Conditions: Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 22
Healthy volunteers: no

Brief summary:
This is a dose escalation study to evaluate Omacetaxine when given in combination with a standard induction regimen of "7+3" (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in patients with newly diagnosed acute myelogenous leukemia (AML).

Detailed description:
This is a dose escalation study to evaluate Omacetaxine when given in combination with a standard induction regimen of "7+3" (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in patients with newly diagnosed acute myelogenous leukemia (AML). Omacetaxine will be given subcutaneously Q12 hours on Days 1-7. The optimally safe and active dose (OD) will be determined using the EffTox design. EffTox is a Bayesian adaptive design that seeks to determine the optimal dose for further study in Phase II by considering a trade-off between efficacy and toxicity. The EffTox design begins by treating a cohort of three patients at dose level 1. These patients' efficacy and toxicity outcomes are used to update the posterior distributions for the probability of efficacy and toxicity and identify acceptable dose levels. The study terminates if no dose levels are acceptable. Otherwise, the acceptable doses are ranked using the Euclidean distance from (1.0, 0.0) and the next cohort is treated at the dose with the minimum distance under the restriction that we may only escalate or deescalate by one dose level at a time (e.g., the second cohort can only escalate to dose level 2 or deescalate to dose level -1). The second cohort is treated at the dose with the minimum distance and posterior distributions, and the list of acceptable doses and distances are updated as before. This process continues until at least 20 subjects are enrolled in the study. The dose with the minimum distance at study completion is considered the optimal dose for further investigation. If none of the dose levels are acceptable at study completion, an optimal dose level will not be identified and the drug does not warrant further investigation.

Post induction therapy will consist of standard cytarabine consolidation chemotherapy or allogeneic stem cell transplantation based on pretreatment risk assessment.

Arms:
arm 1: Patients will receive Omacetaxine at Dose level 0.625mg/m\^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. arm 2: Patients will receive Omacetaxine at Dose level 1.25mg/m\^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. arm 3: Patients will receive Omacetaxine at Dose level 2.0mg/m\^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. arm 4: Patients will receive Omacetaxine at Dose level 3.0mg/m\^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event.

Interventions: intervention 1: Cytarabine intervention 2: Idarubicin intervention 3: Omacetaxine mepesuccinate intervention 4: Omacetaxine mepesuccinate intervention 5: Omacetaxine mepesuccinate intervention 6: Omacetaxine mepesuccinate
Intervention descriptions: intervention 1: Cytarabine (100mg/m\^2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days. intervention 2: Idarubicin (12 mg/m\^2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3. intervention 3: Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 0.625mg/m\^2 intervention 4: Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 1.25mg/m\^2 intervention 5: Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 2.0mg/m\^2 intervention 6: Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 3.0mg/m\^2

Protocol document:
Prot_SAP_000.pdf: 
Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
University of Illinois Cancer Center 
 
 
 
 
 
 
Confidential 
 
 
 
AML-02: Study of the Activity and Safety of the Addition of Omacetaxine to the Standard-of-Care 
Induction Therapy Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML patients 
 
 
 
 
Principal Investigator: 
John Quigley, MD 
Section of Hematology/Oncology, 
Department of Medicine, 
University of Illinois Cancer Center 
Chicago, IL 
 
Sponsor: 
Department of Medicine, University of Illinois Cancer Center 
 
 
NOTE: Omacetaxine is supplied by TEVA Pharmaceuticals 
 
Sub-Investigators: 
Kelly Kozma, MD 
Damiano Rondelli, MD 
Pritesh Patel, MD 
David Peace, MD 
Irum Khan, MD 
Santosh Saraf, MD 
Annie Oh, MD 
Sonia Christian, MD 
Karen Sweiss, PharmD 
 
 
Biostatistician 
Li Liu, PhD 
Associate Professor of Biostatistics 
Division of Epidemiology and Biostatistics School of Public Health 
 
 
Version Date: 
April 20, 2017 
 
 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
Synopsis ................................................................................................................................................................................................ 6 
Study Schema ...................................................................................................................................................................................... 7 
Abbreviations ...................................................................................................................................................................................... 8 
1 
Background/Rationale ........................................................................................................................................................ 10 
1.1. 
Background ...................................................................................................................................................................... 10 
1.2. 
Rationale ........................................................................................................................................................................... 12 
2 
Objectives .................................................................................................................................................................................. 12 
2.1. 
Primary Objective .......................................................................................................................................................... 12 
2.2. 
Secondary Objectives ................................................................................................................................................... 12 
3 
Endpoints .................................................................................................................................................................................. 12 
3.1. 
Primary Endpoint .......................................................................................................................................................... 12 
3.2. 
Secondary Endpoints .................................................................................................................................................... 12 
4 
Overall Design and Study Plan .......................................................................................................................................... 12 
5 
Selection of patients .............................................................................................................................................................. 14 
5.1. 
Inclusion Criteria ........................................................................................................................................................... 14 
5.2. 
Exclusion Criteria ........................................................................................................................................................... 15 
6 
Registration .............................................................................................................................................................................. 15 
6.1. 
Registration with the Clinical Trials Office .......................................................................................................... 16 
6.2. 
Patients Who Do Not Begin Study Treatment .................................................................................................... 16 
7 
Treatment Plan ....................................................................................................................................................................... 16 
7.1. 
Study Drug Administration ........................................................................................................................................ 16 
7.1.1. 
Omacetaxine Administration ............................................................................................................................ 16 
7.1.2. 
Removal of Subjects from Study ...................................................................................................................... 18 
7.2. 
Drug Dose Level Assignment ..................................................................................................................................... 19 
7.3. 
Dose Modifications ........................................................................................................................................................ 20 
7.4. 
Permitted Concomitant Medications and Procedures .................................................................................... 20 
7.5. 
The Effects of Other Drugs on Omacetaxine ........................................................................................................ 20 
7.6. 
Concomitant Medications and Non-Drug Therapies ........................................................................................ 20 
7.7. 
Prohibited Concomitant Medications .................................................................................................................... 20 
7.8. 
Management of Clinical Events and Supportive Care Guidelines ............................................................... 20 
7.9. 
Nausea, Vomiting, Diarrhea ....................................................................................................................................... 21 
7.10. 
Duration of Therapy ................................................................................................................................................. 21 
7.11. 
Follow-up ...................................................................................................................................................................... 21 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
8 
Study Parameters: ................................................................................................................................................................. 22 
9 
Drug Formulation and Procurement .............................................................................................................................. 23 
9.1. 
Omacetaxine .................................................................................................................................................................... 23 
9.1.1. 
Other names ............................................................................................................................................................ 23 
9.1.2. 
Classification ........................................................................................................................................................... 23 
9.1.3. 
How supplied .......................................................................................................................................................... 23 
9.1.4. 
Availability ............................................................................................................................................................... 23 
9.1.5. 
Description .............................................................................................................................................................. 23 
9.1.6. 
Storage, Handling, and Accountability .......................................................................................................... 23 
9.1.7. 
Administration ....................................................................................................................................................... 23 
9.1.8. 
Risks ........................................................................................................................................................................... 23 
9.1.9. 
Warnings and Precautions ................................................................................................................................ 24 
9.2. 
Cytarabine......................................................................................................................................................................... 24 
9.2.1. 
Other names ............................................................................................................................................................ 24 
9.2.2. 
Classification ........................................................................................................................................................... 24 
9.2.3. 
How supplied .......................................................................................................................................................... 24 
9.2.4. 
Availability ............................................................................................................................................................... 24 
9.2.5. 
Description .............................................................................................................................................................. 24 
9.2.6. 
Storage, Handling, and Accountability .......................................................................................................... 25 
9.2.7. 
Administration ....................................................................................................................................................... 25 
9.2.8. 
Risks ........................................................................................................................................................................... 25 
9.2.9. 
Warnings and Precautions ................................................................................................................................ 25 
9.3. 
Idarubicin .......................................................................................................................................................................... 27 
9.3.1. 
Other names ............................................................................................................................................................ 27 
9.3.2. 
Classification ........................................................................................................................................................... 27 
9.3.3. 
How supplied .......................................................................................................................................................... 27 
9.3.4. 
Availability ............................................................................................................................................................... 27 
9.3.5. 
Description .............................................................................................................................................................. 27 
9.3.6. 
Storage, Handling, and Accountability .......................................................................................................... 27 
9.3.7. 
Administration ....................................................................................................................................................... 27 
9.3.8. 
Risks ........................................................................................................................................................................... 28 
9.3.9. 
Warnings and Precautions ................................................................................................................................ 28 
10 
Adverse Event Documentation and Reporting ....................................................................................................... 29 
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10.1. 
Definitions .................................................................................................................................................................... 29 
10.2. 
Adverse Event Documentation............................................................................................................................. 31 
10.3. 
Required Reporting: IRB, FDA, TEVA, and Cancer Center’s Regulatory Coordinator ..................... 31 
11 
Study Data Collection and Monitoring ....................................................................................................................... 33 
11.1. 
Data Management...................................................................................................................................................... 33 
11.2. 
Case Report Forms .................................................................................................................................................... 33 
11.3. 
Data Safety and Monitoring Plan (DSMP) ........................................................................................................ 33 
11.4. 
Monitoring .................................................................................................................................................................... 33 
11.5. 
Record Retention ....................................................................................................................................................... 33 
12 
Statistical Considerations ............................................................................................................................................... 33 
12.1. 
Analysis plan for primary objective ................................................................................................................... 34 
12.2. 
Analysis plan for secondary objectives ............................................................................................................. 34 
13 
Stopping rules ...................................................................................................................................................................... 35 
14 
Conduct of the Study ......................................................................................................................................................... 35 
14.1. 
Good Clinical Practice .............................................................................................................................................. 35 
14.2. 
Ethical Considerations ............................................................................................................................................. 35 
15 
References ............................................................................................................................................................................. 35 
Appendix I – Definitions of Response to Treatment in AML* ........................................................................................ 39 
Appendix II - Definitions of Survival in AML* ...................................................................................................................... 40 
Appendix III – ECOG Performance Status .............................................................................................................................. 41 
Appendix IV – New York Heart Association Classification .............................................................................................. 42 
 
 
PI Contact Information: 
John Quigley, M.D.  
University of Illinois at Chicago  
Division of Hematology/Oncology 
UI Cancer Center - Clinical Trials Office 
914 S. Wood Street, MC 700 
Chicago, IL  60612 
P: 312-413-1300 
F: 312-413-4131 
E: seanq@uic.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
Omacetaxine Provision: Teva Pharmaceuticals 
Contact Information: 
 
Rich Whiteman    
Manager, Global Phase IV and ISS Coordination 
41 Moores Rd, Frazer, PA 19355 
P: 610.727.6606  
Richard.Whiteman@TevaPharm.com    
 
 
REVISION HISTORY 
 
 
Revision # 
Date 
Details of changes 
Consent 
change? 
1.1 
9/15/2014 
Principal Investigator: John Quigley, MD 
In response to UIC PRC queries, the study background has been 
revised to discuss determination of complete response rate.  
Clarifications were made to the following sections:  Primary 
Endpoint, the Dose Finding Component, Treatment Success, 
Eligibility Criteria, Omacetaxine Adminstration & Precautions, the 
Study Schedule of Events, and Adverse Event Documentation & 
Reporting.   
No 
1.2 
3/17/2015 
Revised protocol to clarify Eligibility (remove duplicate criteria and 
clarified exclusion criteria) and Schedule of Events (clarified timing 
of post-induction bone marrow on Day 14-17).  Other minor 
revisions and corrections to references. 
Yes 
1.3 
4/09/2015 
Per IRB request, removed “No” from Exclusion Criteria #3, #8, #9, & 
#10. 
Yes 
2.0 
5/07/2015 
Removed specific timeframe from Lost to Follow-up and reference 
to the DSMC.  Removal of duplicate inclusion/exclusion criteria 
regarding hepatic and renal function.  Clarifications to Dose 
Modifications section to allow treatment to be stopped per PI 
discretion.     
Yes 
3.0 
7/01/2015 
Eligibility criteria revised to allow for subjects up to age 70.  Allow 
MUGA scans to be completed in place of echocardiogram. 
Yes 
4.0 
8/18/2015 
Eligibility criteria modified to remove ≥20% blasts in peripheral blood 
or bone marrow as a requirement, in order to allow for patients with 
atypical presentation of AML like myeloid sarcoma 
No 
5.0 
11.29.2015 
Modified definition of hematologic toxicity as more than 30% of the 
patients having CRi or CRp by day 50 and modified the wording for 
BM examination will be performed at recovery usually 3-4 weeks 
 
No 
6.0 
2.22.2016 
Addition of Bi-weekly BMP procedure, removal of daily BMP 
monitoring, removal of long-term follow up every 2 months for 6 
months for symptom and toxicity checks, addition of HbA1c follow 
up for diabetic patients, update to analysis plan for primary 
objective, and process for collection of adverse event 
documentation updated. 
No 
7.0  
5.19.2016 
Modify the definition of CR to include CRc (complete cytogenetic 
remission), update Teva contact personnel, and references 
No 
8.0 
7.11.2016 
Add insulin sliding scale and hyperglycemia management guidelines 
 
No 
9.0 
1.25.2017 
Changes to Sub-investigator personnel and of biostatistician 
No 
10.0 
4.20.2017 
Changes to consent form (i) allow potential for taking deidentified 
photographs of patients who develop skin changes and (ii) add risk 
for arrhythmias (predominantly atrial fibrillation). Changes to 
definitions of non-hematological toxicities, efficacy, and clarification 
of the Stopping Rules. 
Yes 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
Synopsis 
 
Primary Objective: 
 
The primary objective of this study is to assess the activity and safety of Omacetaxine when it is administered 
with the standard acute myelogenous leukemia (AML) induction therapy of cytarabine and Idarubicin to patients 
under 65 years old with newly diagnosed AML.   
 
