Safety and Efficacy of Eltrombopag in Patients Undergoing Cord Blood or Haploidentical Bone Marrow Transplantation
Phase: PHASE2
Conditions: Bone Marrow Transplantation Recipient, Cord Blood Transplant Recipient, Hematopoietic Cell Transplantation Recipient
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2012-0920 
Protocol Title 
Safety and Efficacy of Eltrombopag in Patients Undergoing Cord Blood 
or Haploidentical Bone Marrow Transplantation 
Protocol Phase 
Phase II 
Protocol Version 
Version 18 
Version Date 
24 November 2020 
 
Protocol PI 
Uday R. Popat, MD 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
106,182 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Safety and Efficacy of Eltrombopag in Patients Undergoing Cord Blood or 
Haploidentical Bone Marrow Transplantation 
 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
Institution Study Number:  2012-0920 
Financial Support:   Novartis 
Novartis Protocol Number:   CETB115AUS09T 
IND Holder:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  106,182 
Principal Investigator:  Uday R. Popat, MBA, MD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: 713.745.3055 
Fax: 713.794.1415 
upopat@mdanderson.org 
 
Co-Chairs:  Chitra M. Hosing, MD1 
 
 
Collaborators:  Roland L. Bassett, MS2 
Richard E. Champlin, MD1 
Katy Rezvani, MD, PhD1 
Elizabeth Shpall, MD1 
 
 

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Table of Contents 
 
1.0 
Objectives ................................................................................................................................ 3 
2.0 
Background ............................................................................................................................. 3 
3.0 
Background Drug Information .................................................................................................. 5 
4.0 
Patient Eligibility ....................................................................................................................... 8 
5.0 
Treatment Plan ........................................................................................................................ 9 
6.0      Pretreatment evaluation ......................................................................................................... 10 
7.0 
Evaluation During The Study ................................................................................................. 10 
8.0      Statistical Considerations....................................................................................................... 11 
9.0 
Adverse Events and Reporting Requirements ........................................................................ 13 
10.0 
References ............................................................................................................................ 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Body 
 
 
 
1.0 Objectives 
 
Primary Objective: To estimate the rate of platelet engraftment by Day 60 in patients 
undergoing cord blood transplant (CBT) or haploidentical donor stem cell transplantation 
treated with eltrombopag. 
Secondary objectives: 
1) To assess safety of eltrombopag in this population 
2) To assess neutrophil engraftment with eltrombopag in this population 
3) To characterize immune reconstitution 
4) To assess overall survival (OS) 
5) To assess progression free survival (PFS) 
6) To assess incidence of acute graft-versus-host disease (GVHD) 
 
 
2.0 Background 
 
Allogeneic hematopoietic cell transplantation (HCT) is the preferred choice for many benign 
and malignant hematological diseases.[1] Unfortunately, only 30% of subjects have a 
matching family donor. Matching unrelated donor is available for another 50% of 
Caucasians, but a significantly lower proportion of non-Caucasian subjects are matched 
after a median time of 4 months. Hence, an alternative source of stem cells is needed. 
Umbilical cord blood transplantation (CBT) and haploidentical bone marrow transplantation 
are potential alternative for these subjects.[2] 
 
Cord Blood Transplantation and Haploidentical Transplantation 
Cord blood transplantation and haploidentical donor transplantation are effective 
alternatives for patients who do not have a suitable matching donor. Results of these 
treatment modalities are slowly improving and in many instances are similar to those 
obtained with matching donors.[2-4] However, there is still a need to further improve 
outcomes with these modalities. 
 
Both engraftment[5] and immune reconstitution[6] are delayed in subjects undergoing CBT and 
haploidentical transplantation compared with matched donors. This results in higher 
incidence of infections, which increase morbidity and mortality.[7] Engraftment data from 
various graft sources are summarized below in table 1. 
 
