety and tolerability of the combination.

SECONDARY OBJECTIVES (not Outcome Measures):

I. To compare the time to hematologic improvement. II. To evaluate the duration of hematologic improvement III. To evaluate the effect of combination treatment on platelet counts, platelet transfusions and bleeding events.

IV. To evaluate the frequency of bone marrow response (complete response \[CR\] + partial response \[PR\]) and cytogenetic response.

V. To evaluate the relationship between mutations in bone marrow stem cells and response.

VI. To evaluate the relationship between various stem and progenitor alterations and response.

OUTLINE: Patients are initially assigned to 1 of 2 treatment arms.

ARM A: Patients with platelet counts \>= 50,000 receive lenalidomide orally (PO) daily or every other day (QOD) on days 1-21. If platelet counts fall below 50,000, patients discontinue lenalidomide and receive eltrombopag olamine PO daily or QOD until platelet count is maintained above 50,000 for 2 weeks. Patients then resume lenalidomide PO daily or QOD. If platelets fall below 50,000 again, patients receive eltrombopag olamine as before. When platelet counts are maintained above 50,000 for 2 weeks, patients resume lenalidomide concurrently with eltrombopag for all subsequent courses.

ARM B: Patients with platelet counts \< 50,000 receive eltrombopag olamine PO daily or QOD on days 1-28 until platelet counts is maintained above 50,000 for 2 weeks. Patients then receive treatment as in Arm A.

In both arms, treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Eligible patients with a diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) (WBC ≤ 12,000/mL) of at least 3-month duration according to WHO criteria and International Prognostic Scoring System categories of low or intermediate-1-risk disease. Patients either had symptomatic anemia untransfused with hemoglobin ≤ 10 g/dL in the 8 weeks before starting the study or had RBC transfusion dependence (i.e., ≥ 2 units/mo) confirmed 8 weeks before starting the study and/or PLTs \<50,000 k/uL with hemoglobin \>10.0 g/dL. Patients must not have received prior therapy with LEN (for \> 2 months) nor ELT

Arms: arm 1: Patients with baseline platelet counts \>= 50,000 receive lenalidomide PO daily or QOD on days 1-21. If platelet counts fall below 50,000, patients discontinue lenalidomide and receive eltrombopag olamine PO daily or QOD until platelet count is maintained above 50,000 for 2 weeks. Patients then resume lenalidomide PO daily or QOD. If platelets fall below 50,000 again, patients receive eltrombopag olamine as before. When platelet counts are maintained above 50,000 for 2 weeks, patients resume lenalidomide concurrently with eltrombopag for all subsequent courses.

Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients with baseline platelet counts \< 50,000 receive eltrombopag olamine PO daily or QOD on days 1-28 until platelet count is maintained above 50,000 for 2 weeks. Patients then receive treatment as in Arm A.

Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Eltrombopag Olamine intervention 2: Laboratory Biomarker Analysis intervention 3: Lenalidomide
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIVERSITY 
MONTEFIORE MEDICAL CENTER 
IRB# 2012-407 
IND# 115770 
 
 
 
 
Version: January 07, 2016 
Protocol Title: PHASE II STUDY OF LENALIDOMIDE AND ELTROMBOPAG IN 
PATIENTS WITH SYMPTOMATIC ANEMIA IN LOW OR INTERMEDIATE I 
MYELODYSPLASTIC SYNDROME (MDS) 
 
GlaxoSmithKline Tracking#:  
115479 
Celgene Tracking#:  
RV--MDS-PI-0645 
Original Protocol:  
08 JULY 2011 
AMENDMENT 1:   
05 DECEMBER 2013 
AMENDMENT 2:   
18 MARCH 2014 
AMENDMENT 3:  
07 January 2016 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless 
law or regulations require such disclosure.  Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by 
them. 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
Principal Investigator: 
  
 
 
 
 
 Signature of Investigator 
 
Date 
 Printed Name of Investigator 
 
 
 By my signature, I agree to personally supervise the conduct 
of this study and to ensure its conduct in compliance with the 
protocol, informed consent, IRB/EC procedures, instructions 
from Celgene representatives, the Declaration of Helsinki, 
ICH Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
 
 
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STUDY PERSONNEL 
 
Supporter: 
 
Celgene Corporation / GSK 
 
Study Location: 
 
ALBERT EINSTEIN COLLEGE OF MEDICINE 
Principal Investigator: 
 
AMIT VERMA, MD 
Co-Principal Investigator: 
 
ULRICH STEIDL, MD, PhD 
 
Sub-Investigators  
 
IRA BRAUNSCHWEIG, MD 
NOAH KORNBLUM,MD 
RAMAKRISHNA BATTINI, MD 
OLGA DERMAN, MD 
IOANNIS MANTZARIS, MD 
ADITI SHASTRI, MD  
SWATI GOEL, MD 
MARK CHAITOWITZ, MD 
MICHELLE ABREU, NP 
ARUN SUNNY, PA-C 
KAREN FEHN, RN 
Research Coordinators: 
 
 
JESSICA YU, M.S. 
LAWRENCE ALMANZAR, MPH 
AMBAR BAEZ, BS 
MARKENYA MIRANDER , BA 
Statistician: 
 
MIMI KIM 
PARTICIPATING 
INSTITUTIONS 
PI’s NAME 
Telephone 
Email 
UNIVERSITY OF 
KANSAS 
CANCER 
CENTER 
Yacoub Abdulraheem, 
MD 
(913)-588-6029 
ayacoub@kumc.edu 
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Table of Contents 
1 PROTOCOL SYNOPSIS .......................................................................................................... 6 
2 SCHEDULE OF STUDY ASSESSMENTS ............................................................................... 9 
3 BACKGROUND AND RATIONALE ...................................................................................... 12 
3.1 
Hypothesis...................................................................................................................... 12 
3.2 
Treatment of Thrombocytopenia in MDS or sAML/MDS ............................................ 12 
3.3 
Treatment of Thrombocytopenia in MDS or sAML/MDS with Eltrombopag .............. 13 
3.4 
Lenalidomide can result in transfusion independence in MDS but leads to a high rate of 
thrombocytopenia....................................................................................................................... 13 
3.5 
Rationale for combining lenalidomide and eltrombopag: .............................................. 14 
4 STUDY OBJECTIVES AND ENDPOINTS ............................................................................ 14 
4.1 
Objectives ...................................................................................................................... 14 
4.1.1 Primary Objectives ....................................................................................................... 14 
4.1.2 Secondary Objectives.................................................................................................... 15 
5 INVESTIGATIONAL PLAN ................................................................................................... 15 
5.1 
Overall design ................................................................................................................ 15 
5.2 
Protocol Therapy ............................................................................................................ 16 
5.2.1 
Lenalidomide Description ...................................................................................... 16 
5.2.2 
Eltrombopag Description ....................................................................................... 18 
6 SCREENING AND ELIGIBILITY .......................................................................................... 22 
6.1 
Inclusion Criteria ........................................................................................................... 22 
6.2 
Exclusion Criteria .......................................................................................................... 24 
6.3 
Visit schedule and assessments ...................................................................................... 24 
7 PATIENT REGISTRATION.................................................................................................... 25 
8 DRUG ADMINISTRATION ................................................................................................... 25 
8.1.1 
Dosing regimen ...................................................................................................... 25 
8.1.2 
Dose Modifications ................................................................................................ 25 
8.2 
SUPPORTIVE CARE .................................................................................................... 31 
8.3 
DURATION OF THERAPY ......................................................................................... 31 
8.4 
DURATION OF FOLLOW-UP ..................................................................................... 32 
8.5 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ....................... 32 
9 ADVERSE EVENTS ............................................................................................................... 34 
9.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for lenalidomide (NSC 
#703813) .................................................................................................................................... 34 
9.2 
Safety considerations with Eltrombopag: ...................................................................... 38 
10 REPORTING REQUIREMENTS ........................................................................................... 42 
10.1 
Definitions ...................................................................................................................... 42 
10.1.1 
Adverse Events ...................................................................................................... 42 
10.1.2 
Unanticipated Problem ........................................................................................... 42 
10.1.3 
Protocol Deviation ................................................................................................. 43 
10.1.4 
Protocol Exception ................................................................................................. 43 
10.1.5 
Systematic Data Collection Error........................................................................... 43 
10.2 
Reporting Events to IRB at Montefiore-Einstein ........................................................... 43 
10.2.1 
Expedited Reporting .............................................................................................. 43 
10.2.2 
Continuing Review Reporting ............................................................................... 44 
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10.3 
Reporting Events to Study Supporters (Celgene Corporation/ GSK) ............................ 44 
10.3.1 
GSK Reporting Requirements ............................................................................... 44 
10.3.2 
Celgene Reporting Requirements .......................................................................... 46 
10.4 
IND Safety Reports to the FDA (Refer to 21 CFR 312.32) ........................................... 49 
10.4.1 
FDA Annual Reports (Refer to 21 CFR 312.33) ................................................... 49 
11 RESPONSE CRITERIA .......................................................................................................... 50 
12 DATA MANAGEMENT .......................................................................................................... 52 
12.1 
Analyses and Reporting ................................................................................................. 52 
12.2 
Study auditing ................................................................................................................ 52 
12.2.1 
Investigator responsibilities ................................................................................... 52 
13 DATA SAFETY AND MONITORING BOARDS .................................................................... 52 
14 BIOSTATISTlCAL ANALYSIS ................................................................................................ 53 
14.1 
Safety evaluation ............................................................................................................ 53 
14.2 
Sample size and power considerations ........................................................................... 53 
15 REGULATORY CONSIDERATIONS ..................................................................................... 54 
15.1 
Institutional Review Board/Ethics Committee approval ................................................ 54 
15.2 
Protocol amendments ..................................................................................................... 54 
15.3 
Continuing Review ........................................................................................................ 55 
15.4 
Deviations and Exceptions ............................................................................................. 55 
15.5 
Informed consent ........................................................................................................... 55 
15.6 
Subject confidentiality ................................................................................................... 55 
15.7 
Study records requirements ............................................................................................ 56 
15.8 
Premature discontinuation of study ................................................................................ 56 
16 CORRELATIVE STUDIES:.................................................................................................... 56 
17 REFERENCES ....................................................................................................................... 58 
 
 
 
Appendix 1: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth  
                    Control Methods  
 
 
 
Appendix 2: ECOG Performance Status Scale  
 
 
 
Appendix 3: Cockcroft-Gault estimation of CrCL 
Appendix 4: International Prognostic Scoring System (IPSS) for MDS 
Appendix 5: NCI CTC Version 4.0 
Appendix 6: Correlative Studies 
 
 
 
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1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE:PHASE II STUDY OF LENALIDOMIDE AND ELTROMBOPAG IN 
PATIENTS WITH SYMPTOMATIC ANEMIA IN LOW OR INTERMEDIATE I 
MYELODYSPLASTIC SYNDROME (MDS) 
DATE PROTOCOL FINAL: 
08 JULY 2011 
INDICATION: 
MDS 
STUDY PHASE: 
Phase II 
BACKGROUND AND RATIONALE:The rationale for this studyis that combined treatment with 
eltrombopag (PROMACTA) and lenalidomide (REVLIMID) will reduce the incidence of 
lenalidomide induced thrombocytopenia thus enabling patients to tolerate the required duration of 
lenalidomide therapy leading to higher rates of response to lenalidomide. A major reason why 
lenalidomide cannot be used for the treatment of MDS is because of the occurrence of 
thrombocytopenia. The use of eltrombopag will potentially raise platelet counts in these patientsand 
enable a longer exposure to lenalidomide.  Secondly, thrombocytopenia in the first 2 months after 
lenolidomide therapy predicts the subsequent response to lenalidomide treatment in patients with low 
risk MDS Thus raising platelet counts to enable continuation of Lenalidomide therapy is important in 
these patients. Lastly, an increase in blasts has been a potential concern with the use of 
thrombopoietin mimetics. Preclinical studies have indicated that eltrombopag is less likely to increase 
blasts thus making it a possible potential therapeutic candidate in low risk MDS.  
STUDY OBJECTIVES: 
Primary Objectives: 
To evaluate the rate of hematologic improvement of the eltrombopag/lenalidomide combination as 
defined by the IWG 2006 criteria  
To evaluate the safety and tolerability of the eltrombopag/lenalidomide combination in patients with 
low –intermediate risk MDS 
 
Secondary Objectives 
To compare the time to hematologic improvement 
To evaluate the duration of hematologic improvement 
To evaluate the effect of combination treatment on platelet counts, platelet transfusions.and bleeding 
events. 
To evaluate the frequency of bone marrow response (CR+PR) and cytogenetic response. 
To evaluate the relationship between mutations in bone marrow stem cells and response 
To evaluate the relationship between various stem and progenitor alterations and response 
 
 
STUDY DESIGN: 
This is a multicenter, phase II study evaluating the efficacy and safety of the combination of 
lenalidomide and eltrombopag in low risk MDS.  
 
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Patients will be treated based on their baseline platelet counts: 
 
Arm A: Patients with platelet counts >=50k at baseline:  
These patients will start Len at 10mg/d for 3 weeks/month, and will not start eltrombopag until the 
platelet counts drop below 50,000. If platelets drop less than 50,000, Len will be stopped and 
eltrombopag will be started at a dose of 100mg initially (50 mg for subjects of East Asian heritage) 
and titrated up to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage) to achieve 
a platelet count above 50,000/L. Once a platelet count above 50,000 is achieved, the same dose of 
eltrombopag will be continued for an additional two weeks. Once a platelet count > 50,000 is 
maintained for two weeks, eltrombopag will be discontinued and Len will be started as a single agent. 
If the platelets again fall below 50,000 then Len will stopped and  eltrombopag will be re-initiated at 
the dose that was last given to the patient. Once the platelets are increased to above 50,000 and 
maintained at this level for 2 weeks, Len will be started again and this time will be given concurrently 
with eltrombopag. These agents will subsequently be used concurrently for all subsequent cycles.  
 
