Concomitant Omacetaxine Mepesuccinate and Azacitidine for Patients With Previously Untreated High Grade Myelodysplastic Syndromes
Phase: PHASE1
Conditions: High Grade Myelodysplastic Syndromes
Sponsor: University of Colorado, Denver

NCT03564873 
Version January 13, 2023 
Concomitant Omacetaxine Mepesuccinate and AzaciƟdine for PaƟents with Previously Untreated High 
Grade MyelodysplasƟc Syndromes 
Daniel A. Pollyea, MD, MS 
University of Colorado Cancer Center 
1655 Aurora Court 
Mail Stop F754 
Aurora, CO 80045 

Confidential 
 
 
 
Concomitant Omacetaxine Mepesuccinate and Azacitidine for Patients with 
Previously Untreated High Grade Myelodysplastic Syndromes 
 
 
Study Sponsor / 
Principal Investigator 
Daniel A. Pollyea, MD, MS 
University of Colorado Cancer Center 
1665 Aurora Court 
Mail Stop F754 
Aurora, CO 80045 
Phone: 720-848-8084 
Fax: 720-848-1786 
Daniel.pollyea@cuanschutz.edu 
 
Study Location 
University of Colorado Cancer Center 
Protocol / COMIRB# 
17-2215 
Version Date 
January 13, 2023 
Indication to be 
studied 
Previously untreated patients with high grade 
myelodysplastic syndromes (MDS) and a 
small expansion cohort of relapsed or 
refractory MDS patients 
Study Agents: 
1. Omacetaxine mepesuccinate (Synribo™, 
Teva) 
2. Azacitidine (Vidaza™, Celgene) 
 
 

 
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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. 
 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The principal investigator (PI), 
Daniel A. Pollyea, is conducting the study and acting as the sponsor.  As the 
sponsor-investigator, both the legal/ethical obligations of a PI and those of a 
sponsor will be followed. 
The trial will be carried out in accordance with Good Clinical Practice 
(GCP) as required by applicable United States (US) laws and applications, 
including but not limited to United States (US) Code of Federal Regulations 
(CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR 
Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
The PI will assure that no changes to the protocol will take place without 
documented approval from the Institutional Review Board (IRB). All personnel 
involved in the conduct of this study have completed Human Subjects Protection 
Training.  
I agree to ensure that all staff members involved in the conduct of this 
study are informed about their obligations in meeting the above commitments.  
 
 
Daniel A. Pollyea, MD 
  
Print/Type Name  
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
  
Date 
 
 

 
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STUDY PERSONNEL 
A complete and current listing of investigators, research personnel, research facilities 
and other study centers (if applicable) participating in this study will be maintained 
throughout the duration of this study on applicable study required forms such as an FDA 
Form 1572, the COMIRB Research Personnel Form, and/or a UCCC Protocol Contact 
List, incorporated herein by reference.  
 
LIST OF ABBREVIATIONS 
 
ACRONYM 
DESCRIPTION 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CMML 
Chronic myelomonocytic leukemia 
CR 
Complete emission 
CRi 
Complete remission with incomplete blood count recovery 
CYP 
Cytochrome P 
eCRF 
Electronic case report form 
IIT 
Investigator-Initiated Trial 
INR 
International normalized ratio 
LDH 
Lactate dehydrogenase 
LSC 
Leukemia stem cell 
MDS 
Myelodysplastic syndrome 
MRD 
Minimal residual disease 
PI 
Principal Investigator 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
SAE 
Serious adverse event 
TLS 
Tumor lysis syndrome 
UAP 
Unanticipated Problem 
IRB 
Institutional Review Board 
BID 
Twice Daily 
ORR 
Overall Response Rate 
CR 
Complete Response 
IWG 
International Working Group 
CML 
chronic myeloid leukemia 
FAB 
French-American-British 
RBC 
Red Blood Cells 
NCI 
National Cancer Institute 
Hgb 
Hemoglobin 

 
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ECOG 
Eastern Cooperative Oncology Group 
EKG 
Electrocardiogram 
SQ 
Subcutaneous 
HHT 
Homoharringtonine 
DNA 
Deoxyribonucleic acid  
TKI 
tyrosine kinase inhibitor 
CHR 
complete hematologic response 
NYHA 
New York Heart Association 
DMC 
Data Monitoring Committee 
IND 
Investigational New Drug 
RNA 
Ribonucleic acid 
WBC 
White Blood Cells 
BUN 
Blood urea nitrogen 
LDH 
Lactate dehydrogenase 
DSMC 
Data and Safety Monitoring Committee 
CTCAE 
Common Terminology Criteria for Adverse Events 
NADPH 
nicotinamide adenine dinucleotide phosphate 
WHO 
World Health Organization 
AST 
aspartate aminotransferase 
ALT 
Alanine transaminase 
ULN 
Upper Limit of Normal 
HIV 
human immunodeficiency virus 
HBV 
hepatitis B virus 
PR 
Partial Response 
IUD 
intrauterine device  
IUS 
Intrauterine hormone-releasing system 
eCRF 
Electronic Case Report Form 
SAE 
Serious Adverse Event 
FCBP 
Female of Child Bearing Potential  
HMA 
Hypomethylating Agent 
 
 
 

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Table of Contents 
LIST OF ABBREVIATIONS ........................................................................................................ iii 
1 PROTOCOL SYNOPSIS .......................................................................................................... 7 
2 SCHEDULE OF STUDY ASSESSMENTSa ............................................................................ 10 
3 INTRODUCTION .................................................................................................................. 12 
3.1 
Background and Rationale ............................................................................................. 12 
3.2 
Omacetaxine Mepesuccinate .......................................................................................... 14 
 
Pharmacokinetic Profile ......................................................................................... 14 
 
Toxicology ............................................................................................................. 15 
 
Clinical Data .......................................................................................................... 16 
3.3 
Azacitidine ..................................................................................................................... 17 
 
Preclinical Pharmacokinetic Profile ....................................................................... 17 
 
Clinical Data .......................................................................................................... 18 
4 STUDY OBJECTIVES ............................................................................................................ 18 
4.1 
Primary Objectives ......................................................................................................... 18 
4.2 
Secondary Objectives ..................................................................................................... 19 
5 INVESTIGATIONAL PLAN ................................................................................................... 19 
5.1 
Overall Study Design ..................................................................................................... 19 
 
Study Schema ......................................................................................................... 19 
 
Response Assessments ........................................................................................... 20 
5.2 
Study Endpoints ............................................................................................................. 21 
5.3 
Selection of Study Population and Enrollment Procedures ........................................... 22 
 
Inclusion Criteria ................................................................................................... 22 
 
Exclusion Criteria .................................................................................................. 23 
5.4 
Duration of Study ........................................................................................................... 24 
5.5 
Drug Administration ...................................................................................................... 24 
 
Omacetaxine Administration ................................................................................. 24 
 
Azacitidine Administration .................................................................................... 25 
5.6 
Assuring Patient Compliance ......................................................................................... 25 
5.7 
Drug Accountability ....................................................................................................... 26 
5.8 
Concomitant Therapy ..................................................................................................... 26 
 
Permitted Concomitant Therapy ............................................................................ 26 
 
Prohibited Concomitant Therapy ........................................................................... 26 
5.9 
Contraception Recommendations .................................................................................. 27 
5.10 
Study Procedures ........................................................................................................... 27 
5.11 
Response Assessments ................................................................................................... 31 
5.12 
Hematologic Improvement (HI)1 ................................................................................... 32 
5.13 
Reporting of Results ...................................................................................................... 33 
5.14 
Stopping Rules ............................................................................................................... 33 
 
Individual Patient Stopping Rules .......................................................................... 33 
 
Study Stopping Rules ............................................................................................. 34 
5.15 
Dose Escalation for Phase I ........................................................................................... 34 
5.16 
Dosing Delays and Modifications .................................................................................. 35 
 
Missed Doses ......................................................................................................... 35 
 
Dose-limiting toxicity (DLT) definition ................................................................ 35 
 
Additional Doses .................................................................................................... 35 
 
Dose Delays ........................................................................................................... 36 
 
Dose De-Escalation ................................................................................................ 36 
6 SAFETY PLAN ....................................................................................................................... 37 
6.1 
Adverse Event ................................................................................................................ 37 

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6.2 
Serious Adverse Events ................................................................................................. 38 
6.3 
Adverse Events Commonly Associated with MDS ....................................................... 40 
6.4 
Adverse Event Severity .................................................................................................. 40 
6.5 
Relationship to Study Drug ............................................................................................ 41 
6.6 
Deaths ............................................................................................................................ 41 
6.7 
Recording Adverse Events ............................................................................................. 42 
6.8 
Investigator Reporting Responsibilities ......................................................................... 42 
 
Adverse Event Reporting ....................................................................................... 42 
 
Reporting to Teva .................................................................................................. 42 
 
Reporting From Teva ............................................................................................. 43 
6.9 
Pregnancy ....................................................................................................................... 44 
6.10 
Decreased Spermatogenesis ........................................................................................... 44 
6.11 
Management of Infection ............................................................................................... 45 
6.12 
Management of Other Toxicities ................................................................................... 45 
7 PROTOCOL DEVIATIONS ................................................................................................... 45 
8 STATISTICAL METHODS ..................................................................................................... 46 
8.1 
Demographics ................................................................................................................ 46 
8.2 
Efficacy Analysis ........................................................................................................... 46 
8.3 
Safety Analysis .............................................................................................................. 46 
8.4 
Deaths ............................................................................................................................ 46 
8.5 
Sample Size Determination ............................................................................................ 46 
9 ETHICS .................................................................................................................................. 48 
9.1 
Institutional Review Board ............................................................................................ 48 
9.2 
Ethical Standards ........................................................................................................... 48 
9.3 
Informed Consent Process ............................................................................................. 49 
10 SOURCE DOCUMENTS AND CASE REPORT FORMS ...................................................... 49 
11 STUDY OVERSIGHT – Quality Assurance and Quality Control .......................................... 50 
11.1 
Data Safety and Study Oversight ................................................................................... 50 
11.2 
Clinical Monitoring ........................................................................................................ 51 
11.3 
Study Auditing ............................................................................................................... 51 
12 REFERENCES ....................................................................................................................... 52 
 
 
 
 

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1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE:  Concomitant Omacetaxine Mepesuccinate and Azacitidine 
for Patients with Previously Untreated High Grade Myelodysplastic Syndromes 
INDICATION:  Previously untreated patients with high grade myelodysplastic 
syndromes (MDS) 
STUDY PHASE: I/II 
BACKGROUND AND RATIONALE:  High grade myelodysplastic syndromes 
(MDS), defined as MDS with increased blasts in the bone marrow or peripheral 
blood, has a very poor prognosis with a median survival of 10-20 months. The 
two FDA approved therapies for MDS are epigenetic modifiers (azacitidine and 
decitabine) and response rates to these agents are low (~20% complete 
remission rate) and transient (remission durations <1 year). When patients either 
do not respond or respond and then relapse, there are no FDA-approved 
salvage therapies; patients in this situation have a very poor prognosis and a 
short life expectancy, highlighting the importance of delivering the most effective 
treatment possible in the up-front setting. Recent work characterizing the 
leukemia stem cell population in high grade MDS has shown a protein synthesis 
inhibitor may be effective against this population, and has additive/synergistic 
properties with azacitidine. Omacetaxine is an FDA approved protein synthesis 
inhibitor that was studied pre-clinically with azacitidine, suggesting these two 
therapies may be highly active in patients with high grade MDS.  
STUDY OBJECTIVES: 
Primary 
Phase I: To determine the recommended omacetaxine dose in combination with 
azacitidine 
Phase II: To determine the response rate of omacetaxine in combination with 
azacitidine in the newly diagnosed setting, and to assess toxicity and early 
efficacy of omacetaxine in combination with azacitdine in MDS patients who 
have not responded to or responded and relapsed after at least one line of 
therapy containing a hypomethylating agent 
Secondary   
• To evaluate the safety of the combination of omacetaxine and azacitidine 
(phase I and phase II) 

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• To determine the hematologic improvement from this combination (phase 
II) 
• To determine the duration of response (phase II) 
• To determine the progression free survival (phase II) 
• To determine the rate of transformation to acute myeloid leukemia (AML) 
(phase II) 
• To determine the percentage of patients deemed eligible for allogeneic 
stem cell transplantation who are able to proceed to this intervention 
without a second-line therapy (phase II) 
• To determine the overall survival (phase II) 
STUDY DESIGN: 
This is an open label, phase I/II study for previously untreated patients with high 
grade MDS using concomitant omacetaxine and azacitidine with a small 
expansion cohort for relapsed and refractory MDS patients. 
 
During phase I dose escalation, patients will receive omacetaxine 
subcutaneously at one of three cohorts (0.75, 1.0 and 1.25 mg/m2 BID) on days 
1-7. Azacitidine will be given at the standard dose and schedule (75 mg/m2) 
daily, days 1-7. A treatment cycle is defined as a 28-day period and will repeat 
indefinitely in the absence of disease progression or patient intolerance/toxicity 
or preference. 
 
On cycle 1 day 8, a bone marrow biopsy will be performed. On cycle 1 day 28, a 
bone marrow biopsy will be performed to determine response status. This will be 
repeated at the conclusion of cycles 4 and 6, and every 6 cycles thereafter.  
 
During phase II the above design will be replicated with all patients being treated 
at the maximum tolerated dose (MTD). An additional expansion cohort of 10 
MDS patients who have failed to respond to or responded and relapsed after at 
least one line of therapy containing a hypomethylating agent therapy will also be 
accrued. 
 