Patient Population: 
 
• 
Newly diagnosed, untreated male or female patients, 18-70 years of age, with AML according to the WHO 
classification for AML  
• 
Previously untreated AML (≥20% blasts). Prior short-term therapy (≤7 days) with hydroxyurea, steroids, 
biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors, azacitidine, ATRA), or 
hematopoietic growth factors is allowed. A single or two-day dose of cytarabine (up to 3 g/m2) for 
emergency use is also allowed as prior therapy. 
• 
ECOG status 0-3 (Appendix III) 
• 
Adequate hepatic and renal function as defined in section 5.1 (inclusion criterion #6) 
 
Study Design: 
 
This is a dose escalation study to evaluate Omacetaxine when given in combination with a standard induction 
regimen of “7+3” (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in patients with newly diagnosed acute 
myelogenous leukemia (AML). Omacetaxine will be given subcutaneously Q12 hours on Days 1-7. The optimally 
safe and active dose (OD) will be determined using the EffTox design. EffTox is a Bayesian adaptive design that 
seeks to determine the optimal dose for further study in Phase II by considering a trade-off between efficacy and 
toxicity. The EffTox design begins by treating a cohort of three patients at dose level 1. These patients’ efficacy 
and toxicity outcomes are used to update the posterior distributions for the probability of efficacy and toxicity and 
identify acceptable dose levels. The study terminates if no dose levels are acceptable. Otherwise, the acceptable 
doses are ranked using the Euclidean distance from (1.0, 0.0) and the next cohort is treated at the dose with the 
minimum distance under the restriction that we may only escalate or deescalate by one dose level at a time (e.g., 
the second cohort can only escalate to dose level 2 or deescalate to dose level -1). The second cohort is treated 
at the dose with the minimum distance and posterior distributions, and the list of acceptable doses and distances 
are updated as before. This process continues until at least 20 subjects are enrolled in the study. The dose with 
the minimum distance at study completion is considered the optimal dose for further investigation. If none of the 
dose levels are acceptable at study completion, an optimal dose level will not be identified and the drug does 
not warrant further investigation. 
Post induction therapy will consist of standard cytarabine consolidation chemotherapy or allogeneic stem cell 
transplantation based on pretreatment risk assessment.  
 
Treatment Plan: 
 
Omacetaxine (assigned dose) administered subcutaneously Q12 hours Days 1 to 7; Cytarabine (100mg/m2/day) 
in 1000ml NS as a continuous IV infusion over 24 hours x 7 days; and Idarubicin (12 mg/m2/day) IVPB in 100 
mL NS over 15 minutes daily from Days 1 to 3. 
 
 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction Chemotherapy Regimen 
Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Cytarabine 
100mg/m2 CI 
100 mg/m2 CI 
100 mg/m2 CI 
100 
mg/m2 
CI 
100 mg/m2 CI 
100 mg/m2 CI 
100 mg/m2 CI 
Idarubicin 
12mg/m2 IV 
12mg/m2 IV 
12mg/m2 IV 
 
 
 
 
Omacetaxine 
Assigned dose 
subQ q12h 
Assigned dose 
subQ q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned dose 
subQ q12h 
Phase I Dose Levels 
 
Dose Level 
Omacetaxine mg/m2 
-1 
0.5 
1 
0.625 
2 
1.25 
3 
2.0 
4 
3.0 
5 
4.2 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
 
Abbreviations 
 
Abbreviation 
Definition 
4'-DMHHT 
AD 
AE 
4'desoxyhomoharringtonine 
cytarabine and daunorubicin  
adverse event 
AML 
ANC 
acute myelogenous leukemia 
absolute neutrophil count 
ALT 
alanine aminotransferase 
AST 
BCL-2 
β-HCG 
aspartate aminotransferase 
B-Cell lymphoma 2 protein 
β-human chorionic gonadotropin 
CML 
CTO 
chronic myelogenous leukemia 
clinical trial office 
CR 
CRc 
CRi 
complete response 
complete cytogenetic response 
complete response with incomplete hematologic recovery 
CTCAE 
CI 
(NCI) Common Terminology Criteria for Adverse Events 
continuous infusion 
CTEP 
cancer therapy evaluation program 
D 
dL 
day 
deciliter 
DLT 
dose-limiting toxicity 
ECOG 
ECG 
Eastern Cooperative Oncology Group 
electrocardiogram 
FDA 
FLT3 
G-CSF 
HT 
HAA 
Food and Drug Administration 
Fms-like tyrosine kinase 3 
granulocyte colony-stimulating factor 
Hematologic Toxicity 
homoharringtonine, cytarabine and aclarubicin  
HAD 
homoharringtonine, cytarabine and daunorubicin 
IND 
investigational new drug 
IRB 
IV 
institutional review board 
intravenous 
kg 
kilogram 
MCL-1 
myeloid cell leukemia-1 protein 
mg 
milligram 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
Abbreviation 
Definition 
Min 
μL 
minute 
microliter 
mL 
milliliter 
mm3 
cubic millimeters 
MTD 
maximum tolerated dose 
NCI 
NCCN 
NYHA 
OD 
PARP 
National Cancer Institute 
National Comprehensive Cancer Network 
New York Heart Association 
optimally safe and active dose 
Poly [ADP-ribose] polymerase 
SAE 
subQ 
serious adverse event 
subcutaneous 
US 
United States 
Wt 
WHO 
weight 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 Background/Rationale 
1.1. Background 
Acute myelogenous leukemia (AML) has been treated with standard “7+3” induction chemotherapy 
comprising cytarabine (days 1-7) and an anthracycline (such as daunorubicin, mitoxantrone or Idarubicin for 
days 1-3) since the regimen was first introduced more than 30 years ago.1 Few modifications have been 
made to this induction regimen over the years despite complete response rates that remain in the range of 
60-80% for adults less than 60 years old and 30-50% for adults over age 60.2-6 In the United States in 2009, 
there were about 13,000 new cases of AML and more than 9,000 deaths, demonstrating the continued overall 
poor outcome associated with this disease. 
 
With this regimen a bone marrow is normally performed 7 days after completion of induction 
chemotherapy; patients then receiving a second induction chemotherapy if this day 14 bone marrow 
examination shows residual leukemia. Note that the CR rate is dependent on the number of induction cycles 
given; for example, in a retrospective analysis of almost 2000 adult patients treated with 1 or 2 inductions 
(from 1983-1997)6, the overall CR rate at the end of the induction was 64%, with 75% (48%) of the total 
attaining CR after the first, and 25% (16%) after the second induction cycle.6 With the improvement in CR 
rates in recent years2-5, the CR rate with one induction is likely 60%. The median duration of neutropenia and 
thrombocytopenia in large recent trials of “7+3” is 29-30 days, with ~30% of patients having more prolonged 
cytopenias (>30 days).2 
 
Homoharringtonine: 
Homoharringtonine is a naturally occurring cephalotaxine alkaloid, extracted from the bark of the 
Cephalotaxus species, trees indigenous to China and parts of Japan. The bark has been used in traditional 
Chinese medicine for the treatment of cancers for over 30 years. In early studies, the cephalotaxine esters 
(harringtonine, isoharringtonine, homoharringtonine and deoxyhomoharringtonine) were used, for example, 
to successfully treat mice harboring leukemia cell lines, demonstrating promising results.7,8  
 
Omacetaxine: 
Further investigations were hindered by both a lack of purity of the drug and drug availability until a purified 
semisynthetic form of homoharringtonine, now termed Omacetaxine mepesuccinate, was developed. 9,10 
Omacetaxine can be administered either subcutaneously or as a continuous infusion.   
 
Cortes et al. conducted a phase II trial of Omacetaxine in chronic phase chronic myeloid leukemia (CML) 
patients with the BCR-ABL protein T315I mutation who had failed imatinib. Hematologic responses were 
observed in 77% of subjects and the duration of response was 9.1 months. A major cytogenetic response 
was seen in 23% of subjects.11 These study results led to FDA approval of Omacetaxine mepesuccinate for 
the treatment of CML in October 2012.  
 
Omacetaxine mepesuccinate clearly has efficacy in the treatment of CML, however its role in AML is 
unclear. Omacetaxine mepesuccinate induces apoptosis in cell lines by inhibiting protein synthesis. It acts 
by inhibiting aminoacyl-tRNA binding to the ribosomal acceptor site, thus preventing peptide bond 
formation.9,11 Other studies indicate it significantly down regulates myeloid cell leukemia-1 protein (MCL-1), 
an important anti-apoptotic regulator in AML, which is part of the BCL-2 superfamily.13 Homoharringtonine 
was also found to mediate apoptosis in vitro through the Poly [ADP-ribose] polymerase (PARP) pathway.14 
Of interest, a synergistic in vitro effect was observed against a myeloid leukemia cell line when 
homoharringtonine was combined with cytarabine.7 
 
Trials in AML: 
Both homoharringtonine and semisynthetic homoharringtonine have been used as single agents in early 
clinical trials of the drug in patients with AML. The complete remission (CR) rates in Chinese and US trials 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
ranged from 0-25%, similar to the responses observed with other single agent treatments in patients with 
AML.15 Jin et al. demonstrated that homoharringtonine in combination with cytarabine and aclarubicin can be 
administered safely to patients with de novo AML. The overall CR rate in this phase II trial was 79%16, 
suggesting that combining homoharringtonine (or semisynthetic homoharringtonine) with standard induction 
therapy would improve CR rates. 
 
In 2013 Jin et al. reported on a phase III, multicenter randomized controlled trial in China that involved 
620 patients with de novo AML.17 The three comparison arms included: homoharringtonine, cytarabine and 
aclarubicin (HAA), homoharringtonine, cytarabine and daunorubicin (HAD), and cytarabine and daunorubicin 
(AD). The CR rate for the HAA arm was significantly higher than for the AD arm, 73% vs 61% (p=0.0108). 
All three groups had similar event free and overall survival rates. However, subgroup analysis of patients 
with favorable and intermediate cytogenetic profiles demonstrated that the HAA arm had significantly better 
event free and overall survival compared to the standard therapy (AD) group.  
 