Arm B: Patients with Plts <50k at baseline  
These patients will not receive Len initially. Eltrombopag will be started alone at a dose of 100mg 
initially and titrated up (Table 4) to achieve a platelet count above 50,000. Once the platelet count 
above 50,000 is achieved, the same dose of eltrombopag will be continued for an additional two 
weeks. Once the plt count > 50,000 is maintained for two weeks, the patients will discontinue 
eltrombopag and follow the treatment algorithm described for patients in arm A.  
 
 
 
 
Figure 1: Schema of the study (* starting dose of Eltrombopag for Asian subjects is 50mg) 
STUDY ENDPOINTS 
Primary: 
Hematologic improvement 
Lenalidomide 10mg po/day x 21 
days. Repeat cycle every 28 days 
for 4 cycles (16 weeks)
Stop Eltrombopag
Start Lenalidomide 10mg po/day x 
21 days. Repeat cycle every 28 
days for 4 cycles (16 weeks)
Eltrombopag .50mg po qday till plt
> 50,000/l for 2 weeks
PLATELET COUNT < 
50,000/l
PLATELET COUNT 
>=  50,000/l
MDS (LOW/Int-1)
Symptomatic with 
Hgb < 9.5 OR
RBC Transfusion 
dependant
If PLATELET COUNT 
< 50,000/l
If PLATELET COUNT 
< 50,000/l
Continue Eltrombopag
Add Lenalidomide 10mg po/day x 
21 days. Repeat cycle every 28 
days for 4 cycles (16 weeks)
Eltrombopag .50mg po qday till plt
> 50,000/l for 2 weeks
Achieve Major Erythroid response
Do not Achieve Major Erythroid 
response
Continue till Relapse / Progression
Discontinue Treatment 
100mg* 
100mg* 
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Secondary: 
Time to attain and duration of hematologic improvement 
Bone marrow morphologic and cytogenetic response 
Platelet counts and Bleeding events 
 
STUDY DURATION:2 years 
TOTAL SAMPLE SIZE:52patients 
DOSING REGIMEN(S): 
The lenalidomide starting dose will be based on 
baseline calculated creatinine clearance (see 
Appendix 3). Eltrombopag starting dose will be 
100mg (50mg for patients with east Asian 
descent) and dosing will be based on regimen as 
detailed in protocol. 
DRUG SUPPLIES: 
For study participants, Celgene Corporation will 
provide lenalidomide at no charge through the 
Revlimid REMS™program.  GSK will provide 
eltrombopag at no charge. 
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2 
SCHEDULE OF STUDY ASSESSMENTS 
  
Screening 
Assessment 
(30 days 
prior to 
initiation) 
Weekly  
Every 28 
days (Day 1 
of each 
cycle) 
Week 16 and 
treatment 
discontinuati
on 
Follow up 
11 
Medical History 
x 
 
 
 
 
Prior 
MDSTreatment  
x 
 
 
 
 
ECOG Performance 
Status  
x 
X8 
x 
 
 
Pregnancy test 1  
x 2 
 
x3 
X 
 
Serum ferritin level  
x 
 
 
X 
 
Serum 
erythropoietin 
x 
 
 
 
 
Thyroid function 
tests 4 
x 
 
 
X 
 
aaPT/PTT/INR 
x 
 
 
 
 
Serum chemistry 5 
x 
X8 
x 
X 
 
Hematology, 
peripheral blood 
smear and RBC 
transfusion history 6  
x 7 
x8 
x 
X 
 
x 
Physical 
examination  
x 
 
x 
x 
 
x 
 
ECG  
x 
x 12 
Review medication 
log  
 
 
 
x 
 
 
Response 
 
 
 
x 
 
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assessment 9 
Bone marrow 
aspirate & biopsy10 
x 
 
 
x 
 
Cheek swab and toe 
nail clipping 
x 
 
 
 
 
1. Women of childbearing potential only. Serum or urine pregnancy testing for β-HCG 
with a sensitivity of at least 50 mIU/mL. For further requirements for pregnancy testing 
and birth control, please see Appendix 1. 
2. Within 7 days prior to the first day of study therapy. 
3. Every 4 weeks while on study drug. 
4. TSH (thyroid-stimulating hormone), T3, and T4 levels. Repeat thyroid function tests 
every three months. 
5. Includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood 
urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, aspartate transaminase (SGOT/AST) or glutamic pyruvic transaminase 
(SGPT/ALT), lactate dehydrogenase (LDH), and uric acid. 
6. Red blood cell (RBC) count, reticulocyte count, hemoglobin, hematocrit, white blood 
cell (WBC) count and differential, absolute neutrophil count (ANC), and platelet count 
required for protocol therapy must be done < 24 hours prior to the treatment cycle. 
Pretreatment CBC with differential and LFT’s should be done < 1 week before 
randomization. 
 
7. If not obtained within 7 days of the first day of study therapy, repeat the CBC on Day 
0 of study treatment prior to start of study therapy. 
8. Perform weekly for 4 weeks, then every 2 weeks for 5 to 8 weeks and monthly 
thereafter. Weekly CBC should be done when titrating or starting eltrombopag dosing 
until a stable platelet count is achieved. 
9. Hematologic, pathologic, and cytogenetic response will be assessed according to 
criteria outlined in Section 6.1.2. 
10. Bone marrow aspirate and biopsy with cytogenetic analysis and iron stains will be 
performed pre-study, and after 16 weeks of study treatment, and at the time of final 
response analysis. Additional biological studies obtained with bone marrow aspiration 
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are summarized in Section 14. 
11. Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-
5 years from study entry, every 12 months if patient is 5-10 years from study entry. No 
specific requirements if patient is more than 10 years from study entry. 
12. Only for patients receiving  300 mg eltrombopag dose or higher, resting 12-lead ECG 
will be obtained pre-dose on Day 1. A post-dose ECG should be obtained at Tmax (3 
hours); if assessment cannot be performed at 3 hours, record actual time ECG was 
performed within a 2-6 hour window post-dose. A pre- and post-dose ECG as described 
above is required   Week 2, week 4, 8 and 16. 
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3 
BACKGROUND AND RATIONALE 
3.1 Hypothesis 
 
Combined treatment with eltrombopag (EP) and lenalidomide (CC-5013;REVLIMID) 
will reduce the incidence of thrombocytopenia due to Lenalidomide and enable patients 
to tolerate duration of therapy leading to higher rates of response. 
 
3.2 Treatment of Thrombocytopenia in MDS or sAML/MDS 
In a review of patients with MDS referred to the M. D. Anderson Cancer Center, the 
incidence of life-threatening thrombocytopenia was 16-40% depending on the MDS 
risk status, with a median survival of only 6 to 12 months.  The incidence of 
thrombocytopenia increases with disease progression, and without effective therapies, 
some patients may experience life-threatening bleeding(1) 
In MDS, the disease clone includes the megakaryocytic lineage.  Megakaryocytes from 
patients with MDS show impaired proliferation and differentiation, thus causing 
thrombocytopenia (2).  Additional aspects potentially contributing to thrombocytopenia 
in MDS are premature cell death of megakaryocytes and decreased platelet life span(3).  
Interestingly, these aspects can be observed in both patients with MDS, and patients with 
Idiopathic Thrombocytopenic Purpura (ITP).  In MDS, the megakaryocytic proliferation 
is unresponsive to recombinant thrombopoietin (TPO), possibly due to deregulated TPO-
receptor-mediated signaling(4) .  In addition to the qualitative disturbance of the TPO-
receptor, there is also a quantitative disturbance in terms of the number of TPO receptors, 
which show a reduced expression by 50% on MDS platelets, as well as on CD41+ and 
CD34+ cells as compared to normal cells.  However, an in vitro study showed that 
CD61+ cells in suspension cultures increased with PEG-rHuMGDF (pegylated 
recombinant human MGDF)alone in 31 out of 39 patient samples from MDS patients (5).  
The clinical development of PEG-rHuMGDF was aborted owing to the development of 
cross-reacting autoantibodies against endogenous TPO.  More recently, Phase II data 
were presented for another TPO-R agonist, romiplostim, which showed efficacy in 41% 
of the patients with low- or intermediate-1 risk MDS (6)  However, few patients showed 
some direct or indirect evidence for disease progression [FDA Oncology Drug Advisory 
Committee Meeting, March 2008].   
 
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3.3 Treatment of Thrombocytopenia in MDS or sAML/MDS with Eltrombopag 
Eltrombopag is an orally available, non-peptide TPO-receptor (TPO-R) agonist that 
stimulates platelet production by a mechanism similar, but not identical to endogenous 
TPO.  Eltrombopag has been investigated at dose ranges of up to 200 mg daily for 5 
days in healthy volunteers, and a dose-platelet response relationship was observed.  In 
ITP, patients received up to 75 mg daily, and response rates were 28% with 30 mg, 
67% with 50 mg, and 86% with 75 mg (response defined as a platelet count >50 Gi/L; 
the studied patients had platelet counts <30 Gi/L).  The safety profile was similar to 
placebo (7).  The positive results with eltrombopag in ITP are encouraging but the 
required dose and response in MDS are unknown.  A phase I/II study in high risk MDS 
is presently evaluating the efficacy of eltrombopag at different doses with dose 
escalations of up to 300 mg. 
 
It is theoretically possible that eltrombopag could worsen the disease in patients with 
MDS.  However, in vitro preclinical studies in leukemia and lymphoma cell lines 
indicate that eltrombopag does not stimulate leukemia cell growth.  In contrast to TPO, 
it may in fact suppress leukemic cell growth, as evidenced by the fact that 12 out of 14 
leukemic/lymphoid cell lines tested demonstrated decreased proliferation when treated 
with eltrombopag, with an IC50 of 0.5 to 15 g/mL.  This effect occurs even in the 
presence hematopoietic cytokines. (8-11).  There is additional evidence from an ex vivo 
study indicating that eltrombopag does not stimulate leukemic cell growth.  In 7 out of 
7 BM specimens taken from patients with MDS or AML secondary to MDS, no 
increase in proliferation due to co-incubation with eltrombopag was seen (12).  
 
3.4 Lenalidomide can result in transfusion independence in MDS but leads to a 
high rate of thrombocytopenia 
Ineffective erythropoiesis remains the hallmark of myelodysplastic syndromes (MDS) 
forwhich few treatments offer sustained erythropoietic improvement (13). Lenalidomide) 
(CC-5013; REVLIMID) is an oral 4-amino glutarimide derivative of thalidomide that 
lacks the neurological toxicities of the parent compound. In a safety and efficacy study 
(MDS-001) investigating erythroid response to CC-5013 (lenalidomide) monotherapy in 
43 patients with MDS, CC-5013 (lenalidomide) yielded a high frequency of major 
erythroid response (MER) in patients that had either failed prior treatment with 
erythropoietin or had high endogenous levels and high transfusion burden (14). Patients 
received treatment with one of three CC-5013 (lenalidomide) dose schedules, 25 or 10 
mg daily, or 10 mg/day x 21 days every 4 weeks. Neutropenia (67%) and 
thrombocytopenia (57%) > grade 3 NCI-CTC version 2.0 were dose limiting, 
necessitating treatment interruption and dose-reduction in 25 (61%) patients. Other 
adverse effects were infrequent and of mild to moderate severity including pruritus, 
fatigue, diarrhea, edema,thyroid dysfunction and joint discomfort. Among the 36 patients 
completing more than one cycle of treatment, 24 (67%) experienced an erythroid 
response according to International Working Group (IWG) criteria. MER defined by 
sustained transfusion-independence (> 8 weeks) or a rise in hemoglobin >2 g/dl was 
achieved in 21 patients and 3 patients experienced a >50% reduction in red blood cell 
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(RBC) transfusions. Response rate was highest among evaluable patients with a 
chromosome 5q31.1 deletion (91%) compared tothose with a normal karyotype (68%) or 
other chromosome abnormality (17%) [P=0.009],and response rate was higher in patients 
with lower (Low-/Intermediate-1) InternationalPrognostic Scoring System (IPSS) risk 
categories (72% vs. 25%) [P=0.098] (15). Eleven of17 (65%) patients with karyotypic 
abnormalities had a 50% or greater reduction in abnormalmetaphases, including ten 
(57%) complete cytogenetic remissions. After a median follow-upof 109 weeks in 
November 2004, median duration of transfusion-independence had notbeen reached (81+; 
range, 19 to >128 weeks) with a median sustained hemoglobin (Hgb) of13.4 g/dL (range, 
11.5-15.8 g/dL) and median Hgb rise of 5.6 g/dL. The results of this studyindicate that 
CC-5013 (lenalidomide) has significant and sustained erythropoietic andcytogenetic 
remitting activity in patients with Low/Intermediate-1 IPSS risk MDS that havefailed or 
are unlikely to benefit from conventional cytokine therapy.Two phase II multicenter trials 
were completed in the past year, evaluating the frequency ofMER to lenalidomide in 
patients with transfusion-dependent Low/Int-1 risk MDSwith (MDS-003; N=148) or 
without a chromosome 5q31.1 deletion (MDS-002; N=215).Intent-to-treat analysis of the 
data confirm the high response rate in patients with del 5q31.1(MER 66%, MER + Minor 
erythroid response 75%, cytogenetic response 70%) compared toa MER rate of 27% and 
Minor + MER rate of 44% in the MDS-002 results (15, 16). Grade 3or greater 
neutropenia or thrombocytopenia were the principal reasons for treatment interruption 
and dose-reduction. 
 