Table 1 
 
Matched 
Bone 
[8] 
Marrow 
Matched 
Peripheral 
[8] 
Blood 
Single 
[5] 
Cord 
Double 
[9] 
Cord 
Haploidentical 
[10] 
donor 
Median time to neutrophil 
engraftment days 
20 
12 
27 
24 
15 
Median time to platelet 
engraftment days 
20 
15 
60 
49 
28 
 

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Poor engraftment and poor immune reconstitution results in higher treatment related 
mortality. In a study of 742 subjects who had received myeloablative therapy and a single 
CB unit in North America or Europe through 2005, the 100-day treatment-related mortality 
rate was 44%.[11] In an attempt to improve engraftment and hence morbidity and mortality, 
investigators have combined two units of cord blood and infused them as allogeneic 
hematopoietic support improving engraftment by several days, but it still remains 
significantly inferior to transplant from fully matched donor.[9,12,13] 
 
Likewise platelet engraftment is delayed occurring at a median of 28 days (0-395 days) in 
patients undergoing haploidentical transplantation using T replete marrow graft with post-
transplant cyclophosphamide.[10] This is likely due to use of bone marrow as a graft source 
and use of cyclophosphamide after transplant, which results in significantly delayed 
engraftment. A major cause of mortality in these patients is infection resulting from poor 
immune reconstitution.[2,7,14] Further effort at improving engraftment and immune 
reconstitution is clearly needed. 
 
At MD Anderson Cancer Center, we have previously reported engraftment data in a 
smaller number of patients in both of these groups.[15- 18] In order to get detailed data for 
engraftment in a larger number of patients and to serve as a baseline for this proposal, we 
reviewed our historic platelet engraftment data in these two groups of patients and they 
are summarized in Table 2. 
 
Table 2 
 
Cord blood (n=91) 
Haploidentical Donor (n=54) 
Time to platelet >20K 
Median (range) days 
43 (0-126) 
29 (0-59) 
At Day 30 proportion of 
patients with 
Platelet >20K 
19% 
61% 
Platelet >50K 
2% 
20% 
At Day 60 proportion of 
patients with 
Platelet >20K 
60% 
88% 
Platelet >50K 
44% 
63% 
 
 
Hence at Day 30 after transplant only 2% (2/91) of patients receiving cord blood and only 
20% (11/54) of patients receiving haploidentical graft achieved platelet count greater than 
50,000/µl. We wish to improve these results in the current study. 
 
Rationale for eligibility criteria and study design 
We would like to include as many patients as possible therefore all patients receiving cord 
blood or haploidentical transplant treated on any protocol will be eligible for this study. 
Following exceptions are made for safety concerns. 
 
a) 
Patients with liver dysfunction are excluded from this study because the drug 
exposure is higher in patients with severe liver dysfunction and modest hepatic toxicity 
was observed in few patients in previous clinical trials of this drug. Likewise patients 
with renal dysfunction are excluded as limited data are available in the setting of kidney 
failure. 

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b) 
East Asians (Chinese, Korean, and Japanese) have 87% higher drug exposure 
as determined by AUC than non-east Asians( see investigator’s brochure) and therefore 
they may require a lower dose and a dose of 300mg may not be safe. Furthermore, at 
the most we are likely to see only one or at the most two patients if any of these ethnic 
groups during the course of this study, so doing a separate lower dose cohort for these 
groups is not realistic. Hence, it will be safer to exclude them. We will exclude patients 
whose one parent or grandparent is of Chinese, Korean, or Japanese origin. 
 
Correlative Studies 
Thrombopoietin acts on early stem cells and progenitor cells. Eltrombopag was shown to 
increase not only platelets but also white cells and hemoglobin. It is possible that it may 
impact recovery of immune system after transplant.[19,43,45] We will therefore do immune 
reconstitution studies, which include enumeration of various lymphocyte subsets (T cells and 
subsets, B cells, NK cells, etc.) at various time points after transplant and compare it to 
historical control to assess impact of Eltrombopag on immune recovery. 
 
 
3.0 Background Drug Information 
 
Thrombopoietin 
Thrombopoietin (TPO) is the primary regulator of platelet production and is required for 
proliferation and differentiation of its precursors.[19,20] It was identified as a ligand for c-mpl 
receptor, a previously identified oncogene.[21-24] Mice deficient in this protein or its receptor 
produce 10-15% of normal platelet mass. It is a polypeptide of 353 amino acids mainly 
produced in liver. It is cleared by megakaryocytes and its precursors. The production 
occurs at a fixed rate and the plasma levels are therefore determined by 
megakaryocytic mass with high levels occurring in patients with low megakaryocytic mass 
(e.g., aplastic anemia).[19,20] With the discovery of thrombopoietin, the next step was 
development of recombinant molecule and its use in thrombocytopenic disorders. 
 