Treatments will be administered in the outpatient setting if possible, with 
azacitidine administered as a standard of care intervention in the infusion clinic 
and the omacetaxine self-administered by the patient while maintaining a diary. 
STUDY ENDPOINTS: 

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Primary 
Phase I: To determine the recommended dose for the phase II study based on 
the maximum tolerated dose (MTD) 
Phase 2: Overall response rate (ORR), defined by the proportion of patients who 
achieve any category of complete remission (CR, includes CR and marrow CR) 
or partial remission (PR) based on the 2006 International Working Group (IWG) 
criteria for MDS1. 
Secondary 
• Safety assessments in the form of surveillance of adverse events, 
laboratory test measures, physical exam findings and concomitant 
medication records (phase I and phase II) 
• Hematologic improvement rate 
• Duration of response 
• Progression free survival 
• Rate of transformation to AML 
• Percentage of eligible patients for allogeneic stem cell transplantation who 
proceed to this intervention 
• Overall survival 
ESTIMATED DURATION FOR ACCRUAL: 3-4 years 
ACCRUAL SAMPLE SIZE: 
Phase I: 4-18 
Phase II: 33 
TOTAL: 37-51 

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2 
SCHEDULE OF STUDY ASSESSMENTSa 
 
Procedures 
Screenb 
Cycle 1 
Cycles 
2+ 
End of 
Study 
Safety 
Follow-uph 
Long-term 
Follow-upi 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 28 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
X 
X 
Xc 
X 
X 
 
Vital Signs 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
X 
Xc 
X 
X 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
 
 
AEsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
 
X 
X 
Xc 
X 
 
 
Chemistry 
X 
X 
 
 
 
 
 
 
X 
X 
Xc 
X 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Xj 
 
 
 
 
 
 
 
 
 
Xj 
 
 
 
Azacitidine 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Xd 
 
 
 
Omacetaxine 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Xd 
 
 
 
Bone Marrow 
Aspirate & 
Biopsy 
X 
 
 
 
 
 
 
 
Xe 
X 
Xf 
X 
 
 
Dispense 
Calendar & Diary 
 
X 
 
 
 
 
 
 
 
 
Xc 
 
 
 

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Procedures 
Screenb 
Cycle 1 
Cycles 
2+ 
End of 
Study 
Safety 
Follow-uph 
Long-term 
Follow-upi 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 28 
 
 
 
 
Collect Calendar 
& Diary 
 
 
 
 
 
 
 
 
 
X 
Xg 
X 
 
 
Relapse & 
Survival Contact 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
a. For detailed description of all elements please see section 5.10 
b. Screening assessments must occur within 14 days of cycle 1 day 1, except the bone marrow, which may be done up to 28 days prior to cycle 1 day 1. 
c. Required on day 1 of each cycle (+/- 3 days) 
d. Days 1-7 of each cycle 
e. Aspirate only required 
f. After cycle 4, cycle 6 and every 6 cycles thereafter 
g. At the completion of each cycle 
h. Perform for patients who discontinue for adverse events around 30 days after discontinuation and include a history, physical examination and review of systems; repeat 
as clinically appropriate. A separate safety visit does not need to be performed for subjects with a final visit ≥30 days after discontinuation of study drug and did not require 
additional AE follow up. If the safety follow-up visit occurs before 30 days, the provider must make a documented phone call or telehealth evaluation to assess AEs—this 
cannot be a coordinator calling. 
i. After treatment discontinuation, all patients will be followed at least annually, in the form of a telephone call or clinic visit, for information on whether the patient has 
relapsed or not, and whether they are alive or deceased for up to 5 years (or death, whichever comes first). 
j. For all woman of childbearing potential, a serum or urine pregnancy test is required at screening and prior to the initiation of each cycle. 
k. Height will be measured at screening only. 
J AEs will be documented through 30 days after the last dose of study drug.

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3 
INTRODUCTION 
3.1 
Background and Rationale 
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of 
stem cell malignancies characterized by morphologic dysplasia and 
cytopenias resulting in bone marrow failure. A significant number of patients 
with MDS will evolve into AML2. Epidemiologic data for MDS is limited, but 
it is believed that over 10,000 new cases of MDS occur in the United States 
each year, and that over 60,000 patients carry this diagnosis3. High risk 
MDS can be defined pathologically as MDS with increased (>5%) blasts 
(high grade disease), or clinically using the International Prognostic Scoring 
System4. High risk MDS has a very poor prognosis with a median survival 
of 10-20 months4. There are two FDA approved therapies for the most 
common subtypes of MDS, both in the same class of drugs called 
hypomethylating agents2. Response rates to these agents are low (~20% 
complete remission rate), and overall survival is between 13-16 months5. 
When patients either do not respond or respond and then relapse, there are 
no FDA-approved salvage therapies; patients in this situation have a very 
poor prognosis with a short life expectancy6,7, highlighting the importance 
of delivering the highest impact treatment possible in the up-front setting. 
 
Relatively little is known about the stem cell population in MDS. In AML, 
surface antigens have been used to define LSCs, including CD123 (IL3-R 
alpha chain)8-10. Expression of CD123 in the CD34+/CD38- of primary MDS 
cells has been reported11, and a subsequent report noted progressive 
increases of CD123 expression during MDS pathogenesis12. We found that 
the expression of CD123 within the stem cell population was detectable in 
all high risk MDS patient samples tested, and not detected in low risk MDS 
(Figure 1). Upregulation of CD123 within the MDS stem cell compartment 
results in a change in cellular physiology, specifically with respect to 
upregulation of protein synthesis machinery (Figure 2, manuscript 
Figure 1: MDS bone marrow cells 
showing a high-risk specimen 
containing a distinct CD123+ 
population in comparison with a low 
risk specimen that does not stain for 
CD123  

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submitted). This raised the question of whether targeting protein synthesis 
could result in the specific targeting of MDS stem cells.  
 
 
 
 
 
 
Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine 
derived from a semi-synthetic process utilizing the leaves of the evergreen 
plum yew Cephalotaxus fortunei and is chemically identical to the natural 
product homoharringtonine.13 Omacetaxine acts by binding to the A-site 
cleft of ribosomes transiently inhibiting protein synthesis and may induce 
apoptosis of leukemic cells by a selective decrease in short-lived proteins, 
including mediators of apoptosis like Mcl-1, Bcl-2, Bax, Bcl-xl, Mapk, and 
Akt14-16. The safety and efficacy of omacetaxine has been evaluated in 
tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML), for which 
this therapy has been FDA approved, and it may have activity against CML 
stem cells16.  
 
Based on its protein synthesis inhibiting properties, we explored whether 
omacetaxine would have specific activity in the CD123+ population, and 
tested this in vitro and in vivo with a primary human MDS xenograft model. 
The results were promising, and also showed additive properties with 
azacitidine, the standard of care for newly diagnosed MDS patients, when 
dosed concomitantly (Figure 3). Based on this data we propose a 
combination therapy study with omacetaxine and azacitidine for high grade, 
previously untreated MDS patients.  
 
In addition, given the poor outcomes for MDS patients who fail to respond 
to or relapsed after responding to a hypomethylating agent (HMA) therapy, 
and the very limited treatment options for these patients, we propose a small 
Figure 2: CD123+ cells sorted from Lin-/CD34+/CD38- high 
risk bone marrow specimens exhibit increased protein 
synthesis as measured by op-puromycin and flow cytometry of 
Lin-/CD34+/CD38- subpopulations. 

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expansion cohort of these patients to receive this regimen to determine if it 
is tolerated and associated with preliminary signs of efficacy. 
 
 
 
  
 
 
 
 
Hypothesis: The combination omacetaxine and azacitidine will be well 
tolerated and effective in untreated high grade MDS patients. 
 
3.2 
Omacetaxine Mepesuccinate 
Omacetaxine is a first-in-class cephalotaxine derived from a semi-synthetic 
process utilizing the leaves of the evergreen plum yew Cephalotaxus 
fortunei 
and 
is 
chemically 
identical 
to 
the 
natural 
product 
homoharringtonine.13 Omacetaxine acts by binding to the A-site cleft of 
ribosomes transiently inhibiting protein synthesis and may induce apoptosis 
of leukemic cells by a selective decrease in short-lived proteins, including 
the anti-apoptotic protein Mcl-1, Bcl-2, Bax, Bcl-xl, Mapk, and Akt 14-16. 
Omacetaxine has two known metabolites, 4’-DMHHT and cephalotaxine. 
The concentration of the primary metabolite 4’-DMHHT is approximately 
10% of that of omacetaxine following subcutaneous administration and the 
half-life is about twice as long. Cephalotaxine, a minor metabolite, is 
typically not quantifiable in the plasma. 
 Pharmacokinetic Profile 
The dose proportionality of omacetaxine is unknown. A 90% 
increase in systemic exposure to omacetaxine was observed 
between the first dose and steady state. 
Figure 3: In vivo treatment of primary human MDS xenografts with 
omacetaxine and azacitidine. 

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The absolute bioavailability of omacetaxine has not been 
determined. Omacetaxine is absorbed following subcutaneous 
administration, and maximum concentrations are achieved after 
approximately 30 minutes. 
The steady-state (mean ± SD) volume of distribution of omacetaxine 
is approximately 141 ± 93.4 L following subcutaneous administration 
of 1.25 mg/m2 twice daily for 11 days. The plasma protein binding of 
omacetaxine mepesuccinate is less than or equal to 50%.  
Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT 
via plasma esterases with little hepatic microsomal oxidative and/or 
esterase-mediated metabolism in vitro. 
Based on the results of in vitro studies, there is a low probability of 
omacetaxine or 4′-DMHHT to inhibit metabolism via CYP enzymes 
or to inhibit P-gp-mediated efflux at clinically relevant concentrations. 
In vitro data also demonstrate a low probability of omacetaxine or 4′-
DMHHT to induce the metabolism of concomitantly administered 
CYP1A2 substrates at clinically relevant concentrations. There is the 
potential for CYP3A4 activity to be induced by 4′-DMHHT at clinically 
relevant concentrations. 
The major elimination route of omacetaxine mepesuccinate is 
unknown. The mean percentage of omacetaxine mepesuccinate 
excreted unchanged in the urine is less than 15%. The mean half-life 
of 
omacetaxine 
mepesuccinate 
following 
subcutaneous 
administration is approximately 6 hours. 
 Toxicology 
No correlation between concentration and QTc was observed. 
Omacetaxine concentrations in patients with higher QTc intervals are 
within the range of omacetaxine concentrations observed in patients 
with QTc values less than 450 msec. There was no evidence for 
concentration-dependent increases in QTc for omacetaxine or 4’-
DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% 
CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to 
the absence of a placebo and positive controls. 
No carcinogenicity studies have been conducted with omacetaxine. 
Omacetaxine was genotoxic in an in vitro chromosomal aberration 
test system in Chinese hamster ovary cells, but was not mutagenic 
when tested in an in vitro bacterial cell assay (Ames test), and it did 
not induce genetic damage using an in vivo mouse micronucleus 
assay. 

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Omacetaxine may impair male fertility. Studies in mice demonstrated 
adverse effects on male reproductive organs. Bilateral degeneration 
of 
the 
seminiferous 
tubular 
epithelium 
in 
testes 
and 
hypospermia/aspermia in the epididymides were reported in the 
highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 
5 mg/m2 day) following subcutaneous injection of omacetaxine for 
six cycles over six months. The doses used in the mice were 
approximately two to three times the clinical dose (2.5mg/m2/day) 
based on body surface area. 
Omacetaxine can cause fetal harm when administered to a pregnant 
woman. Omacetaxine caused embryo-fetal death in animals. 
Pregnant mice were administered omacetaxine SQ during the period 
of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug related 
adverse 
effects 
included 
embryonic 
death, 
reduced 
bone 
ossification, and decreased fetal body weights.  
 Clinical Data 
The efficacy of omacetaxine was evaluated using a combined cohort 
of adult patients with CML from two trials. The combined cohort 
consisted of patients who had received 2 or more approved TKIs and 
had, at a minimum, documented evidence of resistance or 
intolerance to dasatinib and/or nilotinib. Resistance was defined as 
one of the following: no complete hematologic response (CHR) by 
12 weeks (whether lost or never achieved); or no cytogenetic 
response by 24 weeks (i.e., 100% Ph positive [Ph+]) (whether lost or 
never achieved); or no major cytogenetic response (MCyR) by 52 
weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or 
progressive leukocytosis. Intolerance was defined as one of the 
following: 1) Grade 3-4 non-hematologic toxicity that does not 
resolve with adequate intervention; or 2) Grade 4 hematologic 
toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is 
unacceptable to the patient. Patients with NYHA class III or IV heart 
disease, active ischemia or other uncontrolled cardiac conditions 
were 
excluded. 
Patients 
were 
treated 
with 
omacetaxine 
mepesuccinate 
at 
a 
dose 
of 
1.25 
mg/m2 
administered 
subcutaneously twice daily for 14 consecutive days every 28 days 
(induction cycle). Responding patients were then treated with the 
same dose and twice daily schedule for 7 consecutive days every 28 
days (maintenance cycle). Patients were allowed to continue to 
receive maintenance treatment for up to 24 months. Responses 
were adjudicated by an independent Data Monitoring Committee 
(DMC). 

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Harringtonine and homoharringtonine (HHT) have been used as a 
single agent to treat patients with high-risk MDS17,18. Combinations 
using HHT and other agents have also been reported, in largely 
retrospective studies.19-21
3.3 
Azacitidine 
Azacitidine, an analog of the pyrimidine nucleoside cytidine, has 
effects on cell differentiation, gene expression, DNA synthesis and 
metabolism, and causes cytotoxicity. Since the early 1970s, 
azacitidine has been investigated in the US for the treatment of MDS 
and acute leukemia. 
 