3.5 Rationale for combining lenalidomide and eltrombopag: 
 
The rationale for combination is based on the following: 
 
1. A major reason why lenalidomide cannot be used in MDS is because of the occurrence 
of thrombocytopenia. The use of EP will potentially raise platelet counts in these patients. 
 
2. Thrombocytopenia in the first 2 months after Len therapypredicts the subsequent 
response to lenalidomide treatment in patients with low risk MDS (17)Thus raising 
platelet counts to enable continuation of lenalidomide therapy is important in these 
patients.  
 
3. An increase in blasts has been a potential concern with the use of  thrombopoietin 
mimetics and has been reported in a study with romiplostim (6) Preclinical studies have 
indicated that  eltrombopag is less likely to increase blasts thus making it a possible 
potential therapeutic candidate in low risk MDS(12). 
4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 Objectives 
 
4.1.1 Primary Objectives 
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 To 
evaluate 
the 
rate 
of 
hematologic 
improvement 
of 
the 
eltrombopag/lenalidomide combination (as per Modified IWG criteria) 
 To evaluate the safety and tolerability of the combination 
 
4.1.2 Secondary Objectives 
 
 To compare the time to hematologic improvement 
 To evaluate the duration of hematologic improvement 
 To evaluate the effect of combination treatment on platelet counts, platelet 
transfusions.and bleeding events. 
 To evaluate the frequency of bone marrow response (CR+PR) and cytogenetic 
response. 
 To evaluate the relationship between mutations in bone marrow stem cells and 
response 
 To evaluate the relationship between various stem and progenitor alterations and 
response 
5 
INVESTIGATIONAL PLAN 
5.1 Overall design 
 
This is a multicenter, Phase II study evaluating the efficacy and safety of the 
combination of lenalidomide and eltrombopag in low risk MDS. This study will 
include patients with low risk MDS (IPSS low and Int-1) with symptomatic anemia 
or transfusion dependence. Patients will be treated in 2 separate arms based on 
their baseline platelet counts: 
 
Arm A : Patients with platelet counts >=50k at baseline:  
These patients will start Len at 10mg/d for 3 weeks/month, and will not start 
Eltrombopag until the platelet counts drop below 50,000. If platelets drop less than 
50,000, Len will be stopped and Eltrombopag will be started at a dose of 100mg 
initially and titrated up (similar schema to 509 study) to achieve a platelet count 
above 50,000. Once the platelet count above 50,000 is achieved, the same dose of 
Eltrombopag will be continued for an additional two weeks. Once a platelet count > 
50,000 is maintained for two weeks, Eltrombopag will be discontinued and Len will 
be started as a single agent. If the plts again fall below 50k then Len will stopped and  
Eltrombopag will be re-initiated at the dose that was last given to the patient. Once 
the platelets are increased to above 50,000 and maintained at this level for 2 weeks, 
Len will be started again and this time will be given concurrently with Eltrombopag. 
These agents will now be used concurrently for all subsequent cycles.  
 
Arm B: Patients with Plts <50k at baseline  
These patients will not receive Len initially. Eltrombopag will be started alone at a 
dose of 100mg initially and titrated up (similar schema to 509 study) to achieve a 
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platelet count above 50,000. Once the platelet count above 50,000 is achieved, the 
same dose of eltrombopag will be continued to additional two weeks. Once the plt 
count > 50,000 is maintained for two weeks, the patients will discontinue 
eltrombopag and follow the treatment algorithm described for patients in arm A. 
Patients that never drop their platelet counts below 50,000 will not receive any 
additional eltrombopag. (Figure 1) 
 
Treatment with myeloid growth factors is permittedfor the management of 
neutropenia atthe discretion of the treating investigator. 
 
Study drugs will be continued until disease progression or unacceptable toxicities. 
 
Bone marrow examinations will be performed at baseline, at every 4 months and at 
study discontinuation. 
 
52 evaluable adult subjects with MDS will be evaluated. 
 
5.2 Protocol Therapy 
5.2.1 Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
 
Figure 2: Structure of lenalidomide: 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) 
piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
CLINICAL PHARMACOLOGY 
N
N
H
O
O
O
NH2
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Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide 
possesses 
immunomodulatory 
and 
antiangiogenic 
properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the 
secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells.  
Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in some but 
not all cell lines.  Of cell lines tested, lenalidomide was effective in inhibiting growth of 
Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) 
but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell 
line, also with a deletion of one chromosome 5) and other cell lines without chromosome 
5 deletions.(18, 19)  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-
2) but not COX-1 in vitro. 
Pharmacokinetics and Drug Metabolism: 
Absorption:Lenalidomide, in healthy volunteers, is rapidly absorbed following oral 
administration with maximum plasma concentrations occurring between 0.625 and 1.5 
hours post-dose. Co-administration with food does not alter the extent of absorption 
(AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The 
pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC increase 
proportionately with increases in dose. Multiple dosing at the recommended dose-
regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 
25mg, and 50mg).  No plasma accumulation was observed with multiple daily dosing.  
Plasma lenalidomide declined in a monophasic manner with elimination half-life ranging 
from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses.  Peak and overall plasma 
concentrations were dose proportional over the dosing range of 5mg to 50mg.  Exposure 
(AUC) in multiple myeloma patients is 57% higher than in healthy male volunteers.  
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through 
urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active.  Half-life of elimination is approximately 3 hours. 
As the majority of lenalidomide is excreted unchanged by the kidney (where OATP1B1 
and BCRP are not involved in xenobiotic excretion), no pharmacokinetic interactions 
between lenalidomide and eltrombopag are expected. 
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Supplier(s) 
Celgene Corporation will supply Revlimid®(lenalidomide) to study participants at no 
charge through the Revlimid REMS™program. 
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
Packaging 
Lenalidomide will be shipped to the clinic site for IND studies.   Bottles will contain a 
sufficient number of capsules for one cycle of dosing.    
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
Prescribing Information  
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide 
will be provided in accordance with the Revlimid REMS™program of Celgene 
Corporation.  Per standard Revlimid REMS™requirements all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in and must comply with all requirements of the 
Revlimid REMS™program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for 
IND studies. Only enough lenalidomide for one cycle of therapy will be supplied to 
the patient each cycle. 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® 
program material. 
 
 
5.2.2 Eltrombopag Description 
Promacta®  (Eltrombopag),is an agonist of the thrompoietin receptor that stimulates 
platelet production.   The chemical name is 3'-(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-
5-oxo- 1,5-dihydro-4H-pyrazol-4-ylidene] hydrazino-2'-hydroxy-3-biphenylcarboxylic 
acid -2-aminoethanol and it has the following chemical structure:  
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Chemical Structure of Eltrombopag 
 
 
Figure 3: Eltrombopag (3'-(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-
4H-pyrazol-4-ylidene] hydrazino-2'-hydroxy-3-biphenylcarboxylic acid -2-aminoethanol) 
The empirical formula for eltrombopag is C25 H22 N4 O4 . 2 (C2 H7 N O) and its 
molecular weight is 564.65.  
Eltrombopag is ared/brown solid and is practically insoluble in aqueous buffer across a 
pH range of 1 to 7.4, and is sparingly soluble in water.  
CLINICAL PHARMACOLOGY 
Mechanism of Action:  
Eltrombopag olamine, the bis-monoethanolamine salt form of eltrombopag, is an 
orallybioavailable, 
small 
molecule 
thrombopoietin 
receptor 
(TPO-R) 
agonist. 
Eltrombopagfunctions in a similar manner to endogenous thrombopoietin (TPO), 
inducingproliferation and differentiation of megakaryocytes from bone marrow 
progenitor cells. 
Pharmacokinetics and Drug Metabolism: 
Absorption and Bioavailability 
Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after 
oraladministration. Administration of eltrombopag concomitantly with antacids and 
otherproducts containing polyvalent cations such as dairy products and mineral 
supplementssignificantly reduces eltrombopag exposure.The absolute oral bioavailability 
of eltrombopag after administration to humans has not been established. Based on urinary 
excretion and metabolites eliminated in faeces, the oral absorption of drug-related 
material following administration of a single 75 mg eltrombopag solution dose was 
estimated to be at least 52 %. 
 
Distribution 
Eltrombopag is highly bound to human plasma proteins (> 99.9 %). Eltrombopag is 
asubstrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. 
 
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Metabolism 
Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation 
withglucuronic acid, glutathione, or cysteine. In a human radiolabel study, 
eltrombopagaccounted for approximately 64 % of plasma radiocarbon AUC0-∞. Minor 
metabolites,each accounting for < 10 % of the plasma radioactivity, arising from 
glucuronidation andoxidation were also detected. Based on a human study with radiolabel 
eltrombopag, it isestimated that approximately 20 % of a dose is metabolised by 
oxidation. In vitro studiesidentified CYP1A2 and CYP2C8 as the isoenzymes responsible 
for oxidativemetabolism, uridine diphosphoglucuronyl transferase UGT1A1 and 
UGT1A3 as theisozymes responsible for glucuronidation, and that bacteria in the lower 
gastrointestinaltract may be responsible for the cleavage pathways. 
 
Elimination 
Absorbed eltrombopag is extensively metabolised. The predominant route of 
eltrombopag excretion is via faeces (59 %) with 31 % of the dose found in the urine 
asmetabolites. Unchanged parent compound (eltrombopag) is not detected in 
urine.Unchanged eltrombopag excreted in faeces accounts for approximately 20 % of the 
dose.The plasma elimination half-life of eltrombopag is approximately 21-32 hours. 
 
Special Patient Populations 
 
Renal Impairment 
The pharmacokinetics of eltrombopag has been studied after administration 
ofeltrombopag to adult patients with renal impairment. Following administration of a 
single50 mg-dose, the AUC0-∞of eltrombopag was decreased by 32 % (90 % CI: 63 
%decrease, 26 % increase) in patients with mild renal impairment, 36 % (90 % CI: 66 
%decrease, 19 % increase) in patients with moderate renal impairment, and 60 % (90 % 
CI:18 % decrease, 80 % decrease) in patients with severe renal impairment compared 
withhealthy volunteers. There was a trend for reduced plasma eltrombopag exposure 
inpatients with renal impairment, but there was substantial variability and 
significantoverlap in exposures between patients with renal impairment and healthy 
volunteers.Patients with impaired renal function should use eltrombopag with caution and 
closemonitoring. 
 
Hepatic Impairment 
The pharmacokinetics of eltrombopag has been studied after administration of 
eltrombopag to adult subjects with liver cirrhosis (hepatic impairment). Following 
theadministration of a single 50 mg dose, the AUC0-∞of eltrombopag was increased by 
41 %(90 % CI: 13 % decrease, 128 % increase)in subjects with mild hepatic impairment, 
93 %(90 % CI: 19 %, 213 %) in subjects with moderate hepatic impairment, and 80 % 
(90 %CI: 11 %, 192 %) in subjects with severe hepatic impairment compared with 
healthyvolunteers. There was substantial variability and significant overlap in exposures 
betweensubjects with hepatic impairment and healthy volunteers.The influence of hepatic 
impairment on the pharmacokinetics of eltrombopag followingrepeat administration was 
evaluated using a population pharmacokinetic analysis in 28healthy adults and 79 
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patients with chronic liver disease. Based on estimates from thepopulation 
pharmacokinetic analysis, patients with liver cirrhosis (hepatic impairment)had higher 
plasma eltrombopag AUC(0-τ) values as compared to healthy volunteers, andAUC(0-τ) 
increased with increasing Child-Pugh score. Compared to healthy volunteers,patients 
with mild hepatic impairment had approximately 87 % to 110 % higher 
plasmaeltrombopag AUC(0-τ) values and patients with moderate hepatic impairment 
hadapproximately 141 % to 240 % higher plasma eltrombopag AUC(0τ) values.Patients 
with liver cirrhosis (hepatic impairment) should use eltrombopag with cautionand close 
monitoring.  
 
Race 
The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag 
wasevaluated using a population pharmacokinetic analysis in 111 healthy adults (31 
EastAsians) and 88 patients with ITP (18 East Asians). Based on estimates from 
thepopulation pharmacokinetic analysis, East Asian (i.e. Japanese, Chinese, Taiwanese 
andKorean) ITP patients had approximately 87 % higher plasma eltrombopag AUC(0-
τ)values as compared to non-East Asian patients who were predominantly 
Caucasian,without adjustment for body weight differences. 
 
Gender 
The influence of gender on the pharmacokinetics of eltrombopag was evaluated using 
apopulation pharmacokinetic analysis in 111 healthy adults (14 females) and 88 
patientswith 
ITP 
(57 
females). 
Based 
on 
estimates 
from 
the 
population 
pharmacokineticanalysis, female ITP patients had approximately 50 % higher plasma 
eltrombopagAUC(0-τ) as compared to male patients, without adjustment for body weight 
differences. 
Supplier(s) 
GSK will supply eltrombopag for study participants at no charge. 
Dosage form 
Eltrombopag will be supplied as tablets for oral administration.   
 
Packaging and Labeling 
The tablets will be packaged in white opaque, HDPE bottles with child resistantclosures. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Tablets will be provided to the sponsor-investigator by GSK.  The tablets provided would 
be as follows:  25mg, 50mg, 75mg and 100mg SB497115: A white to off-white 13/32" 
standard round tablet 
 
Pharmaceutical Information  
 
GlaxoSmithKline Document Number UM2005/00217/05. Clinical Investigator’s 
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Brochure for SB496115-GR. Version 07. Effective date March 03, 2010. 
 