In previous studies, the maximum tolerated dose (MTD) of semisynthetic homoharringtonine as a single 
agent was determined to be 5 mg/m2/day subcutaneously for 9 days, in a phase I trial of the drug in patients 
with acute leukemia.15 Myelosuppression was a dose limiting toxicity (DLT) and the median duration of 
myelosuppression was 31 days. Grade III hyperglycemia and pulmonary aspergillosis were also observed in 
this heavily pretreated group. Conversely, in the treatment of patients with CML, the MTD was determined 
to be 1.25 mg/m2 when given subcutaneously for 14 days every 28 days.18 The incorporation of Omacetaxine 
mepesuccinate into a standard AML induction regimen of cytarabine and an anthracycline (such as 
Idarubicin), however, has not been performed and the optimally active and safe dose (OD) of Omacetaxine 
mepesuccinate in combination with cytarabine and Idarubicin is unknown. 
 
Definition of CR in AML: 
 
The International Working Group originally developed the diagnostic and response criteria for AML in 
1990. Due to major advances in the understanding of AML, revised recommendation were published in 
2003. They acknowledged that cytogenetics confer one of the most important prognostic information in 
AML, and recommended that cytogenetic complete remission (CRc) be reported as part of the response 
criteria19.  
 
 
Marcucci et al evaluated the usefulness of cytogenetic analysis performed on the first day of complete 
response (CR) as a predictor for clinic outcome in a retrospective study. They found that patients with 
abnormal cytogenetics at CR had significantly shorter overall survival (OS) (1.1 vs 2.1 years, p=0.006) and 
disease free survival (0.6 vs 1.0 years, p=0.001), and higher cumulative incidence of relapse (CIR) (1.2 vs 
0.6, p=0.0001) compared to patients with normal cytogenetics at CR (all patients had abnormal 
cytogenetics at diagnosis)20. Chen et al also investigated the prognostic impact of persistent cytogenetic 
abnormalities at CR on relapse-free survival (RFS) and OS. Patients with persistent cells with abnormal 
karyotype at CR had significantly shorter RFS (6 months vs 21 months, p=0.001) and OS (11 months vs 46 
months, p<0.001) compared to patients who had normal cytogenetics at CR21.  
 
Based on these studies, recent NCCN guidelines, and recommendations from the expert panel on behalf 
of European LeukemiaNet, we will like to include cCR in the definition of CR in our study in patients with 
abnormal karyotype at the time of diagnosis. cCR will be defined as normal karyotype as evaluated in a 
minimum of 20 metaphase cells analyzed from bone marrow to establish the diagnosis of a normal 
karyotype22,23. 
 
 
 
 
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1.2. Rationale 
Based on previous studies, we propose that combining this drug with the standard AML induction regimen 
of “7+3” will result in a significant increase in the CR rate among newly diagnosed patients with AML. We 
propose a dose-finding study to determine the activity and safety of Omacetaxine mepesuccinate in 
combination with standard induction chemotherapy in newly diagnosed AML patients.  
 
2 Objectives 
 
2.1. Primary Objective 
The primary objective of this component of the study is to determine the activity and safety of Omacetaxine 
when it is administered with the standard AML induction therapy of cytarabine and Idarubicin to patients 
under 65 years old with newly diagnosed AML.  
 
2.2. Secondary Objectives    
2.2.1. Describe the adverse events associated with Omacetaxine when administered in combination 
with cytarabine and Idarubicin as induction therapy for AML, using CTCAE grading and the time to 
hematologic recovery. 
2.2.2. Determine the overall survival of patients treated with Omacetaxine when administered in 
combination with cytarabine and Idarubicin as induction therapy for AML. 
2.2.3. Determine the relapse-free survival in patients who achieve CR or CRi (complete remission with 
incomplete blood count recovery) following treatment with Omacetaxine in combination with cytarabine 
and Idarubicin as induction therapy for AML. 
2.2.4. Determine the event-free survival in patients who achieve CR or CRi following treatment with 
Omacetaxine in combination with cytarabine and Idarubicin as induction therapy for AML. 
 
3 Endpoints 
 
3.1. Primary Endpoint  
The primary endpoint is determination of the optimally active and safe dose (OD) of Omacetaxine when 
added to the standard-of-care induction chemotherapy for AML and the estimation of the efficacy and 
response rate. OD will be defined as a dose level at which fewer than 30% of patients experience hematologic 
toxicity and greater than 60% of patients achieve a CR (as a second induction is not being given in this 
study).2-6 
 
3.2. Secondary Endpoints 
3.2.1. 
Adverse effects (AE) as defined by CTCAE v4.1 24 
3.2.2. 
Overall survival of patients 
3.2.3. 
Relapse-free survival of patients 
3.2.4. 
Event-free survival in patients 
 
 
4 Overall Design and Study Plan 
This is a dose escalation study to evaluate Omacetaxine when given in combination with cytarabine and 
Idarubicin. The study will evaluate Omacetaxine dose escalation using an EffTox design (see Section 11 for 
statistical considerations). Post induction therapy will consist of standard high dose cytarabine consolidation 
chemotherapy or allogeneic stem cell transplantation based on pretreatment cytogenetic risk assessment. 
 
 
 
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4.1 Dose Finding Component: 
Up to 5 dose levels of Omacetaxine will be tested (refer to Omacetaxine dosing in Section 7). The OD of 
Omacetaxine in combination with cytarabine and Idarubicin will be determined using the EffTox design (as 
described in Section 12.1), and will follow the standard rules for evaluation of hematologic toxicity (HT).  
 
If none of the dose levels are acceptable at study completion, an optimal dose level will not be identified and 
the drug does not warrant further investigation. 
 
Note however that if, for example, addition of a lower dose of Omacetaxine (e.g., dose level 1 (0.625mg/m2) 
to “7+3” results in a lack of efficacy and no toxicity and the next higher dose used (i.e., level 2 (1.25mg/m2)) 
results in unacceptable toxicity we may seek to modify the protocol to allow use of a dose of Omacetaxine 
intermediate to the current dose increments (in this example we would use 1mg/m2).  
 
4.1.1 Hematologic toxicity 
Hematologic toxicity is defined as the following event occurring during induction: 
Treatment-related hematologic toxicity, defined as bone marrow hypoplasia present for more than 6 
weeks duration from the last day of treatment; specifically, failure to recover peripheral ANC > 1000/μL 
and platelets > 100,000/μL with the bone marrow documented to be free of leukemic infiltration. 
 
4.1.2 Evaluation of Activity 
Activity evaluation will be performed by looking at treatment failure and CR rates. 
 
Treatment Failure:  
If hypoplasia is not established on the Day 7-10 post-induction treatment bone marrow biopsy/aspirate–
defined as cellularity <10%-20% with residual blasts comprising <5%-10% of these cells–and a second 
induction is required, then the subject will be removed from the study and this dose will be considered a 
treatment failure.  
If the Day 7-10 bone marrow biopsy/aspirate is ambiguous for residual leukemic blasts, then a repeat 
bone marrow biopsy will be performed 1-2 weeks later. If persistent leukemia is present at that time, then 
this will be defined as treatment failure.  
 
Treatment Success: Defined as a complete remission (CR) per the European LeukemiaNet criteria (i.e., 
BM blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil 
count > 1.0 x 109/L (1000/µL); platelet count > 100 x 109/L (100,000/µL); independent of red cell 
transfusions; see appendix I) or CRi (all CR criteria present except for residual neutropenia < 1.0 x 109/L 
(1000/µL) or thrombocytopenia < 100 x 109/L (100 000/µL); see appendix I). 
 
In patients with abnormal cytogenetics at diagnosis, CR (or CRi) will be delineated as above plus 
evidence of complete cytogenetic response (also known as CRc)—defined as a finding of normal 
cytogenetics at the time of the BM examination performed at day 7-10 and at 3-4 weeks after induction 
therapy.  
If subjects obtain a CR or CRi rate that is equal or better than 60% after treatment, then this will be 
considered active treatment. BM examination(s) will be performed at recovery (usually 3-4 weeks) and 
may be repeated at 6 weeks (and later if necessary) if BM recovery has not occurred. 
The rules for dose (de) escalating are described in Section 12.1  
The EffTox design begins by treating a cohort of three patients at dose level 1. The efficacy and toxicity 
outcomes for these three patients are used to update the posterior distributions for the probability of 
efficacy and toxicity and identify acceptable dose levels. The study terminates if no dose levels are 
acceptable. Otherwise, the acceptable doses are ranked using the Euclidean distance from (1.0, 0.0) and 
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the next cohort is treated at the dose with the minimum distance, under the restriction that we may only 
escalate or deescalate one dose level at a time (e.g., the second cohort can only escalate to dose level 
2 or de-escalate to dose level -1). The second cohort is treated at the dose with the minimum distance 
and posterior distributions, and the list of acceptable doses and distances are then updated as before. 
This process continues until at least 20 subjects are enrolled in the study. The dose with the minimum 
distance at study completion is considered the optimal dose for further investigation. If none of the dose 
levels are acceptable at study completion, an optimal dose level will not be identified and the drug does 
not warrant further investigation. 
 
Note that additional patient cohorts will not be enrolled until all patients at the current dose level have 
completed the planned induction treatment (defined as 14 doses of Omacetaxine) and are able to 
proceed with consolidation or salvage therapy (or if a patient in the cohort is removed from the study). 
 
The OD will be defined as a dose level at which 30% or less of patients experience a hematologic toxicity 
and 60% or more patients achieve a CR. 
 
5 Selection of patients 
 
Study entry is open to adults regardless of gender or ethnic background. While there will be every effort to 
seek out and include women and minorities, the patient population is expected to be no different than that of 
other hematologic malignancy studies at the University of Illinois. 
 
5.1. Inclusion Criteria 
 
1. Newly diagnosed, untreated patients with AML according to the WHO classification for AML.25 Prior short-
term therapy (≤7 days) with hydroxyurea, steroids, biological or targeted therapy (e.g. FLT3 inhibitors, 
other kinase inhibitors, azacitidine, ATRA), or hematopoietic growth factors is allowed. A single or two-
day dose of cytarabine (up to 3 g/m2) for emergency use is also allowed as prior therapy. 
 
2. Patients age 18 to 70 years old who meet diagnostic criteria for AML. 
 
3. ECOG performance status of 0-3 (appendix III).26 
 
4. Adequate organ function, if not suspected to be due to AML, within 14 days of study registration, defined 
as: 
 
System 
Laboratory Values 
Hepatic 
 
Total bilirubin 
≤ 2.0 x ULN (unless due to hemolysis) 
AST and ALT 
≤ 3 X ULN (unless believed to be due to  
tumor involvement) 
Renal 
 
Serum Creatinine 
Creatinine Clearance 
≤ 1.5 x ULN 
> 30 ml/min 
 
6. Negative urine or serum pregnancy test in females. Patients of reproductive potential (males and 
females) must consent to and practice double-barrier methods of contraception during treatment and 
for 12 weeks following the last dose of Omacetaxine. Adequate contraception is defined as double-
barrier protection (i.e., condom plus spermicide in combination with a diaphragm, cervical/vault cap, or 
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intrauterine device). Birth control pills, birth control patches and/or injections of hormones to prevent 
pregnancy are not considered an adequate method of preventing pregnancy, and double-barrier 
protection is required while on study and for 12 weeks after last dose. Patients will be instructed to 
notify the investigator if pregnancy is discovered either during or within 12 weeks of completing 
treatment with Omacetaxine. This also applies to male patients whose partners become pregnant while 
the patient is on study or within the 12 week period after the last dose of study drug. 
 
7. Patients must be willing and able to review, understand, and provide written consent before starting 
therapy. 
 
5.2. Exclusion Criteria 
 
1. Patients with AML age 70 or older. 
 
2. Acute promyelocytic leukemia. 
 
3. Investigational drug within 4 weeks of study entry. 
 
4. Cardiac insufficiency grade III or IV New York Heart Association (NYHA)27 (see Appendix IV). 
 
5. Female subjects who are pregnant or breast feeding. 
 
6. Patients who are HIV positive. 
 
7. Active uncontrolled infection or severe systemic infection (enrollment is possible after control of infection). 
 
8. Concurrent malignancy (other than AML) with an estimated life expectancy less than two years and 
requiring active therapy. 
 
9. Psychological, familial, sociological, or geographical condition that would preclude study compliance and 
follow-up. 
10. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of 
acute ischemia or medically relevant active conduction system abnormalities. Prior to study entry, any 
ECG abnormality at screening has to be documented by the investigator as not medically relevant. 
 