Thrombopoietic Growth Factors: First Generation Agents 
Recombinant thrombopoietin (rTPO) and Megakaryocyte growth and development factor 
(MGDF) were developed and studied in the late nineties.[25-30] rTPO is the intact glycosylated 
molecule while MDGF is the truncated molecule. Both were studied in patients developing 
thrombocytopenia post chemotherapy and found to be effective in patients receiving less 
intense chemotherapy for solid tumors. They were also effective in increasing platelet count 
in small number of patients with idiopathic thrombocytopenia purpura (ITP) and increasing 
stem cell yield when given with chemotherapy given for stem cell mobilization. However, in 
patients undergoing high dose chemotherapy for acute myeloid leukemia or for conditioning 
prior to stem cell transplantation, these agents did not reduce the nadir platelet count, time 
to platelet recovery to 20,000/µl, or platelet transfusion requirement,[25,27,29-35] but did cause 
marked thrombocytosis following platelet recovery. This lack of efficacy could be attributed 
first to paucity of megakaryocytic precursors early post high dose chemotherapy, which are 
the targets for the drug. Second, the peak effect of these agents is seen at 10 days, and 
median time to platelet engraftment is 11 to 18 days. Consequently, it would be very difficult 
to demonstrate any benefit in time to platelet recovery or other endpoints detailed above. 
Patients with thrombocytopenia post HCT most likely to benefit from thrombopoietin are 
those with delayed recovery of platelet count like patients undergoing cord blood or 
haploidentical transplantation or those with secondary thrombocytopenia. 
 

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Unfortunately development of these molecules was discontinued because patients 
receiving MDGF developed antibody to thrombopoietin that reacted with the native 
molecule resulting in thrombocytopenia in normal donors.[36,37] This then led to a search for 
a novel molecule, which stimulates thrombopoiesis through its action on thrombopoietin 
receptor and does not stimulate antibody production by virtue of its different structure. 
Eltrombopag is one such small molecule. 
 
Eltrombopag 
 
Mechanism of Action 
Eltrombopag (Appendix C: Investigator’s Brochure) is a nonpeptide small molecule that 
stimulates thrombopoiesis by activating TPO receptor. It binds to TPO receptors near the 
transmembrane domain at a site different from the binding site of native TPO. Like TPO it 
activates Jak Stat and MAP kinase signal transduction pathways, but unlike TPO it does 
not activate AKT pathway. This may account for some of the similarities and differences 
between two molecules. It stimulates proliferation and differentiation of megakaryocytic 
precursors including early committed progenitors. Unlike TPO it does not cause activation 
of platelets. It also does not stimulate proliferation of different tumor cell lines. It is active 
only in humans and chimpanzees.[38] 
 
Pharmacology 
Clinical pharmacology of eltrombopag has been evaluated in more than 500 subjects 
receiving doses ranging from 3mg to 300mgs. Data are detailed in the investigator’s 
brochure (Appendix C) and are summarized here. It is well absorbed orally with a linear 
dose dependent rise in pharmacokinetic (PK) parameters. Its half life is 26-35 hours in ITP 
patients. It is excreted unchanged mainly in feces but also in urine. A small amount is 
metabolized and the resulting metabolites are also excreted in urine and feces. Majority of it 
is protein bound. 
 
Renal failure does not impact pharmacokinetics of eltrombopag, while drug exposure is 
increased 80-93% in patients with liver dysfunction. In this study we will exclude patients 
with significant liver dysfunction. 
 
Efficacy 
Eltrombopag received accelerated approval from the FDA on November 20, 2008 for the 
treatment of chronic Idiopathic Thrombocytopenic Purpura (ITP) and subsequently for 
thrombocytopenia in hepatitis C patients. In clinical trials, it has been shown to increase 
platelet counts in patients with ITP not responsive to standard therapy and in patients with 
cirrhosis due to hepatitis C and thrombocytopenia.[39-42] 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). 
 
In patients with thrombocytopenia (platelet count between 20,000 and 70,000 per µL) and 
cirrhosis due to hepatitis C, at week 4, platelet count increased to > 100,000 per µL in 0%, 
75%, 79%, and 95% of patients treated with placebo, 30mg, 50mg, and 75mg of 
eltrombopag respectively. Antiviral therapy with peginterferon and ribavirin was initiated at 
week 5 and eltrombopag or placebo was continued. After twelve weeks, antiviral therapy 
was completed by 6%, 36%, 53%, and 65% of patients receiving placebo, 30mg, 50mg, 
and 75mg of eltrombopag. 
 
