Clinical trial NCT01000051
Conditions: Thrombocytopenia
Keywords: Transplant Thrombocytopenia Hematopoietic cell transplantation HCT Low platelet count Bleeding Blood clot Stem Cell Transplant Blood And Marrow Transplantation Eltrombopag Promacta
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-02-17; Completion date: 2018-04-04
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if eltrombopag can help to improve platelet counts in patients with low platelets after they have had a stem cell transplant. The safety of this drug will also be studied.

Detailed description:
The Study Drug:

Platelets are cells that help the blood clot. Platelet counts are often lower after receiving a stem cell transplant. When the number of platelets in your body gets too low, it can cause bleeding. Eltrombopag is designed to imitate a protein in your body that helps make platelets. This may help your platelet counts stay normal.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups:

* If you are in Group 1, you will receive eltrombopag.
* If you are in Group 2, you will receive a placebo. A placebo is a substance that looks like the study drug but has no active ingredients.

If you are 1 of the first 20 participants enrolled in this study, you will have an equal chance of being assigned to either group. If you join the study after 20 participants have been enrolled, you will have a better chance of being assigned to Group 1 if eltrombopag has been shown to be more effective.

Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Drug Administration:

You will take the study drug/placebo pills by mouth 1 time each day while you are on study. The study drug/placebo should be taken on an empty stomach (1 hour before or 2 hours after food/drink). You may drink water, coffee, and/or tea with the study drug/placebo. You should drink any coffee or tea without milk or cream.

The dose of study drug/placebo may be adjusted (raised or lowered) throughout the study based on your reaction to the study drug/placebo.

Study Visits:

Every 2 weeks, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any side effects you may have had.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* Blood (about 1 teaspoon) will be drawn for PK testing.
* Blood (about 1 tablespoon) will be drawn to check your immune system.

If your blood tests show that you may have fiber deposits (build-up) in the bone marrow, you will have a bone marrow biopsy to check the status of the disease

If you have symptoms of cataracts (clouding of the lens of the eye) anytime during the study, you will have an eye exam.

Length of Study:

You will take the study drug for up to 8 weeks. You will have study visits for 12 weeks. You will be taken off study if you have intolerable side effects.

End-of-Treatment Visit:

After completion of study drug, you will have the following tests and procedures performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any side effects you may have had.
* Blood (about 3 tablespoons) will be drawn for routine tests.
* Blood (about 1 tablespoon) will be drawn to check your blood's clotting ability.
* Blood (about 1 tablespoon) will be drawn to check your immune system.

Weeks 10 and 12 (+/- 3 days), you will have the following tests and procedures performed:

* You will have a telephone interview.
* You will be asked about any side effects you may have had.
* Blood (about 3 tablespoons) will be drawn for routine tests.
* Blood (about 1 tablespoon) will be drawn to check your blood's clotting ability.
* You will either have blood drawn locally or where you live regionally.

Within the 3 months after your last dose of study drug, you will have a bone marrow biopsy to check the status of the disease and an eye exam. The eye exam may be performed sooner if you develop symptoms of a cataract, such as blurry vision.

This is an investigational study. Eltrombopag is FDA approved and commercially available for the treatment of low platelet counts in patients with idiopathic thrombocytopenic purpura (ITP -- a severe bleeding disease). Its use in patients with low platelet counts after a stem cell transplant is investigational.

Up to 64 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Starting dose 50 mg/day orally for 8 weeks arm 2: Once a day orally for 8 weeks
Interventions: intervention 1: Eltrombopag intervention 2: Placebo
Intervention descriptions: intervention 1: Starting daily dose 50 mg orally on empty stomach (1 hour before or 2 hours after a meal) for 8 weeks. East Asians start at 25 mg daily. intervention 2: Once a day, orally for 8 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
2009-0106
July 8, 2015
Abstract - Page 1
Protocol Abstract Page
Eltrombopag for post transplant thrombocytopenia
2009-0106
Core Protocol Information
Study Chairman: 
Uday Popat
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
423
Full Title: 
Eltrombopag for post transplant thrombocytopenia
Protocol Phase:
Phase II
Version Status:
Terminated 04/16/2018
Version:
20
Document Status:
Final
Abstract
Objectives:
Primary Objective
 