11. Pregnant or breastfeeding: Omacetaxine is a Pregnancy Category D medication and has caused embryo-
fetal death in animals. Confirmation that the subject is not pregnant must be established by a negative 
urine β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening.  
Pregnancy testing is not required for post-menopausal or surgically sterilized women.  
 
12. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would make the 
patient inappropriate for enrollment in this study. 
 
 
 
 
6 Registration 
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Registration will occur after the patient has signed the patient consent and eligibility is confirmed, but before 
any treatment has been administered.  To be eligible for registration to this study, the patient must meet each 
of the criteria listed on the eligibility checklist based on the eligibility assessment documented in the patient’s 
medical record.  A copy of the eligibility checklist is maintained by the Clinical Trial Office (CTO) and can be 
found for each individual subject within the subject shadow chart. 
 
6.1. Registration with the Clinical Trials Office 
 
Upon completion of the screening evaluation, eligibility checklist and obtaining consent, the study 
coordinator or designee will enroll the patient into the CTO data management system.  
 
Omacetaxine dose levels will be assigned at registration. 
 
6.2. Patients Who Do Not Begin Study Treatment 
If a patient signs consent and is registered to the study, and is later found not able to begin the planned 
study treatment, for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion. The patient will be considered a screen/baseline failure and be replaced.   Further 
data will not be collected if the patient has not begun study treatment at the time of removal from trial. 
The reason for removal from study will be clearly indicated in CTO data management system.   
If a patient begins treatment, and then treatment is discontinued for whatever reason, the patient must 
be followed per section 7.12. 
7 Treatment Plan 
7.1. Study Drug Administration 
 
 
  
Cytarabine (100mg/m2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days   
 
  
Idarubicin (12 mg/m2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3 
Omacetaxine (assigned dose) administered subcutaneously Q12 hours Days 1 to 7 
Induction Chemotherapy Regimen 
Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Cytarabine 
100 mg/m2 
CI 
100 mg/m2 
CI 
100 mg/m2 
CI 
100 mg/m2 
CI 
100 mg/m2 
CI 
100 mg/m2 
CI 
100 mg/m2 
CI 
Idarubicin 
12 mg/m2 
IV 
12 mg/m2 
IV 
12 mg/m2 
IV 
 
 
 
 
Omacetaxine 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
Assigned 
dose subQ 
q12h 
 
7.1.1. Omacetaxine Administration 
 
Omacetaxine will be given subcutaneously every 12 h for Days 1-7. Cytarabine will be administered at a 
dose of 100 mg/m2 as a 24 h continuous infusion for Days 1-7. Idarubicin will be injected intravenously 
at a dose of 12 mg/m2 over 15 minutes Days 1, 2 and 3.  
 
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Pre-medication 
Omacetaxine and Cytarabine, at low doses (i.e. 100mg/m2) are classified as having a low emetic risk per 
the National Comprehensive Cancer Network (NCCN) guidelines.28 However Idarubicin is classified as 
having a moderate emetic risk. Therefore requiring acute anti-emetic premedication prior to 
administration of the drug. Antiemetic medications for breakthrough nausea will be prescribed at the 
primary investigator’s discretion. 
PREMEDICATION REGIMEN DESCRIPTION 
Agent 
Premedication 
Precautions 
Dose Route 
Schedule 
Cycle Length  
Ondansetron 
ODT 
EPS, QT 
prolongation 
8 mg  IV 
Day 1, 2, 3  
Administered 30 minutes 
prior to Idarubicin 
Dexamethasone Hyperglycemia, 
10 mg IV 
Day 1, 2, 3 
Administered 30 minutes 
prior to Idarubicin 
 
Monitoring 
All patients will be hospitalized during the induction chemotherapy regimen. All doses of Omacetaxine 
will be administered in an inpatient setting. Patients will be closely monitored for toxicities. 
 
Supportive Measures 
Monitoring for tumor lysis is recommended and aggressive hydration and allopurinol prophylaxis is 
strongly encouraged. 
It is recommended that the patient’s fluid status and hepatic and renal function and blood glucose levels 
be carefully monitored during the drug administration period. 
Venous Access: A central venous access device is strongly recommended for this study. 
Blood Product Support: Appropriate use of all blood products is recommended. Use of CMV negative 
products is strongly encouraged for patients documented to be CMV negative and who may later undergo 
bone marrow transplantation. Blood products should be irradiated following the current FDA guidelines 
found at: http://www.fda.gov/cber/gdlns/gamma.html 
Hematopoietic Growth Factors: Filgrastim (G-CSF) may be used at the treating physician’s discretion, 
provided bone marrow evaluation demonstrates no evidence of AML, to enhance neutrophil recovery 
when clinically indicated. Routine use of filgrastim in clinically well patients awaiting count recovery is not 
recommended. 
Prevention of Fungal Infections: Antifungal prophylaxis can reduce morbidity and fungal infection-related 
mortality in severely neutropenic chemotherapy recipients. Evidence for benefit is strongest for those 
conditions associated with > 15% rate of systemic fungal infection such as prolonged neutropenia, as 
observed in AML patients and stem cell transplant (SCT) recipients and is recommended for study 
patients. The choice of the prophylaxis should be made in consultation with institutional infection profiles 
and infectious disease guidelines. 
Management of Fever and Neutropenia: Patients with an ANC < 500/μL (or < 1000/μL and falling) and 
an oral temperature > 38°C twice in 24 hours or > 38.3°C once, should have empiric systemic antibiotics 
initiated immediately after appropriate cultures are drawn. The specific choice of empiric antibiotics 
should be guided by the resistance patterns seen at the individual institution.  
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The antibiotic regimen chosen for febrile neutropenia should contain activity against gram-negative 
organisms and Pseudomonas aeruginosa in particular. Note: aminoglycosides increase the risk of 
nephrotoxicity.  
The persistence of fever for > 3 days despite broad spectrum antibiotic therapy or the emergence of a 
new fever in a neutropenic patient warrants investigation for invasive fungal infection and initiation of 
empiric antifungal therapy. Antifungal options include amphotericin B (or lipid amphotericin products), 
voriconazole, echinocandins (micafungin, caspofungin, and anidulafungin), as well as combination 
therapy. The choice of specific agent(s) and length of therapy will be dictated by the suspected or 
confirmed fungal species, site of infection, and clinical status. Consultation with an Infectious Disease 
physician is recommended. 
Hyperglycemia: Patients blood glucose will be checked three times a day with meals and at bedtime 
(TIDAC and QHS) if patient eating, and if patient is not eating or NPO will monitor blood glucose every 6 
hours. Note: If no hyperglycemia observed after 4 doses of Omacetaxine, blood glucose will be only 
checked once daily thereafter. Insulin aspart high dose correction bolus sliding scale will be administered 
for elevated serum blood glucose as following:  
If Premeal blood glucose (mg/dL):  
- Notify physician if less than 70 mg/dL 
    150 - 200   3 Units  
    201 - 250   6 Units  
    251 - 300   8 Units  
    301 - 350   10 Units 
    351 - 400   12 Units  
    >400          14 Units and Notify physician 
- if correction bolus given at bedtime, will check blood glucose 2-4 hours after insulin administration 
 
Hypoglycemia: Patients will have blood glucose measurements as noted above. Patients with 
hypoglycemia will be treated with oral glucose or if necessary IV glucose to maintain blood glucose levels 
above 70 mg/dl. All patients will have a order for IV dextrose 50% for IV push, 25ml, if needed for blood 
glucose less than 70mg/dL 
 
Precautions 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she must 
inform the investigator immediately and must permanently discontinue study drug. Male patients whose 
partners become pregnant while the patient is on study or within the 12 week period after last dose of 
study drug must inform the investigator immediately. Patients of reproductive potential (males and 
females) must practice double-barrier methods of contraception during treatment and for 12 weeks 
following the last dose of Omacetaxine. Adequate contraception is defined as double-barrier protection 
(i.e., condom plus spermicide in combination with a diaphragm, cervical/vault cap, or intrauterine device). 
Birth control pills, birth control patches and/or injections of hormones or (in males) surgical sterilization 
(i.e., status post-vasectomy) to prevent pregnancy are not considered an adequate method of preventing 
pregnancy, and double-barrier protection is required while on study and for 12 weeks after last dose, or 
the patient must completely abstain from heterosexual intercourse. 
7.1.2. Removal of Subjects from Study 
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Patients can be taken off the study treatment and/or study at any time at their own request, or they may 
be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation will be documented and may include: 
7.1.2.1 Patient voluntarily withdraws from treatment (follow-up permitted);  
7.1.2.2 Follow up bone marrow biopsy performed 7-10 days after completion of induction therapy 
demonstrates significant residual leukemic blasts, or significant cytoreduction with a high 
percentage of residual leukemic blasts and the patient requires a second induction therapy 
(see also Section 4.1.2). 
7.1.2.3 Patient withdraws consent (termination of treatment and follow-up) or patient is unable to 
comply with protocol requirements; 
7.1.2.4 Patient demonstrates disease progression 
7.1.2.5 Patient experiences toxicity that makes continuation on the protocol unsafe; 
7.1.2.6 Treating physician judges that continuation on the study would not be in the patient’s best 
interest; 
7.1.2.7 Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
7.1.2.8 Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment which would interfere with this study; 
7.1.2.9 Lost to follow-up. If a research subject cannot be located to document survival, the subject 
may be considered “lost to follow-up.” All attempts to contact the subject must be 
documented. 
 
7.2. Drug Dose Level Assignment 
7.2.1. 
Dose Finding Component 
 
Dose level assignment will occur at the time of study registration 
Dose Level 
Omacetaxine mg/m2 
-1 
0.5 
1 
0.625 
2 
1.25 
3 
2.0 
4 
3.0 
5 
4.2 
 
7.2.2 Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for 
Adverse Events Version 4.0 (CTCAE v 4) 24 
 
The initial cohort will be 3 patients, and the following rule of hematologic toxicity will take effect. 
 
7.2.3 Hematologic toxicity (HT) is defined as the following event occurring during induction: 
• 
Incomplete hematologic recovery, ANC < 1.0 x 109/L (1000/µL) and platelet count < 100 x 
109/L (100,000/µL) with the bone marrow documented to be free of leukemic infiltration. 
7.2.4 Non-hematological toxicity is defined as any Grade 4 toxicity (excluding grade 4 infection), or an 
unresolved treatment-related ≥grade 3 non-hematologic toxicity that is present 6 weeks after the 
last dose of Omacetaxine (i.e., at day 50). 
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Dose escalation will occur based on the schema found in Section 12, and after consultation with the study 
statistician (Dr. Liu). HT’s will be counted based on the number of patients with HT at a given dose level, 
not the absolute number of HTs. No single patient can trigger more than one HT event. Intra-patient dose 
escalation is not permitted. 
 
7.3. Dose Modifications 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for 
Adverse Events Version 4.0 (CTCAE v 4). A copy of the CTCAE can be downloaded from the CTEP 
home page.24 
The intent of the study design is for all patients to complete the induction therapy of Omacetaxine, 
Idarubicin and cytarabine, except for those patients who exhibit evidence of disease progression, 
experience an unacceptable toxicity or if the investigator determines that discontinuation of treatment is 
in the best interest of the patient. 
Hematologic Toxicity: There will be no dose delays or dose reductions of study drugs for hematologic 
toxicity during Induction. 
In the event of non-hematologic toxicity during Induction, the study drug may be stopped per the 
discretion of the Principal Investigator if the toxicity is determined to be clinically significant. 
 
7.4. Permitted Concomitant Medications and Procedures 
All other manifestations of the patient’s malignancy and medical conditions should be treated at the 
discretion of the investigator in accordance with standards of medical care. 
In appropriate settings, such as combinations with agents known to produce frequent thrombocytopenia, 
restricted uses of anticoagulants, antiplatelet agents and non-steroidal anti-inflammatory medication 
should be considered. 
 
7.5. The Effects of Other Drugs on Omacetaxine 
 
Cytochrome P450 Enzymes (CYPs): Omacetaxine mepesuccinate is not a substrate of CYP450 
enzymes in vitro. Omacetaxine mepesuccinate and its derivative 4'desoxyhomoharringtonine (4'-
DMHHT) do not inhibit major CYPs in vitro at concentrations expected clinically. The potential for 
Omacetaxine mepesuccinate or 4'-DMHHT to induce CYP450 enzymes has not been determined. 
 
Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. 
Omacetaxine mepesuccinate and 4'-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at 
concentrations expected clinically. 29 
 
7.6. Concomitant Medications and Non-Drug Therapies 
 
All patients will be asked to provide a complete list of prescription and over-the-counter medications that 
have been taken within the previous 4 weeks prior to screening.  The investigator must be informed as 
soon as possible about any new medication(s) taken from the time of screening until the completion of 
the post-treatment follow-up visit. 
 
7.7. Prohibited Concomitant Medications 
Patients should not receive other anti-cancer therapy (cytotoxic, biologic, or radiation) while on treatment 
in this study. 
7.8. Management of Clinical Events and Supportive Care Guidelines 
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Optimal patient care is to be provided to all patients. Patients should receive full supportive care during 
the study, including transfusion of blood and blood products, treatment with antibiotics, or analgesics, 
when appropriate. Although acetaminophen at doses of ≤2 grams/day is permitted, it should be used with 
caution in patients with impaired liver function. 
 
7.9. Nausea, Vomiting, Diarrhea 
Prophylactic antiemetic therapy will be used in this study. 5-HT3 receptor antagonist with corticosteroids 
will be administered. Because of the potential of benzodiazepines to cause sedation, the use of 
benzodiazepines for antiemetic prophylaxis should be reserved for patients who cannot be satisfactorily 
managed otherwise. There is no prohibition against antiemetic use in the management of a patient who 
develops nausea or vomiting, or both. 
Antidiarrheal medications will not be used prophylactically; however, patients determined to be free of 
infectious diarrhea can be instructed to take loperamide, 4 mg, at the occurrence of the first loose stool 
and then 2 mg every 2 hours until they are diarrhea-free for at least 12 hours.  During the night, patients 
may take 4 mg of loperamide every 4 hours.  Fluid intake should be maintained to avoid dehydration. 
 
7.10. 
Duration of Therapy 
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this protocol are detrimental to 
the patient’s health, protocol treatment should be discontinued.  
• 
Patient withdraws consent. 
• 
There is evidence of progressive disease or unacceptable toxicity. 
• 
The treating physician thinks a change of therapy would be in the best interest of the patient. 
 
7.11. 
Follow-up 
Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final 
study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study 
participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this 
case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse 
event. 
 
 
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8 Study Parameters: 
 
Baseline, 
within 14 
days of 
enrollment 
Induction Phase1 
Post-Induction 
Studies 
[~3-6 weeks]5 
Long Term 
Follow up 
Q2 months 
for 6 months 
 
Daily 
 
Biweekly 
Weekly 
Day 14-
176 
Signed consent 
x 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
Review of prior therapy 
x 
 
 
 
 
x 
x 
Physical exam11  
x 
x 
 
 
 
 
 
Vital signs 
x 
x 
 
 
 
x 
x 
Height10, weight 
x 
 
x 
 
 
x 
x 
Concomitant meds review 
x 
x 
 
 
 
x 
 
x 
 
Performance status2 
x 
 
 
x 
 
x 
x 
Symptom and toxicity    
x 
x 
 
 
 
x 
 
CBC w/ diff 
x 
x 
 
 
 
x 
x 
BMP 
x 
 
x 
 
 
x 
x 
Albumin, ALT, AST, 
bilirubin, alkaline 
phosphatase, total protein, 
uric acid, LDH, PT/INR, 
PTT, fibrinogen 
x 
 
x 
 
 
x 
 
 
x 
Bone Marrow Aspirate and 
Biopsy and/or evaluation 
of extramedullary site 
x 
 
 
 
 
x 
x3 
 
 
Cytogenetics (karyotype ± 
FISH) 
x 
 
 
 
 
x 
x 
 
Bone Marrow or 
extramedullary site 
Immunophenotyping and 
cytochemistry  
x 
 
 
 
 
x 
x 
 
Echocardiogram or MUGA 
scan 
x 
 
 
 
 
x 
 
HbA1C for diabetic 
patients 
x 
 
 
 
 
 
x 
x  
Urine pregnancy test for 
females of child-bearing 
potential 
x 
 
 
 
 
 
 
EKG 
x 
 
 
 
 
 
 
Lumbar puncture, if 
symptomatic or 
asymptomatic with special 
circumstances 
x 
 
 
 
 
x 
 
1: see section 7.1 for Induction Chemotherapy Regimen 
2: For patients with unresolved treatment related toxicity, follow as medically appropriate until resolution or stabilization 
3: BM to document status upon hematologic recovery (3-6 wks). BM may be repeated at later time points if recovery is delayed. 
4: For patients with major neurologic signs or symptoms at diagnosis, appropriate imaging studies should be performed to detect 
meningeal disease, chloromas, or CNS bleeding, and an LP with intrathecal administration of chemotherapy should then be performed 
on these patients if no mass/lesion is detected on the imaging study. Consider screening LP at first remission for patients with M4 or M5 
morphology or if WBC count >100,000/mcL at diagnosis.23. 
5: Post-Induction procedures will occur once upon bone marrow recovery with a window of 3-6 weeks. Note labs should be performed 
twice weekly from D14-17 BM to count recovery (or “off-study”) 
6: BM aspirate should be performed between 7 and 10 days after Induction chemotherapy is completed (i.e., Day 14-17). 
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7: If diabetic at baseline only. 
8: Height at baseline only. 
9: De-identified photographs of patients who develop skin changes that could potentially be related to Omacetaxine will be taken daily to 
document skin changes occurring on study. 
 
9 Drug Formulation and Procurement  
9.1. Omacetaxine29 
 
9.1.1. Other names 
Synribo, Omacetaxine mepesuccinate  
9.1.2. Classification 
Antineoplastic Agent, Cephalotaxine, Protein Synthesis Inhibitor 
9.1.3. How supplied 
Omacetaxine for Injection contains 3.5 mg Omacetaxine mepesuccinate; as a sterile, 
preservative-free, white to off-white lyophilized powder in a single-use vial. 
9.1.4. Availability 
Omacetaxine will be provided by Teva Pharmaceuticals.  
9.1.5. Description 
Omacetaxine contains the active ingredient Omacetaxine mepesuccinate, a cephalotaxine ester. 
It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic 
process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name 
of Omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-
methylpentyl) butanedioate (ester). 
The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. Omacetaxine for 
injection is a sterile, preservative- free, white to off-white, lyophilized powder in a single-use vial. 
Each vial contains 3.5 mg Omacetaxine mepesuccinate and mannitol. 
9.1.6. Storage, Handling, and Accountability 
SYNRIBO is intended for subcutaneous administration after reconstitution with 1.0 mL of 0.9% 
Sodium Chloride Injection, USP. The pH of the reconstituted solution is between 5.5 and 7.0. 
Protect reconstituted solution from light. After administration, any unused solution should be 
discarded properly. 
9.1.7. Administration 
Omacetaxine mepesuccinate is an antineoplastic product. Follow special handling and disposal 
procedures. 
Reconstitute Omacetaxine with one mL of 0.9% Sodium Chloride Injection, USP, prior to 
subcutaneous injection. After addition of the diluent, gently swirl until a clear solution is obtained. 
The lyophilized powder should be completely dissolved in less than one minute. The resulting 
solution will contain 3.5 mg/mL Omacetaxine. 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration whenever solution and container permit. 
Use Omacetaxine within 12 hours of reconstitution when stored at room temperature and within 
24 hours of reconstitution if stored at 2°C to 8 °C (36°F to 46°F). 
9.1.8. Risks 
The main toxic effect of Omacetaxine is bone marrow suppression with leukopenia, 
thrombocytopenia and anemia. Blood counts will be monitored frequently. Patients will be 
monitored closely for signs of infection or neutropenic fever due to neutropenia or bleeding due 
to thrombocytopenia. Less serious toxicity includes hyperglycemia, nausea, vomiting, diarrhea  
abdominal pain, oral ulceration and atrial tachyarrhythmias such as atrial fibrillation. 
 
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See section 9.1.9 - Warnings and Precautions. 
 
9.1.9. Warnings and Precautions 
 
Myelosuppression: In uncontrolled trials with Omacetaxine, patients with chronic phase and 
accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia 
(85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to 
myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with 
neutropenia are at increased risk for infections, and should be monitored frequently and advised 
to contact a physician if they have symptoms of infection or fever. 
 
Bleeding: Omacetaxine causes severe thrombocytopenia which increases the risk of 
hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 
thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral 
hemorrhage occurred in 2% of patients treated with SYNRIBO in the safety population. Severe, 
non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most 
bleeding events were associated with severe thrombocytopenia. 
 
Hyperglycemia: Omacetaxine can induce glucose intolerance. Grade 3 or 4 hyperglycemia was 
reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia 
occurred in 1 patient treated with Omacetaxine in the safety population. Monitor blood glucose 
levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid 
Omacetaxine in patients with poorly controlled diabetes mellitus until glycemic control has been 
established. 
 
Embryo-Fetal Toxicity: Omacetaxine can cause fetal harm when administered to a pregnant 
woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of 
reproductive potential should avoid becoming pregnant while being treated with Omacetaxine. 
There are no adequate, well-controlled studies of Omacetaxine in pregnant women. If this drug is 
used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient 
should be apprised of the potential hazard to the fetus.  
 
9.2. Cytarabine30 
9.2.1. Other names 
Cytosine arabinoside, Ara-C, Cytosar  
9.2.2. Classification 
Antineoplastic Agent, Antimetabolite; (Pyrimidine Analog) 
9.2.3. How supplied 
NDC 55390-131-10.....................100 mg boxed vial; pack of 10 
NDC 55390-132-10.....................500 mg boxed vial; pack of 10 
NDC 55390-133-01.....................1 g boxed vial 
NDC 55390-134-01.....................2 g boxed vial 
9.2.4. Availability 
Commercially available from various manufacturers.  
9.2.5. Description 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but significant, 
incorporation of cytarabine into both DNA and RNA has also been reported. It exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain 
conditions blocking the progression of cells from the G1 phase to the S-phase. Cytarabine is 
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metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate 
(Ara-CTP), an effective inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). It appears that 
the balance of kinase and deaminase levels may be an important factor in determining sensitivity 
or resistance of the cell to cytarabine. It has an initial distributive phase t½ of about 10 minutes, 
with a secondary elimination phase t½ of about 1 to 3 hours. Peak levels after intramuscular or 
subcutaneous administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized and eliminated 
more slowly with a t½ of about 2 hours. 
 
9.2.6. Storage, Handling, and Accountability 
Cytarabine should be stored in a controlled room temperature between 20° and 25°C (68° and 
77°F). Hazardous agent: Use appropriate precautions for handling and disposal. Procedures for 
proper handling and disposal of anti-cancer drugs should be considered. Cytarabine Injection is 
supplied in a sterile, preserved solution. 
 
9.2.7. Administration 
Cytarabine is not active orally. The schedule and method of administration varies with the program 
of therapy to be used. Cytarabine may be given by intravenous infusion, injection/subcutaneously 
or intrathecally. Thrombophlebitis has occurred at the site of drug injection or infusion in some 
patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In 
most instances, however, the drug has been well tolerated. 
Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection 
as compared with slow infusion. This phenomenon is related to the drug's rapid inactivation and 
brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. 
Normal and neoplastic cells seem to respond to somewhat parallel fashion to these different 
modes of administration and no clear-cut clinical advantage has been demonstrated for either. 
Relatively constant plasma levels can be achieved by continuous intravenous infusion. 
In many chemotherapeutic programs, cytarabine is used in combination with other cytotoxic 
drugs. The addition of these cytotoxic drugs has necessitated changes and dose alterations. The 
dosage schedules for combination therapy outlined below have been reported in the literature. 
9.2.8. Risks 
Immediate side effects include allergic reactions associated with low blood pressure, shortness 
of breath, hypotension, back pain and hives.  These will be treated with medications, fluids and 
oxygen. Anaphylaxis resulting in acute cardiopulmonary arrest has been reported, but is rare. 
 
The main toxic effect of cytarabine is bone marrow suppression with leukopenia, 
thrombocytopenia and anemia. Blood counts will be monitored frequently. Patients will be 
monitored closely for signs of infection or neutropenic fever due to neutropenia or bleeding due 
to thrombocytopenia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal 
pain, oral ulceration, and hepatic dysfunction. See section 9.2.9 Warnings and Precautions.   
 
9.2.9. Warnings and Precautions 
Cytarabine for the use in induction therapy should be administered in a facility with laboratory and 
supportive resources sufficient to monitor drug tolerance and protect and maintain a patient 
compromised by drug toxicity. The main toxic effect of cytarabine is bone marrow suppression 
with leukopenia, thrombocytopenia and anemia. Less serious toxicity includes nausea, vomiting, 
diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction. When large intravenous 
doses are given quickly, patients are frequently nauseated and may vomit for several hours post 
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injection. This problem tends to be less severe when the drug is infused. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility: Extensive chromosomal damage, 
including chromatid breaks have been produced by cytarabine and malignant transformation of 
rodent cells in culture has been reported. Cytarabine is embryotoxic and teratogenic and 
produced peri- and postnatal toxicity in various species. Sperm head abnormalities were observed 
following cytarabine treatment in mice.  
 
Cardiovascular: An increase in cardiomyopathy with subsequent death has been reported 
following experimental high dose cytarabine and cyclophosphamide therapy when used for bone 
marrow transplant preparation. This may be schedule dependent. 
 
Gastrointestinal: Peritonitis and Typhlitis with concurrent neutropenia and thrombocytopenia, 
have been reported in patients treated with conventional doses of cytarabine in combination with 
other drugs. Patients have responded to nonoperative medical management. 
Severe and at times fatal, GI toxicity (different from that seen with conventional therapy regimens 
of cytarabine) has been reported following high dose (2-3 g/m2) schedules of cytarabine). These 
reactions include severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis, 
leading to peritonitis, bowel necrosis; and necrotizing colitis. 
 
Tumor Lysis Syndrome: Like other cytotoxic drugs, cytarabine may induce hyperuricemia 
secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric 
acid level and be prepared to use such supportive and pharmacologic measurements as might 
be necessary to control this problem. 
 
Hematologic Effects: Cytarabine is a potent bone marrow suppressant; the severity depends on 
the dose of the drug and schedule of administration. Therapy should be started cautiously in 
patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug 
must be under close medical supervision and during induction therapy, should have leukocyte 
and platelet counts performed daily. Bone marrow examinations should be performed frequently 
after blasts have disappeared from the peripheral blood. Facilities should be available for 
management of complications (possibly fatal) of bone marrow suppression (infection resulting 
from granulocytopenia and other impaired body defenses, and hemorrhage secondary to 
thrombocytopenia). 
 
Hepatic/Biliary/Pancreatic and/or Renal Function: The human liver apparently detoxifies a 
substantial fraction of an administered cytarabine dose. In particular, patients with renal or hepatic 
function impairment may have a higher likelihood of CNS toxicity after high-dose treatment with 
cytarabine. Use the drug with caution and at reduced dose in patients whose liver function is poor. 
Periodic checks of bone marrow, liver and kidney function should be performed in patients 
receiving cytarabine. Acute pancreatitis has been reported to occur in patients being treated with 
cytarabine in combination with other drugs. 
 
Hypersensitivity Reactions: Anaphylactic reactions have occurred with cytarabine treatment. 
Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been 
reported. This occurred immediately after the intravenous administration of cytarabine. 
 
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or 
live- attenuated vaccines in patients immunocompromised by chemotherapeutic agents including 
cytarabine may result in serious or fatal infections. Vaccination with a live vaccine should be 
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avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; 
however, the response to such vaccines may be diminished. 
 
Neurologic: Severe and at times fatal, CNS toxicity (different from that seen with conventional 
therapy regimens of cytarabine) has been reported following high dose (2-3 g/m2) schedules of 
cytarabine. These reactions include cerebral and cerebellar dysfunction including personality 
changes, somnolence, convulsion and coma, usually reversible. Delayed progressive ascending 
paralysis resulting in death has been reported in children with AML following intrathecal and 
intravenous cytarabine at conventional doses in combination with other drugs. 
 
Respiratory: Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome 
and pulmonary edema have occurred following high dose schedules with cytarabine therapy. A 
syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and 
radiographically pronounced cardiomegaly has been reported following experimental high dose 
cytarabine therapy used for the treatment of relapsed leukemia. 
 
Skin: Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia 
is more commonly seen with high dose therapy than with standard cytarabine treatment 
programs. 
 
9.3. Idarubicin31   
9.3.1. Other names 
Idamycin PFS, Idamycin® 
9.3.2.  Classification 
Antineoplastic Agent, Anthracycline, Antibiotic 
9.3.3.  How supplied 
IDARUBICIN (Idarubicin hydrochloride for injection, USP) NDC 0013-2526-86 20 mg single dose 
vial. Available in single vials. 
9.3.4. Availability 
Commercially available from various manufacturers. See package insert for further information. 
 
9.3.5. Description 
IDARUBICIN® (Idarubicin hydrochloride for injection, USP) is a sterile, semi-synthetic 
antineoplastic anthracycline for intravenous use. Chemically, Idarubicin hydrochloride is 5,12-
Naphthacenedione, 
9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-
tetrahydro-6,9,11-trihydroxyhydrochloride, (7S-cis).  
 
9.3.6. Storage, Handling, and Accountability 
Store at controlled room temperature, 15° to 30°C (59° to 86°F), and protect from light. 
IDARUBICIN, a sterile lyophilized powder for reconstitution and intravenous administration, is 
available in a 20 mg single use only vial. Each 20 mg vial contains 20 mg Idarubicin Hydrochloride, 
USP and 200 mg of Lactose NF (hydrous) as an orange-red, lyophilized powder. 
 
9.3.7. Administration 
For I.V. administration only. Do not administer I.M. or SubQ; administer as slow push over 3-5 
minutes, preferably into the side of a freely-running saline or dextrose infusion or as intermittent 
infusion over 10-15 minutes into a free-flowing I.V. solution of NS or D5W. 
 
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9.3.8. Risks 
Idarubicin is a potent bone marrow suppressant. Idarubicin should not be given to patients with 
pre-existing bone marrow suppression induced by previous drug therapy or radiotherapy unless 
the benefit warrants the risk. 
Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for 
induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due 
to infection and/or bleeding have been reported during the period of severe myelosuppression. 
Facilities with laboratory and supportive resources adequate to monitor drug tolerability and 
protect and maintain a patient compromised by drug toxicity should be available. It must be 
possible to treat rapidly and completely a severe hemorrhagic condition and/or a severe infection. 
Pre-existing heart disease and previous therapy with anthracyclines at high cumulative doses or 
other potentially cardiotoxic agents are co-factors for increased risk of Idarubicin-induced cardiac 
toxicity and the benefit to risk ratio of Idarubicin therapy in such patients should be weighed before 
starting treatment with Idarubicin. 
Myocardial toxicity as manifested by potentially fatal congestive heart failure, acute life- 
threatening arrhythmias or other cardiomyopathies may occur following therapy with Idarubicin. 
Appropriate therapeutic measures for the management of congestive heart failure and/or 
arrhythmias are indicated. 
Cardiac function should be carefully monitored during treatment in order to minimize the risk of 
cardiac toxicity of the type described for other anthracycline compounds. The risk of such 
myocardial toxicity may be higher following concomitant or previous radiation to the mediastinal-
pericardial area or in patients with anemia, bone marrow depression, infections, leukemic 
pericarditis and/or myocarditis. While there are no reliable means for predicting congestive heart 
failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the 
left ventricular ejection fraction (LVEF) from pretreatment baseline values. 
Since hepatic and/or renal function impairment can affect the disposition of Idarubicin, liver and 
kidney function should be evaluated with conventional clinical laboratory tests (using serum 
bilirubin and serum creatinine as indicators) prior to and during treatment. In a number of Phase 
III clinical trials, treatment was not given if bilirubin and/or creatinine serum levels exceeded 2 
mg%. However, in one Phase III trial, patients with bilirubin levels between 2.6 and 5 mg% 
received the anthracycline with a 50% reduction in dose. Dose reduction of Idarubicin should be 
considered if the bilirubin and/or creatinine levels are above the normal range.  
See section 9.3.9 Warnings and Precautions.  
 
9.3.9. Warnings and Precautions 
Idarubicin for the use in induction therapy in AML should be administered in a facility with 
laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain 
a patient compromised by drug toxicity. The main toxic effect of Idarubicin is bone marrow 
suppression with leukopenia, thrombocytopenia and anemia. Idarubicin can induce myocardial 
toxicity and pre-existing cardiac function should be evaluated. Less serious toxicity includes 
nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction. 
 
Myelosuppression: Severe myelosuppression is the major toxicity associated with Idarubicin 
therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the 
period of myelosuppression, patients are at risk of developing infection and bleeding which may 
be life-threatening or fatal. 
Gastrointestinal: Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported 
frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe 
enterocolitis with perforation is rare. The risk of perforation may be increased by instrumental 
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intervention. Perforation should be considered in patients who develop severe abdominal pain 
and appropriate steps for diagnosis and management should be taken. 
 
Dermatologic: Alopecia was reported frequently and dermatologic reactions including 
generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have 
occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. 
Local reactions including hives at the injection site have been reported. Recall of skin reaction 
due to prior radiotherapy has occurred with Idarubicin administration. 
 
Hepatic and Renal: Changes in hepatic and renal function tests have been observed. These 
changes were usually transient and occurred in the setting of sepsis and while patients were 
receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe 
changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, 
while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% 
of patients. 
 
Cardiac: Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias 
including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF 
have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency 
and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and 
aggressive intravenous fluid administration. The events were reported more frequently in patients 
over age 60 years and in those with pre-existing cardiac disease. 
 
10 Adverse Event Documentation and Reporting 
Toxicity and adverse events will be classified according to NCI’s Common Terminology Criteria for Adverse 
Events V 4.0 (CTCAE) and reported on the schedule below. 22 
Note: throughout this section the generic term “drug” refers to Omacetaxine. 
 
10.1. 
Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 Part 312.32 
(21CFR312.32(a)). 
Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event.  
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse Reaction: An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of the investigator its 
occurrence places the patient or subject at immediate risk of death. 
 
Serious Adverse Event or Serious Suspected Adverse Reaction: An adverse event or suspected adverse 
reaction is considered “serious” if, in the view of the investigator, it results in any of the following outcomes:  
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
• 
A congenital anomaly/birth defect.  
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
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If either the investigator or TEVA believes the event is life-threatening or serious, the event must be 
evaluated by the investigator for expedited reporting (21CRF 312.32(a)). 
 
The primary Investigator of the study will report all serious adverse events to the University Of Illinois IRB 
(the IRB of record), TEVA pharmaceuticals and, if serious and either likely, possibly, probably, or 
definitely related to study drug, to the FDA. The Investigator will communicate the occurrence of serious 
adverse events to both the IRB and Teva within 24 hours of becoming aware of the event. The information 
will be reported to TEVA via us.clinops.sae@tevapharm.com or via fax at 215-619-3825. Reporting of 
Adverse Events to Teva does not preclude the responsibility of the Investigator to report adverse events 
to the FDA. The reporting period begins when the subjects starts study drug, and ends after the 
discontinuation of dosing or completion of the subject’s participation in the study if the last scheduled visit 
occurs at a later time.  The investigator must notify Teva of any serious adverse events of which he 
becomes aware that may occur after this time which he believes to be definitely, likely or possibly related 
to the study product.  
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended. Thus, adverse events that occur as part of the 
disease process or underlying medical conditions are considered unexpected; however, they will not be 
reportable per section 11.3. 
 