The cytotoxic effects of azacitidine may result from multiple 
mechanisms, including inhibition of DNA, RNA and protein synthesis, 
incorporation into RNA and DNA, and activation of DNA damage 
pathways. The ability of azacitidine to cause differentiation is 
attributed to its activity as a hypomethylating agent. Therefore, an 
inhibitor of DNA methylation such as azacitidine would be a rational 
approach to revert epigenetic changes in the malignant clone and re-
establish 
the 
anti-proliferative 
signals 
extinguished 
by 
hypermethylation.  
 
 Preclinical Pharmacokinetic Profile 
Early PK studies used 14C-radiolabeled azacitidine to evaluate drug 
disposition. Based on total radioactivity in plasma, azacitidine was 
absorbed when given subcutaneously (SC), with maximum 
concentrations found 0.5 to 2 hours after dosing. Azacitidine and/or 
its metabolites were then cleared by the kidneys. The plasma t1/2 (3.4 
to 6.2 hours) and amount of radioactivity recovered in urine (50-98% 
of administered dose) were similar after IV and SC dosing.  
 
Drug-drug interaction studies of azacitidine have not been conducted 
in clinical trials. Two in vitro metabolism studies and three in vitro 
drug interaction studies have been completed. Some evidence of 
hepatic metabolism was observed when azacitidine was incubated 
in human liver fractions. The metabolism of azacitidine was 
compared using [14C]5-azacitidine and hepatic S9 fractions from 
human and mouse origin; the formation of deaminated metabolites 
(formylamidinoribofuranosylbiuret 
and 
ribofuranosylbiure) 
was 
independent of nicotinamide adenine dinucleotide phosphate 
(NADPH), implying that metabolism was catalyzed by cytosolic 
enzymes. Azacitidine was not an inducer of the isozymes 1A2, 2C19, 
or 3A4/5. Azacitidine showed no notable inhibition of P450 

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isoenzymes (Cytochrome P450 [CYP450] 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1 and 3A4) in the concentration range of 0.1 to 100 
μM. Therefore, clinically relevant inhibitory or inductive effects on the 
metabolism of CYP450 substrates are unlikely. Azacitidine is neither 
a substrate nor an inhibitor of P-glycoprotein (P-gp) and therefore 
unlikely to produce any clinically relevant interactions as a P-gp 
substrate or an inhibitor. The effect of inducers or inhibitors on the 
metabolism of azacitidine has not been studied. 
 Clinical Data 
The safety profile of azacitidine has been well characterized and is 
based on an extensive amount of patient exposure across a wide 
range of doses and indications. Adverse events (AEs) reported most 
frequently 
were 
hematologic 
events 
of 
thrombocytopenia, 
neutropenia, anemia, and leukopenia, and were typically assessed 
as grade 3 or 4 events. Despite the increased percentages of these 
hematologic events, azacitidine did not appear to increase the risk of 
events of infection or bleeding when compared with patients treated 
with best supportive care only. Non-hematological AEs that were 
reported most often were events related to either the administration 
of the drug (injection site reactions, nausea, vomiting) or 
consequences of the antiemetic treatment (constipation). These 
events were generally graded 1 or 2 in intensity. The reporting 
frequencies for the common hematologic and non-hematological 
events were generally highest during cycles 1 and 2, after which time 
the frequencies decreased over subsequent treatment cycles. Within 
the cycle, the hematologic events tended to occur across the first 3 
to 4 weeks of the cycle, whereas the events associated with the 
administration of azacitidine tended to occur in the first week. These 
findings suggested a lack of cumulative toxicity and that adverse
effects of azacitidine attenuate over time. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objectives 
Phase I: To determine the recommended omacetaxine dose in 
combination with azacitidine 
Phase II: To determine the response rate of omacetaxine in 
combination with azacitidine in the newly diagnosed setting, and to 
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azacitdine in MDS patients who have failed to respond to or 
responded and relapsed after at least one line of therapy containing 
a hypomethylating agent  
4.2 
Secondary Objectives 
o To evaluate the safety of the combination of omacetaxine and 
azacitidine (phase I and phase II) 
o To determine the hematologic improvement from this combination 
(phase II) 
o To determine the duration of response (phase II) 
o To determine the progression free survival (phase II) 
o To determine the rate of transformation to acute myeloid leukemia 
(AML) (phase II) 
o To determine the percentage of patients deemed eligible for 
allogeneic stem cell transplantation who are able to proceed to this 
intervention without a second-line therapy (phase II) 
o To determine the overall survival (phase II) 
5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is an open label, phase I/II single institution pilot study for 
previously untreated high grade MDS patients to receive 
concomitant therapy with omacetaxine and azacitidine, with a small 
pilot study of relapsed or refractory MDS patients. 
 Study Schema 
Phase I 
After consent and screening, patients will be assigned to the 
appropriate omacetaxine dose cohort (Figure 4).  
 

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Cohort 1 will receive 0.75 mg/m2, cohort 2 1.0 mg/m2 and cohort 3 
1.25 mg/m2 of omacetaxine subcutaneously BID. In the event that >1 
dose limiting toxicity (DLT) event occurs in cohort 1, a dose de-
escalation cohort (cohort 0) will enroll and patients will receive 0.5 
mg/m2 omacetaxine subcutaneous BID. Omacetaxine will be 
administered by the patient subcutaneously BID on days 1-7. 
Concomitantly, azacitidine 75 mg/m2 IV (preferred) or subcutaneous
will be administered in the outpatient infusion center or the inpatient 
facility, depending on the needs of the patient, on days 1-7. Patients 
will not receive therapy for the subsequent 21 days, constituting a 
28-day cycle. Cycles will continue in the absence of disease 
progression or patient intolerance/toxicity or preference. 
 
On cycle 1 day 8, a bone marrow biopsy will be performed.  
On cycle 1 day 28, a bone marrow biopsy will be performed to 
determine response status. This will be repeated at the end of cycles 
4 and 6, and every 6 cycles thereafter.  
 
Patients enrolled at dose cohorts lower than cohorts later found to 
be safe may dose escalate to the highest dose level deemed safe, 
at the discretion of the investigator. 
Phase II 
After the establishment of the MTD or the phase II dose if the MTD 
is not reached, phase II will commence. Patients enrolled at the MTD 
or phase II dose in phase I will roll over to phase II. The same schema 
for phase I will apply to phase II, except there will not be omacetaxine 
dose escalation. An expansion phase of 10 patients who did not 
respond to or responded and relapsed after at least one prior line of 
an HMA-containing therapy will also be accrued and treated with the 
same dose and schedule of omacetaxine and azacitidine as the other 
phase II patients. 
 Response Assessments 
Response assessments will be made by evaluation of peripheral 
blood findings and bone marrow biopsies at end of cycle time points, 
using the 2006 International Working Group (IWG) criteria for MDS 
which will apply for response assessments as well as hematologic
improvement criteria1 (Section 5.12).  
5.1.3 Continuation and Interruptions 

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Patients who achieve a response and are tolerating therapy can 
continue to receive sequential treatment cycles indefinitely. Patients 
who experience disease progression or significant treatment-related 
toxicity, as assessed by the investigator or the patient, will 
discontinue therapy. Patients who are deemed to be appropriate for 
allogeneic stem cell transplantation and have the requisite reduction 
in disease burden will come off study to proceed to transplant. 
 
After cycle 1, subsequent cycle delays are not required for any grade 
of hematologic toxicity; however, cycles may be delayed for any 
grade of hematologic toxicity, particularly in the setting of a patient 
who achieves a marrow CR.   
 
Subjects who require brief interruption of omacetaxine for reasons 
other than progression of disease will continue azacitidine therapy 
alone until they resume omacetaxine. When the following cycle is 
resumed, omacetaxine and azacitidine will resume on the same day.  
 
Dose decreases can be considered, see Section 5.15. 
 
Intra-patient dose escalation for patients in phase 1 is allowable if 
higher dose cohorts are proved to be safe, as defined by at least 
three patients completing a higher dose cohort without a DLT event, 
or if a DLT occurs, no more than 1/6 patients in a cohort experiencing 
a DLT. Patients may escalate to the highest safe dose after review 
and approval by the PI.  
5.2 
Study Endpoints 
Primary 
Phase I: To determine the recommended dose for the phase II study 
based on the maximum tolerated dose (MTD) 
Phase 2: Overall response rate (ORR), defined by the proportion of 
patients who achieve any category of complete remission (CR, 
includes CR and marrow CR) or partial remission (PR) based on the 
2006 International Working Group (IWG) criteria for MDS1. 
Secondary: 
o Safety assessments in the form of surveillance of adverse events, 
laboratory test measures, physical exam findings and concomitant 
medication records (phase I and phase II) 
o Hematologic improvement rate 

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o Duration of response 
o Progression free survival 
o Rate of transformation to AML 
o Percentage 
of 
eligible 
patients 
for 
allogeneic 
stem 
cell 
transplantation who proceed to this intervention 
o Overall survival 
5.3 
Selection of Study Population and Enrollment Procedures 
All subjects will be screened for eligibility.  The investigators will be 
responsible for keeping a record of all subjects who sign an informed 
consent form for entry into the study. After the patient has signed and 
dated the informed consent form, all screening procedures have 
been completed and clinical eligibility has been confirmed, the 
patient can be officially enrolled in the study.  All patients must meet 
the qualifications as outlined below. 
 Inclusion Criteria 
A subject will be eligible for study participation if he/she meets the 
following criteria within 14 days prior to the first day of therapy (bone 
marrow biopsy can be performed 28 days prior to the first day of 
therapy). 
1. Subject must have confirmation of high grade MDS (MDS with 
excess blasts by WHO criteria22) or chronic myelomonocytic 
leukemia with greater than 5% bone marrow blasts22 
2. Subjects in the newly-diagnosed Phase 2 cohort must have 
received no prior treatment with a hypomethylating agent for 
MDS. Subjects in the relapsed/refractory Phase 2 cohort must 
have received at least 1 prior line of an HMA-containing 
regimen. “Refractory” is defined as having received at least 
four cycles of any HMA or HMA-containing regimen with >5-
19% bone marrow blasts. “Relapsed” is defined as having >5-
19% bone marrow blasts after having achieved a morphologic 
remission (≤5% bone marrow blasts) after at least one cycle 
of any HMA or HMA-containing regimen. 
3. Subject must be ≥ 18 years of age 
4. Subject must have a projected life expectancy of at least 12 
weeks 

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5. Subject must have an Eastern Cooperative Oncology Group 
(ECOG) Performance status of ≤2  
6. Subject must have adequate renal function as demonstrated 
by a calculated creatinine clearance ≥ 30 mL/min; determined 
via urine collection for 24-hour creatinine clearance or by the 
Cockcroft Gault formula 
7. Subject must have adequate liver function as demonstrated by:
• aspartate aminotransferase (AST) ≤ 3.0 × ULN 
• alanine aminotransferase (ALT) ≤ 3.0 × ULN 
• direct bilirubin ≤ 3.0 × ULN 
8. Non-sterile male subjects must use contraceptive methods 
with partner(s) from time of enrollment and continuing up to 90 
das after the last dose of study drug. Male subjects must agree 
to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
 
9. Female subjects must agree to use two reliable forms of 
contraception simultaneously or to practice complete 
abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) for at least 28 days before 
starting omacetaxine; 2) throughout the entire duration of 
omacetaxine treatment; 3) during dose interruptions; and 4) 
for at least 90 days after omacetaxine discontinuation.  
10. Subject must voluntarily sign and date an informed consent, 
approved by an Institutional Review Board (IRB), prior to the 
initiation of any screening or study-specific procedures. 
 Exclusion Criteria
A subject will not be eligible for study participation if he/she meets 
any of the following criteria: 
1. Subject is known to be positive for HIV. HIV testing is not 
required. 
2. Subject is known to be positive for hepatitis B or C infection 
with the exception of those with an undetectable viral load. 
Hepatitis B or C testing is not required and subjects with 
serologic evidence of prior vaccination to HBV (i.e., HBs Ag, 
anti-HBs+ and anti-HBc–) may participate. 

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3. Subject has any history of clinically significant condition(s) 
that in the opinion of the investigator would adversely affect 
his/her participating in this study including, but not limited to: 
• New York Heart Association heart failure > class 2 
• Renal, neurologic, psychiatric, endocrine, metabolic, 
immunologic, hepatic, cardiovascular disease, or bleeding 
disorder independent of leukemia 
4. Subject exhibits evidence of uncontrolled systemic infection 
requiring therapy (viral, bacterial or fungal). Patients on 
antibiotics with controlled systemic symptoms will not be 
excluded. 
5. Subject has uncontrolled diabetes 
6. Subject has had a recent major hemorrhage or has a bleeding 
diathesis associated with a high risk of bleeding 
7. Pregnant and breastfeeding females. 
8. Subject has a history of other malignancies prior to study entry, 
except for: 
• Adequately treated in situ carcinoma of the breast or cervix 
uteri 
• Basal cell carcinoma of the skin or localized squamous cell 
carcinoma of the skin 
• Prostate cancer with no plans for therapy of any kind 
• Previous malignancy confined and surgically resected (or 
treated with other modalities) with curative intent. 
5.4 
Duration of Study 
After treatment discontinuation, all patients will be followed at least 
annually, in the form of a telephone call or clinic visit, for information 
on whether the patient has relapsed or not, and whether they are 
alive or deceased. 
5.5 
Drug Administration 
 Omacetaxine Administration 
Omacetaxine 
will 
be 
provided 
by 
Teva 
Pharmaceuticals.
Omacetaxine will be dispensed by the investigational pharmacy and 
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treatment cycle. Doses should be administered at the same time 
each day.  
Omacetaxine dose decreases may be considered, see Section 
5.16.5, and for adverse event management guidelines please refer 
to Section 6. 
 