1.1 
To compare the efficacy of eltrombopag and placebo as defined by proportion of 
patients achieving platelet count >/= 30 x 10
9/l by day 57 in patients with 
thrombocytopenia post hematopoietic cell transplantation (HCT).
Secondary Objectives
1.2 
To describe and estimate toxicity graded as per National Cancer Institute (NCI) 
criteria.
1.3 
To estimate clinical benefit as defined by: 
1.3.1 Proportion of patients achieving platelet count >/= 50 x 10
9/l by day 57
1.3.2 Number of platelet and red cell transfusions
1.3.3 Bleeding as determined by NCI criteria
1.4
To determine the optimum dose of eltrombopag in this patient population.
1.5 
To estimate pre and post treatment thrombopoietin levels and correlate these 
with platelet response.
1.6
To measure drug level and correlate it with response. 
Rationale: (Be as concise as possible)


2009-0106
July 8, 2015
Abstract - Page 2
Low platelet count, which is usual after HCT, significantly increases   the risk of 
bleeding. The incidence of bleeding post HCT is 34%, which is moderate or severe in 
23% of the patients. Currently regular platelet transfusion remains the mainstay of 
therapy, with most patients requiring platelet transfusion several times a week. This 
imposes a significant burden on transfusion services and increases the cost. 
Reduced platelet production is a major cause of thrombocytopenia post transplant with 
increased platelet destruction playing a minor role. Platelet recovery occurs between 11 
– 28 days post transplant.  Delayed platelet recovery (primary thrombocytopenia) 
occurs in 5%-25% of patients 8 weeks after HCT. Furthermore, 20% of patients develop 
secondary thrombocytopenia, defined as a drop in platelet count not due to disease 
relapse after an initial platelet recovery. Secondary thrombocytopenia is caused by both 
impaired production and increased destruction resulting from dysregulated immune 
system. It is often associated with Graft versus host disease and drugs like ganciclovir.
Thrombopoietin (TPO) is the primary regulator of platelet production, and is required for 
proliferation and differentiation of its precursors. Eltrombopag  is a nonpeptide small 
molecule that stimulates thrombopoiesis by activating TPO receptor. 
Eltrombopag received approval from the FDA for the treatment  of chronic Idiopathic 
Thrombocytopenic Purpura (ITP).   In a randomized placebo controlled trial in patients 
with ITP, 59% eltrombopag patients and 16% placebo patients responded achieving a 
platelet count >/= 50,000 per µL with an odds ratio of 9.61 (95% CI 3.31-27.86; 
p<0.0001). It also increases platelet counts in patients with thrombocytopenia and 
cirrhosis due to hepatitis C. 
In light of its significant efficacy in increasing platelet production and modest toxicity, It 
is certainly a promising agent for patients who develope thrombocytopenia post stem 
cell transplantation.
Eligibility: (List All Criteria)
Inclusion:
1)
Patients >/= 35 days post HCT with Platelet count </= 20 x 10^9/l sustained for 7 days or patients 
are platelet transfusion dependent, and
2)
Neutrophil count >/= 1.5 x 10^9/l anytime within the last seven days before enrollment. Patients can 
be on myeloid or erythroid growth factors for example filgrastim), and
3)
Age >/= 18
Exclusion:
1)
Recurrence or progression of primary malignancy after HCT
2)
ALT >/= 2.5 times the ULN