Unanticipated (unexpected) problems/events as defined by the University Of Illinois IRB (the IRB of 
record) are those that are not already described as potential risks in the consent form, not listed in the 
Investigator’s Brochure or not part of an underlying disease. 
Note:  The major discord between the FDA and IRB definitions is whether or not the underlying disease 
is included when considering expectedness. 
 
UPIRSO: Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure 
that researchers promptly report “any unanticipated problems involving risk to subjects or others” 
(UPIRSOs). The University of Illinois IRB defines a UPIRSO as any problem or event which in the opinion 
of the local researcher was unanticipated, reflects new or increased risk to the subjects and at least 
possibly related to the research procedures.  
In addition, the IRB has defined the following problems/events as reportable using the Prompt Report 
form found on the IRB website: 
• 
Any accidental or unintentional change to the IRB-approved protocol that increases risk or has the 
potential to recur  
• 
Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject  
• 
Any publication in the literature, safety monitoring report (including Data and Safety Monitoring 
Reports), interim result or other finding that indicates an unexpected change to the risk/benefit ratio 
of the research  
• 
Any breach in confidentiality that may involve risk to the subject or others  
• 
Any complaint of a subject that cannot be resolved by the research staff 
• 
Any other possibly related event which in the opinion of the investigator constitutes an unanticipated 
risk  
 
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Expedited (Rapid) Reporting: Certain events may require rapid notification to entities providing patient 
safety oversight (e.g. IRB) as detailed in section 11.3. For the IRB this is 5 working days. 
 
10.2. 
Adverse Event Documentation 
Adverse events occurring from the first dose of Omacetaxine up to and including 30 days after 
administration of the last dose must be documented. Adverse events attributed to a study-related 
procedure which occur prior to the initiation of study treatment must be documented as well.  
For the purposes of this study, all adverse events will be documented with the grade, expectedness 
and relationship to study therapy determined by the principal investigator. 
All patients will be monitored with appropriate event documentation in the CTO data management 
system through the final study visit per Section 7, as it is expected that most treatment related adverse 
events will occur during this period.   
Adverse Event toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.   
The investigator must appraise all abnormal laboratory results for their clinical significance. If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details about 
the action taken with respect to the test drug and about the patient’s outcome. 
Assessment of Attribution  
When assessing whether an adverse event is related to a medical treatment or procedure, the following 
attribution categories are utilized:  
Definitely: A causal relationship that can only be the result of the investigational medicinal product and 
there is no other plausible cause of the AE.  
Probable: A causal relationship is clinically / biologically highly plausible and there is a plausible time 
sequence between onset of the AE and administration of the investigational medicinal product and 
there is a reasonable response on withdrawal.  
Possible: A causal relationship is clinically / biologically plausible and there is a plausible time 
sequence between onset of the AE and administration of the investigational medicinal product.  
Unlikely: A causal relation is improbable and another documented cause of the AE is most plausible.  
Unrelated: A causal relationship can be definitely excluded and another documented cause of the AE 
is most plausible. 
 
When an investigational agent(s) is used in combination with a commercial agent(s), the combination is 
considered investigational. Reporting of adverse events follows the guidelines for investigational 
agents.  
 
10.3. 
Required Reporting: IRB, FDA, TEVA, and Cancer Center’s Regulatory Coordinator 
 
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Agency 
Criteria 
for 
reporting 
Timeframe 
Form to Use 
Submission 
address/ 
fax 
numbers 
Copy AE to: 
University of 
Illinois IRB 
UPIRSO:  Events 
which are 
Unanticipated 
Problems, 
Involving Risk to 
Subjects or Others 
(e.g. serious and 
unexpected 
adverse events) 
5 Working 
Days 
UIC IRB Prompt 
Report Form 
University of Illinois IRB 
 
UICC’s CTO 
Regulatory 
Coordinator 
 
Other Problems 
or Events meeting 
the definition of 
UPIRSO in section 
11.1 
5-15 
Working 
Days per 
IRB 
requirements 
UIC IRB Prompt 
Report Form  
FDA 
 
Unexpected and 
fatal or life 
threatening 
suspected adverse 
reaction 
As soon as 
possible but 
no later than 
7 Calendar-
Day 
Medwatch Form 
FDA 3500A  for 
Mandatory 
Reporting* 
*Copy sponsor 
on this 
correspondence. 
Fax SAE to IND/IDE 
Regulatory Health Project 
Manager, Techiya (Thea) 
Toaff, R.N., B.S.N., Division of 
Oncology Products 1 at 1-301-
796-9845. E-mail: 
techiya.toaff@fda.hhs.gov 
 
– follow-up with written report 
submitted as an amendment 
to: 
 
MedWatch,  
5600 Fishers Lane, Rockville, 
MD  
20852-9787 
1) Serious and 
unexpected 
suspected adverse 
reaction or 
2) increased 
occurrence of 
serious suspected 
adverse reactions 
over that listed in 
the protocol or 
investigator 
brochure or 
3) findings from 
other sources 
(other studies, 
animal or in vitro 
testing) 
As soon as 
possible but 
no later than 
15 Calendar-
Day 
 
All other events 
per CRF 312.33 
At time of 
IND annual 
report 
Summary format 
Submit as part of the IND 
annual report 
Note:  Events due to the disease under treatment or an underlying medical condition will not require 
expedited reporting to the FDA for the purposes of this study 
TEVA 
Pharmaceuticals. 
All serious 
adverse events 
regardless of 
expectedness or 
relationship with 
any study drug per 
section 11.4 
Within 24 
hours of 
knowledge 
OnCore (Paper 
report can be 
generated from 
system) 
TEVA Pharmaceuticals SAE 
and Pregnancy Reporting 
Contact Information: 
TEVA Pharmaceuticals 
Pharmacovigilance 
 
Email to: 
us.clinops.sae@tevapharm.com 
 
Or Fax to: (215) 619-3825 
 
 
 
 
Pregnancy in a 
female patient or 
the partner of a 
male patient per 
section 11.5 
Pregnancy 
Reporting Form 
OnCore (Paper 
report generated 
from system)  
UICC’s 
CTO 
Regulatory 
Coordinator 
All serious events 
regardless of 
expectedness or 
attribution through 
180 days (+1 
week)  after the 
last dose of  study 
drug(s) 
Within 24 
hours of 
knowledge 
OnCore (Paper 
report generated 
from system) 
UICC’s CTO Regulatory 
Coordinator 
 
Not 
applicable 
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11 Study Data Collection and Monitoring 
11.1. 
Data Management 
This study will report clinical data using the CTO data management system utilizing study specific case 
report forms.  Key study personnel are trained on the use of case report forms and will comply with 
protocol specific instructions for data collection. 
  
Patient demographics, patient specific study treatment calendars, adverse events and other information 
required for IRB annual reporting will be maintained with the CTO data management system. 
 
11.2. 
Case Report Forms 
Participant data will be collected using protocol specific case report forms (CRFs). The CRFs will be 
approved by the study’s Principal Investigator and the study biostatistician prior to release for use.  The 
Study Coordinator or designee will be responsible for registering the patient into the CTO data 
management system at time of study entry, completing CRFs based on the patient specific calendar, and 
updating the patient record until patient death or end of required study participation. 
 
11.3. 
Data Safety and Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the University of Illinois Cancer 
Center's Data & Safety Monitoring Plan (DSMP). 
For the purposes of data and safety monitoring, this study is classified as moderate. Therefore the 
following requirements will be fulfilled: 
 
The PI will complete and submit a semi-annual Trial Progress Report to the Cancer Center Data and 
Safety Monitoring Committee (DSMC) with the understanding the Cancer Center Protocol Review 
Committee (CCPRC) may require more frequent reporting. 
 
The PI will comply with at least yearly monitoring of the project by the Cancer Center monitoring 
services. 
 
The PI will oversee the submission of all reportable adverse events per the definition of reportable in 
section 10.3 to the Cancer Center’s SAE Coordinator and the University of Illinois IRB.   
 
In addition, at the time of the continuing review with the University of Illinois IRB, a copy of the report with 
any attachments will be submitted to the Protocol Review Committee (PRC). 
 
11.4. 
Monitoring 
The investigator will permit study-related monitoring, audits, and inspections by the study’s Sponsor-
Investigator and/or any designees, the local IRB, government regulatory bodies, and University of Illinois 
compliance groups.   The investigator will make available all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data, etc.).  The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory inspections. 
 
11.5. 
Record Retention 
The investigator will retain study records including source data, copies of case report form, consent forms, 
HIPAA authorizations, and all study correspondence in a secured facility for at least 6 years after the 
study file is closed with the IRB. 
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients participating in the study 
with sufficient information to allow retrieval of the medical records for that patient.  
 
Please contact the CTO before destroying any study related records. 
 
12 Statistical Considerations 
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12.1. 
Analysis plan for primary objective 
The OD will be determined using the EffTox Design.32 EffTox is a Bayesian adaptive design that seeks 
to determine the optimal dose for further study in Phase II by considering a trade-off between efficacy 
and toxicity. EffTox uses the Bayesian paradigm and, therefore, all inference will be based on the 
posterior distributions of the parameters of interest. Efficacy is summarized by the probability of CR and 
toxicity is summarized by the probability of HT. Efficacy will be modeled using a Bayesian logistic 
regression model with linear and quadratic terms for dose, while toxicity will use a Bayesian logistic 
regression model with only a linear term for dose. The two logistic regression models will be linked using 
a copula model that accounts for correlation between efficacy and toxicity.32 Using the posterior 
distributions for the logistic regression parameters we are able to derive the posterior distribution for the 
probability of efficacy and toxicity at each dose. A dose is considered acceptable if there is a 0.2 posterior 
probability that the probability of efficacy is greater than 0.6 and 0.2 posterior probability that the 
probability of toxicity is less than 0.3.  
 
Acceptable doses are ranked using the Euclidean distance between the estimated probabilities of efficacy 
and toxicity and the point (1.0, 0.0), which represents the ideal combination of perfect efficacy with no 
toxicity. The dose with the minimum distance is considered the optimal dose. 
 
The EffTox design begins by treating a cohort of three patients at dose level 1. The efficacy and toxicity 
outcomes for these three patients are used to update the posterior distributions for the probability of 
efficacy and toxicity and identify the acceptable dose levels. The study terminates if no dose levels are 
acceptable. Otherwise, the acceptable doses are ranked using the Euclidean distance from (1.0, 0.0) and 
the next cohort is treated at the dose with the minimum distance under the restriction that we may only 
escalate or deescalate one dose level at a time (i.e. the second cohort can only escalate to dose level 2 
or de-escalate to dose level -1). The second cohort is treated at the dose with the minimum distance and 
the posterior distributions, and the list of acceptable doses and distances are then updated as before. 
This process continues until at least 20 subjects are enrolled in the study. The dose with the minimum 
distance at study completion is considered the optimal dose for further investigation. If none of the dose 
levels are acceptable at study completion, an optimal dose level will not be identified and the drug does 
not warrant further investigation. 
 
Summary of the Basic EffTox algorithm 
Step 1 
Treat the first cohort of three patients at dose level 1 
Step 2 
Observe the efficacy and toxicity outcomes and estimate the 
probability of toxicity and efficacy for each dose 
Step 3 
Identify the acceptable doses and calculate the desirability 
measure for all acceptable doses 
Step 4 
If no doses are found to be acceptable, the trial is terminated 
and no doses are selected for further evaluation 
Step 5 
Otherwise, treat the next cohort at the most desirable dose 
under the restriction that no untried dose may be skipped 
when escalating. Cohorts will include 3 patients. Return to 
step 2 until the maximum sample size is reached. 
Step 6 
When the trial reaches the maximum sample size and there is 
at least one acceptable dose, the dose with the maximum 
desirability will be considered the OD. 
 
12.2. 
Analysis plan for secondary objectives 
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(i) Activity. Clinical response will be measured using European LeukemiaNet criteria (see 
appendix I and II) and proportion of responders will be presented along with 95% confidence 
intervals. Proportion of patients with clinical response will be presented by each dose level along 
with 95% confidence intervals. We will use Chi-square/Fisher/s exact test to evaluate whether the 
proportions of clinical response vary among dose level. We will also consider using the logistic 
regression model to test for specific forms (e.g., a linear trend) of dose-response relationship. 
Such analysis can potentially provide more power to detect dose-response relationships and 
provide more information about the nature of dose-response relationships, as compared with the 
chi-square/Fisher’s Exact test. We will use SAS 9.3 (Cary, NC) to perform these analyses. Overall 
survival, relapse-free survival and event-free survival will be computed using Kaplan-Meier 
estimates. The means of the survival times and their 95% confidence intervals will also be 
computed using SAS 9.3 (Cary, NC). 
 
(ii) Adverse effects will be graded using the NCI’s Common Terminology Criteria for Adverse 
Events CTCAE v4. Hematologic toxicity is defined in section 7.2.3. Proportion of patients with 
each grade of adverse events will be presented by each dose level along with 95% confidence 
intervals. We will use Chi-square/Fisher/s exact test to evaluate whether the distribution over the 
grades of adverse events vary among dose level. We will also consider using the logistic and/or 
ordinal regression model to test for specific forms (e.g., a linear trend) of dose-AE relationship. 
Such analysis can potentially provide more power to detect dose-AE relation and provide more 
information about the nature of dose-AE relation, as compared with the chi-square/Fisher’s Exact 
test. We will use SAS 9.3 (Cary, NC) to perform these analyses.  
 
13 Stopping rules 
Criteria for Stopping 
Study will be stopped if >35% of patients develop Grade 3 or greater treatment-related clinical non-
hematological toxicity (excluding ≥ grade 3 infection, nausea, vomiting, diarrhea or alopecia without 
maximal medical intervention and/or prophylaxis) during the induction therapy or up to 4 weeks after 
Omacetaxine therapy.  Toxicity will be measured according to the CTCAE v4.123 
 
14 Conduct of the Study 
14.1. 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirement(s). Essential 
clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data 
collected. Master files will be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations.  
 
14.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki.  
The IRB will review all appropriate study documentation in order to safeguard the rights, safety and well-
being of the patients.  The study will only be conducted at sites where IRB approval has been obtained. 
The protocol, consent, written information given to the patients, safety updates, progress reports, and 
any revisions to these documents will be provided to the IRB by the Investigator. 
 
 
 
 
15 References 
 
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1. Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, 
Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, 
Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF. Cytosine arabinoside with 
daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 
Aug;60(2):454-62. 
2. Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, Park JH, Kim DY, Lee 
WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH. A randomized trial comparing standard 
versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011 
118(14):3832-41. 
3. Roboz GJ. Current treatment of acute myeloid leukemia. Curr Opin Oncol. 2012 Nov;24(6):711-9. 
4. Kantarjian, H. Acute myeloid leukemia--major progress over four decades and glimpses into the future. 
Am J Hematol. 2016 91(1):131-45. 
5. Büchner T, Schlenk RF, Schaich M, et al. Acute Myeloid Leukemia (AML): different treatment strategies 
versus a common standard arm--combined prospective analysis by the German AML Intergroup. J Clin 
Oncol. 2012 Oct 10;30(29):3604-10. 
6. Rowe JM, Kim HT, Cassileth PA, Lazarus HM, Litzow MR, Wiernik PH, Tallman MS.  Adult patients with 
acute myeloid leukemia who achieve complete remission after 1 or 2 cycles of induction have a similar 
prognosis: a report on 1980 patients registered to 6 studies conducted by the Eastern Cooperative 
Oncology Group. Cancer. 2010 Nov 1;116(21):5012-21. 
7. Zhou JY, Chen DL, Shen ZS, et al. Effect of homoharringtonine on proliferation and differentiation of 
human leukemic cells in vitro. Cancer Res.1990;50:2031-5. 
8. Wu L, Li X, Su J, He Q, Zhang X, Chang C, Pu Q. 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 Oct;137(10):1563-9. 
9. Kim TD, Frick M, le Coutre P. Omacetaxine mepesuccinate for the treatment of leukemia. Expert Opin 
Pharmacother. 2011 Oct;12(15):2381-92. 
10. Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm 
Des. 2011;17(1):59-64. 
11. Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, 
Nicolini FE, Kantarjian H; Omacetaxine 202 Study Group. Phase 2 study of subcutaneous Omacetaxine 
mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 
Sep 27;120 (13):2573-80.  
12. Gürel G, Blaha G, Moore PB, Steitz TA. U2504 determines the species specificity of the A-site cleft 
antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol 
Biol. 2009 May 29;389(1):146-56. 
13. Tang R, Faussat AM, Majdak P, et al. Semisynthetic homoharringtonine induces apoptosis via inhibition 
of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. 
Mol Cancer Ther 2006;5:723-31. 
14. Yinjun L, Jie J, Weilai X, Xiangming T. Homoharringtonine mediates myeloid cell apoptosis via up-
regulation of pro-apoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) 
polymerase (PARP). Am J Hematol. 2004;76:199-204. 
15. Lévy V, Zohar S, Bardin C, Vekhoff A, Chaoui D, Rio B, Legrand O, Sentenac S, Rousselot P, Raffoux 
E, Chast F, Chevret S, Marie JP. A phase I dose-finding and pharmacokinetic study of subcutaneous 
semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia. Br J 
Cancer. 2006 Aug 7;95(3):253-9. 
16. Jin J, Jiang DZ, Mai WY, Meng HT, Qian WB, Tong HY, Huang J, Mao LP, Tong Y, Wang L, Chen ZM, 
Xu WL. Homoharringtonine in combination with cytarabine and aclarubicin resulted in high complete 
remission rate after the first induction therapy in patients with de novo acute myeloid leukemia. Leukemia. 
2006 Aug;20(8):1361-7.  
17. Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu 
AML-02 Protocol, v 10.0 
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Addition of Omacetaxine to Standard-of-Care Therapy in Newly-Diagnosed AML patients 
 
 
 
XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen 
Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute 
myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013 
Jun;14(7):599-608. 
18. Quintás-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, Omacetaxine mepesuccinate, and 
chronic myeloid leukemia circa 2009. Cancer. 2009 Dec 1;115(23):5382-93. 
19. Revised recommendation of the internal working group for diagnosis, standardization of 
response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute 
myeloid leukemia. Journal of Clinical Oncology. 2003 21:4642-4649.  
20. Marcucci G, Morozek K, Ruppert AS, etal. Abnormal cytogenetics at date of morphologic 
complete remission predicts short overall and disease-free survival, and higher replase rate in 
adult acute myeloid leukemia: results from Cancer and leukemia group B study 8461. Journal 
of Clinical Oncology. 2004 22:2410-2418. 
21. Chen Y, Cortes J, Esrov Z, etal. Persistence of Cytogenetic abnormalities at complete 
remission after induction in patients with acute myeloid leukemia: prognostic significance and 
the potential role of allogeneic stem-cell transplantation. Journal of Clinical Oncology. 2011 
29:2507-2513.  
22. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia 
in adults: recommendations form an international expert panel, on behalf of the European 
LeukemiaNet. Blood. 2010 Jan 21:115(3):453-74. 
23. National Comprehensive Cancer Network. Acute Myeloid Leukemia v1.2016. AccessedApril 19th 2016. 
http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf 
24. Common Terminology Criteria for Adverse Events (CTCAE). v4.0. Accessed February 8, 2014. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
25. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, 
Hellström-Lindberg E, Tefferi A, Bloomfield CD.The 2008 revision of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 
2009 Jul 30;114(5):937-51. 
26. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. 1982 Am. J. Clin. Oncol. 5 (6): 649–55. 
27. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, 
Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith 
SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura 
R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task 
Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and 
Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and 
Management of Chronic Heart Failure in the Adult: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update 
the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration 
with the American College of Chest Physicians and the International Society for Heart and Lung 
Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20;112(12):e154-235.  
28. National Comprehensive Cancer Network. Antiemesis v1.2014. Accessed February 8, 2014. 
http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf 
29. Highlights of Prescribing Information for Omacetaxine Mepesuccinate. Accessed February 8, 2014. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203585lbl.pdf 
30. Drug 
Information 
for 
Cytarabine. 
Accessed 
February 
8, 
2014. 
http://medlibrary.org/lib/rx/meds/cytarabine-1/ 
31. Drug Information for Idarubicin. Accessed February 8, 2014. http://medlibrary.org/lib/rx/meds/idamycin-
pfs-1/ 
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32. Peter F. Thall and John D. Cook. Dose-Finding Based on Efficacy-Toxicity Trade-Offs. Biometrics 60, 
pp. 684-693, September 2004. 
33. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, 
Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, 
Tallman MS, Löwenberg B, Bloomfield CD. Diagnosis and management of acute myeloid leukemia in 
adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. 
Othus M, Kantarjian H, Petersdorf S, Ravandi F, Godwin J, Cortes J, Pierce S, Erba H, Faderl S, 
Appelbaum FR, Estey E. Declining rates of treatment-related mortality in patients with newly diagnosed 
AML given 'intense' induction regimens: a report from SWOG 
 
 
 
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Appendix I – Definitions of Response to Treatment in AML* 
Category 
Definition 
Complete remission (CR) 
 
Bone marrow blasts < 5%; absence of blasts with Auer rods; 
absence of extramedullary disease; absolute neutrophil count > 
1.0 x 109/L (1000/µL); platelet count > 100 x 109/L (100,000/µL); 
independent of red cell transfusions 
CR with incomplete recovery 
(CRi) 
 
All CR criteria except for residual neutropenia < 1.0 x 109/L 
(1000/µL) or thrombocytopenia < 100 x 109/L (100 000/µL) 
Morphologic leukemia-free 
state 
 
Bone marrow blasts < 5%; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery 
required 
Partial remission (PR) 
 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5% to 25%; and decrease of pretreatment bone 
marrow blast percentage by at least 50% 
Cytogenetic CR (CRc) 
 
Reversion to a normal karyotype at the time of morphologic CR 
(or CRi) in cases with an abnormal karyotype at the time of 
diagnosis; based on the evaluation of 20 metaphase cells from 
bone marrow 
Molecular CR (CRm) 
No standard definition; depends on molecular target 
Treatment Failure 
Resistant Disease 
Failure to achieve CR or CRi or failure to achieve CR, CRi, or 
PR; only includes patients surviving ≥ 7 days following 
completion of initial treatment, with evidence of persistent 
leukemia by blood and/or bone marrow examination 
Death in aplasia 
Deaths occurring ≥ 7 days following completion of initial 
treatment while cytopenic; with an aplastic or hypoplastic bone 
marrow obtained within 7 days of death, without evidence of 
persistent leukemia 
Death from indeterminate 
cause 
Deaths occurring before completion of therapy, or < 7 days 
following its completion; or deaths occurring ≥ 7 days following 
completion of initial therapy with no blasts in the blood, but no 
bone marrow examination available 
Relapse 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the 
blood; or development of extramedullary disease 
*Adapted from European LeukemiaNet 31 
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Appendix II - Definitions of Survival in AML* 
Overall Survival 
Defined for all patients of a trial; measured from the date of entry into 
a study to the date of death from any cause; patients not known to have 
died at last follow-up are censored on the date they were last known to 
be alive 
Relapse-free Survival 
Defined only for patients achieving CR or CRi; measured from the date 
of achievement of a remission until the date of relapse or death from 
any cause; patients not known to have relapsed or died at last follow-
up are censored on the date they were last examined 
Event-free Survival 
Defined for all patients of a trial; measured from the date of entry into 
a study to the date of induction treatment failure, or relapse from CR or 
CRi, or death from any cause; patients not known to have any of these 
events are censored on the date they were last examined 
*Adapted from European LeukemiaNet 33 
 
 
 
 
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Appendix III – ECOG Performance Status 
 
ECOG Score 
Performance Status 
0 
Asymptomatic 
1 
Symptomatic, fully ambulatory 
2 
Symptomatic, in bed < 50% of the day 
3 
Symptomatic, in bed > 50% of the day but not bedridden 
4 
Bedridden 
5 
Dead 
 
 
Adapted from ECOG Definitions 26 
 
 
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Appendix IV – New York Heart Association Classification 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations 
of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation 
of physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of 
moderately 
severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  
If any physical activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Adapted from the American Heart Association Guidelines 27 
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