 

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Hence, eltrombopag is effective for treatment of thrombocytopenia in patients with ITP and 
patients with cirrhosis due to hepatitis C (HCV). Further studies are currently underway in 
patients with thrombocytopenia post chemotherapy, and it is certainly promising for 
accelerating engraftment post cord or haploidentical transplantation. 
 
Thrombopoietin not only promotes growth and development of platelet progenitor and 
megakaryocytes, but also promotes growth of all hematopoietic progenitors including 
hematopoietic stem cells and multipotent progenitor cells.[19] It therefore may follow that 
eltrombopag may have effect on other hematopoietic lineages in addition to megakaryocytic 
lineage. Mice lacking thrombopoietin receptor (c-mpl) have stem cell deficiency.[43] 
Furthermore, humans with congenital deficiency of this receptor also develop pancytopenia 
and aplastic anemia.[44] In fact the role of thrombopoietin receptor agonist in expansion of 
early hematopoietic progenitors including stem cells was very elegantly shown in a recent 
study of patients with refractory aplastic anemia conducted at NIH. In this study with 
eltrombopag a 41% hematologic response was seen with improvement in all 3 lineages.[45] 
 
A similar acquired trilineage hypoplasia or a bone marrow failure state exists in patients 
undergoing transplantation due to chemotherapy or radiotherapy give as a part of 
conditioning regimen. The regeneration of normal mature blood cells occurs due to infused 
stem cells. It therefore follows that when recovery of blood cells is impaired as detailed 
above in cord or haploidentical transplant, a growth factor like eltrombopag may significantly 
improve engraftment and immune reconstitution and thereby improve patient outcome. In 
this study we hypothesize that eltrombopag will not only improve platelet recovery acting on 
megakaryocytic lineage, but also improve immune recovery acting on very early progenitors. 
 
Toxicity 
In clinical studies, eltrombopag was well tolerated with modest toxicity, which are detailed in 
the enclosed “Investigator’s Brochure” and summarized here. More than 1000 patients have 
been treated on various clinical efficacy studies with doses of eltrombopag ranging from 3 
mg to 300 mg given for 1- 560 days. In placebo controlled ITP studies, only nausea and 
vomiting occurred more frequently (>5%) in eltrombopag treated subjects than placebo. 
These were mild and resolved without treatment. No significant difference between the two 
groups was seen in the incidence of other adverse events or serious adverse events. Mild, 
reversible, abnormalities of liver function tests (AST, ALT, ALP, and Bilirubin) were noted 
(10% eltrombopag vs 7% placebo) in ITP studies but were infrequently seen in HCV studies 
and chemotherapy related thrombocytopenia studies. Increase in reticulin and collagen in 
bone marrow biopsy was seen in some subjects but was not clinically relevant.[46,47] Likewise 
no difference in cataract incidence was reported between patient and controls.[48] No 
increase in incidence of malignancies was seen in patients receiving the drug. Transient 
decrease in platelet count following discontinuation of the drug was seen, but this was not 
associated with clinically meaningful bleeding events. In summary, eltrombopag is well 
tolerated without any major dose dependent adverse effects. 
 
Rationale for dose 
1. The effective dose in subjects with thrombocytopenia post stem cell transplantation is 
unknown, and 300 mg is the maximum dose that is currently being considered in 
eltrombopag studies for patients with chemotherapy-induced thrombocytopenia, 
myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML) and advanced 
sarcoma. Four studies recently reported safety of this dose including one in patients 
undergoing stem cell transplantation.[49-52] 
 

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2. In healthy subjects, a clear dose and exposure response was seen for eltrombopag 
doses of 10 mg to 200 mg once daily for 5 days, with geometric mean AUC values of 302 
µg.h/mL for the 200 mg once daily regimen. Eltrombopag was well tolerated in healthy 
subjects at all dose levels. 
 
3. In ITP subjects, a dose response was seen for eltrombopag doses of 30 mg to 75 mg 
once daily, with geometric mean AUC values of 169 µg.h/mL for the 75 mg once daily 
regimen. There was no significant difference between the safety profile of ITP subjects 
receiving 30, 50 or 75 mg of eltrombopag. 
 