2009-0106
July 8, 2015
Abstract - Page 3
3)
Serum bilirubin >2mg/dl (unless due to Gilbert’s syndrome)
4)
Documented deep vein thrombosis within 1 year before enrollment on the study, except if upper 
arm thrombosis related to central venous catheters, within 3 months before enrollment on the study.
5)
ECOG Performance status >2
6)
Pregnancy: Women of child-bearing potential and men must agree to use contraception prior to 
study entry and for the duration of study participation. A woman of child-bearing potential is defined as a 
woman who has not been naturally post-menopausal for at least 12 consecutive months or with no 
previous surgical sterilization. A negative pregnancy test result will be required before any study drug is 
given.
Is there an age limit?  Yes
Why?  Provide scientific justification:
It is a new molecule that has not been previously tested in children.
Disease Group:
Blood And Marrow Transplantation
Treatment Agents/Devices/Interventions:
Eltrombopag
Proposed Treatment/Study Plan:
Dosage and Administration 
Eltrombopag will be given as a single daily dose orally on an empty stomach (1 hour 
before or 2 hours after a meal). Starting dose will be 50 mg. Dose will be modified as 
detailed below. Eltrombopag or placebo will be continued for 8 weeks.  East Asians will 
start at 25mg daily.
Allow at least a 4-hour interval between eltrombopag and other medications (e.g., 
antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or 
supplements containing polyvalent cations such as iron, calcium, aluminum, 
magnesium, selenium, and zinc.
5.1
Monitoring and Dose adjustment 
5.1.1 Patients in the treatment group will be started at dose level 0 (table 1), the 
dose will be modified every 2 weeks based on the schema outlined in 
table 2 after a careful review of safety information at the previous dose 
level. 
Table 1 Dose Level
Dose level
Eltrombopag dose


2009-0106
July 8, 2015
Abstract - Page 4
-1
25mg
0
50mg
1
75mg
2
125mg
   3
   150mg
Table 2 Dose Modification Schema
Platelet count X 10
9/l
Dose 
< 50
Increase by 1 dose level
50-200
No change
201-400 
Decrease by 1 dose level
> 400 at any time 
Stop the drug
5.1.2 Drug will be stopped and patients will be taken off study if at any time 
platelet count is >/= 400 X 10
9/l. This count will be carried forward to day 
57 for analysis of primary endpoint and counted as success.
5.1.3 Patients of East Asian ancestry will start at dose level -1 and dose 
escalation will stop at dose level 2 (maximum dose 125 mgs). 
5.1.4 The study drug will be stopped after 8 weeks and all patients will be 
monitored for additional 4 weeks after the last dose of study drug.
5.1.5 Patients will be taken off study: 1) at patient request, or 2) after completing 
12 weeks.


2009-0106
July 8, 2015
Abstract - Page 5
5.2
Evaluations During Study
Table 3 Monitoring
Pre Study 
(within 3 days of 
consent)
 Week 1-12 
 (every 2 wks)###
Post Completion of study 
drug**
CBC, Na, K, Cl, CO2, 
ALT, Bili, Alk Phos, 
albumin, tot protein, 
BUN & creatinine
 X
X
X
  PT/PTT
  X
      X
Thrombopoietin 
X
X
PK Studies 
 
    X^^
Toxicity assessment 
(history and PE) 
(Graded per NCI 
toxicity criteria)
 X
X
X
Bone Marrow (incl 
reticulin and collagen 
staining)
 X# 
X^
B-HCG pregnancy test in 
women of child- bearing 
age
 
  X## 
No. of Platelet & RBC 
transfusions
X (in the 4 wks prior to 
study entry)
X
X
Immune Reconstitutional 
Studies
+++
 X
X     
       
Ophthalmic Evaluation
X
+
X
++
# A previous biopsy done within one year is acceptable for baseline purposes and a separate bone 
marrow biopsy will not be required. To assess for fibrosis, special staining for reticulin and collagen will 
be performed.
## Negative pregnancy test is required prior to receiving drug but is not required prior to consent.
### Visits at Week 10 and 12  will done by telephone interview and blood work can be drawn locally.
 ^ First routine bone marrow done after study completion for assessment of disease status will be stained 
for reticulin and collagen to assess fibrosis.The bone marrow will be performed within 3 months after 
the last dose of study drug.
^^ No PK studies will be drawn for weeks 10 and 12.
**Date of last dose of study drug.