Patients who take more than the prescribed dose of omacetaxine 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately. If a dose of omacetaxine is missed 
or forgotten, it should be taken as soon as possible provided it is not 
more than 2 hours past the planned time. If it is more than two hours 
it should not be given. The next dose should be given at the originally 
planned time. Missed doses should not be made up.  
Omacetaxine will be stored and reconstituted in normal saline 
according to the package insert. Drug syringes will be stored at 20-
25 degrees Celsius (68-77 degrees Fahrenheit); excursions 
permitted from 15-30 degrees Celsius (59-86 degrees Fahrenheit). 
Carton will be protected from light until administration.    
 
 Azacitidine Administration 
Azacitidine will be commercially obtained. Azacitidine 75 mg/m2
should be prepared and administered per the package insert and 
institutional guidelines via an intravenous route, or, if necessary, 
subcutaneously. 
5.6 
Assuring Patient Compliance 
The investigator and designated and qualified representatives will 
dispense omacetaxine only to subjects enrolled in the study in 
accordance with the protocol. The study drug must not be used for 
reasons other than that described in the protocol. 
Patients will receive all dosages of azacitidine in the inpatient or 
outpatient setting.  
Patients will receive a diary to record the specific time each dose of 
omacetaxine was taken and to record reasons for any missed doses. 
Patient compliance will be assessed on day 28 of a completed cycle 
or day 1 of a subsequent treatment cycle. Patients will be required to 
bring their diary and any remaining vials, to clinic during this visit. 
Research personnel will record any unused drug at each visit and 
reconcile with the patient diary. Compliance will be monitored and 

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documented by the study coordinator. Poor compliance will result in 
counseling of the subject by study site personnel. Any unused 
omacetaxine will be returned to the pharmacy. 
5.7 
Drug Accountability
The investigator and his representatives will verify that study drug 
supplies are received intact and in the proper amounts. This will be 
documented. The investigator or his representatives will administer 
study drug only to subjects enrolled in the study. A current (running) 
and accurate inventory of study drug will be kept by the investigator 
and will include shipping invoices and the date on which study drug 
is dispensed to the subject. Upon completion or termination of the 
study, all original containers (containing partially used or unused 
study drug) will be returned to the sponsor according to their 
instructions. Empty containers will be destroyed at the site. 
5.8 
Concomitant Therapy 
 Permitted Concomitant Therapy 
Transfusion of blood and blood products, antibiotics, anti-emetics 
and other standard supportive care medications are permitted as 
needed. Hydroxyurea is permitted as needed according to 
institutional guidelines, as needed. Filgrastrim may be used 
according to institutional guidelines.  Antibiotics will be used for 
patients with infections or neutropenic fevers per institutional 
guidelines. 
 
If a subject reports taking any over-the-counter or prescription 
medications, vitamins, and/or herbal supplements or if administration 
of any medication becomes necessary, beginning with the screening 
visit through the end of the study, the name of the medication, 
dosage information including dose, route and frequency, date(s) of 
administration including start and end dates, and reason for use must 
be recorded on the appropriate electronic case report form (eCRF). 
 Prohibited Concomitant Therapy 
Chemotherapy, 
systemic 
or 
intrathecal, 
immunotherapy, 
radiotherapy and prednisone >20 mg/day are prohibited. 

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5.9 
Contraception Recommendations 
Male subjects must be surgically sterile (vasectomy with medical 
assessment confirming surgical success) or if the male subject has a female 
partner who is postmenopausal or permanently sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy), no contraception 
is required. 
 
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree from enrollment through 90 days after the last dose 
of investigational product to practice contraception with a partner who 
agrees to at least one of the following contraceptive measures: 
o Combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) associated with the 
inhibition of ovulation, initiated at least 1 month prior to enrollment 
o Progestogen-only 
hormonal 
contraception 
(oral, 
injectable, 
implantable) associated with inhibition of ovulation, initiated at least 
1 month prior to enrollment 
o Bilateral tubal occlusion/ligation 
o Intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
o True abstinence: Refraining from heterosexual intercourse when this 
is in line with the preferred and usual lifestyle of the subject (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable) 
 
Additionally, male subject agrees not to donate sperm from enrollment 
through 90 days after the last dose of investigational product. 
Females of childbearing potential (FCBP) enrolled in this protocol must 
agree to use two reliable forms of contraception (listed above) 
simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting omacetaxine; 2) throughout the entire duration 
of omacetaxine treatment; 3) during dose interruptions; and 4) for at least 
90 days after omacetaxine discontinuation.  
 
5.10 Study Procedures 
Study procedures listed in section 2 are detailed in this section, with the 
exception of adverse event information (see Section 6). All study data will 
be recorded on eCRFs. 
 
Procedures performed at screening will serve as baseline, unless repeated 
on cycle 1 day 1 prior to dosing, in which case this will serve as baseline. 

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Any abnormal laboratory or vital sign between screening and prior to 
administration of therapy will be recorded in the subject’s medical history 
and will also serve as the subject’s baseline.  
 
Subjects who signed the informed consent will obtain a screening/subject 
number. Subjects who signed informed consent, have had at least one 
study procedure conducted, and who are determined to be a screen failure 
will not proceed to the study. The reason for the screen failure will be 
documented in the source document and captured in the eCRF. Screening 
procedures must be performed within 14 days prior to study drug 
administration, with the exception of the screening bone marrow biopsy, 
which can occur 28 days prior. Subjects who complete all screening 
procedures and meet the inclusion criteria (see section 5.3.1) and none of 
the exclusion criteria (see Section 5.3.2) will proceed to enrollment. 
 
Informed consent 
Signed informed consent will be obtained from the subject or the subject’s 
legally acceptable representative in order to participate in the study. The 
IRB approved informed consent must be signed and dated by the subject 
or representative prior to undergoing any study procedures or before any 
prohibited medications are withheld from the subject in order to participate 
in the study.  
 
History 
Involves a complete medical history, with documentation of clinically 
significant medical conditions, and MDS history including the date of 
diagnosis of MDS and any precursor conditions. Also includes review of 
current medications and allergies. 
 
Physical Exam 
Symptom directed, per institutional protocol. 
 
Vital Signs 
Includes height (height at the screening only), weight, temperature, blood 
pressure, pulse, and respiratory rate. All methods of measurement and 
practices will be per institutional protocol. 
 
ECOG PS23 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 

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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 
 
AEs and Con Meds 
On cycle 1 day 1, any serious adverse events observed from the signing of 
informed consent but prior to administration of omacetaxine and azacitidine 
will be reported, if considered by the investigator to be causally related to 
study-required procedures. At each visit, including the end of treatment visit, 
the subject’s medical history will be reviewed and any changes from 
baseline will be recorded on the adverse event eCRF. 
 
All medications, prescription and over the counter, including vitamins and/or 
herbal supplements, will be recorded beginning with the screening visit and 
through the EOS visit. No new medications will be reported after. . 
 
12 Lead EKG 
A single 12-lead resting EKG will be obtained at screening or as clinically 
needed. It will be recorded after the subject has been in the supine position 
for at least 5 minutes. Subjects will be instructed to remain stationary for the 
duration of the recording. An investigator will then evaluate it as clinically 
significant or not clinically significant, which will be entered into the CRFs.  
 
Clinical Laboratory Tests 
All laboratory tests will be performed at the time points listed in the schedule 
of study assessments, and will be performed at additional time points based 
on institutional guidelines. 
 
Hematology 
• Hematocrit 
• Hemoglobin 
• WBC count 
• Differential (if WBC high enough, per institutional standard) 
• Platelet count 

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Chemistry 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Total bilirubin 
• Albumin 
• Alkaline phosphatase 
• Sodium 
• Potassium 
• Chloride 
• Carbon dioxide 
• Glucose 
• Blood urea nitrogen (BUN) 
• Creatinine 
• Calcium 
• Magnesium 
• Phosphorus 
• Total Protein 
• Uric acid 
• Lactate dehydrogenase (LDH) 
 
Coagulation 
• Prothrombin time (PT) 
• International normalized ratio (INR) 
• Partial thromboplastin time (PTT) 
• Fibrinogen 
 
Azacitidine 
See Section 5.5.2 
 
Omacetaxine 
See Section 5.5.1  
 
Bone marrow aspirate and biopsy  
To be performed at all time points outlined in the schedule of study 
assessments, in addition to at any time upon concern for relapse.  
Historical bone marrow aspirates and biopsy at screening may be 
acceptable per Investigator discretion. 
 
Attempts to obtain an aspirate and biopsy are required at all listed time 
points except day 8, when an aspirate alone is sufficient. If a patient is not 
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be attempted per institutional protocol. On all time points except for day 8, 
samples should be sent for morphological assessment, flow cytometry, 
cytogenetic analysis and molecular testing, as is clinically appropriate. All 
results will be captured in the eCRF. Day 8 aspirates may not involve 
cytogenetic and molecular assessments, as is clinically appropriate.  
 
Dispensing and Collecting Calendar and Diary 
Subject calendars/diaries will be provided at the time of discharge from the 
hospital. Subjects will bring their calendars/diaries back to be reviewed at 
each visit.  
 
Subjects will record the date and time of each dose of study drug taken, 
including whether any doses of the study drug are missed. 
 
The calendars/diaries will be reviewed at each visit and relevant pages will 
be photocopied by study staff. At the end of participation, the 
calendars/diaries will be returned to the site and filed with the subject’s 
source documents.  
 
5.11 Response Assessments 
Assessment of clinical responses will be made according to 2006 IWG MDS 
criteria1. The major criteria for judging responses will include physical 
examination and examination of blood and bone marrow. In the event that 
peripheral blood findings improve 14 days after a bone marrow biopsy, 
whether or not in the setting of a delay in treatment, the response 
assessment will be adjusted accordingly. Only subjects who complete cycle 
1 will be evaluable for response. Patients with un-evaluable bone marrows 
should be reported as indeterminate and a repeat bone marrow should be 
completed within 1 week. Response duration is measured from the time all 
response criteria are first met until relapse is documented. 
 
Complete Remission (CR) 
CR requires all of the following: 
• Bone marrow myeloblasts ≤5% with normal maturation of all cell lines 
• Hemoglobin ≥11 g/dL 
• Absolute neutrophil count ≥1.0 x 109/L 
• Platelet count >100 x 109/L 
• No peripheral blood blasts 
Partial Remission (PR)  
• All CR criteria if abnormal before treatment except:  

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o Bone marrow blasts decreased by ≥50% over pretreatment 
but still >5% 
• Cellularity and morphology not relevant  
Marrow CR 
• Bone marrow: ≤5% myeloblasts and decrease by ≥50% over 
pretreatment 
• Peripheral blood: if hematological improvement responses, they 
will be noted in addition to marrow CR 
Stable disease  
• Failure to achieve at least PR, but no evidence of progression for 
> 8 weeks  
Failure  
• Death during treatment or disease progression characterized by 
worsening of cytopenias, increase in percentage of bone marrow 
blasts, or progression to a more advanced MDS FAB subtype 
than pretreatment 
5.12 Hematologic Improvement (HI)1 
The HIs are measured in patients with pretreatment abnormal values: 
hemoglobin <11 g/dL or RBC-transfusion dependence, platelet count 
<100x109/L or platelet-transfusion dependence, absolute neutrophil count 
(ANC) <1.0x109/L. Pretreatment baseline measures of cytopenias are 
averages of at least 2 measurements (not influenced by transfusions, i.e., 
no RBC transfusions for at least 1 week and no platelet transfusions for at 
least 3 days) over at least 1 week prior to therapy. 
Erythroid Response 
• Hgb increase by ≥1.5 g/dL  
• Relevant reduction of units of RBC transfusions by an absolute 
number of at least 4 RBC transfusions/8 week compared with the 
pretreatment transfusion number in the previous 8 weeks. Only 
RBC transfusions given for a Hgb of 9.0 g/dL pretreatment will 
count in the RBC transfusion response evaluation 
Platelet Response  
• Absolute increase of ≥30x109/L for patients starting with > 
20x109/L platelets  
• Increase from <20x109/L to >20x109/L and by at least 100%  
 
Neutrophil Response  

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• At least 100% increase and an absolute increase > 0.5x109/L  
Progression or Relapse After HI 
• 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  
5.13 Reporting of Results 
At the conclusion of each bone marrow biopsy performed after C1D8, all 
patients will be assessed as one of the following responses: 
• CR 
• PR 
• Marrow CR 
• Stable disease 
• Failure 
5.14 Stopping Rules 
 Individual Patient Stopping Rules 
All subjects will be included for analysis of safety data. Subjects have 
the right to withdraw from the study at any time. The investigator will 
discontinue a subject if this is felt to be necessary for any reason 
including:  
• Non-compliance with the study protocol 
• Is it believed to be in the best interests of the subject 
• Disease progression  
• Toxicity related to study drug that requires more than a 4-
week dose interruption of therapy and in the absence of 
clinical benefit 
• Need for other anti-neoplastic agents or radiotherapy for 
the development of a new primary cancer diagnosis 
• Adverse event that precludes further investigational drug 
administration 
• Development of unrelated illness which compromises 
further participation in the study 
 

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In the event of withdrawal or discontinuation, the reason for 
discontinuation will be recorded and a final visit, including a physical 
examination, vital signs, ECOG PS, bone marrow aspirate and 
biopsy, AE assessment with con meds, hematology/chemistry 
laboratories and collection of the calendar/diary, will be performed as 
soon as possible after discontinuation. 
A safety follow-up visit should be performed approximately 30 days 
following discontinuation for adverse events, and should include a 
history, physical examination, and review of systems, and then 
should be repeated as clinically appropriate for safety assessments. 
Patients will be followed until a satisfactory clinical resolution of 
adverse events is achieved. A separate safety visit does not need to 
be performed for subjects with a final visit ≥30 days after 
discontinuation of study drug and did not require additional AE follow 
up. Patient refusal or inability to attend safety follow up visits will be 
noted in the source documentation. After treatment discontinuation, 
all patients will be followed at least annually, in the form of a 
telephone call or clinic visit, for information on whether the patient 
has relapsed or not, and whether they are alive or deceased for up 
to 5 years (or death, whichever comes first).  
 