4. In HCV subjects, a dose and exposure response was seen for eltrombopag doses of 
30 mg to 75 mg once daily, with geometric mean AUC values of 307 µg.h/mL for the 75 
mg once daily regimen (approximately 2-fold the exposures observed in ITP patients at 
the same dose. There was no significant difference between the safety profile of HCV 
subjects receiving 30, 50 or 75 mg of eltrombopag, and the frequency of adverse events 
in these subjects did not increase in a dose-dependent manner. 
 
5. In aplastic anemia study from NIH dose was escalated to 150 mg and all responding 
patients received this dose. 
 
In summary, there is a dose response effect of this molecule, and 300 mg is the highest 
dose safely used in other studies. We will therefore use this dose in current study. 
 
Rationale for Duration 
Thrombopoietin not only promotes growth and development of platelet progenitor and 
megakaryocytes, but also promotes growth of all hematopoietic progenitors including 
hematopoietic stem cells and multipotent progenitor cells.[19] In this study we not only would 
like improve platelet engraftment but assess if it has any impact on recovery of other 
lineages and immune system. Therefore we would like to continue it for 60 days irrespective 
of platelet recovery unless the platelet count rises above 250 x 109/l. 
 
Supply 
Eltrombopag is provided by Novartis Pharmaceuticals Corporation. 
 
 
4.0 Patient Eligibility 
 
We would like to include as many patients as possible. Therefore, any patient receiving cord 
blood or haploidentical transplant treated on any protocol or as standard of care will be 
eligible for this study. Following exceptions are made for safety concerns. 
 
a) Patients with liver dysfunction are excluded from this study because the drug 
exposure is higher in patients with severe liver dysfunction and modest hepatic toxicity 
was observed in few patients in previous clinical trials of this drug. Likewise patients 
with renal dysfunction are excluded as limited data are available in the setting of kidney 
failure. 
b) East Asians (Chinese, Korean, and Japanese) have 87% higher drug exposure as 
determined by AUC than non-east Asians and therefore they may require a lower dose 
and a dose of 300mg may not be safe. Furthermore, at the most we are likely to see 
only one or at the most two patients if any of these ethnic groups during the course of 
this study, so doing a separate lower dose cohort for these groups is not realistic. 

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Hence, it will be safer to exclude them. 
 
4.1 Inclusion Criteria: 
1. 
Patients undergoing a cord blood or haploidentical transplantation on 
any protocol or standard of care treatment plan.  
2. 
Age >/= 18. 
3. 
Females of child bearing potential defined as not post-menopausal for 12 months 
or no previous surgical sterilization or breast- feeding must be willing to use an effective 
contraceptive measure until 30 days after the last dose of eltrombopag. Males who have 
had sexual contact with female of child-bearing potential must be willing to use 
contraceptive techniques until 30 days after the last dose of eltrombopag. 
4. 
Patient or patient’s legal representative(s) is/are able to provide written informed 
consent to participate. 
 
4.2 Exclusion Criteria: 
1. ALT and AST >/= 2.5 ULN. 
2. Serum direct bilirubin >/= 1 mg/dl (except Gilbert's syndrome or hemolysis). 
3. Patients of east Asian ancestry (Chinese, Japanese, or Korean Origin). 
4. Calculated creatinine clearance < 30ml./min. Creatinine clearance will be calculated 
using the MDRD method. 
5. Arterial or venous thrombosis in the last year except for line-related venous thrombosis 
more than 3 months ago. 
6. Positive beta HCG within 7 days prior to consent in female of child-bearing potential 
defined as not post-menopausal for 12 months or no previous surgical sterilization or 
breast-feeding. 
 
 
5.0 Treatment Plan 
 
Dosage and Administration: 
For inpatients: documentation of drug administration will be on the medication administration 
record (MAR). 
For outpatients: patients will be given a pill diary to record dose taken, missed, or vomitted. 
Dose may be repeated if the patient vomits within 30 minutes of taking the drug. 
1. Eltrombopag will be given as a single daily dose of 300mg orally on an empty stomach 
(1 hour before or 2 hours after a meal) for 60 
total days. 
2. Eltrombopag will be started on Day -1 (the day prior to stem cell infusion in cord 
blood patients) and Day +5 in patients receiving haploidentical transplant. 
3. If for any reason patient is unable to take oral drug, number of days missed and reason 
will be documented. 
4. Allow a 4-hour interval between eltrombopag and other oral 
medications/supplements containing polyvalent cations, such as iron, calcium, 
aluminum, magnesium, selenium, and zinc. 
5. Drug will be stopped and not resumed: 
a) 
if at any time platelet count is >/= 250 X 109/l, or 
b) 
after completing 60 days of treatment, or 
c) 
at patient request, or 
d) 
per PI discretion if patient misses more than 10 consecutive doses of drug, 

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or 
e) 
if it is deemed unsafe and detrimental to patient health by the treating 
physician or the principal investigator. 
6. 
Patients will be taken off the study: 
a) 
at patient request, or 
b) 
if it is deemed unsafe and detrimental to patient health by the treating 
physician or the principal investigator based on CTCAE Version 4.0 toxicity grading, 
or 
c) 
1 year after drug initiated. 
 
Unused and/or expired drug will be disposed per institutional policy. 
 
Concomitant medications will be documented in the medical record but will not be entered 
into PDMS/CORE. These medications are considered standard of care and have no 
scientific contributions to the protocol, therefore no data will be captured on the various 
medications needed or their side effects. 
 
The use of medications that cause thrombocytopenia is permitted if needed, at the discretion 
of the patient's physician. 
 
 
6.0 Pretreatment evaluation 
 
Standard work up for transplant as well as disease assessment is done prior to study 
entry as part of diagnostic or routine pre-transplant evaluation as per departmental 
standards. Patient may be consented at the time of consent for transplant. 
 
Beta HCG within 7 days prior to consent in female of child-bearing potential defined as not 
post-menopausal for 12 months or no previous surgical sterilization or breast-feeding. 
 
 
7.0 Evaluation During The Study 
 
The required lab tests and time points are part of the standard post-transplant care. 
1. 
Following lab studies will be done daily until neutrophil engraftment and then at 
least once a week during active treatment period and for 4 weeks after completion of 
eltrombopag: CBC, Na, K, Cl, CO2, BUN, Creatinine. 
2. 
Liver function tests, Bilirubin, 
Alkaline Phosphatase and ALT 
will be done weekly during active 
treatment period and for 4 weeks 
after completion of eltrombopag. 
3. 
Total number of red cell and platelet transfusion given will be collected during 
active treatment period. 
 
Correlative Studies 
Thrombopoietin acts on early stem cells and progenitor cells. Eltrombopag was shown to 
increase not only platelets but also white cells and hemoglobin. It is possible that it may 
impact recovery of immune system after transplant.[19,43,45] We will therefore do immune 
reconstitution studies at various time points and compare it to historical control to assess 
impact of Eltrombopag on immune recovery. Samples will be sent to Dr. Katy Rezvani's 

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laboratory at MD Anderson for analysis. 
 
Required: Immune reconstitution studies on peripheral blood (70 mL) will be done on Day 30 
(±7 days), 60 (±7 days), 90 (±10 days), 180 
(±30 days), 365 (±30 days). 
 
Optional: Immune reconstitution studies on bone marrow (5 mL) will be done on Day 30 (±7 
days) and Day 90 (±10 days). 
 
 
8.0 Statistical Considerations 
 
General 
This will be a two-arm Phase II trial of eltrombopag in patients receiving an allogeneic stem 
cell transplant. One arm will be for patients receiving cord blood, and the other will be for 
patients with haploidentical donors. The primary objective of the trial will be to estimate the 
rate of platelet engraftment by Day 60 in patients undergoing cord blood transplant (CBT) 
or haploidentical donor stem cell transplantation treated with eltrombopag. We will use a 
dose of 300 mg/day for 60 days in each arm. With no dose increase, we originally planned 
to enroll a minimum of 20 patients and a maximum of 30 patients in each arm, and the total 
accrual for the study would have been no more than 60 patients. In October 2015, because 
the vast majority of patients accrued have entered the haploidentical arm, the study was 
modified to allow for up to 20 additional patients (for a total of 50) in this arm. In January 
2016, the protocol will be further modified to allow for up to 55 patients in the haploidentical 
arm. The protocol will still enter a maximum of 60 patients total. When registering patients 
in CORe, treatment arm assignment will be designated. 
Primary Endpoint: Sample Size Justification 
Historical data for cord blood transplants at MDACC indicates that approximately 44% of 
patients experienced platelet engraftment of > 50K/µl by Day 60. We expect to increase this 
to at least 71% in this trial with the addition of eltrombopag. With 20 patients in the cord 
blood arm, we will have 80% power to detect an increase to 71%, assuming a one-sided 
exact binomial test with a 5% Type I error rate. Only patients who complete treatment 
without missing the drug for more than 10 days will be included in this analysis, although 
patients who are removed because of high platelet count will be counted as successes. We 
expect that 80% of patients will be evaluable for the primary endpoint under these criteria. If 
we enroll more than 20 patients in this arm, we will have greater power to detect this 
increase. As discussed above, we now (October 2015) expect fewer than 20 patients to 
enter this arm. We accept that this arm will be underpowered to detect the specified 
difference. 
 
For the haploidentical arm, historically at MDACC, approximately 63% of patients have 
experienced platelet engraftment of > 50K/µl by Day 
60. With 20 patients, we will have 80% power to detect an increase in this proportion to 
88%, assuming a one-sided exact binomial test with a 5% Type I error rate. Only patients 
who complete treatment without missing the drug for more than 10 days will be included in 
this analysis, although patients who are removed because of high platelet count will be 
counted as successes. We expect that 80% of patients will be evaluable for the primary 
endpoint under these criteria. With a greater number of patients in this arm, we will have 
the same power to detect a smaller increase. 

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Each hypothesis will be tested with a 5% Type I error rate. We recognize that the 
overall Type I error rate of the study is 9.75%. Patients who experience graft failure or 
who do not take the study treatment for more than 10 days will be replaced. 
Safety Monitoring Rule: Grade 4 Non-Hematologic Toxicity 
We will monitor the rate of grade 4 and higher non-hematologic toxicity attributable to the 
drug through Day 60 in this trial by using the method of Thall, Simon, and Estey.[53] All 
patients who enter the study will be evaluable for toxicity. The following statistical monitoring 
rule will be applied separately to each arm: discontinue the arm if at any time during the 
trial: 
 
Pr (TN > 0.20 | Data from patients evaluated at Day 60) > 0.95 
 
where TN represents the grade 4 or higher non-hematologic rate in arm N=1 or N=2. We 
assume a Beta(0.4, 1.6) prior distribution for qT1 and qT2. This rule will be evaluated as each 
patient reaches Day 60 for up to 55 patients in each arm. The rule leads to the stopping 
boundaries in the table below: 
 
If there are this 
many patients with 
Grade 4 
non-hematologic 
toxicity 
Stop the arm if this 
many (or fewer) 
patients have been 
evaluated at Day 
60 
2 
2 
3 
4 
4 
4-8 
5 
5-11 
6 
6-14 
7 
7-18 
8 
8-22 
9 
9-25 
10 
10-29 
11 
11-33 
12 
12-37 
13 
13-41 
14 
14-34 
15 
15-49 
16 
16-53 
17 
17-54 
 
 
This rule was simulated using the program Multc Lean Desktop, version 1.0, and the 
operating characteristics are provided in the table below. 
 
 
 
 

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True T 
Early Stopping 
Probability 
Sample Size 
25th 
Median 
75th 
5% 
0.003 
55 
55 
55 
10% 
0.017 
55 
55 
55 
15% 
0.063 
55 
55 
55 
20% 
0.188 
55 
55 
55 
25% 
0.425 
21 
55 
55 
30% 
0.696 
10 
29 
55 
35% 
0.887 
7 
17 
33 
40% 
0.971 
6 
11 
21 
 
 
Secondary Endpoints 
Secondary endpoints in the trial include platelet engraftment > 20K/µl at Day 60, 
platelet engraftment > 20K/µl and > 50K/µl at Day 30, neutrophil engraftment, the 
time to platelet and neutrophil engraftment, overall survival (OS), progression free 
survival (PFS), the cumulative incidence of acute and chronic graft vs. host 
disease (GVHD), and toxicity. Neutrophil engraftment is defined as the first of three 
consecutive days that the ANC is > 0.5 k/L. 
 
We will estimate the cumulative incidence of each of the engraftment 
parameter with death or relapse as a competing risk. Neutrophil and platelet 
engraftment will be recorded as per our departmental standard practice. 
 
For survival parameters, we will use the method of Kaplan and Meier to estimate the 
distribution of survival times, and we will compare distributions using the log-rank 
test. We will use Cox proportional hazards regression methods to model survival 
parameters as a function of disease and demographic covariates of interest. We will 
use the method of Gooley et al to estimate the cumulative incidence of GVHD.  We 
will use logistic regression to model the association between engraftment endpoints 
and covariates of interest. Analyses will be performed separately by arm (cord blood 
or haploidentical). 
 
We will provide descriptive summaries of toxicity by arm and dose and immune 
recovery parameters at various time points. 
 
 
9.0  
Adverse Events and Reporting Requirements 
 
9.1 Grading assessment 
The severity of the adverse events (AEs) will be graded according to the Common 
Terminology Criteria v4.0 (CTCAE). Adverse events and protocol specific data will be 
entered into PDMS/CORe. PDMS/CORE will be used as the electronic case report 
form for this protocol. 
 
9.2 
Causality Assessment 

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For the purpose of this study events known to be caused by Eltrombopag will be assessed as 
definitely related. 
Events known to be caused by components of the transplant package and its direct 
consequences as well as those events known to be related to drugs used for the 
treatment of GVHD, infections and supportive treatment will be scored as unrelated. 
When the relationship of the adverse event cannot be ruled out with certainty the AE may be 
considered possibly related. 
 
The PI will be responsible for assessing the casuality and will be final arbiter. Documentation 
of grade, onset/resolution date and attribution will be entered into the patient's medical record 
and signed by the PI. 
 
9.3 
Collection of adverse events 
 
Only those events known to be caused by Eltrombopag will be recorded in the designated 
case report form (PDMS/CORE). Collection of adverse events will reflect the onset and 
resolution date and maximum grade. Intermittent events should be labeled as such and 
followed until resolution. If a patient is taken off study while an event still ongoing, this will 
be followed until resolution unless another therapy is initiated. 
 
Events known to be caused by components of the transplant package and its direct 
consequences as well as those events known to be related to drugs used for the treatment 
of GVHD, infections and supportive treatment will not be collected in the designated case 
report form/database. Concurrent medications considered standard of care for transplant 
patients will not be captured in the case report form. They will be documented in the 
medical record. 
 
Adverse events related to the study drug will be collected and recorded for the duration of 
active treatment plus 30 days. 
 
9.4 
List of expected adverse events related to Eltrombopag 
 
1. 
Thrombotic episodes related to thrombocytosis. 
2. 
Allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; 
swelling of the mouth, face, lips, or tongue); 
3. 
Abnormal liver function tests (possible liver damage-ascitis, jaundice). 
4. 
New onset of bone marrow fibrosis. 
5. 
Stroke symptoms (e.g., confusion, slurred speech, sudden vision changes, one-
sided weakness). 
6. 
Muscle aches or pain (arms and/or legs). 
7. 
Bleeding problems after discontinuation of treatment. 
 
9.5 Treatment Duration Definitions 
 
Active Treatment: the therapy administered to the participant as specified in the 
"Dosage and Administration" part of the proposal. Supportive care and standard 
forms of post-transplant immunosuppressive therapy are not considered active 
treatment. 
 
Last day of "Active Treatment": is the last day of the study intervention. 

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Active Treatment Period: is the period of time from the first day of "Active Treatment" until 
30 days after the "Last day of Active Treatment" as specified above. 
 
Follow-up Period is the period of time that immediately follows the end of the "Active 
Treatment Period." This period ends when the patient is removed from the study. 
 
9.6 
Reporting Requirement 
Serious Adverse Event Reporting (SAE) Language 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 Death
 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death.
 Inpatient hospitalization or prolongation of existing hospitalization
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
 A congenital anomaly/birth defect.
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
· 
Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an SAE 
if deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
· 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the 
IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
· 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 
24 hours (next working day) of knowledge of the event to the Safety Project Manager in the 
IND Office. 
 
· 
Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB. 
· 
Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 

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participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of 
the event. 
 
· 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
· 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
Reporting to Novartis Pharmaceuticals Corporation: 
 
The institution and investigator shall report to Novartis Pharmaceuticals Corporation within 
24 hours (next working day) of knowledge of the unexpected and related event: all life 
threatening or fatal events; and within five (5) working days of knowledge of the unexpected 
and related event any adverse drug experience, as defined by applicable law or regulation, 
or pregnancy experienced by any study subject receiving a Novartis Pharmaceuticals 
Corporation study drug(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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