 
6 
SCREENING AND ELIGIBILITY 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Schedule of Study Assessments and unless otherwise specified, must take place within 28 
days prior to initiation of therapy.  
Approximately 52 subjects with Low / Int-1 MDS will be screened for enrollment and 
must meet the eligibility criteria below. 
6.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
1 Age ≥ 18 years. 
 
2.  Patient must have a documented diagnosis of MDS according to World Health 
Organization (WHO) criteria (see Appendix IV) or non-proliferative chronic 
myelomonocytic leukemia (CMML) (WBC ≤ 12,000/ul). 
 
3.  Patients must have International Prognostic Scoring System (IPSS) categories ofLow- 
or Intermediate-1-risk disease (see Appendix 4). 
 
4.Patients must have symptomatic anemia untransfused with hemoglobin ≤  
10.0g/dLwithin 8 weeks of registration or with RBC transfusion-dependence (i.e., ≥ 2 
units/month) confirmed for a minimum of 8 weeks before randomization. Or patients 
have platelet <50,000/uL with hemoglobin > 10.0 g/dL. 
 
5.  Patients must have IPSS score determined by cytogenetic analysis prior to 
randomization. Patients with cytogenetic failure and ≤ 10% marrow blasts will be 
eligible. 
 
6.  Patients must be off all disease modifying therapy for MDS for 28 days prior to 
initiation of study treatment. Patients may receive hydrocortisone prophylactically to 
prevent transfusion reactions. 
 
7.  Patients must not have documented iron deficiency. All patients must 
havedocumented marrow iron stores. If marrow iron stain is not available, thetransferrin 
saturation must be ≥ 20% or a serum ferritin ≥ 100 ng/100 mL or soluble transferring 
receptor < 5mg/L. 
 
8.  Women must not be pregnant or breastfeeding. Females of childbearing 
potentialshould have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The 
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firsttest should be performed within 10-14 days, and the second test within 24 hoursprior 
to prescribing lenalidomide. 
 
9.Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. Able to take aspirin (81 or 325 mg) daily as 
prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low 
molecular weight heparin). 
 
 
10.  Women of childbearing potential and sexually active males must agree to use 
2methods of an accepted and effective method of contraception and counseled onthe 
potential teratogenic effects of lenalidomide. Effective contraceptionmust be used by 
patients for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide 
therapy, during doseinterruptions and for 4 weeks following discontinuation of 
lenalidomidetherapy. Reliable contraception is indicated even where there has been a 
history ofinfertility, unless due to hysterectomy or because the patient has 
beenpostmenopausal naturally for at least 24 consecutive months. Two reliable forms 
ofcontraception 
must 
be 
used 
simultaneously 
unless 
continuous 
abstinence 
fromheterosexual sexual contact is the chosen method. Females of childbearingpotential 
should be referred to a qualified provider of contraceptive methods, ifneeded. Sexually 
mature females who have not undergone a hysterectomy or whohave not been 
postmenopausal naturally for at least 24 consecutive months (i.e.,who have had menses at 
some time in the preceding 24 consecutive months) areconsidered to be females of 
childbearing potential.It is not known whether CC-5013 (lenalidomide) is present in the 
semen of patientsreceiving the drug. Therefore, males receiving CC-5013 (lenalidomide) 
must alwaysuse a latex condom during any sexual contact with females of childbearing 
potentialeven if they have undergone a successful vasectomy. 
 
11.  Patients must not have received prior therapy with lenalidomide (for more than 2 
months) nor eltrombopag. 
 
12.  Patients must not have uncontrolled hypertension 
 
 
 
13. 
ECOG Performance 0-3 (ECOG).   
14. Subject is able to understand and comply with protocol requirements and 
instructions. 
15. Patient has signed and dated informed consent. 
 
16. 
Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) 
must be within 80 to 120% of the normal range at baseline. 
 
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17. 
All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of the REMS® 
program. 
 
 
6.2 Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
1. Pre-existing cardiovascular disease (including congestive heart failure, New York 
Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk 
of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 
msec (Male ) and QTc > 470 msec  (Female). Patients with history of atrial 
fibrillations or arrhythmias may be considered if in normal sinus rhythm at the time 
of registration and if cardiac echocardiogram shows no evidence of any cardiac 
thrombus. 
 
2. Patients determined to be at increased risk of arterial or venous thrombosis by the 
investigator 
 
3. Bone marrow fibrosis that leads to a dry tap. 
 
4. Female subjects who are nursing or pregnant (positive serum or urine -human 
chorionic gonadotropin (-hCG) pregnancy test) at screening or pre-dose on Day 1. 
 
5. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is 
longer) preceding the first dose of study medication. 
 
6. Patients with documented liver cirrhosis 
 
 
 7.  Patients with known Splenic Vein Thrombosis. 
6.3 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in 
Section 2 Table of Study Assessments.  
At treatment discontinuation, subjects will undergo off study evaluations per the 
Schedule of Assessments, Section 2.   In addition, a safety assessment will be done 
approximately 28 days post the last dose of protocol therapy.  
 
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7 
PATIENT REGISTRATION 
Central registration for this study will take place at the Montefiore-Einstein Center 
Monday through Friday 9:00am – 5:00pm Eastern Standard Time. Eligibility Checklist 
with supporting documentation, On Study Form and the signed Patient Consent Form 
must be faxed to the clinical trials office at the Montefiore-Einstein Center, Fax:  718-822 
-0335, at the time of registration and prior to patient treatment. 
At the time of registration, all eligibility criteria must be checked. Patients must meet all 
of the eligibility requirements listed in the Eligibility Checklist. Patients must not start 
protocol treatment prior to registration. 
It is the treating physician’s responsibility to review all data submitted to the Clinical 
Trials Office for accuracy and completeness and he/she must sign the off study form. 
 
8 
DRUG ADMINISTRATION 
8.1.1 Dosing regimen 
 
All toxicities should be graded according to the Common Terminology Criteria for 
Adverse Events (NCI CTC ver4.03). For patients who experience treatment delays due to 
toxicity, finalresponse assessment will be delayed according to the number of 28 day 
cycles off of studytreatment.  
 
Subjects will be evaluated for adverse events (AEs) at each visit. 
8.1.2 Dose Modifications 
 
Dose Reductions for lenalidomide 
Table 1 gives the dose levels for the dose reduction steps for adverse events. 
 
Table 1: Dose Reduction Steps for lenalidomide 
 
Starting dose 10 mg/day on days 1-21, followed by 7 days of no therapy  
Dose level -1  5 mg daily  
Dose level -2  5 mg every other day (qod) 
 
Patients who experience limiting neutropenia after prolonged treatment with 5 mg 
every other day may resume treatment at the same dose upon hematologic 
recovery. 
 
Dose Modifications for Neutropenia 
Hold lenalidomide for a decline in neutrophil count to < 500/µL that does not respond to 
myeloid growth factor administration. Lenalidomide should be resumed at thenext dose 
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reduction step when neutrophil count is > 500/µL.Dose Modifications for 
Thrombocytopenia  
 
For patients with a baseline platelet count<50,000/uL; 
Start eltrombopag when the platelet count is < 50,000/uL. Start Lenalidomide (AND 
STOP eltrombopag) only after platelet count > 50,000 (non transfused) for atleast 2 
weeks. If platelet fall <50,000/uL after resuming lenalidomide again then again hold dose 
and start Eltrombopag again. Once plt count > 50,000 for two weeks, then start 
lenalidomide and give eltrombopag concomitantly.  
 
For patients with a baseline platelet count =>50,000/uL; 
Start Lenalidomide alone. If plt count falls below 50,000/L then follow algorithm as 
above. 
 
Patients who do not experience platelet recovery within 8weeks of starting Eltrombopag 
should be removed from study and complete all offstudyevaluations. 
 
Dose modifications for hemoglobin levels:  
For those patients experiencing arise in hemoglobin > 14 g/dL, Lenalidomide should be 
withhelduntil the hemoglobin is < 12 g/dL, at which time treatment can be resumed 
accordingto the dose adjustment recommendations in Table 1. For thosepatients 
previously adjusted to the lowest CC-5013 (lenalidomide) dose, the CC-5013 
(lenalidomide) schedule should be changed to a 2 week treatment scheduleevery 4 weeks. 
 
Dose Modifications for Other Adverse Events 
Dose interruption and modification guidelines for other adverse events are in Table 2.  
Lenalidomide should be held for any > grade 3 adverse events withsuspected drug 
association until resolution to < grade 2. For any patients who doesnot experience 
resolution to < grade 2 within 4 weeks should be removed from studyand complete all 
off-study evaluations. For patients with thromboembolic events,both agents should be 
discontinued and not resumed until resolution with properprophylaxis according to the 
discretion of the treating investigator.  
NOTE: Patients will be removed from study if lenalidomide is held forlonger than 8 
weeks for treatment-related toxicity. 
 
Table 1: Dose Modifications for CC-5013 (lenalidomide) 
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Dosing for Eltrombopag 
 
Patients will initially be started on 100 mg eltrombopag (50 mg for subjects of East 
Asian heritage). Thereafter, dependent on the platelet response (see Table 3 below), the 
dose of study medication can be increased every 2 weeks, up to a maximum dose of 
300 mg/day (150 mg/day for subjects of East Asian heritage).   
 
Modified dosing for subjects of East Asian heritage (i.e., Japanese, Chinese, Taiwanese 
and Korean) has been implemented for the following reasons.  In healthy Japanese 
subjects, plasma eltrombopag AUC(0-) was approximately 80% higher when compared 
to non-Japanese healthy subjects who were predominantly Caucasian.  Similarly, in 
patients with ITP, plasma eltrombopag exposure was approximately 70% higher in East 
Asian (i.e., Japanese, Chinese, Taiwanese and Korean) subjects as compared to non–East 
Asian subjects who were predominantly Caucasian. 
 
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Intra-individual dose adjustments will be made in a stepwise fashion, by sequentially 
increasing to dose levels of 100 mg, 200 mg or 300 mg as needed (50, 100, 150 mg for 
subjects of East Asian heritage).  Titration of study medication with different dosages 
on different days will be permitted where needed in order to maintain a stable platelet 
count in the safe range without exceeding platelet counts >400 Gi/L.The dosing 
regimen of eltrombopag must be individualized based on platelet counts. Use the 
lowest effective dosing regimen to maintain platelet response. 
 
Figure 4: Schema of dose adjustments for eltrombopag 
 
Eltrombopag must be taken either in a fasted state (i.e., 1 hour before or 2 hours after 
food) or taken with food low in calcium (no dairy products). There must be at least a 4-
hour interval between eltrombopag and other medications, food, or supplements 
containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, 
and zinc, including dairy products. After any eltrombopag dose adjustment, monitor 
platelet counts at least weekly for 2-3 weeks. 
 
At eltrombopag dose levels 200 mg and above, subjects who have discontinued other 
drugs known to prolong QT and who still have a QTc >480 msec will be excluded 
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Table 2:Guidelines for Eltrombopag Dose Adjustments 
Platelet Counts 
Dose Adjustments 
No platelet response 
Increase daily dose to the next 
dose level 
If platelet counts do not stabilize 
at desired levels, consider dosing 
regimens such as different dose 
levels on alternating days. 
 
Wait for 2 weeks to see the effect 
of the dose increase on platelet 
response before another dose 
increase is considered. 
200-400 k/uL 
If no post-baseline BM 
examination has been 
performed: 
Decrease daily dose considering dosing 
regimens such as different dose levels on 
alternating days. 
 
If platelet counts remain between 200-
400 k/uL, wait for 2 weeks to see the effect 
of the dose decrease on platelet response 
before another dose decrease is considered. 
If BM blasts have decreased: 
Maintain dose level and monitor platelet 
counts weekly. 
If BM blasts have increased: 
Decrease daily dose considering dosing 
regimens such as different dose levels on 
alternating days. 
 
If platelet counts remain between 200-
400 k/uL, wait for 2 weeks to see the effect 
of the dose decrease on platelet response 
before another dose decrease is considered 
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>400k/uL 
Interrupt treatment and monitor 
platelets twice a week until 
platelet counts fall below 
150 k/uL and restart treatment by 
reducing the daily dose to the 
next dose level considering 
dosing regimens such as 
different dose levels on 
alternating days. 
 
 
 
 
During eltrombopag therapy, CBCs, including platelet count and peripheral blood 
smears, should be assessed weekly until a stable platelet count has been achieved. CBCs 
including platelet counts and peripheral blood smears, should be obtained monthly 
thereafter. Blasts will be monitored as indicated in flowchart: 
 
Algorithm for Blast Count Monitoring
PBB : increased on 2 consecutive weeks
BM Exam
BMB increased
PBB = peripheral blood blasts
BMB = bone marrow blasts
BMB stable
Interrupt Epag
Continue Epag
PBB returns to baseline
PBB stable
Terminate Epag
Re-Exam BM
BMB returns to baseline
BMB increased
Terminate Epag
Resume Epag if B/R positive 
“increased” = higher than
baseline
B/R = benefit/risk ratio
 
Figure 5: Schema for blast count monitoring 
 
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Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 
 
 
8.2 SUPPORTIVE CARE 
 
1. All supportive measures consistent with optimal patient care will be given 
throughoutthe study. 
 
2. Therapies considered necessary for the patient’s well being may be administered atthe 
discretion 
of 
the 
Investigator. 
These 
therapies 
include 
antibiotics, 
analgesics,antihistamines, or other medications, and transfusions of red blood cells, 
platelets,or 
fresh 
frozen 
plasma 
given 
to 
assist 
in 
the 
management 
of 
complicationsassociated with MDS or study treatment. 
 
3.Packed RBCs: Transfusions of two units of packed RBCs should be considered 
fordecline in hematocrit (HCT) to < 25% or symptoms of cardiovascular compromise. 
The following transfusion thresholds and guidelines are recommended for 
studyparticipants: HCT < 25%, two units of packed RBCs; HCT < 21%, three units 
ofpacked RBCs; HCT < 18%, four units of packed RBCs. 
 
4 Platelets: Eight to ten units of random donor platelets or one cytopheresis unit ofsingle 
donor platelets should be administered to all subjects with signs of hemostaticfailure (i.e., 
bleeding or petechiae) or life threatening thrombocytopenia (i.e., plateletcount < 
10,000/μL). 
 
5 Patients should not receive androgens or steroids for supportive treatment of their 
anemia or thrombocytopenia  
 
6 Patients may receive hydrocortisone prophylactically to prevent transfusion 
reactions. Steroids given for adrenal failure, hormones administered for non-
cancerrelatedconditions (e.g. insulin for diabetes), and intermittent uses of 
dexamethasoneas an antiemetic are permitted concomitantly with study drug. Short 
courses ofsteroids to treat study drug-induced skin rashes are also permitted.  
 
8.3 DURATION OF THERAPY 
Patients will receive protocol therapy unless: 
1. 
 Extraordinary Medical Circumstances: If at any time the constraints of this 
protocolare detrimental to the patient's health, protocol treatment should be discontinued 
2. 
Patient withdraws consent. 
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3. 
Adverse event(s) (AEs) occur that, in the judgment of the Investigator, may 
causesevere or permanent harm or which rule out continuation of study drug. 
4. 
Lack of therapeutic effect 
5. 
 Patient’s disease converts to acute myeloid leukemia or disease progression. 
6. 
Patient is lost to follow-up. 
7. 
if a patient has a QTc >500 msec or QT >600 msec; 
8. 
if a patient meets any of the following liver chemistry threshold criteria: 
ALT 3xULN and bilirubin 1.5xULN (>35% direct).ALT 5xULN. 
ALT 3xULN if associated with the appearance or worsening of hepatitis symptoms or 
rash. 
All subjects who discontinue study medication should continue to participate in the 
follow-up visits. 
8.4 DURATION OF FOLLOW-UP 
For this protocol, all patients, including those who discontinue protocol therapy early,will 
be followed for response until progression and for survival for 10 years from thedate of 
registration. All patients must be followed through completion of protocoltherapy.  
 
8.5 CONCOMITANT MEDICATIONSAND NON-DRUG THERAPIES 
 
Permitted Medications and Non-Drug Therapies 
A reasonable effort will be made to document any medications the subject receivedwithin 
30 days prior to Day 1. Any medication taken within 7 days of study 
medicationadministration must be recorded in the eCRF as a prior medication.All 
concomitant medications taken during the study will be recorded in the eCRF 
withindication, dose information, including any changes in dose, as well as start and 
stopdates and frequency of administration. The minimum requirement is that drug 
name,dose, and the dates of administration are to be recorded.If any medication is 
required at any time within 7 days before study medicationadministration until 
completion of last follow-up procedures, subjects should consult theinvestigator and 
details should be recorded in the eCRF. 
 
Antacids, Cations and Vitamin/Mineral Supplements 
Administration 
of 
eltrombopag 
with 
a 
polyvalent 
cation-containing 
antacid 
decreasedplasma eltrombopag exposure by 70%, and a similar reduction was observed 
wheneltrombopag was administered with a high-calcium meal. Therefore, every effort 
must bemade to educate subjects on how to take study medication with medications or 
foodscontaining these polyvalent cations. Details of these and all concomitant 
medicationsshould be recorded in the eCRF. 
Eltrombopag should be taken on an empty stomach (1 hour before or 2 hours aftera 
meal) or taken with food low in calcium (no dairy products). Allow at least a 4 hour 
interval between eltrombopag and othermedications, foods, or products containing 
polyvalent cations (e.g. calcium, magnesium,aluminium, zinc, selenium or iron) such 
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as antacids, dairy products, and mineralsupplements to avoid significant reduction 
in eltrombopag absorption due tochelation. 
 
Antacids 
Subjects requiring routine (e.g. daily) acid suppression should be encouraged to take 
H2antagonists like ranitidine, famotidine or nizatidine, or proton pump inhibitors 
likeomeprazole, esomeprazole or lansoprazole. 
Subjects requiring occasional acid suppression may take liquid or chewable 
antacids(calcium carbonate, aluminum hydroxide or magnesium hydroxide), provided 
studymedication is taken at least 4 hours before and 4 hours after consumption of 
cationcontainingantacids. 
AL UM2008/00289/00 
Mineral Supplements and Dairy Products 
Mineral supplements (such as calcium, magnesium, aluminium, zinc, selenium or 
iron)are permitted during the study but study medication must be taken at least 4 hours 
beforeand 4 hours after consumption of these supplements. Similarly, eltrombopag must 
betaken at least 4 hours before and 4 hours after consumption of dairy products (such 
asmilk, yogurt, and cheese). 
 
HMG-CoA Reductase Inhibitors (statins) 
Subjects will be permitted to use HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl- 
CoA) inhibitors during the study, but these drugs should be used with caution and a 50% 
dose reduction of the HMG-CoA reductase inhibitor is recommended, with close 
monitoring for safety, such as liver chemistry and signs and symptoms of myolysis, and 
efficacy, such as cholesterol and triglycerides (refer to individual product information for 
monitoring recommendations). 
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 
and BCRP. Therefore, a clinical drug interaction study to evaluate the impact of 
eltrombopag on the PK of rosuvastatin, an OATP1B1 and BCRP substrate, was 
conducted in healthy subjects. Co-administration of eltrombopag 75 mg once daily for 5 
days with a single 10mg dose of rosuvastatin administered on Day 5 increased plasma 
rosuvastatin Cmax 2.03-fold and AUC(0-∞) 55%. Concomitant administration of 
eltrombopag and other OATP1B1 or BCRP substrates should be used with caution. 
NFIDENTIAL UM2008/00289/00 
Concomitant MDS Therapy 
G-CSF is allowed during the study for subjects with severe neutropenia and 
recurrentinfections. Subjects who enter the study on G-CSF should continue at the same 
doseschedule until the optimal dose of study medication has been established. 
Any change in dosage of any concomitant medication (change in dose or 
frequency)MUST be recorded in the eCRF, to include: drug name, dose, frequency 
ofadministration, start and stop dates and indication. 
 
Prohibited Medications and Non-Drug Therapies 
Subjects must abstain from using prohibited prescription or non-prescription drugs 
within7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
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medication anduntil completion of follow-up procedures (Section 5.3, Exclusion 
Criteria). 
The following medications are prohibited during the study: 
• Any other TPO-R agonists 
• Treatment with deferasirox. Deferasirox shares some aspects of the safety profile 
ofeltrombopag, and should therefore not be combined with eltrombopag to allow for 
abetter identification of potential, eltrombopag-related events. 
• Drugs that affect platelet function (including, but not limited to, aspirin, 
clopidogreland/or NSAIDS) may also affect the results of the bleeding scale assessments 
duringthe study and are therefore prohibited. In the event their use is clinically 
indicated,those drugs will be permitted, but the subject(s) will be excluded from 
bleedinganalyses. 
• Anticoagulants (e.g. warfarin, heparin) may also affect results of the bleeding 
scaleassessments during the study unless and therefore are prohibited. In the event 
theiruse is clinically indicated, those drugs will be permitted, but the subject(s) will 
beexcluded from bleeding analyses. 
 
9 
ADVERSE EVENTS 
 
9.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
lenalidomide (NSC #703813) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single,complete list of reported and/or potential adverse events (AE) associated with an 
agentusing a uniform presentation of events by body system. In addition to the 
comprehensive list,a subset, the Agent Specific Adverse Event List (ASAEL), appears in 
a separate column andis identified with bold and italicized text. This subset of AEs 
(ASAEL) contains events thatare considered 'expected' for expedited reporting purposes 
only. Refer to the 'CTEP, NCIGuidelines: Adverse Event Reporting Requirements’ 
http://ctep.cancer.gov/reporting/adeers.html for further clarification. The CAEPR does 
notprovide frequency data; refer to the Investigator's Brochure for this  information. 
Below is theCAEPR forLenalidomide. 
 
Version 1.3, February 23, 20061 
Category(BodySystem)Adverse Events with PossibleRelationship to CC-5013 
(Lenalidomide)(CTCAE v3.0 Term) 
'Agent Specific Adverse Event List'(ASAEL) 
 
ALLERGY/IMMUNOLOGY 
Allergic reaction/hypersensitivity (including drugfever) 
Allergic rhinitis (including sneezing, nasalstuffiness, postnasal drip) 
 
AUDITORY/EAR 
Tinnitus 
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BLOOD/BONE MARROW 
Blood/Bone Marrow - Other (Eosinophilia) 
Hemoglobin Hemoglobin 
Hemolysis (e.g., immune hemolytic anemia, drugrelatedhemolysis) 
Leukocytes (total WBC) Leukocytes (total WBC) 
Lymphopenia Lymphopenia 
Neutrophils/granulocytes (ANC/AGC) Neutrophils/granulocytes (ANC/AGC) 
Platelets Platelets 
 
CARDIAC ARRHYTHMIA 
Atrial fibrillation 
Palpitations 
Prolonged QTc interval 
Sinus bradycardia 
Supraventricular tachycardia 
Ventricular tachycardia 
 
CARDIAC GENERAL 
Cardiac ischemia/infarction 
Hypertension 
Hypotension 
 
COAGULATION 
DIC (disseminated intravascular coagulation) 
INR (International normalized ratio of prothrombintime) 
 
CONSTITUTIONAL SYMPTOMS 
Fatigue (asthenia, lethargy, malaise) Fatigue (asthenia, lethargy, malaise) 
Fever (in the absence of neutropenia, whereneutropenia is defined as ANC <109/L) 
Fever (in the absence of neutropenia,where neutropenia is defined as ANC<109/L) 
Insomnia 
Rigors/chills 
Sweating (diaphoresis) 
Weight loss Weight loss 
 
DERMATOLOGY/SKIN 
Dermatology/Skin - Other (Sweet's syndrome) 
Dry skin 
Hair loss/alopecia (scalp or body) 
Photosensitivity 
Pruritus/itching Pruritus/itching 
Rash/desquamation Rash/desquamation 
Rash: acne/acneiform 
Urticaria (hives, welts, wheals) 
 
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ENDOCRINE 
Endocrine - Other (Low testosterone) 
Thyroid function, high (hyperthyroidism,thyrotoxicosis) 
Thyroid function, low (hypothyroidism) 
 
GASTROINTESTINAL 
Anorexia 
Constipation Constipation 
Dehydration 
Diarrhea 
Distension/bloating, abdominal 
Dry mouth/salivary gland (xerostomia) 
Dysphagia (difficulty swallowing) 
Flatulence 
Gastritis (including bile reflux gastritis) 
Heartburn/dyspepsia 
Ileus, GI (functional obstruction of bowel, i.e.,neuroconstipation) 
Mucositis/stomatitis (functional/symptomatic)  
Nausea Nausea 
Perforation, GI: colon 
Taste alteration (dysgeusia) 
Vomiting Vomiting 
 
HEMORRHAGE/BLEEDING 
Hemorrhage GU - Select 
Hemorrhage, CNSHemorrhage, pulmonary/upper respiratory:respiratory tract NOS 
 
HEPATOBILIARY/PANCREAS 
Hepatobiliary/Pancreas - Other (Cholelithiasis) 
Pancreatitis 
 
INFECTION 
Febrile neutropenia (fever of unknown originwithout clinically or microbiologically 
documented 
infection)(ANC <109/L, fever $38.5°C) 
Infection with Grade 3 or 4 neutrophils  
Infection with normal ANC or Grade 1 or 2neutrophils  
Opportunistic infection associated with Grade 2Lymphopenia 
 
LYMPHATICS 
Edema: limb 
 
METABOLIC/LABORATORY 
ALT, SGPT (serum glutamic pyruvictransaminase) 
AST, SGOT (serum glutamic oxaloacetictransaminase) 
Bilirubin (hyperbilirubinemia) 
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Calcium, serum-low (hypocalcemia) 
Cholesterol, serum-high (hypercholesteremia) 
Creatinine 
Glucose, serum-high (hyperglycemia) 
Magnesium, serum-low (hypomagnesemia) 
Lipase 
Potassium, serum-low (hypokalemia) 
Sodium, serum-low (hyponatremia) 
Uric acid, serum-high (hyperuricemia) 
 
MUSCULOSKELETAL/SOFT TISSUE 
Arthritis (non-septic) 
Muscle weakness (not due to neuropathy)  
Muscle weakness (not due to neuropathy): wholebody/generalized 
 
NEUROLOGY 
CNS cerebrovascular ischemia 
Confusion 
Dizziness 
Encephalopathy 
Mental status 
Mood alteration: agitation 
Mood alteration: anxiety 
Mood alteration: depression 
Myelitis 
Neuropathy: motor 
Neuropathy: sensory 
Psychosis (hallucinations/delusions) 
Seizure 
Somnolence/depressed level of consciousness 
Speech impairment (e.g., dysphasia or aphasia) 
Syncope (fainting) 
Tremor 
 
OCULAR/VISUAL 
Dry eye syndrome 
Retinopathy 
Vision-blurred vision 
Vision-flashing lights/floaters 
PAIN 
Pain - abdomen NOS 
Pain - back 
Pain - bone 
Pain - chest/thorax NOS 
Pain - head/headache 
Pain - joint 
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Pain - muscle 
Pain - oral-gums 
Pain NOS 
 
PULMONARY/UPPER RESPIRATORY 
Atelectasis 
Cough 
Dyspnea (shortness of breath) 
Nasal cavity/paranasal sinus reactions 
Pleural effusion (non-malignant) 
 
RENAL/GENITOURINARY 
Renal failure 
Urinary electrolyte wasting (e.g., Fanconi'ssyndrome, renal tubular acidosis) 
Urinary frequency/urgency 
 
SYNDROMES 
Tumor lysis syndrome 
 
VASCULAR 
Thrombosis/thrombus/embolism Thrombosis/thrombus/embolism 
 
Also reported on lenalidomide trials but with the relationship to lenalidome still 
undetermined: 
NEUROLOGY - hemiparesis 
PAIN - limb pain 
RENAL/GENITOURINARY - urinary incontinence 
 
9.2 Safety considerations with Eltrombopag: 
 
The information in this section reflects the revised Prescribing Information for 
PROMACTA dated Feb 2011 
 
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 a 
Grade 4 liver test abnormality. 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 three 
controlled studies, four patients (1%) treated with eltrombopag and three patients in the 
placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. 
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Seven of the patients treated with eltrombopag in the controlled studies with 
hepatobiliary laboratory abnormalities were re-exposed to eltrombopag in the ITP 
extension study. Six 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 (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. 
 
 
Pharmacokinetic evaluations in patients with hepatic impairment show that plasma 
eltrombopag AUC(0-) increases with increasing degree of hepatic impairment (as 
measured by Child-Pugh). Exercise caution when administering eltrombopag to patients 
with hepatic impairment (Child-Pugh Class A, B, C) . Use a lower starting dose of 
eltrombopag in patients with any degree of hepatic impairment i.e. cirrhosis and monitor 
closely  
 
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis 
Eltrombopag is a thrombopoietin (TPO) receptor agonist and TPO-receptor agonists may 
increase the risk for the development or progression of reticulin fiber deposition within 
the bone marrow.  
 
 
In the ITP extension study, 151 patients have had bone marrow biopsiesevaluated for 
increased reticulin and collagen fiber deposition. Bone marrow biopsies taken after 1 year 
of therapy showed predominantly myelofibrosis (MF) Grade 1 or less in 140/151 (93%) 
of patients. There were 11/151 (7%) of patients with MF Grade 2. Four patients had 
collagen deposition reported. One patient with a pre-existing MF Grade 1 developed a 
MF Grade 2 and subsequently discontinued treatment with eltrombopag.  Clinical studies 
have not yet excluded a risk of bone marrow fibrosis with cytopenias. 
 
 
Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely 
to establish a baseline level of cellular morphologic abnormalities. Following 
identification of a stable dose of eltrombopag, peripheral blood smears and CBCs should 
be examined monthly for new or worsening morphological abnormalities (e.g., teardrop 
and nucleated red blood cells, immature white blood cells) or cytopenia. If the patient 
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develops new or worsening morphological abnormalities or cytopenia, treatment with 
eltrombopag should be discontinued and a bone marrow biopsy, including staining for 
fibrosis considered.  
 
Recurrence of Thrombocytopenia After Cessation of Eltrombopag 
Discontinuation of eltrombopag may result in recurrence of thrombocytopenia. This 
recurrence of 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 patients in the placebo group.  
 
 
Following discontinuation of eltrombopag, weekly CBCs, including platelet counts for at 
least 4 weeks should be obtained and alternative treatments for recurrence 
ofthrombocytopenia, according to current treatment guidelines, considered. 
 
Thrombotic/thromboembolic complications  
Eltrombopag may increase the risk of thrombotic/thromboembolic events.. Excessive 
doses of eltrombopag may increase platelet counts to a level that produces 
thrombotic/thromboembolic complications.  
In the 3 controlled ITP clinical studies, thrombotic/thromboembolic complications 
occurred in four patients in the groups that received eltrombopag and none in the placebo 
groups.Thrombotic/thromboembolic complications have also been reported in the ITP 
extension study. The thrombotic/thromboembolic complications in patients with chronic 
ITP included both venous and arterial events and were observed at low and normal 
platelet counts. 
Use caution when administering eltrombopag to patients with known risk factors for 
thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, 
chronic liver disease). To minimize the risk for thrombotic/thromboembolic 
complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow 
the dose adjustment guidelines to achieve and maintain a platelet count of 50 x 109/L as 
necessary to decrease the risk for bleeding 
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 portal 
venous thrombosis was increased in patients treated with 75 mg eltrombopag once daily 
for 2 weeks in preparation for their invasive procedure. Seven thrombotic complications 
(six patients) were reported within the group that received eltrombopag and three 
thrombotic complications were reported in the placebo group (two patients). All of the 
thrombotic complications reported within the eltrombopag group were of the portal 
venous system. Five of the six patients in the group that received eltrombopag 
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experienced a thrombotic complication within 30 days of completing treatment with 
eltrombopag and at a platelet count above 200 x 109/L. Malignancy is known to increase 
the risk for developing a thrombotic event and four  of the 6 patients either had a 
diagnosis or suspicion of malignancy (2 hepatocellular carcinoma; 1 possible lymphoma 
and 1 brain tumor).     
 
Caution should be exercised when administering eltrombopag to patients with hepatic 
impairment (Child-Pugh Class A, B, C) and  a lower starting dose of eltrombopag should 
be used in patients with any degree of hepatic impairment.  Such patients should be 
monitored very closely. Eltrombopag is not indicated for the treatment of 
thrombocytopenia in patients with chronic liver disease. 
The ELEVATE study was terminated in November 2009 and a Dear Health Care 
Professional Letter (DHCPL) was sent to all physicians enrolled in Promacta Cares in 
May 2010.   
 
Hematologic 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. In the controlled clinical studies, 
patients were treated with eltrombopag for a maximum of 6 months. During this period 
no hematologic malignancies were reported in patients treated with eltrombopag. One 
hematologic malignancy (non-Hodgkin's lymphoma) was reported in the extension 
study.Eltrombopag is not indicated for the treatment of thrombocytopenia due to diseases 
or treatments that cause thrombocytopenia (e.g., myelodysplasia or chemotherapy) other 
than chronic ITP.  
 
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 
 
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10 REPORTING REQUIREMENTS 
10.1 Definitions 
10.1.1 Adverse Events 
Any untoward or unfavorable medical occurrence in a human subject, including any  
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or  
disease, temporally associated with the subject’s participation in the research, whether  
or not considered related to the subject’s participation in the research. Adverse Events  
encompass both physical and/or psychological harms.  
 
10.1.2 Unanticipated Problem 
Any event, deviation, or problem, that meets ALLof the following criteria:  
 Is unexpected, AND 
 Is possibly, probably or definitely related to participation in the research; AND 
 fatal, life-threatening, or serious OR suggests greater risk of harm to study 
participant(s)or others than was previously known or recognized.  
(A) Unexpected:  
An event can be categorized as unexpected ifit occurs in one or more subjects  
participating in a research protocol; and the nature, severity, or frequency of  
which is not consistent with either:  
 The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in protocol-related 
documents such as: the IRB-approved research protocol; any applicable 
investigator brochure: the current IRB-approved informed consent document; 
or other relevant sources of information, such as product labeling and package 
inserts; or  
 The expected natural progression ofany underlying disease, disorder, or 
condition of the subject(s) experiencing the adverse event and the subject’s 
predisposing risk factorprofile for the adverse event.  
 
(B) Serious Adverse Event (SAE): 
A serious adverse event is one that at any dose (including overdose): 
 Results in death 
 Is life-threatening1 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity2 
 Is a congenital anomaly or birth defect 
 Is an important medical event3 
 Pregnancy 
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 1“Life-threatening” means that the subject was at immediate risk of death at the 
time of the serious adverse event; it does not refer to a serious adverse event that 
hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a 
substantial disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in situations where none of the outcomes listed 
above occurred.  Important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious.  Examples of such 
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.  
A new diagnosis of cancer during the course of a treatment should be considered 
as medically important.  
 
10.1.3 Protocol Deviation 
Any change in the processes or procedures of research that were not approved by  
amendment of an IRB-approved protocol.  
10.1.4 Protocol Exception 
A planned, one-time deviation from the IRB-approved protocol (e.g. enrollment of a 
subject who does not meet inclusion criteria, or one-time dose changes for a single  
subject).  
10.1.5 Systematic Data Collection Error 
Data collection errors that may affect the scientific soundness ofthe investigational plan.  
 
10.2 Reporting Events to IRB at Montefiore-Einstein 
10.2.1 Expedited Reporting 
The Protocol PI will report the following events to the IRB within 5 business days of the clinical 
team’s awareness via the reportable events form:  
 All deaths  
 Protocol Deviations that place subjects at greater risk 
 All Unanticipated Problems 
 All serious non-compliance  
The PI’s signature and the date it was signed are required on the completed report.  
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10.2.2 Continuing Review Reporting 
At the time of continuing review, the IRB requires an internal log of all AE (except non-
serous AEs), UP and PD events that have occurred on the protocol since the previous 
continuing review and in aggregate. 
 
For additional information please refer to the IRB Reportable Events Policy located on 
the intranet: http://www.einstein.yu.edu/docs/administration/institutional-review-
board/policies/reportable-events.pdf 
10.3 Reporting Events to Study Supporters (Celgene Corporation/ GSK) 
All SAEs must be reported to the Montefiore-Einstein PI or designee within 24 hours of 
being aware of the event. The Montefiore-Einstein Research team will inform study 
supporters and collaborating centers of reportable events.  
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should 
have access to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, 
whether observed by the investigator or reported by the patient, must be recorded, with 
details about the duration and intensity of each episode, the action taken with respect to 
the test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific occurrence of one 
or more adverse events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication. All 
AEs considered related to trial medication will be followed until resolution even if this 
occurs post-trial. 
10.3.1 GSK Reporting Requirements 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, must 
be reported by the investigator. In addition, any SAEs which occur as a result of protocol 
specific diagnostic procedures or interventions must also be reported. 
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All serious adverse events must be reported by facsimile within 24 hours to 
GlaxoSmithKline. MDC - Oncology Fax: 1 610 422 2527 (make sure you include the 
1 prior to the 610 as otherwise it doesn't work!) 
For medical emergencies contact: 
Toll Free Number: (800) 877-7074, ext. 7194 
After Hours or Weekends: (800) 366-8900, ask for physician on call 
GlaxoSmithKline UP4420 
1250 S. Collegeville Road, 
P.O. Box 5089 
Collegeville, PA 19426-0989 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question. Where applicable, information from relevant hospital case 
records and autopsy reports should be included. Follow-up information should be 
forwarded to GSK within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of 
eltrombopag and considered by the investigator to be related or possibly related to 
eltrombopag must be reported to GSK if and when they occur. Additionally, in order to 
fulfill international reporting obligations, SAEs that are related to study participation 
(e.g., procedures, invasive tests, change from existing therapy) or are related to a 
concurrent medication will be collected and recorded from the time the subject consents 
to participate in the study until he/she is discharged. 
.  
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Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
1 Documents 
Time Frame 
Documents 
All SAEs 
1
“SAE” 
data 
collectio
n tool 
24 hours 
Updated “SAE” 
data collection 
tool  
Pregnancy 
1 Pregnancy 
Notification Form 
2 Weeks 
Pregnancy 
Follow-up Form 
Table 3 
 
10.3.2 Celgene Reporting Requirements 
Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject is 
on lenalidomide, or within  28 days of the subject’s last dose of lenalidomide, are 
considered immediately reportable events. Lenalidomide  is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Celgene Drug Safety immediately by facsimile or email using the 
Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 
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The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form.  If the outcome of the pregnancy was abnormal (e.g., spontaneous or 
therapeutic abortion), the Investigator should report the abnormal outcome as an AE. 
If the abnormal outcome meets any of the serious criteria, it must be reported as an 
SAE to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject taking lenalidomide  should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
IND Annual Reports to Celgene 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder, and a copy provided to 
Celgene Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations  
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
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Berkeley Heights, NJ  07922 
 
 
 
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, 
unknown relationship, definitely not related), date and time of administration of test 
medications and all concomitant medications, and medical treatment provided.   The 
investigator is responsible for evaluating all adverse events to determine whether criteria 
for “serious” and as defined above are present.  The investigator is responsible for 
reporting adverse events to Celgene as described below. 
 
Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writingusing a Celgene SAE form or MEDWATCH 3500A formof any SAE within 24 
hours of being aware of the event.The written report must be completed and supplied to 
Celgene by facsimilewithin 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report. A final report to 
document resolution of the SAE is required.  The Celgene trackingnumber (RV-MDS-PI-
0645)and the institutional protocol number should be included on SAE reports(or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
 Any AE associated with the use of drug in this study or in other studies that is 
both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 11.4 for records retention information). 
 
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10.4 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
The Sponsor will notify the FDA of any unexpectedfatal or life-threateningsuspected 
adverse reactions as soon as possible but no later than 7 calendar days of initial receipt of 
the information using the MedWatch Form 3500a.  
The Sponsor is also responsible for reporting any:  
 suspected adverse reaction that is both serious and unexpected 
 any findings from clinical, epidemiological, or pooled analysis of multiple studies 
or any findings from animal or in vitro testing that suggest a significant risk in 
humans exposed to the drug 
 clinically important increase in the rate of a serious suspected adverse reaction 
over that listed in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that 
the information qualifies for reporting using the MedWatch Form 3500a. If FDA requests 
any additional data or information, the sponsor must submit it to the FDA as soon as 
possible, but no later than 15 calendars days after receiving the request. 
 
10.4.1 FDA Annual Reports (Refer to 21 CFR 312.33) 
 
The study Sponsor will submit a brief report annually of the progress of the trial within 
60 days of the anniversary date that the IND went into effect as indicated in 21CFR 
312.33, and any associated FDA correspondences regarding the IND annual report.  
 
Responsibility of Participating Sites 
Responsibility of Montefiore-Einstein 
 Participating sites are responsible for 
reporting all events to their local IRB 
per local guidelines 
 
 
 Participating sites are responsible for 
reporting all SAEs (section 10.3) to the 
Montefiore-Einstein PI via fax or email 
within 24 hours of learning of the 
event. 
 
 
 
 The Montefiore-Einstein Research Staff 
is 
responsible 
for 
submitting 
all 
reportable events to the IRB as 
specified in section 10.2  
 
 The Montefiore-Einstein PI will be 
responsible for reporting all drug 
related serious adverse events to the 
FDA (section 10.4) and events noted in 
section 10.3 to study supporters 
 
 The 
Montefiore-Einstein 
PI 
is 
responsible 
for 
informing 
all 
participating sites about unanticipated 
problems and fatalities within 30 days 
of receiving the stamped reportable 
events form from the IRB.  
 
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11 RESPONSE CRITERIA 
MDS Response Criteria: Modified International MDS Working Group (IWG) Criteria 
forMeasurement of Response/Treatment Effect in MDS (20) will be used to assess 
response. 
 
Complete Remission (CR) 
Bone marrow evaluation (>4 weeks): Bone marrow showing =< 5% myeloblastswith 
normal maturation of all cell lines. When erythroid precursors constitute < 50% of 
bonemarrow nucleated cells, the percent of blasts is based on allnucleated cells; when 
there are > 50% erythroid cells, the percentblasts should be based on the non-erythroid 
cells. This response should last for atleast 4 weeks. Dysplasia if present will be noted. 
 
Peripheral Blood Counts (Absolute values must last >4 weeks) 
o Hemoglobin greater than 11 g/dL (untransfused, patientnot on erythropoietin). 
o Neutrophils 1000/mm3 or more (not on a myeloid growthfactor) 
o Platelets 100 000/mm3 or more (not on a thrombopoeticagent) 
o Blasts – 0% 
o Hematologic improvement should be obtained. 
 
Marrow CR: Bone marrow: < 5% myeloblasts and decrease by > 50% over pretreatment 
marrow. Peripheral blood: if hematologic improvement occurs, it will be noted in 
addition to marrow CR 
 
Partial Remission (PR) 
All of the CR criteria (if abnormal prior to treatment), except 
o Bone marrow evaluation: Blasts decreased by 50% overpretreatment, b 
 
Stable Disease 
Failure to achieve at least a PR, but with no evidence ofprogression for >8 weeks. 
 
Failure 
Death during treatment or disease progression characterizedby worsening of cytopenias, 
increase in the percent of bonemarrow blasts, or progressionto an MDS FAB subtype 
more advanced than pretreatment. 
 
Relapse (following a CR or PR) 
One or more of the following: 
o Return to pretreatment bone marrow blast percentage. 
o Decrement of > 50% from maximum remission responselevels in neutrophils or 
platelets. 
o RBC transfusion dependence (> 2 unites RBCtransfusions over an 8 week period) or a 
reduction inhemoglobin concentration by >1.5 g/dL in the absence ofacute infection, 
gastrointestinal bleeding, hemolysis,treatment hiatus etc. 
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6. Disease Progression 
A 50 % increase in blasts, depending on baseline blastpercent, if confirmed by 
subsequent BM examination (Fig 5). 
o For patients with < 5% blasts: increase to > 10% blasts 
o For patients with 5% to 10% blasts: > 50% increase to> 10% blasts 
o For patients with 10% to 20% blasts: > 50% increase to20% blasts 
o For patients with 20% to 30% blasts: > 50% increase to30% blasts 
 
Any of the following: 
At least 50% decrement from maximum remission/response in granulocytes or platelets 
Reduction in Hgb by 2 g/dL 
Transfusion dependence 
 
7. Disease Transformation 
Transformation to AML (> 30% blasts). 
 
Cytogenetic Response 
Requires 20 analyzable metaphases when using conventionaltechniques. Analysis of data 
will require 20 metaphases before andafter treatment. Fluorescent in situ hybridization 
(FISH) may be used asa supplement to follow a specifically defined cytogenetic 
abnormality,but it is not a substitute for conventional cytogenetic studies. 
 
Cytogenetic response is defined as follows: 
 
Complete response: Restoration of a normal karyotype in patientswith a documented 
pre-existing clonal (>2 metaphases abnormal)chromosome abnormalities. 
Partial response: > 50% reduction in the percentage of bone marrowmetaphases with 
only clonal abnormality. 
 
Hematologic Improvement 
Improvements must last >8 consecutive weeks. 
 
1.Erythroid Response 
Hgb increase by 1.5 g/dL if not transfusion dependent Relevant reduction of units of 
RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared 
with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions 
given for a Hgb of 9.0 g/dL pretreatment will count in the RBC transfusion response 
evaluation 
 
2. Platelet Response 
For patients with a pretreatmentcount < 100,000/mm3, an absolute increase of > 
30,000/mm3 (for patients with pretreatment counts >20,000). 
For patients with pretreatment counts < 20,000, an increase to absolute count above 
20,000 by at least 100% increase will be considered as response. 
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†;for platelet transfusion-dependent patients, stabilization ofplatelet counts and platelet 
transfusion independence. 
 
3. Neutrophil Response 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
4. Progression/Relapse Following Erythroid HematologicImprovement 
At least 1 of the following: 
At least 50% decrement from maximum response levels in granulocytes or platelets 
Reduction in Hgb by 1.5 g/dL 
Transfusion dependence 
 
Duration of Response 
Time 
to 
disease 
progression 
(as 
per 
Bone 
Marrow 
Responses 
above) 
orprogression/relapse 
following 
hematologic 
improvement 
(as 
perHematologic 
Improvement above). 
 
12 DATA MANAGEMENT 
12.1 Analyses and Reporting 
Data will be analyzed and reported after 25 patients are enrolled. All subsequent data 
collected will be analyzed and reported in a follow-up clinical report by the PI.  
12.2 Study auditing 
12.2.1 Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system.  The 
Investigator will permit study-related audits by Celgene or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to 
the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
13 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by Montefiore-Einstein are subject to oversight by the Albert Einstein 
Cancer Center Data Safety Monitoring Board (DSMB). This board meets once a month 
with any additional meetings scheduled when needed. The responsibilities are as follows:  
 
 Familiarize themselves with the research protocol (s)  
 The DSMB reviews trial performance information such as accrual information.   
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 Review interim analyses of outcome data and cumulative toxicity data summaries 
to determine whether the trial should continue as originally designed, should be 
changed, or should be terminated based on these data.   
 The DSMB also determines whether and to whom outcome results should be 
released prior to the reporting of study results. 
 All adverse events are reviewed by the committee, with assurances that these have 
been in fact sent for review to all pertinent IRBs. 
 Review of reports of related studies to determine whether the monitored study 
needs to be changed or terminated. 
 Review major proposed modifications to the study prior to their implementation 
(e.g., termination, dropping an arm based on toxicity results or other reported trial 
outcomes, increasing target sample size). 
 Following each DSMB meeting, provide the study leadership with written 
information concerning findings for the trial as a whole related to cumulative 
toxicities observed and any relevant recommendations related to continuing, 
changing, or terminating the trial.  
 
 The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
14 BIOSTATISTlCAL ANALYSIS 
14.1 Safety evaluation 
Data from all subjects who receive any protocol therapy will be included in the safety 
analyses. Subjects who entered the study and did not receive any protocol therapy and 
had this confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible.  
14.2 Sample size and power considerations 
The primary outcome is major erythroid response. A maximum of 52 patients will be 
enrolled into the study.  An early stopping rule for lack of efficacy will be implemented 
as follows based on Simon’s optimal two-stage design.  After the first 25 patients have 
been enrolled and evaluated for response, the trial will be terminated early if fewer than 7 
patients respond to treatment. If 7 or more responses are observed, the trial will continue 
until a total of 52 patients have been evaluated.  At the end of the trial, the treatment will 
be considered efficacious and worthy of further study if 17 or more patients respond out 
of 52 patients.  
 
The target response rate is assumed to be 40%. (Conservative estimate)  A response rate 
less than 25% is considered to be clinically unimportant(21).  Under these assumptions, 
the design specified above has the following operating characteristics.  The probability 
of accepting the treatment for further study if the response rate is unacceptably low 
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(<25%) is at most 10%.  In contrast, there is a 80% probability of accepting the treatment 
for further study if the response rate is at least 40%.  The expected sample size is 32.4 
subjects.  It is also assumed that 10-20% of patients with plts > 50,000 that receive Len 
may not need Eltrombopag at all as there plts will not fall below 50,000. 
 
Furthermore, since we will accrue patients with both high and low platelet counts, it is 
possible that the response rates to Lenalidomide will be different in these groups. These 
will be analyzed by exploratory  studies. 
15 REGULATORY CONSIDERATIONS 
15.1 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator to the IRB/EC for approval.  The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
15.2 Protocol amendments 
Any amendment to this protocol must be agreed to by the Montefiore-Einstein Principal 
Investigator and reviewed by Celgene and GSK.  Amendments should only be submitted 
to IRB/EC after consideration of Celgene and GSK review.  Written verification of 
IRB/EC approval will be obtained before any amendment is implemented.   
Each change to the protocol document must be first approved by the Einstein IRB. 
Amendments significantly affecting the safety of subjects, the scope of the investigation 
or the scientific quality of the study require additional approval by the IRB at each 
participating study center.  A copy of the written IRB approval and corresponding 
documents must be provided to Montefiore-Einstein.  
 
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15.3 Continuing Review 
Participating sites must submit their continuing review approval letter from their IRB of 
Record accompanied by the most current approved version of the consent form prior to 
expiration.  Suspension of enrollment may be considered if receipt of this document does 
not occur within this time frame.Registration will be halted at any participating institution 
in which a current continuing approval is not on file. 
15.4 Deviations and Exceptions 
A protocol deviation is any change in the process or procedure of research that were not 
approved by amendment of an IRB approved protocol. Participating sites should report 
deviations to Montefiore-Einstein as soon as possible as well as maintain record the event 
on a deviation log that will be collected at the time of the Montefiore-Einstein’s IRB 
continuing review.  
A protocol exception on this study is defined as a planned one-time deviation from the 
IRB approved protocol. If a deviation from the protocol is proposed for a potential or 
existing participant at Montefiore-Einstein or a participating site, approval from 
Montefiore-Einstein IRB is required prior to the action. Participating sites should contact 
the Montefiore-Einstein PI who will in turn seek approval from the Montefiore-Einstein 
IRB. 
Participating sites should report deviations and exceptions to their institution’s IRBs as 
soon as possible per that site’s institutional guidelines. Approvals/acknowledgments from 
the participating site IRB for protocol deviations and exceptions should be submitted to 
Montefiore-Einstein as received.  
15.5 Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
15.6 Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene and GSK require the 
Investigator to permit representatives of Celgene Corporation and GlaxoSmithKline, and 
when necessary, representatives of the FDA or other regulatory authorities to review 
and/or copy any medical records relevant to the study in accordance with local laws. 
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Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
15.7 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the protocol therapy, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
SAE reports, pharmacy dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and drug accountability; 
original signed informed consents, etc.]) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  The 
Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
15.8 Premature discontinuation of study 
The Principal Investigator, institution, GSKand Celgene have the right to discontinue this 
study at any time for reasonable medical or administrative reasons.  Possible reasons for 
termination of the study could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 
 
16 CORRELATIVE STUDIES: 
 
Correlative studies will be performed on all subjects. Specifically, we will study: 
 
a. Whole transcriptome sequencing (RNA-Seq) of MDS bone marrow progenitors and 
correlation with response. Pretreatment bone marrow aspirates will be used for these 
studies. Bone marrow stem cells will be sorted and RNA will be isolated. Sequencing 
libraries will be generated and subjected to massive parallel sequencing using an Illumina 
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HiSeq2000 instrument.. The transcriptome patterns will be correlated with response. In 
addition to gene expression patterns, this study will also correlate mutations and single 
nucleotide polymorphisms with response to lenalidomide and eltrombopag. Somatic 
mutations will be identified by comparison of marrow and germline (toenail clippings or 
cheek swabs) samples. 
 
b. Analysis of “MDS” stem cells pre and post treatment with the combination of 
eltrombopag and lenalidomide and their correlation with response (Study co-chair Dr. 
Ulrich Steidl is an expert in flow sorting of leukemia stem cells and their functional 
characterization, both in vitro and in vivo). Using high-speed multi-parameter 
fluorescence-activated cell sorting we will separate bone marrow progenitors into long-
term and short-term hematopoietic stem cells as well as more committed myeloid, 
erythroid and megakaryocytic progenitors, as performed previously (22, 23). Stem cell 
compartments expanded in MDS as compared to normal bone marrow will be identified.  
Sorted cell fractions will be studied for the presence of pathogenic mutations and 
characteristic chromosomal lesions. Functional validation of sorted cell populations will 
be performed in vitro and in vivo.  
 
Our preliminary studies indicate that primitive stem cells (LT-HSCs and ST-HSCs) are 
expanded in MDS and harbor initiating karyotypic abnormalities and striking alterations 
in DNA methylation with an accumulation of aberrantly hypermethylated loci. 
Furthermore, we and others observe that karyotypically abnormal stem cells persist in the 
bone marrow even after morphological complete remission and thus may potentially lead 
to relapse of MDS (24). These preliminary data lead us to hypothesize that a pool of 
disease-initiating stem or early progenitor cells exists in MDS that contains and 
progressively acquires genetic and epigenetic alterations and may persist after 
conventional treatments.  The study of these MDS cells-of-origin and MDS-initiating cell 
populations will reveal fundamentally new information about early pathogenic events, 
which represent particularly promising targets for therapeutic intervention, as well as the 
modes of MDS progression.   
Quantitative and cytogenetic assessment of MDS stem and progenitor cells from marrow 
samples of responders and non-responders to lenalidomide and eltrombopag will be 
performed. Karyotypic, transcriptomal, as well as methylomic analysis of these cells will 
be conducted for clonal genetic and epigenetic assessment. Comparison of pretreatment 
and post treatment samples from both subsets of patients will demonstrate whether a 
decrease in clonal stem cells correlates with clinical response. We will also determine 
whether persistence of clonal stem cells in responders correlates with a risk of future 
relapse. 
 
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17 REFERENCES 
1. 
Kantarjian, H., Giles, F., List, A., Lyons, R., Sekeres, M.A., Pierce, S., Deuson, 
R., and Leveque, J. 2007. The incidence and impact of thrombocytopenia in 
myelodysplastic syndromes. Cancer 109:1705-1714. 
2. 
Liesveld, J.L., Jordan, C.T., and Phillips, G.L., 2nd. 2004. The hematopoietic 
stem cell in myelodysplasia. Stem Cells 22:590-599. 
3. 
Houwerzijl, E.J., Blom, N.R., van der Want, J.J., Louwes, H., Esselink, M.T., 
Smit, J.W., Vellenga, E., and de Wolf, J.T. 2005. Increased peripheral platelet 
destruction and caspase-3-independent programmed cell death of bone marrow 
megakaryocytes in myelodysplastic patients. Blood 105:3472-3479. 
4. 
Kalina, U., Hofmann, W.K., Koschmieder, S., Wagner, S., Kauschat, D., Hoelzer, 
D., and Ottmann, O.G. 2000. Alteration of c-mpl-mediated signal transduction in 
CD34(+) cells from patients with myelodysplastic syndromes. Exp Hematol 
28:1158-1163. 
5. 
Brereton, M.L., Adams, J.A., Briggs, M., and Liu Yin, J.A. 1999. The in vitro 
effect of pegylated recombinant human megakaryocyte growth and development 
factor (PEGrHuMGDF) on megakaryopoiesis in patients with aplastic anaemia. 
Br J Haematol 104:119-126. 
6. 
Kantarjian, H., Fenaux, P., Sekeres, M.A., Becker, P.S., Boruchov, A., Bowen, 
D., Hellstrom-Lindberg, E., Larson, R.A., Lyons, R.M., Muus, P., et al. 2010. 
Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic 
syndrome and thrombocytopenia. J Clin Oncol 28:437-444. 
7. 
Bussel, J.B., Cheng, G., Saleh, M.N., Psaila, B., Kovaleva, L., Meddeb, B., 
Kloczko, J., Hassani, H., Mayer, B., Stone, N.L., et al. 2007. Eltrombopag for the 
treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 
357:2237-2247. 
8. 
Jenkins, J.M., Williams, D., Deng, Y., Uhl, J., Kitchen, V., Collins, D., and 
Erickson-Miller, C.L. 2007. Phase 1 clinical study of eltrombopag, an oral, 
nonpeptide thrombopoietin receptor agonist. Blood 109:4739-4741. 
9. 
Erickson-Miller, C.L., Pelus, L.M., and Lord, K.A. 2000. Signaling induced by 
erythropoietin and stem cell factor in UT-7/Epo cells: transient versus sustained 
proliferation. Stem Cells 18:366-373. 
10. 
Erickson-Miller, C.L., Kirchner, J., Aivado, M., May, R., Payne, P., and 
Chadderton, A. 2010. Reduced proliferation of non-megakaryocytic acute 
myelogenous leukemia and other leukemia and lymphoma cell lines in response 
to eltrombopag. Leuk Res 34:1224-1231. 
11. 
Erickson-Miller, C.L., Delorme, E., Tian, S.S., Hopson, C.B., Landis, A.J., 
Valoret, E.I., Sellers, T.S., Rosen, J., Miller, S.G., Luengo, J.I., et al. 2009. 
Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide 
thrombopoietin receptor agonist. Stem Cells 27:424-430. 
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12. 
Will, B., Kawahara, M., Luciano, J.P., Bruns, I., Parekh, S., Erickson-Miller, 
C.L., Aivado, M.A., Verma, A., and Steidl, U. 2009. Effect of the non-peptide 
thrombopoietin receptor agonist eltrombopag on bone marrow cells from patients 
with acute myeloid leukemia and myelodysplastic syndrome. Blood. 
13. 
Heaney, M.L., and Golde, D.W. 1999. Myelodysplasia. N Engl J Med 340:1649-
1660. 
14. 
List, A., Kurtin, S., Roe, D.J., Buresh, A., Mahadevan, D., Fuchs, D., Rimsza, L., 
Heaton, R., Knight, R., and Zeldis, J.B. 2005. Efficacy of lenalidomide in 
myelodysplastic syndromes. N Engl J Med 352:549-557. 
15. 
List, A., Gewald, G., Bennett, J., Giagounadis, A., Raza, A., Feldman, E., Powell, 
B., Greenberg, P., Faleck, H., Zeldis, J., et al. 2005. Results of the MDS-002 and -
003 international phase II studies evaluating lenalidomide (CC-5013; Revlimid*) 
in the treatment of transfusion-dependent patients with myelodysplastic syndrome 
(MDS). Haematologica 90:307a. 
16. 
List, A., Gewald, G., Bennett, J., Giagounadis, A., Raza, A., Feldman, E., Powell, 
B., Greenberg, P., Zeldis, J., and Knight, R. 2005. Hematologic and cytogenetic 
response to lenalidomide (CC-5013; REVLIMID*) in patients with transfusion-
dependent (TD) Myelodysplastic Syndrome (MDS) and chromosome 5q31.1 
deletion: Results of the Multicenter MDS-003 Study. Journal of Clinical 
Oncology 23:2a. 
17. 
Sekeres, M.A., Maciejewski, J.P., Giagounidis, A.A., Wride, K., Knight, R., 
Raza, A., and List, A.F. 2008. Relationship of treatment-related cytopenias and 
response to lenalidomide in patients with lower-risk myelodysplastic syndromes. 
J Clin Oncol 26:5943-5949. 
18. 
Escoubet-Lozach, L., Lin, I.L., Jensen-Pergakes, K., Brady, H.A., Gandhi, A.K., 
Schafer, P.H., Muller, G.W., Worland, P.J., Chan, K.W., and Verhelle, D. 2009. 
Pomalidomide and lenalidomide induce p21 WAF-1 expression in both 
lymphoma and multiple myeloma through a LSD1-mediated epigenetic 
mechanism. Cancer Res 69:7347-7356. 
19. 
Verhelle, D., Corral, L.G., Wong, K., Mueller, J.H., Moutouh-de Parseval, L., 
Jensen-Pergakes, K., Schafer, P.H., Chen, R., Glezer, E., Ferguson, G.D., et al. 
2007. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells 
while expanding normal CD34+ progenitor cells. Cancer Res 67:746-755. 
20. 
Cheson, B.D., Greenberg, P.L., Bennett, J.M., Lowenberg, B., Wijermans, P.W., 
Nimer, S.D., Pinto, A., Beran, M., de Witte, T.M., Stone, R.M., et al. 2006. 
Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 108:419-425. 
21. 
Raza, A., Reeves, J.A., Feldman, E.J., Dewald, G.W., Bennett, J.M., Deeg, H.J., 
Dreisbach, L., Schiffer, C.A., Stone, R.M., Greenberg, P.L., et al. 2008. Phase 2 
study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk 
myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111:86-
93. 
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22. 
Steidl, U., Rosenbauer, F., Verhaak, R.G., Gu, X., Ebralidze, A., Otu, H.H., 
Klippel, S., Steidl, C., Bruns, I., Costa, D.B., et al. 2006. Essential role of Jun 
family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat 
Genet 38:1269-1277. 
23. 
Steidl, U., Steidl, C., Ebralidze, A., Chapuy, B., Han, H.J., Will, B., Rosenbauer, 
F., Becker, A., Wagner, K., Koschmieder, S., et al. 2007. A distal single 
nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute 
myeloid leukemia. J Clin Invest 117:2611-2620. 
24. 
Tehranchi, R., Woll, P.S., Anderson, K., Buza-Vidas, N., Mizukami, T., Mead, 
A.J., Astrand-Grundstrom, I., Strombeck, B., Horvat, A., Ferry, H., et al. 2010. 
Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J 
Med 363:1025-1037. 
 
 
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Appendices 
 
Appendix 1: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is 
structurally related to thalidomide.  Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of 
female monkeys who received the drug during pregnancy.  The teratogenic effect of 
lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to 
prevent pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMS™ program, 
and be willing and able to comply with the requirements of Revlimid REMS™. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
The investigator must ensure that: 
 Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of 
understanding 
 Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide 
 Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 
teratogenic risk if engaged in sexual activity with a female of childbearing 
potential, and that he understands the need for the use of a condom even if he has 
had a vasectomy, if engaged in sexual activity with a female of childbearing 
potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
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heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of 
lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after 
lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:   
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
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Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to prescribing lenalidomide.  The patient may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests 
are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual 
contact with pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 days 
following lenalidomide discontinuation, even if he has undergone a successful 
vasectomy.   
During study participation and for 28 days following lenalidomide discontinuation  
Female Patients: 
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of 
lenalidomide 
treatment, 
including 
dose 
interruptions, 
at 
lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the 
first 28 days of lenalidomide treatment, including dose interruptions, and then 
every 14 days throughout the remaining duration of lenalidomide treatment, 
including dose interruptions, at lenalidomide discontinuation, and at Day 14 and 
Day 28 following lenalidomide discontinuation.   
 At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control at each visit during the time that birth 
control is required.   
 If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016


 
 
 
  
 
 
 
 
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 Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after lenalidomide discontinuation. 
Male Patients: 
 Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 
days following lenalidomide discontinuation, even if he has undergone a 
successful vasectomy.   
 If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
 Patients should be instructed never to give lenalidomide to another person. 
 Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
 Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
 Only enough lenalidomide for one cycle of therapy may be prescribed with each 
cycle of therapy.  
 
 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016


 
 
 
  
 
 
 
 
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Appendix 2 – ECOG Performance Status Scale 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016


 
 
 
  
 
 
 
 
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Appendix 3:  Cockcroft-Gault estimation of CrCl: 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85 
   (Females) 
 
72 x (serum creatinine, mg/dL) 
 
 
 
 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016


 
 
 
  
 
 
 
 
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Appendix 4 – International Prognostic Scoring System (IPSS) for MDS 
 
 
 
 
 
 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016


 
 
 
  
 
 
 
 
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Appendix 5 NCI CTC Version 4.0 
 
TOXICITY WILL BE SCORED USING NCI CTC VERSION 4.0 FOR TOXICITY 
AND ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTC 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 CTC VERSION. 
 
 
 
 
 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
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IRB APPROVAL DATE: 05/16/2016
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APPENDIX 6 – CORRELATIVE STUDIES:  
All specimens for correlative studies must be labeled with the patient’s code number, 
which will be assigned by the Data Management Office, and should not bare the patient’s 
identity.  The specimens must be kept at room temperature and sent by fedex to  
 
Amit Verma, MD 
Albert Einstein College of Medicine, 
1300 Morris Park Ave, Chanin 302B 
Bronx, NY 10461 
Tel : 718 430 8761 
Fax: 718 430 8702  
amit.verma@einstein.yu.edu 
.  
Bone Marrow Aspirate: 10cc of heparinized marrow aspirate will be required.  We will 
perform flow cytometry and genome wide sequencing from these samples. RNA and 
DNA from patient bone marrow specimens at baseline will be sequenced to correlate 
expression patterns and mutational patterns with response. Three unstained slides 
containing bone marrow aspirate will be required for further studies 
 
Peripheral Blood: If the bone marrow aspirate cannot be obtained then we will require 3 
green top tubes, with 8 cc of blood each. Mononuclear cells from patient’s peripheral 
blood will be purified by Ficoll-Hypaque sedimentation and these cells used for the 
Immunophenotyping by flow cytometry (CD33, CD34 and CD11b). These samples will 
also be used for possibly interphase FISH studies (if abnormal cytogenetics found at 
diagnosis). Cells will be frozen for future RNA extraction to perform gene expression 
studies. 
 
Buccal swabs:Buccal swabs with brushes will be done at baseline and stored in RNA 
later solution. RNA/DNA will be isolated from these samples and compared to bone 
marrow samples to determine somatic mutations in MDS stem cells. 
 
Banking of Samples: Peripheral blood, bone marrow, cell lysates, and cell products 
obtained from the previously mentioned samples will be stored for subsequent research 
related to this project. 
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016
IRB NUMBER: 2012-407
IRB APPROVAL DATE: 05/16/2016