 Study Stopping Rules 
The study will continue until the last patient is followed one year 
beyond receiving the last dose of study drug. If the investigator 
determines that continued exposure to the study drug represents a 
significant risk to subjects, the study will be stopped. In addition, if 
the expected response rate falls below 4/18 patients in the first stage 
of the phase II study, the study will be stopped (see Section 8.5). All 
enrolled subjects will be notified of the premature discontinuation and 
the investigator will administer treatments with other regimens as is 
appropriate. 
5.15 Dose Escalation for Phase I 
The phase I portion is organized in a standard phase I 3+3 design.  The first 3 
subjects will be assigned to cohort 1. If none of the first three patients experiences 
DLT, escalation to the next dose cohort is permitted. If one of the first three patients 
experiences DLT, a total of six patients will be required in that dose cohort, and 
escalation will only be permitted if five of six patients do not experience DLT. If 
more than one DLT is observed in any cohort, this will be determined to be the 
maximally administered dose, and three more patients will be enrolled in the next 
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be the cohort in which ≤1/6 patients have dose limiting toxicity at the dose prior to 
the maximally administered dose(see Section 5.1.1. Dosing Schema). Once the 
MTD is established the phase II portion of the study will begin; the phase I patients 
treated at the MTD will roll over to the phase II portion of the study. 
5.16 Dosing Delays and Modifications 
 Missed Doses 
If a dose of omacetaxine is missed, it should be taken as soon as 
possible provided it is not more than 2 hours past the planned time. 
If it is more than two hours it should not be given and noted in the 
diary; the next dose should be given at the originally planned time. 
Dosing will be tracked in the patients’ diaries.  
 Dose-limiting toxicity (DLT) definition 
During cycle 1, the following will be considered DLT:  
• Grade ≥ 3 non-hematologic toxicity, uncontrolled despite 
optimal medical management 
o This will exclude:  
 Grade ≥ 3 infection 
 Fever (including febrile neutropenia) 
 Grade 3 or higher electrolyte abnormalities that 
resolve, with or without intervention, to < Grade 
2 in <72 hours; abnormalities that do not 
resolve, with or without intervention, to < Grade 
2 in <72 hours will be considered DLT 
 
• In subjects who achieve a CR or marrow CR, prolonged 
myelosuppression during the first cycle that lasts longer than 
42 days after initiating cycle 1, defined as ANC < 500/μL or 
platelet count < 10 x 109/L, is defined as DLT. 
• Any treatment related death will be defined as a DLT 
DLTs will be assessed during the DLT assessment window of cycle 
1 (up 42 days to account for treatment delays) following the first dose 
of study treatment. 
 Additional Doses 
Patients who take more than the prescribed dose of omacetaxine 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately.  

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 Dose Delays 
After cycle 1, the start of each subsequent cycle can proceed in the 
absence of possibly/related > grade 2 non-hematologic toxicity. In 
the presence of possibly/related > grade 2 non-hematologic toxicity, 
delay of the subsequent cycle for up to 14 days is allowed. If the 
possibly/related > grade 2 non-hematologic toxicity resolves to ≤ 
grade 1 within 14 days, subsequent cycles may resume.  
After cycle 1, subsequent cycle delays are not required for any grade 
of hematologic toxicity; however, cycles may be delayed for any 
grade of hematologic toxicity, and myeloid growth factors may be 
used according to standard practices and at the discretion of the 
investigator, in the absence of evidence of ongoing disease.  
Subjects who require brief interruption of omacetaxine for reasons 
other than progression of disease will continue on azacitidine therapy 
alone until they resume omacetaxine.  
 Dose De-Escalation 
Hematologic toxicity will not be distinguishable between azacitidine 
and omacetaxine; therefore, when dose de-escalation for 
hematologic toxicity is required, it will first occur for omacetaxine. If 
after an additional cycle at the adjusted dose of omacetaxine the 
hematological toxicity persists, azacitadine will be dose adjusted.  
 
For patients with baseline (start of treatment) WBC ≥3.0 x109 /L, 
ANC ≥1.5 x109 /L, and platelets ≥75 x109 /L, adjust the dose of 
azacitidine and omacetaxine as follows, based on nadir counts for 
any given cycle:  
 
Nadir Counts 
% Dose in the Next Course 
ANC (x109/L) 
Platelets (x109/L) 
 
<0.5 
<25 
50% 
0.5-1.5 
25-50
67% 
>1.5 
>50 
100% 
For patients with baseline (start of treatment) WBC <3.0 x109 /L, 
ANC <1.5 x109 /L, or platelets <75 x109 /L, dose adjustments 
should be based on nadir counts and bone marrow biopsy 
cellularity at the time of the nadir as noted below, unless there is 
clear improvement in differentiation (percentage of mature 
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course) at the time of the next cycle, in which case the dose of the 
current treatment should be continued. 
 
WBC or Platelet 
Nadir % 
Decrease in 
Counts from 
Baseline 
Bone Marrow Cellularity at Time of Nadir (%) 
 
 
 
30-60 
15-30 
<15 
% Dose in the Next Course 
50-75 
100 
50 
33 
>75 
75 
50 
33 
 
Non-hematological AEs related to omacetaxine that are >grade 3 
and do not resolve to <grade 2 after a 14 day interruption of therapy 
will result in 5-day treatment courses of omacetaxine for all 
subsequent treatment cycles.  
 
6 
SAFETY PLAN 
6.1 
Adverse Event 
An adverse event (AE) is defined as any untoward medical 
occurrence in a subject on the study. This can include any 
unfavorable or unintended sign, symptom or disease temporally 
associated with the use of the therapy, regardless of causality with 
the therapy. This may include use of the therapy as stipulated in the 
protocol or as labeled or from accidental or intentional overdose. 
Worsening of a pre-existing condition or illness is considered an AE. 
Worsening in severity of a reported AE should be reported as a new 
AE. Laboratory abnormalities and changes in vital signs are AE only 
if they result in study discontinuation, necessitate medical 
intervention, meet protocol specific criteria, and/or are considered by 
the investigator to be clinically significant or AEs. Elective surgeries 
or procedures scheduled to occur during a study are not AEs if the 
surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been pre-planned prior to study entry. 
However, if the pre-existing condition deteriorated unexpectedly 
during the study (e.g. the surgery must be performed earlier than 
planned) then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an AE. 
 
A treatment-emergent AE is defined as any AE reported by a subject 
with onset or worsening from the time that the first dose of study drug 

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is administered until 30 days have elapsed following discontinuation 
of the therapy. 
 
The investigators will have access to updated package inserts for 
omacetaxine and azacitidine as references for safety issues related 
to each drug. 
 
6.2 
Serious Adverse Events 
If an AE meets any of the following criteria it is to be considered a 
serious adverse event (SAE) and must be reported to the PI and 
Teva within 24 hours, see Section 6.8.2. 
 
The PI will then review and submit to the University of Colorado 
regulatory authorities and the FDA, if applicable, in accordance with 
21 CFR 312.32. 
 
All SAEs will be reported using the FDA 3500A Mandatory 
MedWatch report form. SAE form can be found at:  
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/F
orms/UCM048334.pdf 
 
An adverse event will be classified as an SAE if it meets one of the 
following criteria: 
 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the patient at immediate 
risk of death in the opinion of the 
investigator. This classification does not 
apply to an AE that hypothetically might 
cause death if it were more severe. 
Hospitalization 
or 
prolongation 
of 
hospitalization: 
AE that required hospitalization for any 
length of time or prolonged inpatient 
hospitalization. 
Hospitalizations 
for 
elective medical or surgical procedures 
or treatments planned before enrollment 
in the treatment plan are not SAEs by this 
criterion. Admissions to an outpatient 
facility, emergency room, palliative unit or 
hospice care facility are not considered to 
be hospitalizations and are not SAEs. 

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Disabling/incapacitating AE that results in substantial and 
permanent disruption of the patient’s 
ability to carry out normal life functions. 
Does 
not 
include 
experiences 
of 
relatively minor medical significance such 
as 
headache, 
nausea, 
vomiting, 
diarrhea, 
influenza 
and 
accidental 
trauma (e.g. ankle sprain) 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of 
a patient exposed to the treatment 
regimen before conception or during 
pregnancy. 
Important 
medical 
event requiring medical 
or surgical intervention 
to 
prevent 
serious 
outcome 
An important medical event that may not 
be immediately life-threatening or result 
in death or hospitalization, but based on 
medical judgment may jeopardize the 
subject and may require medical or 
surgical intervention to prevent any of the 
outcomes listed above (i.e., death, life-
threatening, 
hospitalization 
or 
prolongation 
of 
hospitalization, 
congenital anomaly or persistent or 
significant 
disability/incapacity). 
Any 
elective or spontaneous abortion or 
stillbirth is considered a SAE.  
 
 
For SAEs that result in death, the date and cause of death will be 
recorded in the case report form.  
 
Deaths due to disease progression will not be recorded as SAEs. 
Patient deaths that are later determined to be unrelated to disease 
progression may be reported outside the 24-hour window. 
 
Hospitalization to allow observation and management for the 
purpose of TLS prophylaxis will not be considered SAEs unless there 
is an additional reason for hospitalization or an additional criterion for 
seriousness other than hospitalization (e.g., abnormal post-dose 
TLS laboratories that necessitate therapeutic medical intervention). 
 

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Hospitalization of a subject in post-treatment follow up or survival  
more than 30 days  after discontinuation of the therapy will not be 
recorded as a SAE. 
 
SAEs occurring after informed consent but prior to initiation of 
therapy will be collected only if felt by the investigator to be causally 
related to the study required procedures. 
 
For hospitalizations or surgical or diagnostic procedures, the illness 
leading to the hospitalization or surgical or diagnostic procedure will 
be recorded as the SAE, not the procedure itself. The procedure will 
be captured in the narrative as part of the action taken in response 
to the illness. 
 
6.3 
Adverse Events Commonly Associated with MDS 
Certain AEs are anticipated to occur in this study population at some 
frequency independent of drug exposure. For example, cytopenias 
(anemia, neutropenia, thrombocytopenia) are part of the natural 
history of MDS. Therefore, persistent cytopenias at the same CTCAE 
grade as at baseline are not be reported as AEs, unless they meet 
criteria for an SAE, result in permanent discontinuation of a study 
drug, or the investigator has an identifiable cause other than the 
underlying disease.  
 
6.4 
Adverse Event Severity 
The investigator will rate the severity of each adverse event 
according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE version 4.0). If a reported 
AE increases in severity, the initial AE should be given final outcome 
date and a new AE must be reported to reflect the change in severity.  
 
For AEs not captured by the CTCAE, the following should be used: 
 
Grade 1 
The AE is transient and easily tolerated by the subject 
(mild). 
Grade 2 
The AE causes the subject discomfort and interrupts the 
subject’s usual activities (moderate) 
Grade 3 
The AE causes considerable interference with the 
subject’s usual activities and may be incapacitating 
(moderate to severe) 

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Grade 4 
The AE is life-threatening requiring urgent intervention 
(severe) 
Grade 5 
The AE resulted in death of the subject (severe) 
 
6.5 
Relationship to Study Drug 
The investigator will use the following definitions to assess the 
relationship of the AE to the use of study drug: 
 
Reasonable Possibility of 
Relationship 
with 
Azacitidine 
An AE where this is evidence to suggest a 
causal relationship between azacitidine 
and the AE 
No Reasonable Possibility 
of 
Relationship 
with 
Azacitidine 
An AE where this is no evidence to 
suggest a causal relationship between 
azacitidine and the AE 
Reasonable Possibility of 
Relationship 
with 
Omacetaxine 
An AE where this is evidence to suggest a 
causal relationship between omacetaxine 
and the AE 
No Reasonable Possibility 
of 
Relationship 
with 
Omacetaxine  
An AE where this is no evidence to 
suggest a causal relationship between 
omacetaxine and the AE 
 
For causality assessments, events assessed as having a reasonable 
possibility of being related to the study drug will be considered 
“associated.” Events assessed as having no reasonable possibility 
of being related to study drug will be considered “not associated.” 
When no reasonable possibility of an association between a study 
drug and a SAE exists, the investigator must provide another cause. 
 
6.6 
Deaths 
Death is an outcome of an event. Deaths that occur during the AE 
reporting period that are attributed by the investigator to MDS 
progression will be recorded as such. For all deaths, the event or 
condition that caused or contributed to the fatal outcome will be 
recorded as the single medical concept on the AE CRF. If the cause 
of death is unknown and cannot be ascertained, “unexplained death” 
should be recorded. If the cause later becomes available, 
“unexplained death” should be replaced with the established cause 
of death. 
 

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6.7 
Recording Adverse Events 
Patient safety will be assessed by reviewing AEs during planned and 
unplanned visits and physical and laboratory examinations from the 
time the patient receives the first dose of study drug until 30 days 
after the patient’s last study treatment. The investigator will assess 
and record AEs in detail including the date of onset, event diagnosis 
(if known) or sign/symptom, severity, time course (end date, ongoing, 
intermittent), relationship of the AE to the study drug, and any action 
taken. For SAEs considered unrelated to study drug, the investigator 
will provide another cause for the event. AEs may be recorded as the 
result of a response to a query, an observation by site personnel, or 
due to a report from a subject. All AEs will be followed to a 
satisfactory conclusion. 
 
6.8 
 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all Food and Drug 
Administration (FDA) safety reporting requirements. If the FDA 
determines an IND is necessary, it is a requirement of 21 CFR 
312.33 that an annual report be provided to the FDA within 60 days 
of the IND anniversary date.  21 CFR 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 Teva as a supporter of this study. 
 