2009-0106
July 8, 2015
Abstract - Page 6
+ Within 6 months of study entry.
++ Within 3 months of last dose of study drug. This will be done earlier if patients develop visual symptoms 
indicative of cataract.
+++ Peripheral blood T-cell subsets, NK and B-cell immune reconstitution
Note: All assessments to be done within 3 days of stated time point.
Statistical Considerations:
Overview
This will be a randomized, double-blind Phase II trial to compare eltrombopag and 
placebo in patients with thrombocytopenia post transplant.  The primary endpoint will be 
development of a platelet count >/= 30 X 10
9/l by day 57 without platelet transfusion.  
Adaptive Randomization
We will use a Bayesian adaptive algorithm (Berry, 1994) to randomize patients between 
the two treatment arms.  The first 20 patients will be randomized fairly (i.e. fixed 
allocation of 1:1) between the two arms, after which the response adaptive 
randomization will begin.  As the trial progresses and data accrue, the randomization 
will be become unbalanced in favor of the treatment that, on average, has better results 
in terms of response, so that each successive patient is more likely to receive the 
treatment showing better results.
The randomization algorithm based upon this method will be implemented by using the 
Clinical Trial Conduct website developed by the Department of Biostatistics at M.D. 
Anderson Cancer Center. 
The target enrollment for the study is a maximum of 64 patients, and we expect to enroll 
an average of 2 patients per month.  We will follow all patients until they go off study.  
We assume a Beta(0.4, 1.6) prior distribution for the probability of response in each 
arm.  We use the following notation:  We denote the response rate in the placebo arm 
as RP, and the response rate in the eltrombopag arm as RE.  We then denote PP as the 
probability that the response rate in the placebo arm is greater than the response rate in 
the eltrombopag arm.  Formally,
PP = Prob (RP  >  RE | data from patients evaluated at day 57) and     
PE = 1-PP = Prob (RE  >  RP | data from patients evaluated at day 57)     
The trial will be stopped early and eltrombopag (placebo) selected as being superior if 
at any time during the course of the trial PP > 0.98 (< 0.02).  If the trial is not stopped 
early and all 64 patients are enrolled and evaluated at day 57, then eltrombopag will be 
declared superior (inferior) if PP > 0.975 (< 0.025).  


2009-0106
July 8, 2015
Abstract - Page 7
After the first 20 patients are randomized fairly, patients will be randomized to the 
eltrombopag arm with probability max(0.20, PP) and to the placebo arm with probability 
max(0.20, PE).  In other words, randomization probabilities are subject to the constraint 
that the minimum randomization probability to either arm is 20%. 
The primary endpoint is development of a platelet count >/= 30 X 109/l at day 57 
without platelet transfusion within 7 days.  Patients who drop out of the trial before 
completion of day 57 with a platelet count >/= 30 X 109/l at the time of discontinuation 
will be considered successes with respect to the primary endpoint.
Patients who drop out of the study after being randomized but before receiving any 
study drug will not be included in the analysis and will be replaced.  All patients who 
receive a single dose of study drug will be included in the analysis.
Safety Monitoring
Patient safety will be monitored during this trial by reviewing the rate of development of 
toxicity, relapse, and mortality.  
If a patient develops a grade 3 or higher toxicity attributed to the drug, the study drug 
will be stopped in that patient. This may be recommenced at the discretion of PI after 
resolution of the toxicity and review of the data. 
For grade 4 toxicity, the PI will routinely review patient data and will temporarily halt the 
study pending study team review if a high rate of unexpected grade 4 toxicity is noticed.  
The case report form used for data collection will be PDMS/CORE.
We will use a formal Bayesian monitoring rule to monitor the rate of death or relapse on 
this study.  We wish to ensure that the rate of death/relapse at day 57 is no more than 
30% in either study arm.  If there is a high probability that this rate is greater than 30% 
in either arm, we will temporarily halt and review the data with the MDACC IRB and 
FDA before continuing. 
The method of Thall, Simon, and Estey will be employed separately in each arm to 
perform this monitoring.  We will assume a noninformative Beta(0.6, 1.4) distribution on 
the prior probability that a patient experiences death or relapse, which has a mean of 
30% but carries little prior information.  We will start monitoring with the first patient in 
each arm and will use the following rule:  halt accrual onto an arm if at any time during 
the course of the study:
Pr{57-day death/relapse on the arm > 30% |
data from patients evaluable at day 57} > 0.925


2009-0106
July 8, 2015
Abstract - Page 8
Where Will Participants Be Enrolled:
Only at MDACC
Is this an NCI-Cancer Therapy Evaluation Protocol (CTEP)?
No
Is this an NCI-Division of Cancer Prevention Protocol (DCP)?
No
Estimated Accrual:
Total Accrual at MDACC:
64
Estimated monthly accrual at MDACC:
2
Accrual Comments:
Do you expect your target population to include non-english 
speaking participants?
Yes
Please select expected languages of non-English speaking participants.  (Select all that apply)
Expected languages of non-English speaking participants:
Spanish
Location of Treatment:
This protocol is performed on an Outpatient basis.


2009-0106
July 8, 2015
Abstract - Page 9
Length of Stay: What is the length & frequency of hospitalization?
N/A
Return Visits: How often must participants come to MDACC?
Every 2 weeks for first  eight weeks during the period of active treatment
Home Care: Specify what, if any, treatment may be given at home.
1) Observation without any treatment from week 9 to 12 and 2) Open label phase after week 12 if  patient 
chooses to enrol in it.  
Name of Person at MDACC Responsible for Data Management:  Man-Yin C. Poon
Prior protocol at M. D. Anderson:
Has the Principal Investigator ever had a clinical or behavioral protocol at MDACC that accrued patients?
Yes
Data Monitoring Committee:
Is treatment assignment randomized? Yes
Is this a blinded or double-blinded study? Yes
Does this Protocol need data safety monitoring?
Yes
Provide the name of the data safety monitoring board (DSMB) monitoring this protocol:
MDACC DMC
Does this protocol have a schedule for interim and final analysis?
Yes
Please describe:
Bayesian adaptive design
Radiation Safety:
Does this study involve the administration of radioisotopes or a radioisotope 
labeled agent?
No
Is the radioactive compound (or drug) FDA approved and/or commercially 
available?
No
Investigational New Drugs:
Does this protocol require an IND?
Yes
Please list the IND holder and provide the IND number:
IND Holder:
MDACC
IND Number:
106,182


2009-0106
July 8, 2015
Abstract - Page 10
Investigational Device:
Is the Investigational Device approved by the FDA?
N/A
Is the Investigational Device being used in the manner approved by 
the FDA?
N/A
Has the Investigational Device been modified in a manner not 
approved by the FDA?
N/A
Name of Device:
N/A
Manufacturer:
N/A
What is the FDA Status of the Investigational Device?
Not Marketed.
Is the study being conducted under an Investigational Device Exemption (IDE)? No
IDE Holder:
N/A
IDE Number: N/A
Risk Assessment:
Please answer the following questions regarding the Investigational Device.
Intended as an implant?
No
Purported or represented to be for use supporting or sustaining human life?
No
For use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health?
No
You may attach sponsor documentation of the risk assessment:
Will participant be charged for the Investigational Device? No
Sponsorship and Support Information:
Does the Study have a Sponsor or Supporter?
Yes
Sponsor or Supporter:
Novartis Pharmaceuticals Corporation
Type(s) of Support:
Funds
Agent
Monitored by Sponsor or Sponsor Represenative (CRO)?
No
Is this Protocol listed on any Federal Grant or Foundation Funding Application?No
Biosafety:


2009-0106
July 8, 2015
Abstract - Page 11
Does this study involve the use of Recombinant DNA Technology? 
No
Does this study involve the use of organisms that are infectious to humans? 
No
Does this study involve stem cells?
No
Technology Commercialization:
Does this study include any agents or devices manufactured or produced at 
MD Anderson Cancer Center?
No
Laboratory Tests:
Where will laboratory tests be performed on patient materials?  (Please select all that apply)
Division of Pathology & Laboratory Medicine CLIA Certified Laboratory
Other
Please provide the name of the test(s), the purpose of the test, and the performing laboratory 
identification and contact information.
1) Thrombopoietin assay :  To check thrombopoietin levels pre and post treatment.
R & D systems 
Mark Dahlquist
Key Account Manager
R&D Systems, Inc.
614 McKinley Place NE
Department 371
Minneapolis, MN 55413-2610
2) Eltrombopag levels: to be done at GlaxoSmithKline
GlaxoSmithKline
Department of Drug Metabolism and PharmacoKinetics
Mail Stop UW2710
709 Swedeland Road
King of Prussia, PA 19406
USA
Attn: Kathleen Dolce/Josh Albert
.
Manufacturing:
Will you manufacture in full or in part (split manufacturing) a drug or biological 
product at the M. D. Anderson Cancer Center for the proposed clinical study?
No