 Adverse Event Reporting  
All AE reports will include the patient’s number, age, sex, weight, 
severity of reaction (mild, moderate, severe), relationship to the study 
(fatal relationship, definitely related, possibly related, unrelated), 
date and time of administration of test medications and the 
investigators will notify the IRB and DSMC of a SAE according to 
institutional policy.   
 Reporting to Teva 
Serious adverse events (SAE) are defined in Section 6.2.  
In addition to compliance with all FDA reporting requirements 
pursuant to 21 CFR 312, the Principal Investigator shall: 
a) Report to Teva all serious adverse events experienced by a study 
subject receiving a Teva product within 24 hours of learning of 
the event regardless of the relationship of the event to the Teva 

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product.  Principal Investigator shall make available to Teva 
promptly such records as may be necessary and pertinent to 
investigate any such event, if specifically requested by Teva. 
b) Copy Teva on the submission to the FDA of events meeting the 
definition of IND safety reports at the time of submission to the 
Agency; and, 
c) Notify Teva upon any subjects receiving a Teva product whose 
pregnancy has resulted in a negative outcome or untoward event 
during the course of pregnancy or upon delivery. 
 
Teva’s contact for reporting serious adverse drug experiences, 
pregnancy experiences, non-serious adverse events of tumor lysis 
syndrome, and communication of FDA submissions of IND safety 
reports is drug.safety@tevapharm.com or fax to 215-795-4052. 
Product Complaints:  In addition to compliance with all FDA 
requirements pursuant to 21 CFR 211 and 21 CFR 820, Principal 
Investigator will report to Teva within 24 hours any suspected quality 
defect in an Teva Product or its Teva-provided packaging, labeling, 
or medical device component (collectively, “Product Complaint”).  
Principal Investigator will report Product Complaints that involve a 
Teva Product, whether Teva has supplied the Teva Product used in 
the Study or not. Teva’s contact for reporting Product Complaints is
888-828-2872 or email at qas@tevapharm.com. 
 Reporting From Teva 
Teva will notify the investigators 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 investigators will notify the IRB promptly of these new 
serious and unexpected AEs or significant risks to subjects.  
The investigators must keep copies of all AE information, 
including correspondence with Teva and the IRB, on file. 

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6.9 
Pregnancy 
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 omacetaxine, or within 28 
days of the subject’s last dose of omacetaxine, are considered 
immediately reportable events. Omacetaxine is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Teva Drug Safety immediately 
by facsimile or email. The female subject should be referred to an 
obstetrician-gynecologist, 
preferably 
one 
experienced 
in 
reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the 
pregnancy, and must notify Teva 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 Teva 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 Teva Drug Safety 
immediately 
by 
facsimile 
215-795-4052 
or 
email 
drug.safety@tevapharm.com, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form (see Section 
6.2).  
 
Pregnancies of female partners of male study subjects are also 
included in the information of interest, however, will require consent 
of female partner with documentation if the partner refuses consent 
to release information on their pregnancy and outcome. 
 
6.10 Decreased Spermatogenesis 
Based on preclinical data, omacetaxine has an adverse effect on 
male reproductive organs. Bilateral degeneration of the seminiferous 
epithelium and hypospermia/aspermia in the epididymides were 
reported in the highest dose group (1.67 to 2.33 mg/kg/day; 5 to 7 

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mg/m2/day) following SQ injection of omacetaxine for 6 cycles over 
6 months. The doses used in mice were approximately 2-3 times the 
clinical dose. The effects on omacetaxine on female and male fertility 
have not been studied. The effect on human fertility is unknown. 
 
6.11 Management of Infection 
Anti-infective prophylaxis will be implemented per institutional 
guidelines with consideration for possible drug interactions.  
 
6.12 Management of Other Toxicities 
If other events occur that are related to the study drugs, the 
investigator may interrupt or dose reduce the therapies has 
appropriate. Grade 3 or greater non-hematologic toxicity that is 
related to the study drugs will require interruption and possible 
discontinuation. Therapy may be re-introduced, potentially at a 
reduced dose, if the toxicity returns to baseline if grade 2 at study 
entry or ≤ grade 1. 
 
7 
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, 
good clinical practice or standard operating procedure requirements. The 
noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. These practices are 
consistent with ICH E6, sections: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
• 5.1 Quality Assurance and Quality Control, section 5.1.1. 
• 5.20 Noncompliance, sections 5.20.1 and 5.20.2. 
Intentional deviations are not allowed unless necessary to eliminate an 
immediate hazard to study subjects. The principal investigator is 
responsible for complying with all protocol requirement and applicable laws 
regarding protocol deviations. If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the study team will keep record of 
deviations and is responsible for reporting to the IRB and DSMC as 
required. 
 

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8 
STATISTICAL METHODS 
Patients who receive at least one dose of azacitidine or omacetaxine will be 
evaluable for safety. Patients who complete at least one cycle of therapy 
will be evaluable for efficacy. 
 
8.1 
Demographics 
 
Descriptive statistics will be provided for demographic variables. 
 
8.2 
Efficacy Analysis  
Efficacy will include analyses of ORR as defined as CR+PR+marrow 
CR, median time to achieve a response, duration of overall response, 
event free survival and overall survival. 
 
8.3 
Safety Analysis 
Safety will be assessed by analysis of AEs, SAEs, all deaths, 
changes in laboratory values and vital sign parameters. Analysis of 
AEs will include only treatment-emergent events (events that had 
onset on or after the first dose of study drug). Analysis of AEs and 
SAEs will not include those that have an onset >30 days after the 
last dose of study drug. Toxicity grades using NCI CTCAE V4.0 and 
relationships to study drugs will be assessed. In addition, incidence 
of febrile neutropenia, ≥ grade 2 bleeding complications and number 
of transfusions received (red blood cells and platelets) will be 
assessed. 
 
8.4 
Deaths 
The number of subject deaths will be analyzed by those that occurred 
within 30 days of the last dose of study drug, those that occurred 
more than 30 days after the last dose of study drug, those that 
occurred within the first 30 days of the study, those that occurred 
within the first 60 days of the study, those that were related to study 
drug and those that were unrelated to study drug.  
 
8.5 
Sample Size Determination 
The total number of patients enrolled in the phase 1 study will depend 
on the number of dose cohorts required to identify the MTD. Design 
consideration were made to obtain preliminary safety information in 
this patient population. Escalation to the next dose cohort will depend 
on the identification of DLT at a given dose. 

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For the phase II study, it is known that hypomethylators such as 
azacitidine used as a single agent in newly diagnosed high-grade 
MDS historically are associated with about a 20% CR/marrow CR 
rate5. Our alternative hypothesis for the use of omacetaxine with 
azacitidine in untreated high-risk MDS patients is a 43% CR/marrow 
CR rate, which would be clinically significant. Using a one-sided 
exact test for a difference in proportion, a sample size of 23 patients 
is needed for this study, assuming a Type 1 error rate of 5% and a 
power of 80%.  At least 9 of 23 patients must have a CR/marrow CR 
to reject the null hypothesis.  
 
Ten MDS patients who have relapsed after or are refractory to at 
least one line of an HMA or HMA-containing regimen will be enrolled 
to determine preliminary toxicity and efficacy assessments. 
 
A “survival” curve and its 90% confidence interval as well as the 
median remission duration will be computed for the data. 
 
8.6 
Statistical Analysis Plan 
This study is being conducted to 1) determine the maximum tolerated 
dose of the treatment regimen and 2) determine efficacy of the 
treatment as defined by overall response rate (those who achieve 
any type of complete remission as well as those who achieve partial 
remission).  A standard Phase I 3+3 design will be employed to 
determine MTD.  All patients treated at the MTD in dose escalation 
will be included in analysis for the Phase II component of this study.  
The primary endpoint, the overall response rate proportion in 
patients enrolled in the Phase II portion of this study, will be assessed 
and formally compared—with a null hypothesis of 20% overall 
response rate vs. the alternative hypothesis of 43% overall response 
rate using a one-sided exact test.  Kaplan Meier estimates of survival 
(overall response) at 12 months and their standard errors will be 
calculated.  Comparisons between categorical groups will be 
conducted using the appropriate parametric or non-parametric 
statistical test (Chi-square, Student’s T, etc.) 
 
Secondary measures of progression free survival, overall survival, 
and duration of response will be explored using Kaplan Meier 
survival analysis methods.  Furthermore, other secondary endpoints 
such as hematologic improvement rate and rate of transformation to 
AML will be calculated along with their 95% confidence intervals.  
Laboratory test measures and physical exam findings will be 
described using summary measures.  Exploratory analyses can 

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describe differences in these findings based on demographic 
variables. 
 
9 
ETHICS 
9.1 
Institutional Review Board 
The protocol, informed consent form(s), and all subject materials will 
be submitted to the Colorado Multiple Institutional Review Board 
(COMIRB) for review and approval. Approval of both the protocol and 
the consent form must be obtained before any subject is enrolled. 
Any amendment to the protocol will require review and approval by 
COMIRB before the changes are implemented to the study. All 
changes to the consent form will COMIRB approved; a determination 
will be made regarding whether previously consented participants 
need to be re-consented. 
9.2 
Ethical Standards 
Good 
clinical 
practice 
(GCP) 
requires 
that 
the 
protocol, 
amendments, the Investigator’s Brochure, the informed consent and 
all other forms of subject information related to the study and any 
other necessary documents be reviewed by the IRB. The IRB will 
review the ethical, scientific and medical appropriateness of the 
study before it is conducted. IRB approval of the protocol, informed 
consent and subject information will be obtained prior to the 
authorization of drug shipment to the study site. 
 
Amendments to the protocol will require IRB approval prior to 
implementation of any changes made to the study design. The 
investigator will be required to submit, maintain and archive essential 
documents. 
 
During the conduct of the study the investigator will promptly provide 
written reports to the IRB of any changes that affect the conduct of 
the study and/or increase the risk to subjects.  
 
The study will be conducted in accordance with the protocol, 
International Conference on Harmonization (ICH) GCP guidelines, 
applicable regulations and guidelines governing clinical study 
conduct and ethical principles that have their origin in the Declaration 
of Helsinki.  

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9.3 
Informed Consent Process 
Prior to the initiation of any screening or study-specific procedures, 
the IRB approved consent form(s) describing in detail the study 
agent, study procedures, and risks will be given to the subject and 
the investigator or her representative will explain the nature of the 
study to the subject and answer all questions regarding the study. 
Each informed consent will be reviewed, signed and dated by the 
subject and the person who administered the informed consent as 
well as the investigator. Written documentation of informed consent 
will be required prior to starting intervention/ administering study 
procedures and a copy of the informed consent will be given to the 
subject with the original placed in the subject’s file. An entry will be 
made in the source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject 
received a signed copy. 
 
Subjects may withdraw consent at any time throughout the course of 
the trial. A copy of the informed consent document will be given to 
the subjects for their records. The rights and welfare of the subjects 
will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to 
participate in this study. 
 
10 
SOURCE DOCUMENTS AND CASE REPORT FORMS 
Accurate, complete, legible and timely records and data will be kept in the 
source documents of all drug administration, including prescribing and 
dosing.  Source documents are defined as original documents, data and 
records that pertain to the conduct of the study and distribution of the 
protocol therapy. These may include but are not limited to, copies of CRFs, 
hospital records, clinical and office charts, laboratory data/information, 
subject diaries or evaluation checklists, SAE reports, pharmacy dispending 
and other records, recorded data from automated instruments, and/or 
imaging studies. Data collected must be recorded on the appropriate source 
document. 
 
Study documents will be retained for as long as necessary to comply with 
all applicable regulations and institutional requirements.  By signing the 
protocol, the investigators agree to adhere to the document/records 
retention procedures. 
 

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The investigator and institution will permit study-related monitoring, audits, 
IRB review and regulatory inspections providing direct access to source 
data documents.  
 
Case report forms (CRFs) must be completed for each subject 
screened/enrolled in the study.  
 
11 
STUDY OVERSIGHT – Quality Assurance and Quality Control  
11.1 Data Safety and Study Oversight 
The sponsor investigator will be responsible for monitoring the trial per the 
trial monitoring plan, in addition to overseeing the safety and efficacy of the 
trial including any specimens collected, executing the data and safety 
monitoring (DSM) plan, and complying with all reporting requirements to 
local and federal authorities. This oversight will be accomplished through 
additional oversight from the Data and Safety Monitoring Committee 
(DSMC) at the University of Colorado Cancer Center (CU Cancer Center). 
The DSMC is responsible for ensuring data quality and study participant 
safety for all clinical studies at the CU Cancer Center, which is the 
coordinating institution of this trial. A summary of the DSMC’s activities is 
as follows:  
 
• Conduct of internal audits  
 
• Ongoing review of all serious adverse events (SAEs) and unanticipated 
problems (UAPs) 
 
• May submit recommendations for corrective actions to the CU Cancer 
Center’s Executive Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are 
reported to the DSMC, IRB and the sponsor investigator per protocol. All 
SAEs and UAPs are to be reported to the DSMC within 7 (for fatal or life-
threatening events) or 15 (non-life-threatening events) calendar days of the 
sponsor investigator receiving notification of the occurrence. 
 
The sponsor investigator will provide a DSM progress report to the CU 
Cancer Center DSMC on a recurring basis (either every six or twelve 
months based on DSMC vote). The DSM report will include a protocol 
summary, current enrollment numbers, summary of toxicity data to include 
specific SAEs, UAPs and AEs, any dose modifications, all protocol 
deviations, and protocol amendments. The DSM progress report submitted 

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51 of  53 
 
to the DSMC will also include, if applicable, the results of any efficacy data 
analysis conducted. Results and recommendations from the review of this 
progress report by the DSMC will then be provided to the sponsor 
investigator in a DSMC review letter. The sponsor investigator is then 
responsible for ensuring this letter is submitted to the site’s IRB of record at 
the time of IRB continuing review.  
 
11.2 Clinical Monitoring 
Clinical site monitoring visits will be performed by the CU Cancer 
Center Clinical Monitor on a regular basis, pursuant to the Clinical 
Monitoring Plan (CMP), incorporated herein by reference. The CMP 
describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of the monitoring reports.  
 
Clinical site monitoring will be conducted to ensure that the rights and 
well-being of human participants are protected, that the reported trial 
data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/ 
amendment(s), 
with 
GCP, 
and 
with 
applicable 
regulatory 
requirement(s). During these visits, information recorded on the 
CRFs will be verified against source documents. When necessary, 
requests for data clarification or correction will be sent to the 
appropriate site PI. 
 
11.3 Study Auditing 
Independent audits will be conducted by the CU Cancer Center 
DSMC to ensure monitoring practices are performed consistently 
across all participating sites, if applicable, and that monitors are 
following good clinical practices. In addition, audits may be 
conducted at any time by appropriate regulatory authorities and/or 
the IRB. 
 
 
 
 
 
 
 
 
 

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12 
REFERENCES 
 
1. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood. 2006;108(2):419-425. 
2. 
Pollyea DA, Gutman JA. Stopping higher-risk myelodysplastic syndrome 
in its tracks. Curr Hematol Malig Rep. 2014;9(4):421-431. 
3. 
Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 
2012;125(7 Suppl):S2-5. 
4. 
Greenberg PL, Tuechler H, Schanz J, et al. Revised international 
prognostic scoring system for myelodysplastic syndromes. Blood. 
2012;120(12):2454-2465. 
5. 
Zeidan AM, Sekeres MA, Garcia-Manero G, et al. Comparison of risk 
stratification tools in predicting outcomes of patients with higher-risk 
myelodysplastic syndromes treated with azanucleosides. Leukemia. 
2016;30(3):649-657. 
6. 
Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic 
syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322-
3327. 
7. 
Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with 
myelodysplastic syndrome after failure of decitabine therapy. Cancer. 
2010;116(16):3830-3834. 
8. 
Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor 
alpha chain is a unique marker for human acute myelogenous leukemia stem 
cells. Leukemia. 2000;14(10):1777-1784. 
9. 
Feuring-Buske M, Frankel AE, Alexander RL, Gerhard B, Hogge DE. A 
diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid 
leukemia progenitors but spares normal progenitors. Cancer Res. 
2002;62(6):1730-1736. 
10. 
Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated 
targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid 
leukemic stem cells. Cell stem cell. 2009;5(1):31-42. 
11. 
Xie W, Wang X, Du W, Liu W, Qin X, Huang S. Detection of molecular 
targets on the surface of CD34+CD38- bone marrow cells in myelodysplastic 
syndromes. Cytometry A. 2010;77(9):840-848. 

Confidential 
Protocol Number – 17-2215 
Version Date – Jan. 13, 2023 
PI – Daniel A. Pollyea, MD, MS 
   
 
53 of  53 
 
12. 
Li LJ, Tao JL, Fu R, et al. Increased CD34+CD38−CD123+ cells in 
myelodysplastic syndrome displaying malignant features similar to those in AML. 
International Journal of Hematology. 2014;100(1):60-69. 
13. 
O'Dwyer PJ, King SA, Hoth DF, Suffness M, Leyland-Jones B. 
Homoharringtonine--perspectives on an active new natural product. J Clin Oncol. 
1986;4(10):1563-1568. 
14. 
Lu S, Wang J. Homoharringtonine and omacetaxine for myeloid 
hematological malignancies. J Hematol Oncol. 2014;7:2. 
15. 
Novotny L, Al-Tannak NF, Hunakova L. Protein synthesis inhibitors of 
natural origin for CML therapy: semisynthetic homoharringtonine (Omacetaxine 
mepesuccinate). Neoplasma. 2016;63(4):495-503. 
16. 
Allan EK, Holyoake TL, Craig AR, Jorgensen HG. Omacetaxine may have 
a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 
and induction of apoptosis in stem/progenitor cells. Leukemia. 2011;25(6):985-
994. 
17. 
Daver N, Vega-Ruiz A, Kantarjian HM, et al. A phase II open-label study of 
the intravenous administration of homoharringtonine in the treatment of 
myelodysplastic syndrome. Eur J Cancer Care (Engl). 2013;22(5):605-611. 
18. 
Feldman EJ, Seiter KP, Ahmed T, Baskind P, Arlin ZA. Homoharringtonine 
in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute 
myeloid leukemia. Leukemia. 1996;10(1):40-42. 
19. 
Wu L, Li X, Chang C, et al. Efficacy and toxicity of decitabine versus CHG 
regimen (low-dose cytarabine, homoharringtonine and granulocyte colony-
stimulating factor) in patients with higher risk myelodysplastic syndrome: a 
retrospective study. Leuk Lymphoma. 2016;57(6):1367-1374. 
20. 
Wu L, Li X, Su J, et al. Effect of low-dose cytarabine, homoharringtonine 
and granulocyte colony-stimulating factor priming regimen on patients with 
advanced myelodysplastic syndrome or acute myeloid leukemia transformed 
from myelodysplastic syndrome. Leuk Lymphoma. 2009;50(9):1461-1467. 
21. 
Wu L, Li X, Su J, et al. Efficacy and safety of CHG regimen (low-dose 
cytarabine, homoharringtonine with G-CSF priming) as induction chemotherapy 
for elderly patients with high-risk MDS or AML transformed from MDS. J Cancer 
Res Clin Oncol. 2011;137(10):1563-1569. 
22. 
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World 
Health Organization classification of myeloid neoplasms and acute leukemia. 
Blood. 2016;127(20):2391-2405. 
23. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
 
 

Consent and Authorization Form
Page 1 of 16
Principal Investigator:
Daniel A. Pollyea, MD
COMIRB No:
17-2215
Version Date:
04.14.2022
Study Title:
Concomitant Omacetaxine Mepesuccinate and Azacitidine 
for Patients with Previously Untreated High Grade 
Myelodysplastic Syndromes (MDS) 
You are being asked to participate in a research study. A member of the research team will 
explain what is involved in this study and how it will affect you. This consent form 
describes the study procedures, the risks and benefits of participation, as well as how your 
confidentiality will be maintained. Please take your time to ask questions and feel 
comfortable making a decision whether to participate or not. This process is called 
informed consent.  If you decide to participate in this study, you will be asked to sign this 
form.  
Why is this study being done?
The purpose of this study is to learn more about a combination of two drugs and how well 
it might work to treat high grade myelodysplastic syndromes (MDS). The two drugs are 
called omacetaxine and azacitadine. You are being asked to be in this research study 
because you have been newly diagnosed with MDS, have relapsed, or refractory MDS. 
Omacetaxine is approved by the U.S. Food and Drug Administration (FDA) to treat a type 
of leukemia called chronic myeloid leukemia (CML) but is not approved to treat your 
specific type of cancer. Azacitadine is approved by the FDA to treat MDS. 
Throughout the rest of this consent form, Omacetaxine and Azacitadine will be called the 
“study drugs” when referenced together. 
How many people will participate? 
Up to 91 people from your area will participate in the study. 
What happens if I join this study?
If you join the study, you will be asked to sign this consent form. You will be given a copy 
to keep and the original form will be kept at the clinic. You can withdraw from the study at 
any time and without giving a reason. This will not affect the standard medical care you 
receive.
COMIRB
APPROVED
For Use
25-May-2022
24-May-2023

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 2 of 16
There are 3 parts to the study: 
1. Screening (before beginning the study drugs) 
2. Phase I (dose escalation)
3. Phase II (dose expansion) including relapsed and refractory MDS
During Phase I, the study doctors are trying to find the highest dose of omacetaxine that 
can be given safely with azacitadine. Certain serious or severe side effects may occur and 
these are likely to occur at higher doses. If certain serious or severe side effects are 
observed, the study will be stopped. Once this dose of omacetaxine has been determined, 
Phase II of the study will begin. 
During Phase II, the study doctors will give the dose of omacetaxine determined during 
Phase I in combination with azacitadine. 
The dose of omacetaxine that you will receive will depend on when you enroll in the study. 
The study doctor will tell you whether you will be participating in the Phase I or the Phase II 
portion. All those with relapsed or refractory MDS, will only be enrolled to Phase II.
The next section of this form lists what will be expected of you if you agree to join this 
study. 
Study Procedures
While you are taking part in this study, some of the tests and procedures are the same 
type that would be performed as part of your regular cancer care even if you did not join 
the study. Some of the tests and procedures are required only for the study and are 
identified below as “research” procedures. 
The screening tests and procedures will be done to see if you are eligible to join this study. 
You may have had some of these tests and procedures done recently as standard care for 
your cancer, and they may not need to be repeated. 

Informed Consent (research) 
This informed consent form will be discussed with you and you will be given a copy 
of this document. If you join the study, you will be asked to sign this consent form 
before you receive any study related tests or procedures.

Medical and Cancer History 
Before you start the study we will record your date of birth, race, ethnicity, and 
complete medical history. This history will look at the background and progress of 
your cancer and any treatments you have received for your disease. 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 3 of 16

Physical Examination
A physical examination will be completed as part of your standard of care. We will 
also assess if the study drug is affecting your body functions including lungs, heart, 
abdomen, extremities, skin, head (eyes, ears, nose, hair, etc.) and neurologically.

Vital Signs 
We will take your blood pressure, heart rate, respiratory rate, body temperature and 
weight.  Height will be measured only during screening.

Performance Status  
We will assess how well you are performing your daily activities.

Review of Current Medications
Your study doctor will let you know which medications you can and cannot take 
while taking part in this study.  From the time you first receive the study drugs 
through 30 days after the last dose, we will record medications you may be taking. 

Review of Side Effects (research) 
Some risks have been identified because of the disease process or through use of 
the study drugs themselves and these will be followed very closely by the Principal 
Investigator and study staff. More information will be provided in the Risk area of 
this consent. 

Electrocardiogram (ECG or EKG)
This is a simple, noninvasive procedure that records the electrical activity of the 
heart. Electrodes are placed on the skin of the chest and connected in a specific 
order to a machine. Output usually appears on a long scroll of paper that displays a 
printed graph.  

Blood Tests
At various time points during the study, you will have blood collected for routine 
testing. 

Bone Marrow Biopsy/Aspirate (research except at screening) 
At various time points during the study, you will have bone marrow examined. This 
involves placing a hollow needle into your hip bone near the small of your back and taking a 
small sample of the bone (bone marrow biopsy) and 2-3 tablespoons of the liquid bone 
marrow inside the bone (bone marrow aspirate).

Study Drug Diary (research) 
You will be provided with a drug diary to write down the date, time, and dose of 
study drug. A new diary will be provided at the beginning of each cycle and the 
completed diary will be collected at the end of each cycle. 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 4 of 16

Azacitadine administration
You will receive the standard dose of azacitadine (75mg/kg2) intravenously as noted 
in the schedule of study visits section of this form. 

Omacetaxine administration (research) 
You will receive the dose of omacetaxine as an injection under the skin as noted in 
the schedule of study visits section of this form. You will receive instruction on how 
to self-administer this drug. 
Study Visits
Screening Visit (within 14 days before treatment)

Informed consent 

Review of medical history

Complete physical exam

Performance status

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH) 
o
Coagulation tests (including PT and PTT/INR)
o
Pregnancy (for women who can get pregnant) 

Electrocardiogram (EKG) 

Bone marrow biopsy/aspirate (may be performed up to 28 days prior to 
treatment) 
  During the Study
Cycle 1 – Day 1 (each cycle is 28 days)

Physical exam

Performance status

Review of side effects

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH)

Receive study drug calendar and diary 

Receive azacitadine (IV) 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 5 of 16

Receive omacetaxine   
Cycle 1 – Day 2-7

Review of side effects

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH) 

Receive azacitadine (IV)

Receive omacetaxine  
Cycle 1 – Day 8

Physical exam

Review of side effects

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH) 

Bone marrow aspirate 
Cycle 1 – Day 28 

Physical exam

Performance status

Review of side effects

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH)

Collect study drug calendar and diary 

Bone marrow biopsy/aspirate 
Cycles 2+ 

Physical exam

Performance status

Review of side effects

Review of current medications 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 6 of 16

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH)

Receive study drug calendar and diary 

Receive azacitadine  (IV)

Receive omacetaxine 

Bone marrow biopsy/aspirate (Day 28 only)

Collect study drug calendar and diary (Day 28 only) 
During cycles 2+, all procedures will be done on Day 1, unless otherwise indicated. 
Omacetaxine and Azacitadine will be given on Days 1-7.  
Bone marrow aspirate and biopsy will occur after Cycle 4, Cycle 6, and every 6 cycles 
thereafter.
End of Study Visit 

Physical exam

Performance status

Review of side effects

Review of current medications 

Vital signs

Blood draw for routine tests, including:
o
Hematology
o
Chemistry (including magnesium, phosphorus and LDH)

Bone marrow biopsy/aspirate 

Collect study drug calendar and diary 
Safety Follow-up Visit (30 days after end of treatment for subjects who stop the study 
as a result of side effects)

Medical history

Physical exam

Performance status

Review of side effects

Review of current medications 
The study team will continue to follow up with you at least once a year, either by phone or 
during a routine clinic visit. Long-term follow up will continue every year up to 5 years.

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 7 of 16
How long will I be in the study?
You may continue receiving study drugs indefinitely or until your doctor determines that 
you should stop receiving the study drug regimen due to side effects, progression of your 
disease, or until you decide to stop participating in the study.
You will be followed long term for disease status and survival information for up to 5 years. 
What are the possible discomforts or risks?
You may have side effects while you are in this study, but you will be carefully checked by 
the study doctor for any problems. There may be risks or side effects of the study 
treatment that are unknown at this time. You should tell the study doctor about anything 
that is bothering you or any side effects you have, even if you do not think they are related 
to the study treatment. Many side effects go away shortly after the medications are 
stopped, but in some cases side effects can be serious, long lasting, or permanent.
Risks of the Study Drugs
Potential Risks Associated with Omacetaxine
COMMON, SOME MAY BE SERIOUS (seen in more than 10% of patients):  

Decrease in your platelets (thrombocytopenia) which can cause bleeding

Decrease in a type of white blood cells called neutrophils (neutropenia) 

Decrease in red blood cells (anemia)

Diarrhea 

Muscle Pain 

Nausea 

Infusion/Injection Site Reactions 

Fatigue 

Fever 

Abdominal Pain 

Weakness 

Headache

Joint Pain 

Nose bleeds 

Swelling in arms & legs 

Cough 

Hair Loss 

Constipation

Vomiting 

Insomnia 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 8 of 16

Rash 

Bone marrow failure

Fever with low number of a type of white blood cell called neutrophils (febrile 
neutropenia) 

Decreased appetite

Chills 
Less Common, SOME MAY BE SERIOUS (seen in more than 1% but less than 10% of 
patients) 

Cardiac Disorders: rapid heart rate, palpitations, chest pain, irregular heart rate, 
slowed heart rate.

Ear Disorders: ear pain, ear hemorrhage, tinnitus (ringing in ear).

Eye Disorders: cataract, blurred vision, broken blood vessels in the eye, dry eye, 
excessive tearing, pink eye, double vision, eye pain, eyelid swelling.

Gastrointestinal Disorders: inflammation to mouth & lips, mouth ulceration, 
abdominal distension, gas, GERD, bleeding gums, dry mouth, hemorrhoids, 
gastrointestinal hemorrhage, black, tarry bowel movements, mouth hemorrhage, 
oral pain, anal fissure, difficulty swallowing,  pain in the gums. 

General Disorders: hot flashes, flu-like illness, swelling.

Immune System Disorders: allergic reaction.

Metabolism and Nutrition Disorders: diabetes mellitus, gout, dehydration.

Musculoskeletal and Connective Tissue Disorders: bone pain, muscular 
weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, 
musculoskeletal stiffness, musculoskeletal discomfort.

Nervous System Disorders: dizziness, bleeding in the brain, numbness & 
tingling, convulsion, sciatica, burning sensation, changes in taste, tremor.

Psychiatric Disorders: anxiety, depression, agitation, confusional state.

Urinary: painful urination, damage to the kidneys.

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 9 of 16

Respiratory: throat pain, nasal congestion, hoarseness, productive cough, lung 
congestion, runny nose, coughing up blood. 

Skin Disorders: redness, itching, dry skin, red spots, excessive sweating, night 
sweats, bruising, purpura, skin lesion, skin ulcer, skin sloughing, skin 
hyperpigmentation.

Vascular Disorders: high blood pressure, low blood pressure 
Potential Risks Associated with Azacitidine  
The following side effects may happen with azacitidine and are common or very common 
(may affect more than 1 in 100 people):

Decrease in your platelets (thrombocytopenia) 

Decrease in red blood cells (anemia)

Decrease in white blood cells (leukopenia)

Decrease in a type of white blood cells called neutrophils (neutropenia)

Fever with low number of a type of white blood cell called neutrophils (febrile 
neutropenia)

Bone marrow failure

Neutropenia with infection and the presence of bacteria in your blood stream 
(neutropenic sepsis)

Bacteria or viral infections including lung infection (pneumonia), upper respiratory 
infection, or urinary tract infection

Fever 

Bleeding including brain and stomach/gut bleeding 

Bruising  

Injection site pain, redness, or bruising (if receiving azacitidine as an injection under 
the skin) 

Damage to the kidneys or kidney failure

Abdominal pain 

Constipation

Diarrhea 

Feeling sick to your stomach (nausea) 

Vomiting 

Chest pain

Shortness of breath

Feeling tired or lethargic 

Lack of appetite or interest in food

Weight loss

Pain including joint, muscle pain and headache

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 10 of 16

Dizziness 

Anxiety and difficulty sleeping

Rash 

Itching

Decrease in blood potassium
The following events have been reported in trials with azacitidine less frequently, but can 
be severe in nature.  These events may or may not be related to azacitidine. 

Severe or fatal infections including severe skin infections (necrotizing fasciitis)

Severe bleeding 

Heart problems: Cardiac arrest (heart stopped), heart attack, irregular heart beat 

Liver damage in individuals with previous liver problems Severe allergic reactions 
(anaphylaxis)  

Tumor lysis syndrome
With both drugs given together, additional risks, warnings, and precautions, as outlined 
should be discussed with your study doctor.  You should contact the study doctor or study 
staff and get medical help if you have any of the above mentioned or any other side effects 
during the study.  Combination of azacitidine with omacetaxine may worsen the potential 
side effects of azacitidine or omacetaxine, or even cause other side effects that were not 
known before.
Risks of the Study Procedures
Blood tests
Blood sampling and needle punctures carry some risk. Possible side effects include, but 
are not limited to, fainting, bleeding, bruising, discomfort, dizziness, infection and/ or pain 
at the puncture site. 
Having an IV inserted in your vein
In this study we will insert a needle, connected to a plastic tube, into a vein in your arm. 
We will use the tube to take blood samples or give you fluids. You will feel some pain when 
we first insert the tube into your vein. You may have some redness, swelling, or bruising 
where the tube goes under your skin. In some cases, this type of tube can cause an 
infection where it goes under the skin. In rare cases, it can cause a blood clot in the vein. 
You will have this tube inserted for about four or five hours.
Bone marrow biopsy
In this study we will take four samples of bone marrow from your pelvic bone. Before we 
take each sample, we will give you some numbing medication on the skin outside your 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 11 of 16
pelvic bone (on your hip). After your skin is numb, we will push a special needle into the 
center of your pelvic bone. Then, we will draw the bone marrow up into the syringe. When 
we do this, you will have a pulling feeling as the marrow leaves the bone and goes into the 
syringe. The area around the bone will be sore for a few days.
There is a very small chance that you will be allergic to the numbing medicine. There is 
also a very small chance that you could bleed or develop an infection.
Electrocardiogram (EKG)
An electrocardiogram (EKG) is a test that records the electrical activity of the heart. Skin 
irritation is rare but could occur during an EKG from the electrodes or the gel that is used.
Risks Associated with Pregnancy
While participating in this research study, you should not become pregnant, nurse a baby, 
or father a baby. Women who are able to have children must use a highly effective means 
of birth control approved by your study doctor.  You must continue the use of birth control 
during the entire time of your study participation at least 3 months after the last dose of 
azacitidine.
If you are a female who has stopped having menstrual periods for at least 1 year 
(menopause), please discuss with your study doctor the need for birth control.  If you 
become pregnant, you must stop taking the study drugs at once and notify your doctor 
immediately.  You will not be allowed to continue in the study.  You may be asked 
questions about the outcome of your pregnancy and the baby. 
Risk of Loss of Confidentiality
There is a risk that people outside the research team will see your research information. 
We will do all that we can to protect your information, but it cannot be guaranteed.
There may be other risks that could arise which are not reasonably foreseeable. If new 
information becomes available which could influence your willingness to continue, this new 
information will be discussed with you.

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 12 of 16
What are the possible benefits of the study?  
If you agree to take part in this study, there may or may not be direct medical benefit to 
you.  We hope the information learned from this study will benefit other individuals with 
MDS in the future.  
Are there alternative treatments? 
There may be other ways of treating your cancer. Instead of taking part in this study:

You may choose to receive treatment with an approved therapy or drug 
combination.

You may choose to participate in a different study with another experimental drug.

You may choose to receive comfort/ palliative care.

You may choose to get no treatment at all.
You should talk to your doctor about your choices. Make sure you understand all of your 
choices before you decide to take part in this study. You may leave this study and still 
have these other choices available to you. 
Who is paying for this study? 
Teva Pharmaceuticals, Inc. is providing a grant of funding support for this study. Teva 
manufactures the study drug, omacetaxine, and will provide this drug for the study.  This 
research is being conducted by Dr. Daniel Pollyea. The research study will only pay for 
procedures not considered standard of care.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
The drug manufacturer, Teva, will pay for the cost of the study drug, omacetaxine. The 
funding for this study will also pay for any tests or procedures that are related to the 
research study. 
The study drug, azacitadine, is considered standard treatment for your disease. This drug 
will be obtained through your insurance, and you will be responsible for any applicable 
copays required by your insurance policy. 
There are some medical procedures that you would get for your condition whether you 
were in this study or not, such as blood draws. These are considered standard of care. 
You and/or your health insurance may be billed for the costs of medical care during this 
study, if these expenses are related to standard of care procedures. If you have health 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 13 of 16
insurance, the cost of these services will be billed to your insurance company. If your 
insurance does not cover these costs, or you do not have insurance, these costs will be 
your responsibility. 
Ask your study doctor to discuss the costs that will or will not be covered by this research 
study. This discussion should include the costs of treating possible side effect. Otherwise, 
you might have unexpected expenses from being in this study.
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this 
study.  If you choose to take part, you have the right to stop at any time.  If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled. 
If you leave this study, you will still receive your normal medical care.  The only medical 
care that you will lose is the medical care you are getting as part of this study.  You might 
be able to get that same kind of medical care outside of the study.  Ask your study doctor. 
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason. 
 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Pollyea immediately. 
His phone number is 720-848-8084.
We will arrange to get you medical care if you have an injury that is caused by this 
research.  However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Daniel A. Pollyea, MD. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may call 
Dr. Pollyea at 720-848-8084. You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. 
Pollyea with questions.  You can also call the responsible Institutional Review Board 
(COMIRB).  You can call them at 303-724-1055. 

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 14 of 16
A description of this clinical trial will be available on http://www.Clinical Trials.gov. This 
Web site will not include information that can identify you. You can search this Web site at 
any time.
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you.  Federal and state laws including the Health Insurance Portability 
and Accountability Act (HIPAA) also protect your privacy.   This part of the consent form 
tells you what information about you may be collected in this study and who might see or 
use it.  
The institutions involved in this study include:

University of Colorado Denver

University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  
You do not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the UCD and its affiliate hospitals 
may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information 
but confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below.  If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected.  Your cancellation would not affect 
information already collected in this study.  
Daniel A. Pollyea, MD
Anschutz Medical Campus
1665 N. Aurora Court
Mail Stop F754
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information, such as:

Consent and Authorization Form
COMIRB #17-2215
PI:  Daniel A. Pollyea, MD
Version Date:  04/14/2022
Page 15 of 16
  

Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB).

The study doctor and the rest of the study team.

Teva Pharmaceuticals, Inc., manufacturer of omacetaxine who is also providing a 
grant of funding support.  

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all 
of the rules for research.
We might talk about this research study at meetings.  We might also print the results of this 
research study in relevant journals.  But we will always keep the names of the research 
subjects, like you, private. 
You have the right to request access to your personal health information from the 
Investigator. 
Information about you that will be seen, collected, used and disclosed in this study: 

Name and demographic information (age, sex, ethnicity, address, phone number, 
etc.

Portions of your previous and current medical records that are relevant to this study, 
including but not limited to diagnosis(es), history and physical, laboratory or tissue 
studies, radiology studies, procedure results.

Research visit and research test records.

Blood or biopsy samples and the data with the samples. 

Billing or financial information.
What happens to Data, Tissue, Blood and Specimens that are collected in this 
study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study 
work to find the causes and cures of disease.  The data, tissue, blood and specimens 
collected from you during this study are important to this study and to future research.  If 
you join this study:

The data, tissue, blood, or other specimens given by you to the investigators for 
this research no longer belong to you.  

Both the investigators and any sponsor of this research may study your data, 
tissue, blood, or other specimens collected from you.

C o n s e nt a n d A ut h o ri z ati o n F o r m
C O MI R B # 1 7- 2 2 1 5
PI:  D a ni el A. P oll y e a, M D
V er si o n D at e:  0 4/ 1 4/ 2 0 2 2
P a g e 1 6 of 1 6

If d at a, ti s s u e, bl o o d, or ot h er s p e ci m e n s ar e i n a f or m t h at i d e ntifi e s y o u, U C D 
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y o ur c o n s e nt or I n stit uti o n al R e vi e w B o ar d (I R B) a p pr o v al.

A n y pr o d u ct or i d e a cr e at e d b y t h e r e s e ar c h er s w or ki n g o n t hi s st u d y will n ot 
b el o n g t o y o u.

T h er e i s n o pl a n f or y o u t o r e c ei v e a n y fi n a n ci al b e n efit fr o m t h e cr e ati o n, u s e or 
s al e of s u c h a pr o d u ct or i d e a. 
A gr e e m e nt t o b e i n t hi s st u d y a n d u s e m y d at a
T h e r e s e ar c h pr oj e ct a n d t h e pr o c e d ur e s a s s o ci at e d wit h it h a v e b e e n e x pl ai n e d t o m e.  
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D at e: 
S u bj e ct Pri nt N a m e: 
C o n s e nt f or m e x pl ai n e d b y: 
D at e: 
Pri nt N a m e: 
-------------------------------------------------- U s e O nl y if A p pli c a bl e ------------------------------------------------
Si g n at ur e Li n e f or wit n e s s; r e q uir e d f or c o n s e nt of n o n-r e a di n g s u bj e ct s a n d c o n s e nt u si n g a s h ort f or m, 
if y o u r e q u e st e d s u c h c o n s e nt pr o c e d ur e s
Wit n e s s of Si g n at ur e

Wit n e s s of c o n s e nt pr o c e s s

Wit n e s s Si g n at ur e:
D at e:
Wit n e s s Pri nt N a m e: