Clinical trial NCT02078960
Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Phase Accelerated Phase CML Chronic Myeloid Leukemia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2014-10-09; Completion date: 2017-11-27
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To satisfy a postmarketing requirement, the sponsor has been requested to conduct a Phase 1/Phase 2 single-group clinical study to investigate the pharmacokinetics and preliminary safety and efficacy of omacetaxine following a fixed-dose administration to patients with CP or AP CML who have failed 2 or more tyrosine kinase inhibitor (TKI) therapies.

Detailed description:
Because the trial was not feasible due to the inability to accrue additional clinical study sites and enroll an adequate number of subjects, the FDA released the sponsor from the postmarketing requirement on 13 November 2017 and the study was stopped prematurely. Therefore, the study did not progress to the Phase 2 portion.

Arms: arm 1: The study will consist of up to a 7-day screening period, and treatment for up to 12 months, in Phase 1 and Phase 2 portions, depending on response and tolerability. Patients will also have an end-of-treatment follow-up visit approximately 28 days after the last dose of omacetaxine. Each patient will be monitored for progression and survival for at least 1 year after their last dose of omacetaxine, death, or lost to follow-up, whichever comes first, regardless of patients receiving other anticancer treatment.
Interventions: intervention 1: Omacetaxine mepesuccinate
Intervention descriptions: intervention 1: 3.5 mg omacetaxine mepesuccinate and 10 mg mannitol; The first dose of the day for cycle 1 will be administered at the investigational center. Subsequent doses (in prefilled syringes) may be administered on an outpatient basis after training takes place

Protocol documents:
Prot_001.pdf: 
Clinical Study Protocol with Amendment 01
An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, 
Safety, and Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed 
Dose in Patients with Chronic Phase or Accelerated Phase Chronic Myeloid 
Leukemia who have Failed 2 or More Tyrosine Kinase Inhibitor Therapies
Study C41443/2057
NCT02078960 
Protocol Amendment 01 Approval Date: 22 April 2015


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Clinical Study Protocol with Amendment 01
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Clinical Study Protocol with Amendment 01
An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, Safety, 
and Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed Dose in 
Patients with Chronic Phase or Accelerated Phase Chronic Myeloid Leukemia who have 
Failed 2 or More Tyrosine Kinase Inhibitor Therapies
Phase 1/Phase 2
Study C41443/2057
IND: 62,384
EudraCT number: 2013-005320-42
Protocol Amendment 01 Approval Date: 22 April 2015
Sponsor 
Monitor
Teva Branded Pharmaceutical Products R&D, Inc.
PPD
41 Moores Road
929 North Front Street
Frazer, Pennsylvania 19355
USA
Wilmington, North Carolina 28401-
3331 USA
Authorized Representative (Signatory)
, 
Teva Pharmaceuticals
Sponsor’s Medical Expert
Sponsor’s Safety Representative
Teva Pharmaceuticals
Teva Pharmaceuticals
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Conference on Harmonization (ICH); United States (US) Code of 
Federal Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the 
study); local country regulations; and the sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc., and its affiliate, Cephalon, Inc. (collectively the “Sponsor”). The 
recipient agrees that no information contained herein may be published or disclosed without written 
approval from the Sponsor.
© 2015 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for study C41443/2057 (original protocol dated 4 December 2013) has been 
amended and reissued as follows:
Administrative Letter
10 June 2014
No patients enrolled at time of administrative letter.
Amendment 01
22 April 2015
5 patients enrolled to date.


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INVESTIGATOR AGREEMENT


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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Data Management
Pharmaceutical Product Development, LLC (PPD)
7551 Metro Center Drive
Suite 300
Austin, Texas 78744
USA
Central Laboratory for Pharmacokinetic Collection
Information will be provided in the Project Plan.
Interactive Response Technology System
Information will be provided in the Project Plan.
External Data Monitoring Committee
The Data Monitoring Committee (DMC) charter will be included in the Trial Master File when 
available.


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
PPD
For protocol and clinical questions, contact:
Teva Pharmaceuticals
For study operational issues, contact the operational lead listed below: 
 
Teva Pharmaceuticals
 
For serious adverse events:
Send by facsimile/email to the sponsor’s Local Safety Officer/CRO. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel identified above for further 
instruction.


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CLINICAL STUDY PROTOCOL SYNOPSIS
Title of Study: An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed Dose in Patients with Chronic Phase or 
Accelerated Phase Chronic Myeloid Leukemia who have Failed 2 or More Tyrosine Kinase Inhibitor Therapies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Study Number: C41443/2057
Investigational Product: Omacetaxine mepesuccinate (C41443), SYNRIBO®
Phase of Clinical Development: 1/2
Number of Investigational Centers Planned: approximately 40
Countries Planned: Countries in North America and European Union
Number of Patients Planned: Approximately 21 patients are planned for Phase 1. For Phase 2, approximately 
45 patient with chronic phase (CP) chronic myeloid leukemia (CML) and 67 patients with accelerated phase (AP) 
CML are planned to be enrolled.
Study Population: Patients with CP CML or AP CML who have failed 2 or more tyrosine kinase inhibitor (TKI) 
therapies. 
Planned Study Period: Enrollment will start in second quarter 2014 and is expected to be completed in 2016. 
Patients may undergo up to 1 year of treatment and an additional year of monitoring for survival.
Primary Objectives: The primary objectives of this study are as follows:

to evaluate the efficacy of omacetaxine when administered subcutaneously as a fixed dose in patients 
with CP CML or AP CML

to evaluate the safety of omacetaxine when administered subcutaneously as a fixed dose in patients 
with CP CML or AP CML

to characterize the pharmacokinetic profile of omacetaxine in cycle 1 when administered 
subcutaneously as a fixed dose 
Secondary Objectives: The secondary objectives of the study are as follows:

to determine the duration of responses

to determine progression-free and overall survival

to determine molecular response

to determine additional pharmacokinetic parameters after cycle 1

to determine additional parameters, such as BCR-ABL transcript
Criteria for Inclusion: Patients may be included in the study only if they meet all of the following criteria:
a.
The patient has a confirmed diagnosis of Philadelphia chromosome (Ph) positive chronic myelogenous 
leukemia in either CP or AP. Accelerated phase will be defined as disease having 1 of the following:
≥15% to <30% blasts in peripheral blood or bone marrow; ≥30% blasts + promyelocytes in peripheral 
blood or bone marrow; ≥20% basophils in peripheral blood or bone marrow; platelet count <100x109/L 
unrelated to therapy; or clonal evolution.
b.
The patient has either failed, demonstrated intolerance, or a combination of prior failure and 
intolerance, to prior treatments with at least 2 tyrosine kinase inhibitors (TKI's). Failure of TKI 
treatment may either be primary (never achieved a response) or secondary resistance (loss of response).

TKI treatment failure will be defined as 1 of the following:
                                                
SYNRIBO is a registered trademark of Ivax International GmbH, Switzerland.


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
no CHR by 12 weeks (whether lost or never achieved)

no partial cytogenetic response by 24 weeks (ie, 1 to 35% Ph-positive) (whether lost or never 
achieved)

no major cytogenetic response by 52 weeks (ie, ≤35% Ph-positive) (whether lost or never 
achieved)

progressive leukocytosis, defined as increasing white blood cell (WBC) count on at least 
2 consecutive evaluations, at least 2 weeks apart and doubling from the nadir to ≥20000/µL or 
absolute increase in WBC by ≥50000/µL above the post-treatment nadir

Intolerance to TKI therapy will be defined as 1 of the following:

grade 3 to 4 nonhematologic toxicity that does not resolve with adequate intervention

grade 4 hematologic toxicity lasting more than 7 days, or a documented inability to sustain the 
TKI therapy because of recurrent grade 3 or 4 hematologic toxicity with re-initiation of the 
same therapy

any grade 2 or greater toxicity that is unacceptable to the patient

Patients with a known T315I mutation must have been treated and failed ponatinib (prior to the 
entry into this study; this would not apply in a country where ponatinib has not been approved or 
where patients otherwise would not have access to this medication) unless medically
contraindicated by the treating study doctor
c.
Patients must have completed all previous anticancer therapy for at least 2 weeks prior to the first 
planned dose of omacetaxine, except as noted below, and must have fully recovered from side effects 
of a previous therapy. 

In patients with rapidly proliferating disease, hydroxyurea may be administered before study entry, 
if clinically indicated, to control disease. In such cases, CHR must be sustained for at least 
4 weeks for accelerated CML, and at least 8 weeks for chronic phase CML, following the 
discontinuation of hydroxyurea, to be considered as a CHR. 

Patients may receive anagrelide for up to 28 days (in countries where the product is registered). 
Leukapheresis is allowed up to 24 hours prior to the first treatment cycle with omacetaxine.
d.
Patients must have adequate hepatic and renal function as evidenced by bilirubin 2.0 times the upper 
limit of the normal range (ULN) or lower, alanine aminotransferase (ALT) and asparate 
aminotransferase (AST) 3 times the ULN or lower, serum creatinine 1.5 times the ULN or lower. 
Patients with nonclinically significant elevations of bilirubin up to 5.0 g/dL (85500 µmol/L) due to 
known or suspected Gilbert’s disease are eligible; this must be documented on the medical history 
page of the case report form (CRF).
e.
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
f.
Patients are men or women at least 18 years of age.
g.
Patients must be able and willing to provide written informed consent prior to any study related 
procedure. (In the event that the patient is re-screened for study participation or if a protocol 
amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
h.
Patients must be able to comply with the requirements of the entire study. 
i.
The patient must take precautions to not become pregnant or produce offspring. Women must be of 
non-childbearing potential (surgically sterile or postmenopausal for at least 12 months, confirmed by 
follicle-stimulating hormone [FSH] >40 IU/L) or agree to use a medically accepted method of 
contraception for the duration of the study and 90 days after treatment. Men must be surgically sterile 


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or agree to use a medically accepted method of contraception for the duration of the study and 90 days 
after treatment. Acceptable methods of contraception include abstinence, barrier method with 
spermicide (excluding cervical cap and sponge), intrauterine device (IUD), or steroidal contraceptive 
(oral, transdermal, implanted, and injected) in conjunction with a barrier method. 
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet any of the following 
criteria:
a.
The patient has New York Heart Association (NYHA) class III or IV heart disease, active ischemia, or 
any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac 
arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.
b.
The patient has had a myocardial infarction in the previous 12 weeks. (Prior to study entry, any other 
electrocardiogram [ECG] abnormalities noted at screening other than myocardial infarction within the 
previous 12 weeks and felt by the investigator not to be medically relevant, must be documented as 
such.)
c.
The patient has received radiotherapy within 30 days prior to the start of study drug, or has not 
recovered from the acute toxicities associated with prior approved therapies including investigational 
drugs.
d.
The patient has another concurrent illness that would preclude study conduct and assessment, 
including, but not limited to, another active malignancy (excluding squamous or basal cell skin cancer 
and in situ cervical cancer), uncontrolled medical conditions, uncontrolled and active infection 
(considered opportunistic, life threatening, or clinically significant), uncontrolled risk of bleeding, or 
uncontrolled diabetes mellitus. 
e.
The patient underwent autologous or allogeneic stem cell transplant within 60 days prior to receiving 
the first dose of omacetaxine and has any evidence of ongoing graft versus host disease (GVHD), or 
GVHD requiring immunosuppressive therapy.
f.
The patient has a human leukocyte antigen (HLA)-matched donor and is eligible for allogeneic
transplantation for CML treatment.
g.
The patient has known positive human immunodeficiency virus (HIV) or known active human t-cell 
lymphotropic virus (HTLV) I/II disease, whether on treatment or not. 
h.
The patient has known active hepatitis B or C. The determination of active hepatitis B or C is left to 
the investigator.
i.
The patient is pregnant or lactating (any women becoming pregnant during the study will be 
withdrawn from the study).
j.
The patient has any medical or psychiatric condition, which may compromise the ability to give 
written informed consent or to comply with the study protocol. 
k.
The patient has lymphoid Ph+ blast crisis or blast phase CML. 


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l.
The patient participated in another clinical investigation within 30 days of enrollment or is receiving 
another investigational agent.
m. The patient received omacetaxine or has a history of hypersensitivity.
n.
The patient has a known hypersensitivity to mannitol.
o.
The patient has a hemoglobin value, which, in the opinion of the investigator, is not adequate given the 
pharmacokinetic blood draw requirements of the Phase 1 portion of the study.
p.
The patient has undergone major surgery within 14 days prior to starting omacetaxine, or has not 
recovered from side effects of such procedure.
Study Drug Dose, Mode of Administration, and Administration Rate:
The investigational drug for this study is omacetaxine mepesuccinate. Omacetaxine drug product is a lyophilized 
vial containing 3.5 mg omacetaxine and 10 mg mannitol in a 10-mL clear glass vial, sealed with rubber stopper and 
aluminum flip-off seal. Investigational centers will be given vials of 3.5 mg omacetaxine. Omacetaxine will be 
reconstituted by a healthcare professional. Omacetaxine will be administered by subcutaneous injection at a fixed 
dose of 2.5 mg twice daily for 7 or 14 consecutive days every 28 days, over a 28-day cycle. The first dose of the day 
for cycle 1 will be administered at the investigational center. Subsequent doses (in prefilled syringes) may be 
administered on an outpatient basis after training takes place, unless the patient must come back to obtain more drug 
or perform test procedures, including pharmacokinetics.
Method of Blinding: This is an open-label study with no blinding. 
Duration of Patient Participation: The study will consist of up to a 7-day screening period, and treatment for up to 
12 months depending on response and tolerability. Patients will also have an end-of-treatment follow-up visit 
approximately 28 days (+2 days) after the last dose of omacetaxine. Patients will be monitored for progression and
survival for at least 1 year after the last dose of omacetaxine, death, or lost to follow-up, whichever comes first, 
regardless of patients receiving other anticancer treatment.
General Design and Methodology: This is a Phase 1/Phase 2, open-label, multicenter, single-group clinical study 
in patients with CP or AP CML who have failed 2 or more TKI therapies to investigate the pharmacokinetic, safety, 
and efficacy of omacetaxine given subcutaneously as a fixed dose twice daily. 
In the Phase 1 portion, there will be 3 cohorts of approximately 7 patients each; patients may have either CP or 
AP CML. All patients will be given a fixed dose of 2.5 mg omacetaxine subcutaneous injection twice daily. Every 
effort will be made to include an equal number of patients in each body surface area (BSA) cohort. Cohort 1 will 
include patients whose BSA is less than 1.7 m2. Cohort 2 will include patients with a BSA between 1.7 m2 to 2.0 m2
inclusive. Cohort 3 will include patients with BSA greater than 2.0 m2. Based on data from previous clinical 
research studies, the range of BSA for patients enrolled in those studies was 1.39 to 2.46 m2 for CP patients, and 
1.34 to 2.31 m2 for AP patients. Because it is known that women usually have a smaller BSA than men, all efforts 
must be made to include at least 2 men in cohort 1 to reduce possible gender bias. After cycle 1, patients will 
continue to receive omacetaxine for 12 months until intolerance or disease progression while safety and efficacy 
parameters are followed.
In the Phase 2 portion, following the analysis of pharmacokinetic and preliminary safety and efficacy data from the 
patients in Phase 1, a decision whether or not to continue to Phase 2 will be made. If the Phase 1 data indicate that a 
fixed-dose regimen is not appropriate for subcutaneously administered omacetaxine, enrollment into the Phase 2 
portion will be stopped and the study will be terminated. It is anticipated that the analysis of pharmacokinetic and 
preliminary safety and efficacy data from the patients in Phase 1 will take approximately 2 months. Assuming a 
fixed-dose regimen is considered appropriate on the basis of the Phase 1 data, a total of up to 45 patients with CP 
CML and a total of up to 67 patients with AP CML will be enrolled in Phase 2.
In both phases, omacetaxine will be administered by subcutaneous injection twice daily. For cycle 1, the first dose 
will be administered at the investigational center. Subsequent doses (in prefilled syringes) may be administered on 
an outpatient basis after training takes place. Patients will be evaluated every 7 days with complete blood and 
platelet counts up to and including cycle 5 and every 2 weeks (±2 days) after cycle 5; the number of consecutive 


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doses of omacetaxine or intervals between subsequent cycles may be adjusted, as clinically indicated. Every 
3 months (ie, every 3 cycles), bone marrow aspiration and cytogenetics, BCR-ABL transcript measurements, 
quantitative BCR-ABL kinase domain analysis of peripheral blood, and ECGs will be performed. Note: After a 
patient achieves a confirmed complete cytogenetic response, RT-PCR BCR-ABL testing should be performed every 
6 months unless clinically indicated to do it more often. Patients not demonstrating evidence of clinical response 
after 6 cycles will be considered for removal from the study; however, with permission of the sponsor’s medical 
monitor, treatment may continue, if clinically indicated, provided there is no evidence of toxicity grade 3 or above. 
In patients achieving a CHR or major cytogenetic response (MCyR) (either complete cytogenic response [CCyR] or 
partial cytogenetic response [PCyR]), the response will be confirmed by a repeat complete blood count (CBC), bone 
marrow aspiration (for patients with a hematologic response), cytogenetics of the bone marrow aspirate (for patients 
with a cytogenetic response), and BCR-ABL transcript levels by quantitative reverse transcription-polymerase chain 
reaction (RT-PCR) of peripheral blood. Confirmations are to be performed at least 8 weeks after the initial 
documentation of response for patients with CP CML and at least 4 weeks after the initial documentation of 
response for patients with AP CML. If the CBC, bone marrow aspiration, and/or cytogenetic results do not confirm 
the clinical response and the patient is already on maintenance treatment cycles, the patient may continue on 
maintenance therapy or may revert back to induction cycles (ie, 14 days of omacetaxine treatment) or the highest 
number of days tolerated previously, if clinically indicated. Patients who demonstrate CHR, hematologic 
improvement (HI), or any cytogenetic response, may convert from induction to maintenance therapy.
Primary Efficacy Variables and Endpoints: The primary efficacy variable for patients with CP CML is the 
proportion of patients who achieve a MCyR (CCyR with no Ph+ metaphases and PCyR with 1 to 35% Ph+ 
metaphases). The primary efficacy variable for patients with AP CML is the proportion of patients who achieve a 
major hematologic response (MaHR: complete hematologic response or no evidence of leukemia) and/or MCyR.
Secondary Efficacy Variables and Endpoints:
The secondary efficacy variables and endpoints for this study are as follows: 

duration of response, defined for responders as the time interval from the first reported date of MCyR 
or MaHR, as defined above, to the earliest date of objective evidence of disease progression 
(ie, development of accelerated-phase CML), relapse (ie, loss of complete hematologic or major 
cytogenetic response), or death

molecular response by site (peripheral transcript of BCR-ABL)

progression-free survival, defined as the time interval from date of first dose to earliest date of 
objective evidence of disease progression (ie, development of AP CML), relapse (ie, loss of complete 
hematologic or major cytogenetic response), or death

overall survival, defined as the time interval from date of first dose to date of death from any cause
Safety Variables and Endpoints: The safety and tolerability of omacetaxine treatment will be assessed throughout 
the study by evaluating the following safety variables:

adverse events (type, frequency, severity, and causality)

clinical laboratory test results (serum chemistry and hematology) at various points in the study

exploratory predictors of toxicity such as myelosuppression to assist with safety signals 

vital signs measurements (blood pressure, heart rate, respiratory rate, body temperature)

physical examination (including weight)

12-lead ECG

concomitant medication usage
Pharmacokinetics: The following pharmacokinetic parameters for omacetaxine and its metabolites will be 
calculated for each patient, when possible, from plasma concentrations obtained following the first dose of 
omacetaxine in Phase 1: 

maximum observed plasma drug concentration (Cmax) by inspection (without interpolation)

time to Cmax, by inspection (tmax)

area under the drug concentration by time curve (AUC) from time 0 to infinity (AUC0–∞)

AUC from time 0 to the time of the last measurable drug concentration (AUC0–t)

AUC from time 0 to 12 hours (AUC0–12)


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
apparent plasma terminal elimination rate constant (λz) and associated terminal elimination half-life 
(t½)

percentage extrapolation calculated as (AUC0-∞-AUC0-t)/(AUC0-∞)x100

apparent plasma clearance (CL/F)

apparent volume of distribution (Vz/F)

predicted accumulation ratio (Rpred) calculated as AUC0–∞/AUC0–12
In Phase 1, to accommodate the pharmacokinetic objective of the study, during cycle 1, omacetaxine will be 
administered by subcutaneous injection as follows: 1 dose will be administered in the morning of day 1, no doses 
will be administered on days 2 or 3, 2 doses will be administered on days 4 through 17. Blood samples (2.5 mL) will 
be obtained during Phase 1 as follows:

20 minutes prior to and 15 (±5 min), 30 (±5 min), and 45 (±5 min) minutes and 1 (±5 min), 
2 (±10 min), 4 (±10 min), 8 to 12 (±15 min), 24 (±1 hr), 48 (±1 hr), and 72 (±1 hr) hours (predose 1 on 
day 4) after administration of the first dose of omacetaxine 

on day 10 or 11 or 12, predose within (<) 1 hour after dose 1, and 1 to 12 hours after dose 1

1 sample on day 13, 14, 15, 16, or 17 either predose 1 or predose 2
In addition, blood samples (2.5 mL) will be obtained in Phase 1 on day 1 of cycles 2 and 3 and in Phase 2 on day 1 
of cycles 1, 2, and 3 as follows:

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
Statistical Considerations: The sample size for Phase 1 is approximately 21 patients in order to meet the 
pharmacokinetic objectives of the study. These 21 patients will also be counted in the sample size for Phase 2 and be 
part of any Phase 2 analyses. Phase 2 sample sizes are based on Simon’s 2-stage optimum design. To reject the null 
hypothesis of MCyR rate 2.5% or lower in patients with CP CML at a target 1-sided alpha of 0.025 and beta of 0.10
(power of 90%) and assuming that the MCyR rate in the current study will be at least 16%, in the first stage 
16 patients with CP CML will be treated. If 1 or more patients respond, then the study will enroll another 29 patients 
with CP CML for a total of 45 patients. If 4 or more of the 45 patients achieve a MCyR, the fixed-dose regimen will 
be deemed effective in patients with CP CML. If the true rate is less than or equal to 2.5%, the probability of 
stopping after stage 1 is 0.667. The alternative hypothesis rate is set at 16% because an 18.4% response rate was 
observed in the registration studies (Studies CGX-635-CML-202 and CGX-635-CML-203) in which patients 
received older generations of TKI drugs, and in the current study patients will be more likely to have received a 
newer generation of TKI drugs and more lines of therapy and may be less likely to respond to omacetaxine. To 
reject the null hypothesis of MCyR rate 2.5% or lower in patients with AP CML at a target 1-sided alpha of 0.025 
and beta of 0.10 (power of 90%), and assuming that the MaHR rate in the current study will be at least 12%, in the 
first stage 40 patients with AP CML will be treated. If 2 or more patients achieve a MaHR, then the study will enroll 
another 27 patients with AP CML for a total of 67 patients. If 5 or more of the 67 patients respond, then the drug 
will be deemed to be effective in patients with AP CML. If the true rate is 2.5% or lower, the probability of stopping 
after stage 1 is 0.736. The alternative hypothesis rate is set at 12%, lower than the observed rate of 14.3 in the above 
mentioned registration studies for the same reason. Response rates by disease phase (CP CML and AP CML) and 
their 2-sided exact 95% confidence intervals (CIs) will be calculated. The lower limit of the CI will be compared 
with a prior value of 2.5%. If the lower limit exceeds 2.5%, the observed response rate will have exceeded the 
minimum threshold required to demonstrate efficacy. When sample size permits, these variables will also be 
compared within a disease phase by age, sex, disease history, and treatment history using a logistic regression 
model.


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TABLE OF CONTENTS
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................5
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................19
1.
BACKGROUND INFORMATION...........................................................................22
1.1.
Introduction.................................................................................................................22
1.1.1.
Chronic Myeloid Leukemia........................................................................................22
1.1.2.
Resistance to Tyrosine Kinase Inhibitors ...................................................................23
1.1.3.
Rationale for the Study...............................................................................................24
1.2.
Name and Description of Investigational Product......................................................25
1.3.
Findings from Nonclinical and Clinical Studies.........................................................25
1.3.1.
Nonclinical Studies: Carcinogenesis and Genotoxicity..............................................25
1.3.2.
Clinical Studies of Subcutaneous Omacetaxine in CML ...........................................26
1.3.2.1.
Phase 1/Phase 2 Dose Response Study of Subcutaneous Omacetaxine 
(Study T99-0044)........................................................................................................26
1.3.2.2.
Phase 2 Studies of Omacetaxine in Patients with CP CML and AP CML 
Following Failure of Tyrosine Kinase Inhibitor (TKI) Therapy ................................27
1.3.3.
Clinical Safety and Tolerability..................................................................................28
1.3.3.1.
Chronic Phase CML ...................................................................................................28
1.3.3.2.
Accelerated Phase CML .............................................................................................28
1.3.4.
Clinical Pharmacology................................................................................................29
1.3.5.
Justification for Study Treatment Plan .......................................................................30
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................30
1.5.
Selection of Drugs and Dosages.................................................................................31
1.6.
Compliance Statement................................................................................................31
1.7.
Population To Be Studied...........................................................................................32
1.8.
Relevant Literature and Data......................................................................................32
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................33
2.1.
Purpose of the Study...................................................................................................33
2.2.
Study Objectives.........................................................................................................33


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3.
STUDY DESIGN .......................................................................................................34
3.1.
General Design and Study Schema.............................................................................34
3.2.
Primary and Secondary Measures and Endpoints ......................................................36
3.2.1.
Primary Efficacy Measures and Endpoints.................................................................36
3.2.2.
Secondary Efficacy Measures and Endpoints.............................................................36
3.2.3.
Safety Measures and Endpoints..................................................................................37
3.2.4.
Pharmacokinetic Measures and Endpoints.................................................................37
3.3.
Randomization and Blinding......................................................................................37
3.4.
Study Drugs and Dosage ............................................................................................37
3.4.1.
Investigational Product and Dosage ...........................................................................37
3.4.2.
Other Study Drugs and Dosage ..................................................................................38
3.5.
Duration of Patient Participation ................................................................................38
3.6.
Stopping Rules and Discontinuation Criteria .............................................................38
3.7.
Study Drug Supply and Accountability......................................................................39
3.7.1.
Study Drug Storage and Security ...............................................................................39
3.7.2.
Study Drug Accountability.........................................................................................39
3.8.
Maintenance of Randomization and Blinding............................................................41
3.9.
Source Data Recorded on the Case Report Form.......................................................41
3.10.
Time Schedule ............................................................................................................42
3.11.
Study Procedures ........................................................................................................42
3.11.1.
Procedures for Screening and Enrollment..................................................................47
3.11.2.
Procedures During Study Drug Treatment (Induction and Maintenance)..................48
3.11.2.1.
Procedures for Day 1 of Each Treatment Cycle .........................................................48
3.11.2.2.
Pharmacokinetic Procedures, Phase 1, Cycle 1 Only.................................................49
3.11.2.3.
Pharmacokinetic Procedures, Phase 1, Cycles 2 and 3 and Phase 2, Cycles 1 
Through 3....................................................................................................................50
3.11.2.4.
Procedures During Cycles 1 Through 5 of Treatment (Days 7 [±2], 14 [±2], 
21 [±2]).......................................................................................................................50
3.11.2.5.
Procedures After Cycle 5 of Treatment......................................................................51
3.11.2.6.
Procedures During Study Drug Treatment–Every 3 Months (ie, every 3 
cycles) on Study–All Patients.....................................................................................51
3.11.2.7.
Confirmation of Complete Hematologic Response or Major or Complete 
Cytogenetic Response (Induction or Maintenance)....................................................52
3.11.3.
Procedures After Study Drug Treatment ....................................................................52


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3.11.3.1.
End-of-Treatment Visit...............................................................................................52
3.11.3.2.
Follow-up....................................................................................................................53
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................55
4.1.
Patient Inclusion Criteria ............................................................................................55
4.2.
Patient Exclusion Criteria...........................................................................................56
4.3.
Withdrawal Criteria and Procedures...........................................................................58
5.
TREATMENT OF PATIENTS..................................................................................59
5.1.
Study Drugs Administered .........................................................................................59
5.1.1.
Training for the Patient or Caregiver..........................................................................60
5.1.2.
Dose Modifications for Toxicity ................................................................................61
5.1.2.1.
Hematologic Toxicity.................................................................................................61
5.1.2.2.
Nonhematologic Toxicity...........................................................................................61
5.2.
Restrictions .................................................................................................................61
5.3.
Prior and Concomitant Therapy or Medication..........................................................61
5.3.1.
Permitted Concomitant Medications ..........................................................................62
5.3.2.
Prohibited Medications...............................................................................................62
5.4.
Procedures for Monitoring Patient Compliance .........................................................63
5.5.
Total Blood Volume ...................................................................................................63
6.
ASSESSMENT OF EFFICACY ................................................................................65
6.1.
Primary Efficacy Variables.........................................................................................65
6.2.
Secondary Efficacy Variables.....................................................................................65
6.2.1.
Duration of Response .................................................................................................65
6.2.2.
Progression-Free Survival ..........................................................................................66
6.2.3.
Overall Survival..........................................................................................................66
6.2.4.
Molecular Response....................................................................................................66
7.
ASSESSMENT OF SAFETY.....................................................................................67
7.1.
Adverse Events ...........................................................................................................67
7.1.1.
Definition of an Adverse Event..................................................................................67
7.1.2.
Recording and Reporting Adverse Events..................................................................69
7.1.3.
Severity of an Adverse Event .....................................................................................69
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................70
7.1.5.
Serious Adverse Events..............................................................................................71
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................71


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7.1.5.2.
Expectedness...............................................................................................................72
7.1.5.3.
Reporting a Serious Adverse Event............................................................................72
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting ......................................74
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................74
7.1.8.
Medical Emergencies..................................................................................................75
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................75
7.2.
Pregnancy ...................................................................................................................75
7.3.
Clinical Laboratory Tests ...........................................................................................76
7.3.1.
Serum Chemistry ........................................................................................................76
7.3.2.
Hematology.................................................................................................................77
7.3.3.
Urinalysis....................................................................................................................77
7.3.4.
Other Clinical Laboratory Tests .................................................................................78
7.4.
Vital Signs ..................................................................................................................78
7.5.
Electrocardiography....................................................................................................79
7.6.
Physical Examinations................................................................................................79
7.7.
Concomitant Therapy or Medication..........................................................................79
7.8.
Eastern Cooperative Oncology Group Performance Status........................................79
7.9.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............79
8.
ASSESSMENT OF PHARMACOKINETICS...........................................................81
8.1.
Pharmacokinetic Variables.........................................................................................81
8.2.
Blood Sampling and Handling....................................................................................81
8.2.1.
Phase 1........................................................................................................................81
8.2.2.
Phase 2........................................................................................................................82
8.3.
Shipment of Samples..................................................................................................82
9.
STATISTICS ..............................................................................................................83
9.1.
Study Design...............................................................................................................83
9.2.
Sample Size and Power Considerations .....................................................................83
9.3.
Analysis Sets...............................................................................................................83
9.4.
Data Handling Conventions........................................................................................84
9.5.
Study Population.........................................................................................................84
9.5.1.
Patient Disposition......................................................................................................84
9.5.2.
Demographic and Baseline Characteristics ................................................................84
9.6.
Efficacy Analysis........................................................................................................84


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9.6.1.
Primary Variables .......................................................................................................84
9.6.2.
Secondary Variables ...................................................................................................85
9.6.3.
Planned Method of Analysis.......................................................................................85
9.7.
Multiple Comparisons and Multiplicity......................................................................86
9.8.
Safety Variables and Analysis....................................................................................86
9.9.
Pharmacokinetic Analysis ..........................................................................................87
9.10.
Planned Interim Analysis............................................................................................87
9.11.
Reporting Deviations from the Statistical Plan ..........................................................88
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................89
11.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................90
11.1.
Protocol Amendments and Protocol Deviations and Violations ................................90
11.1.1.
Protocol Amendments ................................................................................................90
11.1.2.
Protocol Deviations ....................................................................................................90
11.2.
Information to Study Personnel..................................................................................90
11.3.
Study Monitoring........................................................................................................91
11.4.
Audit and Inspection...................................................................................................91
12.
ETHICS ......................................................................................................................92
12.1.
Informed Consent .......................................................................................................92
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.........................................................................................................................92
12.3.
Confidentiality Regarding Study Patients ..................................................................92
12.4.
Declaration of the End of the Clinical Study..............................................................93
12.5.
Registration of the Clinical Study...............................................................................93
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................94
13.1.
Data Collection...........................................................................................................94
13.2.
Data Quality Control...................................................................................................94
13.3.
Archiving of Case Report Forms and Source Documents..........................................95
13.3.1.
Investigator Responsibilities.......................................................................................95
13.3.2.
Sponsor Responsibilities.............................................................................................95
14.
FINANCING AND INSURANCE.............................................................................96
15.
REPORTING AND PUBLICATION OF RESULTS................................................97
16.
REFERENCES ...........................................................................................................98


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17.
SUMMARY OF CHANGES TO PROTOCOL .........................................................99
17.1.
Amendment 01 Dated 22 April 2015..........................................................................99
17.2.
Administrative Letter Dated 10 June 2014...............................................................124
APPENDIX A.
RESPONSE EVALUATION CRITERIA.......................................................126
APPENDIX B.
MOLECULAR STUDIES...............................................................................129
APPENDIX C.
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS.....................................................................................130
APPENDIX D.
LABORATORY TESTS.................................................................................131


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LIST OF TABLES
Table 1:
Time to Administration After Reconstitution.............................................................39
Table 2:
Study Procedures and Assessments............................................................................43
Table 3:
Pharmacokinetic Sampling Schedule, Phase 1, Cycle 1 Induction, Days 1 
Through 17..................................................................................................................46
Table 4:
Pharmacokinetic Sampling Schedule, Phase 1 (Cycles 2 and 3) and Phase 2 
(Cycles 1, 2, and 3).....................................................................................................46


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
βHCG
beta human chorionic gonadotropin
λz
terminal elimination rate constant
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
AP
accelerated phase
APL
acute promyelocytic leukemia
AST
aspartate aminotransferase
AUC
area under the drug concentration by time curve
AUC0–t
area under the drug concentration by time curve from time 0 to the time of the last 
measurable drug concentration
AUC0-12
area under the drug concentration by time curve from time 0 to 12 hours
AUC0–∞
area under the drug concentration by time curve from time 0 to infinity
bid
twice daily
BP
blood pressure/blast phase
BSA
body-surface area
BUN
blood urea nitrogen
CBC
complete blood count 
CDMS
clinical data management system
CEC
Central Ethics Committee
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CHR
complete hematologic response
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
clinical leader
CL/F
total oral clearance
Cmax
maximum observed plasma drug concentration
CML
chronic myeloid leukemia
CO2
carbon dioxide


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Abbreviation
Term
CP
chronic phase
CPP
clinical project physician
CR
complete response
CRF
case report form
CRO
contract research organization
CYP450
cytochrome P450
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EU
European Union
FDA
US Food and Drug Administration
FISH
florescence in situ hybridization
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HI
hematologic improvement 
HIV
human immunodeficiency virus
HR
heart rate
hr
hour
HTLV
human t-cell lymphotropic virus
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
international normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
LSO
local safety officer
MaHR
major hematologic response 
MCyR
major cytogenic response
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities


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Abbreviation
Term
min
minute
ms
milliseconds
NA
not applicable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEL
no evidence of leukemia
NYHA
New York Heart Association
NSAIDS
non-steroidal anti-inflammatory drugs
PCR
polymerase chain reaction
PCyR
partial cytogenic response
P-gp
P-glycoprotein
Ph
Philadelphia
Ph+
Philadelphia chromosome-positive
PMR
postmarketing requirement
PPD
Pharmaceutical Product Development, LLC
RBC
red blood cell
Rpred
predicted accumulation ratio
RR
respiratory rate
RT-PCR
reverse transcription-polymerase chain reaction
SD
standard deviation
SDV
source data verification
SOPs
standard operating procedures
T
temperature
TKI
tyrosine kinase inhibitor
t½
terminal elimination half-life
tmax
time to maximum observed plasma drug concentration
ULN
upper limit of the normal range
US(A)
United States (of America)
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WHO Drug
World Health Organization (WHO) drug dictionary
XML
extensible markup language


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1.
BACKGROUND INFORMATION
1.1.
Introduction 
1.1.1.
Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that can occur with a bi- or 
tri-phasic course. CML occurs with an incidence of about 1 to 1.5 cases per 100000 population 
and accounts for about 7% to 15% of newly diagnosed cases of leukemia in adults. Major 
geographic or ethnic differences are insignificant. The median age at diagnosis is 64 years in the 
United States of America (USA). The median age at diagnosis ranges between 60 and 65 years in 
Europe. It is lower in countries where the population is younger (Baccarani et al 2012). The 
median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years. The 
overall 5-year relative survival for 2003 to 2009 was 59%
(http://seer.cancer.gov/csr/1975_2010/). Survival after development of an accelerated phase is 
usually less than 1 year and after blastic transformation is only a few months.
The typical tri-phasic course of disease is characterized by an initial chronic phase (CP) lasting 
3 to 6 years, followed by an accelerated phase (AP), then blast phase (BP) usually of short 
duration. Seventy-five percent to 80% of patients go through an accelerated phase before the 
blastic phase. The definition for accelerated phase is not uniform. Specific criteria associated 
with a survival less than 18 months by multivariate analysis have been proposed, including the 
presence of 15% or more blasts, or 30% or more blasts and promyelocytes, or 20% or more 
basophils in the blood, or platelet count less than 100x109/L. A cytogenetic clonal evolution is 
also considered a criterion for acceleration. Recent analysis suggests its prognostic effect 
depends on the specific abnormality, its predominance in marrow metaphases, and the time of 
appearance. Secondly, major studies use the definition for AP CML as in the inclusion criteria of 
this protocol (blasts in blood or bone marrow ≥15%) rather than 20% or more blasts. The reason 
is due to the lack of data for the definition of when AP CML is categorized differently. Data 
showed that patients with 20% to 29% blasts have an outcome similar to patients with AP 
criteria, as defined above, having a median survival approximately 12 months longer than those 
with blasts more than or equal to 30% (Cortes and Kantarjian 2012).
The cytogenetic hallmark of CML is a reciprocal t(9;22)(q34;q11) chromosomal translocation 
that creates a derivative 9q+ and a small 22q–, known as the Philadelphia (Ph) chromosome. The 
latter harbors the BCR-ABL fusion gene encoding a chimeric BCR-ABL protein with a 
deregulated tyrosine kinase activity, the expression of which has been shown to be necessary and 
sufficient for the transformed phenotype of CML cells. The activation of multiple signal 
transduction pathways in BCR-ABL–transformed cells leads to increased proliferation, reduced 
growth-factor dependence and apoptosis, and perturbed interaction with extracellular matrix and 
stroma. It is thought that the expression of BCR-ABL endows a pluripotent hematopoietic 
progenitor cell and/or its progeny with a growth and survival advantage over normal cells, which 
in time leads to clinical manifestation of CML. CML is unusual among malignancies in humans
in that a single oncogene product has been identified as playing a central role in its pathology.


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As BCR-ABL kinase, the product of the Philadelphia chromosome, plays an obligatory role in 
the pathogenesis of CML, there was a strong theoretical rational for targeting this function 
therapeutically. This ultimately led to the development and approval of imatinib mesylate 
(STI-571, GLEEVEC™, GLIVEC®, Novartis Pharmaceuticals Corporation), an inhibitor of 
BCR-ABL kinase activity. The clinical success of imatinib mesylate in treatment of CML, 
especially the high durable response rates in patients with CP CML, has validated the therapeutic 
strategy of rationally targeting the causative molecular abnormality of CML, and changed the 
management of the disease.
1.1.2.
Resistance to Tyrosine Kinase Inhibitors
Resistance to imatinib is now well documented. The most common mechanism of acquired 
imatinib resistance is the reactivation of BCR-ABL kinase activity within the leukemic cell, 
despite the presence of imatinib. Two underlying mechanisms account for this, either gene 
amplification or point mutation in the BCR-ABL kinase domain. 
Although many point mutations in the BCR-ABL kinase domain have now been described, 
amino acids 315 and 253 have been found to be critical for efficient imatinib binding. Mutations 
of these 2 amino acids, along with amino acids 255 and 351, were subsequently identified in 
60% of patients with kinase domain mutations at the time of disease relapse, with an overall 
mutation frequency between 30% and 90%. The marked decrease in sensitivity of these mutants 
to imatinib implicates them as the likely cause of resistance. 
New tyrosine kinase inhibitors have been developed to overcome resistance to imatinib, 
including dasatinib (SPRYCEL®, Bristol-Myers Squibb), nilotinib (TASIGNA®, Novartis 
Pharmaceuticals Corporation), bosutinib (BOSULIF®, Pfizer Laboratories), and ponatinib 
(ICLUSIG®, Ariad Pharmaceuticals, Inc.). Dasatinib and nilotinib are both approved for use in 
patients with newly diagnosed CP CML, while bosutinib and ponatinib have been approved for 
patients with CML in all 3 phases with resistance or intolerance to prior therapy. Through their 
sequential use, these kinase inhibitors have extended the overall survival of patients with CML. 
However, eventually patients will relapse and new treatments are continually being sought.
Omacetaxine mepesuccinate (omacetaxine) has demonstrated activity in both early and late CP
CML, as well as other hematologic malignancies, including acute promyelocytic leukemia 
(APL), acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS). 
Omacetaxine works via a different mechanism than the kinase inhibitors. Omacetaxine inhibits 
protein synthesis and binds to the A-site cleft in the peptidyl-transferase center of the large 
ribosomal subunit. In vitro, omacetaxine reduced protein levels of the BCR-ABL oncoprotein 
and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine has also shown activity in 
mouse models of wild-type and T315I mutated BCR-ABL CML. In patients with CP CML 
having the T315I mutation, and after failing treatment with tyrosine kinase inhibitors (TKIs), 
omacetaxine showed clinical activity (Cortes et al 2012).
Therefore, patients with CML who have failed or are intolerant to prior treatment with TKIs may 
still respond to treatment with omacetaxine. Based on the study results for patients with CP and 
AP CML who failed TKIs, the US Food and Drug Administration (FDA) approved omacetaxine 


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for the patients in these 2 phases of CML. SYNRIBO® (omacetaxine mepesuccinate) for 
injection for subcutaneous use is indicated for the treatment of adult patients with CP or AP
CML with resistance and/or intolerance to 2 or more TKIs. This indication is based upon 
response rate. There are no studies verifying an improvement in disease-related symptoms or 
increased survival with SYNRIBO (Package insert Oct 2012 version www.fda.gov).
1.1.3.
Rationale for the Study
In oncology, the dosage of nearly all cytotoxic drugs is based on body-surface area (BSA) of the 
patient (Field et al 2008, Mathijssen et al 2007). However, fixed or “flat dosing”, using a single 
dose for all patients regardless of BSA or weight may offer advantages with regard to 
administration dose errors and patient safety for a drug given subcutaneously. To satisfy a
postmarketing requirement (PMR), the sponsor has been requested by FDA to conduct a 
Phase 1/Phase 2 open label clinical study to investigate the pharmacokinetics and preliminary 
safety and efficacy of omacetaxine following a fixed-dose administration to patients with CP or 
AP CML who have failed 2 or more TKI therapies. Therefore, this study was designed for the 
same patient population for which omacetaxine was approved but with a “fixed or flat” dosing 
approach. If this approach proves safe and efficacious as in the registration trials, this would 
prove to be a benefit to patients and healthcare providers to ensure or avoid less dosing errors 
when given subcutaneously and improve patient compliance due to improved ease of 
administration.
Additionally, this study was requested since the pharmacokinetics of omacetaxine may or may 
not be related to BSA. A BSA-based dose could result in lower drug concentrations and 
potentially reduced efficacy in patients with traditionally lower BSAs, such as women, as women 
have lower body surface areas. Lower exposures may contribute to reported observations of a 
lower response rate in women. Therefore, a fixed dose may increase exposure in any patients 
with low BSA and potentially optimize their probability of response. This PMR study may assist 
to optimize the dosing regimen in future trials.
A population pharmacokinetic model was developed for omacetaxine using the pharmacokinetic 
data collected in Study CGX-635-205 and it was used to predict individual measures of 
omacetaxine exposure in patients enrolled in Studies CGX-635-202 and CGX-635-203, 
respectively. Study CGX-635-205 assessed pharmacokinetics and safety of subcutaneous
omacetaxine in patients with advanced cancers, and had results recently published (Nemunaitis
et al 2013). The relationships between these individual exposure estimates and efficacy and 
selected safety endpoints were investigated. These exposure-response relationships were used to 
simulate anticipated outcomes, with data from the CML registration Studies CGX-635-202 and 
CGX-635-203, respectively, with various fixed treatment regimens. The registration studies did 
not have pharmacokinetics in their study design.
A comparison of fixed-doses between 2 and 3.5 mg, without regard to BSA, illustrates that there 
is potential benefit in terms of an increased predicted probability of efficacy with a dose of 
                                                
SYNRIBO is a registered trademark of Ivax International GmbH, Switzerland.


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2.5 mg over a 2 mg dose (almost 3-fold increase in the predicted probability of major 
hematologic response [MaHR] and almost 2-fold increase in the predicted probability of major 
cytogenic response [MCyR]) (data on file). The 3 mg dose is associated with an even greater 
predicted probability of efficacy in both the AP and CP populations. The increased risk 
associated with these doses, in terms of the predicted probability of experiencing grade 3 or 
grade 4 thrombocytopenia, over the 2 mg dose, is small on the basis of the simulation data, but 
not fully understood due to the limited size of the CGX-635-205 dataset. 
The 3.5 mg dose, which represents a higher dose than any administered in 
Studies CGX-635-205, CGX-635-CML-202, or CGX-635-CML-203, is predicted to provide 
only a small additional improvement in the probability of efficacy and in the risk of neutropenia 
over the 3 mg alternative, and also a slightly increased risk of thrombocytopenia over the 3 mg
alternative; and it comes with the added uncertainty of being outside the range of previously 
tested doses. Therefore, administration of this dose is not recommended.
Because the number of patients in Study CGX-635-205 was small, the predictions from this 
population pharmacokinetic modeling must be used with caution. On the basis of the data 
currently available, the impact of fixed dose on the benefit-risk profile in patients with CML who 
have failed TKI therapy remains unknown. For this reason, a fixed dose of 2.5 mg twice daily 
was selected because it approximates to the dose that would have been given to a patient of 
median BSA under the current 1.25 mg/m2 twice daily regimen. In the phase 1 portion of the 
study, a sample size of approximately 21 patients enrolled in cohorts of small, medium, and large 
BSA is considered sufficient to properly characterize the pharmacokinetics of the 2.5 mg twice 
daily fixed dose.
1.2.
Name and Description of Investigational Product
SYNRIBO (omacetaxine mepesuccinate) for injection, for subcutaneous use, was approved by 
the US FDA on 26 October 2012. It is a semi-synthetic version of a plant alkaloid extracted from 
Cephalotaxus fortunei, a species of evergreen tree that is indigenous to China. The chemical 
name for omacetaxine mepesuccinate is cephalotaxine, 4-methyl-2-hydroxy-2-(4-hydroxy-4-
methylpentyl) butanedioate ester. It has a chemical formula of C29H39NO9 and a molecular 
weight of 545.6 g/mol. The mechanism of action of omacetaxine mepesuccinate has not been 
fully elucidated but includes inhibition of protein synthesis and is independent of direct 
BCR-ABL binding. 
The investigational product in this study is referred to in this document as either omacetaxine or 
omacetaxine mepesuccinate. A more detailed description of the product is given in Section 3.4
and in the current Investigator’s Brochure.
1.3.
Findings from Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies: Carcinogenesis and Genotoxicity
No carcinogenicity studies have been conducted with omacetaxine mepesuccinate. Omacetaxine 
mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese 


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hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay 
(Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay.
For information on other nonclinical studies see the Investigator’s Brochure.
1.3.2.
Clinical Studies of Subcutaneous Omacetaxine in CML
Omacetaxine is a semi-synthetic plant alkaloid initially tested in China. Omacetaxine has shown 
activity in CML and other hematologic cancers, including APL, AML, and MDS. 
Several studies have been conducted of subcutaneous administration of omacetaxine in CML. 
These are summarized in the following sections.
1.3.2.1.
Phase 1/Phase 2 Dose Response Study of Subcutaneous Omacetaxine
(Study T99-0044)
A Phase 1 study of subcutaneous omacetaxine was conducted under Investigational New Drug 
(IND) 19,125 in patients with CML at the MD Anderson Hospital. Sixteen patients in accelerated 
(AP; n=2), blast (BP; n=8), or late chronic (CP, n=6) phase CML were treated. All patients
received an initial intravenous loading dose of omacetaxine over 24 hours, followed by twice 
daily subcutaneous administration at 1of the following dose levels: 0.5, 1.0, or 1.25 mg/m2 twice 
daily (except for the intravenous loading dose that was given as 1 dose over 24 hours, equivalent 
to 2 subcutaneous doses). The latter dose (1.25 mg/m2 twice daily) was the same dose of 
omacetaxine as had been used intravenously in prior CML studies, and thus no further dose 
escalation was pursued beyond this point. 
Three patients were treated at the lowest dose level (1 cycle each), and none experienced any 
nonhematologic toxicity. Three patients were treated at 1.0 mg/m2 (1 cycle each); only grade 1 
toxicity (1 each: nausea, diarrhea, headache) was observed. Four patients received 1.25 mg/m2
(1 cycle in 2 patients, 2 cycles in 1 patient, and 3 cycles in 1 patient); toxicity included grade 1 
diarrhea (n=3), grade 1 abdominal pain (n=1), grade 2 nausea (n=2), and grade 2 anorexia, 
mucositis, allergic reaction, fatigue, and vomiting (n=1 each). 
One complete response (CR) and 1 stable disease have been observed. Three patients had a 1-log 
reduction in peripheral blood basophils (n=2; 2.37 to 0.25x109/L and 8.2 to 0.13x109/L) or blasts 
(n=1; 6.7 to 0.5x109/L), and 2 others had a more than 50% reduction in peripheral blood
basophils (5.6 to 3.2x109/L) or blasts (91.5 to 44.5x109/L). Three of these responses occurred 
among the 4 patients treated at the highest omacetaxine dose level, 1.25 mg/m2 subcutaneous
twice daily. Based on the observations from the initial 10 patients in this study, it was concluded 
that omacetaxine administered by the subcutaneous route was safe and had clinical activity in 
patients with CML. 
Additionally, 6 patients who had been previously treated with imatinib mesylate were treated 
with omacetaxine at 1.25 mg/m2 subcutaneous twice daily for 7 days every month. All of the 
5 evaluable patients in this phase achieved a complete hematologic response (CHR); the longest 
duration of observed response was 8 months. Two (40%) patients achieved a complete and minor 
cytogenetic response, respectively. One patient had both G250E and Y253H mutations present, 


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and the other had a single D276G mutation. Subsequent to omacetaxine therapy, these BCR-
ABL point mutations were not observed in either patient. These results provide encouraging 
evidence that omacetaxine may exhibit particular efficacy in this group of patients. 
1.3.2.2.
Phase 2 Studies of Omacetaxine in Patients with CP CML and AP CML 
Following Failure of Tyrosine Kinase Inhibitor (TKI) Therapy
The efficacy of subcutaneously administered omacetaxine was evaluated using a combined 
cohort of adult patients with CML from 2 studies (CGX-635-CML-202 and 
CGX-635-CML-203). The combined cohort consisted of patients who had received 2 or more 
approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to 
dasatinib and/or nilotinib. Resistance was defined as 1 of the following: no CHR by 12 weeks 
(whether lost or never achieved); or no cytogenetic response by 24 weeks (ie, 100% Ph positive 
[Ph+]) (whether lost or never achieved); or no MCyR by 52 weeks (ie, ≥35% Ph+) (whether lost 
or never achieved); or progressive leukocytosis. Intolerance was defined as 1 of the following: 
1) grade 3 or 4 nonhematologic toxicity that did not resolve with adequate intervention; 
2) grade 4 hematologic toxicity lasting more than 7 days; or 3) any grade 2 or greater toxicity 
that was unacceptable to the patient. Patients with New York Heart Association [NYHA] class 
III or IV heart disease, active ischemia, or other uncontrolled cardiac conditions were excluded.
Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered 
subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding 
patients were then treated with the same dose and twice daily schedule for 7 consecutive days 
every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance 
treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring 
Committee (DMC). 
A total of 76 patients with CP CML were included in the efficacy analysis. The demographics 
were: median age 59 years; 62% were male; 30% were 65 years of age or older; 80% were 
Caucasian, 5% were African-American, 4% were Asian, and 4% were Hispanic. Thirty-six 
(47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also 
received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), 
and/or cytarabine (29%). 
A total of 14 (18.4%) patients achieved a MCyR, including 6 patients with a confirmed complete 
cytogenic response (CCyR) and 3 patients with a confirmed partial cytogenic response (PCyR). 
The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR 
for the 14 patients was 12.5 months (Kaplan-Meier estimate).
A total of 35 patients with AP CML were included in the efficacy analysis. The demographics 
were: median age was 63 years; 57% were male; 46% were 65 years of age or older; 68% were 
Caucasian, 23% were African-American, 3% were Asian, and 3% were Hispanic. Twenty-two 
(63%) of 35 patients with AP CML had failed treatment with imatinib, dasatinib, and nilotinib. 
Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), 
interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR 
and MaHR (CHR or no evidence of leukemia [NEL]). 


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A total of 5 (14.3%) patients achieved a MaHR, including 4 patients with a CHR and 1 patient
with NEL. The mean time to response onset in the 5 patients was 2.3 months. The median 
duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).
1.3.3.
Clinical Safety and Tolerability
The following safety and tolerability data are summarized from the studies of subcutaneously 
administered omacetaxine in adult patients with CML who had received 2 or more approved 
TKIs (studies CGX-635-CML-202 and CGX-635-CML-203), which are the studies on which the 
approval of SYNRIBO was based.
1.3.3.1.
Chronic Phase CML
Adverse events were reported for 99% of the patients with CP CML. A total of 18% of patients
had adverse events leading to withdrawal. The most frequently occurring adverse events leading 
to withdrawal were pancytopenia, thrombocytopenia, and increased alanine aminotransferase 
(ALT) (each 2%). A total of 87% of patients reported at least 1 grade 3 or grade 4 treatment 
emergent adverse event. Serious adverse events were reported for 51% of patients. Serious 
adverse events reported for at least 5% of patients were bone marrow failure and 
thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse events of 
infections were reported for 8% of patients. Deaths occurred while on study in 5e (5%) patients
with CP CML. Two patients died due to cerebral hemorrhage, 1 due to multi-organ failure, 1 due 
to progression of disease, and 1 from unknown causes.
The most commonly reported nonhematologic adverse events (≥20%) were infections (46%), 
diarrhea (42%), infusion and injection site reactions (34%), nausea (32%), fatigue (26%), pyrexia 
(24%), and asthenia (23%). The most commonly reported grade 3 or 4 nonhematologic adverse 
events (≥2%) were infections (11%), fatigue (5%), and back pain (2%). The most common 
(≥10%) grade 3 or 4 laboratory findings were platelets decreased (85%), neutrophils decreased 
(81%), leucocytes decreased (72%), hemoglobin decreased (62%), uric acid increased (56%),
and glucose increased (10%). 
1.3.3.2.
Accelerated Phase CML
Adverse events regardless of investigator attribution were reported for 100% patients with 
AP CML. A total of 33% of patients had adverse events leading to withdrawal. The most 
frequently occurring adverse events leading to withdrawal were leukocytosis (6%), and 
thrombocytopenia (4%). A total of 84% of patients reported at least 1 grade 3 or grade 4 
treatment emergent adverse event. Serious adverse events were reported for 60% of patients. 
Serious adverse events reported for at least 5% of patients were febrile neutropenia (18%), 
thrombocytopenia (9%), anemia (7%), and diarrhea and convulsions (6% each). Serious adverse 
events of infections were reported for 11% of patients. Death occurred while on study in 
5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and 3 due to 
progression of disease.
The most commonly reported nonhematologic adverse events (≥20%) were infections (56%), 
diarrhea (35%), fatigue (31%), pyrexia (29%), nausea (27%), asthenia (24%), and infusion and 


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injection site events (22%). The most commonly reported nonhematologic grade 3 or 4 adverse 
events (≥2%) were infections (20%), fatigue (9%), diarrhea (7%), nausea (4%), and vomiting, 
pyrexia, asthenia, anorexia, pain in extremity, dyspnea, and epistaxis (2% each). The most 
common (≥10%) grade 3 or 4 laboratory findings were platelets decreased (88%), hemoglobin 
decreased (80%), neutrophils decreased (71%), leucocytes decreased (61%), uric acid increased 
(57%), creatinine increased (16%), and glucose increased (10%). 
1.3.4.
Clinical Pharmacology
The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic 
exposure to omacetaxine mepesuccinate was observed between the first dose and steady state. 
Absorption: The absolute bioavailability of omacetaxine mepesuccinate has not been 
determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and 
maximum concentrations are achieved after approximately 30 minutes.
Distribution: The steady-state (mean ±standard deviation [SD]) volume of distribution of 
omacetaxine mepesuccinate is approximately 141±93.4 L following subcutaneous administration 
of 1.25 mg/m2 twice daily for 11 days. The plasma protein binding of omacetaxine 
mepesuccinate is less than or equal to 50%.
Metabolism: Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma 
esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.
Elimination: The major elimination route of omacetaxine mepesuccinate is unknown. The mean 
percentage of omacetaxine mepesuccinate excreted unchanged in the urine is less than 15%. The 
mean half-life of omacetaxine mepesuccinate following subcutaneous administration is 
approximately 6 hours.
Drug Interactions: Omacetaxine mepesuccinate is not a substrate of cytochrome P450 
(CYP450) enzymes in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major 
CYPs in vitro at concentrations that can be expected clinically. The potential for omacetaxine 
mepesuccinate or 4′-DMHHT to induce CYP450 enzymes has not been determined. 
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 that can be expected clinically.
Assessment of Risk for QT Prolongation: In an uncontrolled pharmacokinetic study there were 
no reports of QTcF greater than 480 milliseconds (ms) or change of QTcF greater than 60 ms in 
21 patients who received omacetaxine mepesuccinate 1.25 mg/m2 twice daily (bid) for 
14 consecutive days. There was no evidence for concentration-dependent increases in QTc for 
omacetaxine mepesuccinate or 4’-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 
95% confidence interval [CI]: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the 
absence of a placebo and positive controls.
For more updated information please refer to the current Investigator’s Brochure.


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1.3.5.
Justification for Study Treatment Plan
The purpose of this current study is to evaluate the pharmacokinetics and the preliminary safety 
and efficacy of a fixed-dose regimen of omacetaxine (2.5 mg BID sc) for the treatment of 
patients with CP or AP CML following failure of TKI therapy. For this reason, the treatment 
plan is the same as that used in the Phase 2 registration studies for omacetaxine (Studies 
CGX-635-CML-202 and CGX-635-CML-203) with a fixed dose being used in place of doses
adjusted for BSA and with the precautions to minimize toxicity and improve tolerability as 
described in Section 1.4 called Known and Potential Risks and Benefits to Human Patients. As an 
additional precaution for unforeseeable risks, an independent DMC that will evaluate safety,
pharmacokinetics, and efficacy, has been implemented from the beginning of the study including 
the phase 1 portion as defined in its charter.
The study treatment plan includes recommendations for supportive therapies and management of
toxicities, including hematologic toxicity, if necessary. Refer please, to Section 3 and Section 5
of the protocol CEP 41443/2057 for full details. 
1.4.
Known and Potential Risks and Benefits to Human Patients
Subcutaneous administration of omacetaxine resulted in an 18.4% MCyR rate in patients with 
CP CML, with a median duration of response of 12.5 months. In patients with AP CML a MaHR 
rate of 14.3% was achieved with a median duration or response of 4.7 months.
Myelosuppression: In uncontrolled studies with omacetaxine, patients with chronic phase and 
AP CML experienced National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) (version 3.0) grade 3 or grade 4 thrombocytopenia (85%, 88%, 
respectively), neutropenia (81%, 71%, respectively), 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. In 
clinical studies, myelosuppression was generally reversible and usually managed by delaying the 
next cycle and/or reducing days of treatment with omacetaxine.
Bleeding: Omacetaxine causes severe thrombocytopenia which increases the risk of hemorrhage. 
In clinical studies in patients with CP and AP CML, a high incidence of grade 3 and grade 4 
thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral 
hemorrhage occurred in 2% of patients treated with omacetaxine 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 grade 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.
Embryo-Fetal Toxicity: Omacetaxine can cause fetal harm when administered to a pregnant 
woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals.


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Additional information regarding risks and benefits to human patients may be found in the 
current Investigator’s Brochure.
1.5.
Selection of Drugs and Dosages 
The purpose of this study is to investigate the pharmacokinetic and preliminary safety and 
efficacy of omacetaxine following fixed-dose administration in patients with CP or AP CML 
who have failed 2 or more TKI therapies. The ultimate goal is to investigate whether a fixed 
dose, administered subcutaneously, may be used to treat patients with CP and AP CML 
effectively, with no worsening of the safety profile and no loss of efficacy. 
In order to address variation in BSA, patients will be enrolled in cohorts according to BSA. In 
Phase 1, there will be 3 cohorts, approximately 7 patients each. All patients will be given a fixed 
dose of 2.5 mg bid subcutaneous injection. Every effort will be made to include equal numbers 
of patients across all BSA cohorts. Cohort 1 will include patients whose BSA is less than 1.7 m2.
Cohort 2 will include patients with a BSA between 1.7 m2 to 2.0 m2 inclusive. Cohort 3 will 
include patients with BSA greater than 2.0 m2. Based on previous data from clinical research 
studies, the range of BSA for patients enrolled in those studies was 1.39 m2 to 2.46 m2 (median 
1.94 m2) for CP patients, and 1.34 m2 to 2.31 m2 (median 1.8 m2) for AP patients (data on file). 
Following the analysis of pharmacokinetic and preliminary safety and efficacy data from the 
patients in Phase 1, after all have been administered 1 cycle of omacetaxine, a decision will be 
made whether to move forward to the Phase 2 portion. If patients in Phase 1 tolerate treatment 
and benefit from therapy, treatment will continue.
A more detailed description of study drug administration is presented in Section 5.1.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any 
applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 2001/20/EC on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of the investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities in the country where each investigational 
center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. The investigator and the applicable study staff must be familiar with the 


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background to, and requirements of, the study and with the properties of the study drug(s) as 
described in the Investigator’s Brochure or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities.
1.7.
Population To Be Studied
Patients in this study will be men or women, 18 years of age or older, with a confirmed diagnosis 
of Ph+ CML in either CP or AP. Patients will have either failed, demonstrated intolerance, or a 
combination of prior failure and intolerance, to prior treatments with at least 2 TKIs. Patients
will have adequate hepatic and renal function, controlled blood glucose levels especially in 
patients with diabetes or risk factors for diabetes, and an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 to 2 (see Section 4.1).
1.8.
Relevant Literature and Data
Relevant literature is cited above. Further literature and data may be found in the current 
Investigator’s Brochure.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The purpose of this study is to investigate the pharmacokinetic and preliminary safety and 
efficacy of omacetaxine treatment following a fixed dose administered subcutaneously in 
patients with CP or AP CML who have failed 2 or more TKI therapies. The ultimate goal is to 
investigate a fixed dose to treat patients with CP and AP CML effectively, with no worsening of 
the safety profile and no loss of efficacy. 
2.2.
Study Objectives
The primary objectives of the study are as follows:

to evaluate the efficacy of omacetaxine when administered subcutaneously as a fixed 
dose in patients with CP CML or AP CML 

to evaluate the safety of omacetaxine when administered subcutaneously as a fixed 
dose in patients with CP CML or AP CML (see Section 3.2.3)

to characterize the pharmacokinetic profile of omacetaxine in cycle 1 when 
administered subcutaneously as a fixed dose (see Section 8)
The secondary objectives of the study are as follows:

to determine the duration of responses

to determine progression-free and overall survival

to determine molecular response

to determine additional pharmacokinetic parameters after cycle 1

to determine additional parameters, such as the BCR-ABL transcript


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a Phase 1/Phase 2, open-label, multicenter, single-group clinical study in patients with CP 
or AP CML who have failed 2 or more TKI therapies designed to investigate the 
pharmacokinetic, safety, and efficacy of omacetaxine given subcutaneously as a fixed dose.
The study will consist of up to a 7-day screening period, and treatment for up to 12 months, in 
Phase 1 and Phase 2 portions, depending on response and tolerability. Patients will also have an
end-of-treatment follow-up visit approximately 28 days (+2 days) after the last dose of 
omacetaxine. Each patient will be monitored for progression and survival for at least 1 year after 
their last dose of omacetaxine, death, or lost to follow-up, whichever comes first, regardless of 
patients receiving other anticancer treatment. 
Phase 1 portion: In Phase 1, there will be 3 cohorts of approximately 7 patients each; patients 
may have either CP or AP CML. All patients will be given a fixed dose of 2.5 mg omacetaxine 
subcutaneous injection twice daily. Every effort will be made to include an equal number of 
patients in each BSA cohort. Cohort 1 will include patients whose BSA is less than 1.7 m2.
Cohort 2 will include patients with a BSA between 1.7 m2 to 2.0 m2 inclusive. Cohort 3 will 
include patients with BSA greater than 2.0 m2. Based on data from previous clinical research 
studies, the range of BSA for patients enrolled in those studies was 1.39 to 2.46 m2 for CP 
patients, and 1.34 to 2.31 m2 for AP patients (data on file). Because it is known that women 
usually have a smaller BSA than men, all efforts must be made to include at least 2 men in 
cohort 1 to reduce possible gender bias. After cycle 1, patients will continue to receive 
omacetaxine for 12 months until intolerance or disease progression while safety and efficacy 
parameters are followed.
Phase 2 portion: Following the analysis of pharmacokinetic and preliminary safety and efficacy 
data from the patients in Phase 1, a decision whether or not to continue to Phase 2 will be made.
If the Phase 1 data indicate that a fixed-dose regimen is not appropriate for subcutaneously 
administered omacetaxine, enrollment into the Phase 2 portion will be stopped and the study will 
be terminated. It is anticipated that the analysis of pharmacokinetic and preliminary safety and 
efficacy data from the patients in Phase 1 will take approximately 2 months. Assuming a 
fixed-dose regimen is considered appropriate on the basis of the Phase 1 data, a total of up to
45 patients with CP CML and a total of up to 67 patients with AP CML will be enrolled in 
Phase 2. 
Phase 1 and Phase 2: Omacetaxine will be administered by subcutaneous injection twice daily. 
For cycle 1, the first dose will be administered at the investigational center. Subsequent doses (in 
prefilled syringes) may be administered on an outpatient basis after training takes place. See 
Section 5.1.1 regarding training for the patient or caregiver for administration of omacetaxine. 
Patients will be evaluated every 7 days with complete blood and platelet counts up to and 
including cycle 5, and every 2 weeks (±2 days) after cycle 5 (see Section 3.11.2.5); the number 


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of consecutive doses of omacetaxine or intervals between subsequent cycles may be adjusted, as 
clinically indicated, according to guidelines provided in Section 5.1.2.
The following tests will be performed every 3 months (ie, every 3 cycles) while on study, for all 
patients:

bone marrow aspiration and cytogenetics every 3 months
If patients show other clinical signs of disease progression they may not need to 
undergo a bone marrow evaluation. The treatment cycle following a bone marrow 
procedure for the long-term responders may begin up to 7 (±3) days after the bone 
marrow procedure. Cytogenetic response evaluation will be based on standard 
cytogenetic analysis (at least 20 metaphases are to be analyzed). 
Note: After a patient achieves a confirmed cytogenetic response, bone marrow 
aspiration with cytogenetics will be performed every 12 months or as often as 
clinically indicated. At this stage, after the patient has been on study for at least 
12 months, chromosome banding analysis of marrow cell metaphases (with at least 20 
metaphases analyzed) can be substituted by florescence in situ hybridization (FISH) 
on blood cells once a complete cytogenetic response has been confirmed (Baccarani 
et al 2013, SYNRIBO prescribing information).

measure BCR-ABL transcript levels by real-time, quantitative polymerase chain 
reaction (PCR) of peripheral blood performed locally
Note: After a patient achieves a confirmed complete cytogenetic response, RT-PCR 
BCR-ABL testing should be performed every 6 months unless clinically indicated to 
do it more often (Appendix A).

quantitative BCR-ABL kinase domain mutation analysis of peripheral blood sample
(Appendix B) prior to omacetaxine treatment cycle (performed locally)
However, this may omitted if the patient did not have any clinical sign of failure to 
treatment, or did not show any clinical signs of progression.

electrocardiogram (ECG)
For patient convenience, these studies may be scheduled to be obtained prior to the next 
scheduled omacetaxine treatment cycle.
Note: Any or all of the above procedures may be conducted earlier than a scheduled 3-month 
interval if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
Patients not demonstrating evidence of clinical response after 6 cycles will be considered for 
removal from the study; however, with permission of the sponsor’s medical monitor, treatment 
may continue, if clinically indicated, provided there is no evidence of toxicity grade 3 or above.
In patients achieving a CHR or major cytogenetic response (either complete, or partial 
cytogenetic response, up to 35% Ph+ metaphases) (Appendix A) , the response will be confirmed 
by a repeat complete blood count (CBC), bone marrow aspiration (for patients with a 
hematologic response), cytogenetics of the bone marrow aspirate (for patients with a cytogenetic 


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response), and BCR-ABL transcript levels by quantitative reverse transcription-polymerase chain 
reaction (RT-PCR) of peripheral blood, at the intervals specified below. For patient convenience, 
confirmatory studies may be scheduled to be done prior to the next scheduled omacetaxine
treatment cycle (rather than exactly at 4 or 8 weeks after the initial response, as specified below). 

chronic phase CML: Confirm the response at least 8 weeks after the initial 
documentation of the response, ie, at least 8 weeks after the patient first meets the 
clinical and laboratory criteria for a response, as defined in Appendix A. 

accelerated phase CML: Confirm the response at least 4 weeks after the initial 
documentation of the response, ie, at least 4 weeks after the patient first meets the 
clinical and laboratory criteria for a response, as defined in Appendix A.
If the CBC, bone marrow aspiration, and/or cytogenetic results do not confirm the clinical 
response and the patient is already on maintenance treatment cycles, the patient may continue on 
maintenance therapy or may revert back to induction cycles (ie, 14 days of omacetaxine
treatment) or the highest number of days tolerated previously, if clinically indicated.
Patients who demonstrate CHR, hematologic improvement (HI), or any cytogenetic response, as 
defined in Appendix A, may convert from induction to maintenance therapy (see Section 5.1, 
Treatment Plan).
3.2.
Primary and Secondary Measures and Endpoints
3.2.1.
Primary Efficacy Measures and Endpoints
The primary efficacy variable for patients with CP CML is the proportion of patients who 
achieve a major cytogenetic response (MCyR: complete cytogenetic response with no Ph+ 
metaphases and partial cytogenetic response with 1 to 35% Ph+ metaphases)
The primary efficacy variable for patients with AP CML is the proportion of patients who 
achieve a major hematologic response (MaHR: complete hematologic response or no evidence of 
leukemia) and/or MCyR.
See Appendix A for the measures for response. See Table 2 for the endpoints for response.
3.2.2.
Secondary Efficacy Measures and Endpoints
The secondary efficacy measures and endpoints are as follows:

duration of response, defined for responders as the time interval from the first 
reported date of MCyR or MaHR, as defined above, to the earliest date of objective 
evidence of disease progression (ie, development of accelerated-phase CML), relapse 
(ie, loss of complete hematologic or major cytogenetic response), or death

molecular response by site (peripheral transcript of BCR-ABL) (Appendix B) 
assessed every 3 months (ie, every 3 cycles)


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
progression-free survival, defined as the time interval from date of first dose to 
earliest date of objective evidence of disease progression (ie, development of 
accelerated-phase CML), relapse (ie, loss of complete hematologic or major
cytogenetic response), or death

overall survival, defined as the time interval from date of first dose to date of death 
from any cause
3.2.3.
Safety Measures and Endpoints
The safety and tolerability of omacetaxine treatment will be assessed throughout the study by 
evaluating the following safety variables:

adverse events (type, frequency, severity, and causality)

clinical laboratory test results (serum chemistry and hematology) at various points in 
the study

exploratory predictors of toxicity such as myelosuppression to assist with safety 
signals 

vital signs measurements (blood pressure, heart rate, respiratory rate, body 
temperature)

physical examination (including weight)

12-lead ECG

concomitant medication usage
3.2.4.
Pharmacokinetic Measures and Endpoints
See Section 8.1 for pharmacokinetic measures and endpoints.
3.3.
Randomization and Blinding
This is a nonrandomized, open-label study.
3.4.
Study Drugs and Dosage
3.4.1.
Investigational Product and Dosage
The investigational drug for this study is omacetaxine mepesuccinate. Omacetaxine drug product 
is a lyophilized vial containing 3.5 mg omacetaxine and 10 mg mannitol in an 8-mL clear glass 
vial, sealed with rubber stopper and aluminum flip-off seal. Investigational centers will be given 
vials of 3.5 mg omacetaxine. Omacetaxine will be reconstituted by a healthcare professional.


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Omacetaxine will be administered by subcutaneous injection at a fixed dose of 2.5 mg twice 
daily for 7 or 14 consecutive days every 28 days, over a 28-day cycle. The first dose of the day 
for cycle 1 will be administered at the investigational center. Subsequent doses (in prefilled 
syringes) may be administered on an outpatient basis after training takes place, and recorded and 
verified in the patient diary, unless the patient must come back to obtain more drug or perform 
test procedures, including pharmacokinetics.
A more detailed description of administration procedures is provided in Section 5.1. 
3.4.2.
Other Study Drugs and Dosage
This is an uncontrolled study with no other study drug. 
3.5.
Duration of Patient Participation
The study will consist of up to a 7-day screening period, and treatment for up to 12 months 
depending on response and tolerability. Patients will also have an end-of-treatment follow-up 
visit approximately 28 days (+2 days) after the last dose of omacetaxine. Patients will be 
monitored for progression and survival for at least 1 year after the last treatment dose of 
omacetaxine, death, or lost to follow-up, whichever comes first, regardless of patients receiving 
other anticancer treatment.
3.6.
Stopping Rules and Discontinuation Criteria
During the conduct of the study, serious adverse events will be reviewed (see Section 7.1) as 
they are reported from the investigational center to identify safety concerns along with reviewing 
the adverse events collected and monitored from the clinical investigational centers. The study 
may be terminated by the sponsor at any time.
A review of all pharmacokinetic and preliminary safety and efficacy data will be performed after 
the last patient completes 1 cycle of treatment and undergoes pharmacokinetic sample collection 
in the Phase 1 portion of the study. This review will determine whether it is appropriate to further 
evaluate the fixed-dose regimen or a modified fixed-dose regimen in the Phase 2 portion of the 
study, or terminate the study. 
Safety and efficacy will be reviewed by an independent DMC. The DMC will also review the 
pharmacokinetic analysis from Phase 1. See Section 7 for further information.
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawal, adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, adverse event).


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3.7.
Study Drug Supply and Accountability
An Interactive Response Technology (IRT) system will be used to manage the omacetaxine 
supply at the investigational center and/or central pharmacy. The information regarding the 
vendor will be provided in the project plan.
Omacetaxine will be provided to the principal investigators by the distributer after authorization 
from the sponsor.
Investigational centers will be given vials of 3.5 mg omacetaxine. Saline, syringes, needles that 
are needed may be supplied or reimbursed by sponsor. Spill kits, and written instructions, will be 
provided by the sponsor.
A training pamphlet for the subcutaneous administration of omacetaxine, for handling spills of 
omacetaxine (if they were to occur after reconstitution), for accurate record keeping of 
administered omacetaxine (ie, patient diaries), instructions on how to record data on patient 
diaries, handling, storage, disposal, and shipping of reconstituted omacetaxine will also be 
provided to the study staff and patient. For more details, refer to the Pharmacy Manual.
3.7.1.
Study Drug Storage and Security
The vials of lyophilized powder (3.5 mg per vial) must be kept in their original package, 
protected from light, at controlled room temperature (20°C to 25°C with excursions to 15°C to 
30°C), in a cabinet or other enclosure, which is securely locked. Access should be restricted to 
the principal investigator, investigational pharmacist, or other authorized designee at each 
investigational center. Neither the principal investigator nor any designees may provide the 
investigational drug to any study patient not participating in this protocol. Use omacetaxine 
immediately after reconstitution, or, if not possible, within the timelines provided in Table 1. Do 
not reuse. Updated stability information will be provided in the Pharmacy Manual and also as 
notification to the sites in the event of updates to this information.
Table 1:
Time to Administration After Reconstitution
Storage conditions
Time to administration
Room temperature (20°C to 25°C [68°F to 
77°F])
Within 12 hours of reconstitution
Refrigerated (2°C to 8°C [36oF to 46oF])
Within 6 days (144 hours) of 
reconstitution
3.7.2.
Study Drug Accountability
Each study drug shipment will include a packing slip, listing the contents of the shipment, and 
drug return instructions and any applicable forms.
The investigator is responsible for ensuring that deliveries of study drug and other study 
materials from the sponsor are correctly received and recorded, handled and stored safely and 


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properly in accordance with the CFR or local regulations, and used in accordance with this 
protocol.
A record of study drug accountability (ie, study drug and other materials received, used, unused, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty, partially used, and unused study drug will 
be disposed of, or returned to the sponsor or its designee.
For the first cycle, the first dose will be reconstituted by the healthcare professional and 
administered at the investigational center. For any additional cycles, the first dose may be 
administered at the investigational center by a healthcare professional, self-administered at home 
by the patient, or administered by the Sponsor selected home care agency professional at the 
home of the patient. Except for cycle 1 of Phase 1 (see Table 3 and Table 4 for the different 
dosing schedules), the second dose of day 1 may be dispensed to the patient by the study 
doctor/pharmacist/trained study personnel or central pharmacy in a syringe filled with the correct 
volume of omacetaxine (fixed dose). This will be repeated every day for 14 days or 7 days of 
treatment, for induction or maintenance cycles, respectively (or according to dose delay and 
modifications). Additionally, accurate record keeping of all reconstituted fixed doses of 
omacetaxine administered bid per cycle will be required from the investigational center and the 
patient via the patient diaries and medical source documents. Dosing information from the 
diaries will be entered into a database at approximately weekly visits, unless otherwise noted, 
during dosing periods, and verified by study staff or designee. Patients and investigational 
centers will be provided with instructions on how to complete the patient diaries, and will be 
required to make them available to verify dosing. Patients will also be instructed to bring their 
diary to the clinic at each visit so that the study staff can review it and provide re-training, if 
needed.
Drug Accountability Logs will indicate patient identifying information, as well as the date and 
quantity of study drug received and dispensed by the investigational center pharmacy or central 
pharmacy, expiration of the reconstituted solution, as well as study drug returned to the sponsor. 
These records will be reviewed by the sponsor. The sponsor may supply the Drug Accountability 
Logs to facilitate this inventory control or the principal investigator may use forms authorized by 
the investigational center pharmacy or central pharmacy, providing the institution's forms 
capture all inventory and dispensing data required by the sponsor. When the study is terminated, 
the principal investigator or his/her designees will provide a copy of the completed drug 
accountability records to the sponsor.
All prepared syringes of study drug (fixed dose) and other needed supplies (biohazard container, 
spill kits, etc) will be dispensed from the investigational center pharmacy or central pharmacy
under the direct supervision of study staff and in accordance with the investigational center’s 
standard operating procedures (SOPs). Drug logs will be used to ensure compliance. In general, 
unless otherwise noted with written rationale (ie, reimbursement), the patient will be provided 
with a biohazard container and spill kit with written instructions by the sponsor in order to return 
used syringes as instructed and trained. The patient will be instructed on how to return the used 
syringe syringes and used supplies as recorded in the training materials. To ensure compliance of 
the reconstituted doses of omacetaxine and required procedures, outpatient nursing services may 


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also be available, as needed, by the sponsor, or reimbursed by the sponsor, depending on where 
the patient lives.
Special handling and disposal procedures should be followed according to applicable guidelines 
issued for hazardous drugs, training materials, and training received. Patients will be instructed
and trained with training materials provided by the sponsor, not to place used needles, syringes, 
or vials in household trash or recycle.
For more details regarding training materials and above information, please refer to the 
Pharmacy Manual.
3.8.
Maintenance of Randomization and Blinding
This is an open-label study with no blinding.
3.9.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the case report form (CRF). Data may not be 
recorded directly onto the CRF and considered as source data unless the investigational center 
obtains written documentation from the sponsor, before the beginning of the study, indicating 
which data are permitted to be recorded directly onto the CRF. Source documents, including test 
results and/or assessments (eg, clinical laboratory test results, ECG data and assessments, 
efficacy measurements) collected or performed by institutions outside of the investigational 
center, are retained by the investigational center (see Section 13.3.1). The CRFs are filed in the 
sponsor’s central file.
The principal investigator or his designee(s) will maintain progress notes in the institution’s 
medical records to document all significant observations through the course of each patient’s 
study participation. At a minimum, these notes should contain:

documentation of written informed consent, medical history, and current physical 
condition of patient to verify protocol entry criteria at screening

the dates of all study-related visits, study number, patient number, and drug being 
evaluated

general patient status remarks, including any significant medical findings; the 
severity, frequency, and duration of any adverse events or abnormal laboratory 
findings, and the principal investigator’s assessment of whether or not they are study 
drug-related must also be recorded

any changes in concomitant medications or dosages (including start and stop dates)

any dosing changes, interruptions or discontinuation in study medication and review 
of completed patient diaries


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
a specific reference to the procedures completed at each study-related visit

the signature or initials of all persons making an entry in the progress notes

the date of study completion or termination with assessment of patient’s overall 
condition
In addition, any contact with the patient via telephone or other means that provides significant 
clinical information will also be documented in the progress notes, as described above.
Any changes to information in the study progress notes, other source documents or the case 
report forms will be made by drawing a single line through the incorrect entry, initialing and 
dating on the day the change is made by study personnel authorized to make the change. The 
revised information should be entered adjacent to the corrected entry. Incorrect data must not be 
obliterated by any means, including by correction fluid.
Study participants must not be identified by name on any study documents. Patients will be 
identified by initials and assigned patient numbers only. The principal investigator will allow the 
sponsor or its representative, or an appropriate representative of the competent authorities to 
inspect study documents (eg, consent forms, patient diaries, drug distribution forms, IRB 
approval) and pertinent hospital or clinic records for confirmation of data throughout the study 
period.
3.10.
Time Schedule
The study is expected to start enrolling in approximately the second quarter of 2014 and be 
completed enrollment approximately in 2016. The study is planned to be conducted at 
approximately 24 study centers in North America, Europe, and Asia.
3.11.
Study Procedures
Study procedures and assessments with their timing are summarized in Table 2, Table 3, and
Table 4.


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Table 2:
Study Procedures and Assessments
Procedures and assessments Screening
a
Omacetaxine induction or maintenance treatment
28-day cycles (±1 day)(up to 12 cycles total)
Study 
completion or 
early 
terminationb
Follow-upc
Day 1 
induction 
cycles
Day 1 
maintenance 
cycles
Cycles 1 to 5 
(days 7, 14, 21)
Cycle 6 to 
end of 
treatment
day 14
Every 
3 months 
on studyd
Confirmation 
of responsee
Informed consent
X
Inclusion/Exclusion criteria
X
Medical history
X
Urine or serum pregnancy test
Xf
Physical exam
X
Xg
Xg
X
Prior medications
X
Height
X
Weight
X
Xg
Xg
X
Calculate body surface areah
X
X
X
Vital Signs (HR, RR, BP, T)
X
Xi
Xi
X
Chest x-ray
Xj
ECG
Xj
Xk
Xl
X
X
Hematologym
X
Xg
Xg
Xn
Xo
X
X
Serum chemistryp
X
Xg
Xg
Xn
Xo
X
Bone marrow aspiration and 
cytogeneticsq
Xj
Xr
Xs
Xq
BCR-ABL quantitative
transcript levels by PCRt
X
Xr
X
X
BCR-ABL mutation analysis
Xu
Xrv
Urinalysis
X


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Table 2:
Study Procedures and Assessments (Continued)
Procedures and assessments Screeninga
Omacetaxine induction or maintenance treatment
28-day cycles (±1 day)(up to 12 cycles total)
Study 
completion or 
early 
terminationb
Follow-upc
Day 1 
induction 
cycles
Day 1 
maintenance 
cycles
Cycles 1 to 5 
(days 7, 14, 21)
Cycle 6 to 
end of 
treatment
day 14
Every 
3 months 
on studyd
Confirmation 
of responsee
Document other measures of 
disease and disease symptoms 
X
X
X
X
ECOG performance status
X
Xg
Xg
X
Patient diary review
Xw
X
X
X
X
X
Drug accountability
Xw
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
Adverse event inquiry
X
X
X
X
X
X
X
Omacetaxine dosing
Days 1 through 14 during inductionu and days 1 through 7 during maintenance
Survivalx
X
X
X
X
X
X
X
Other anticancer treatment
X
a Screening period is 7 days before first dose of study drug except for bone marrow aspiration, cytogenetics, ECG, and chest x-ray, which may be performed 
within 30 days before start of study drug.
c Follow-up visits every 3 months (±7 days); the first visit will be in person but the rest may be by telephone contact. Follow-up will continue until patient's 
death, is lost to follow-up, or until 12 months after the last treatment cycle, whichever occurs first, regardless of receiving other anticancer treatment. Follow-up 
is required even if a patient is withdrawn from treatment with omacetaxine.
d For patient convenience, these studies may be scheduled to be obtained prior to the next scheduled omacetaxine treatment cycle. Additional studies may be 
conducted earlier than a scheduled 3-month interval if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
e For patients with chronic phase CML, confirm the response at least 8 weeks after the patient first meets the clinical and laboratory criteria for a response. For 
patients with accelerated phase CML, confirm the response at least 4 weeks after the patient first meets the clinical and laboratory criteria for a response. For 
patient convenience, confirmatory studies may be scheduled to be done prior to the next scheduled omacetaxine treatment cycle (rather than exactly at 4 or 
8 weeks after the initial response).
b If a patient completes treatment with omacetaxine or is withdrawn from treatment, assessments will be performed at an end-of-treatment visit 28 days (+2 days)
after the last dose of study drug. If the patient is withdrawn from treatment, an end-of-treatment visit may occur before 28 days after the last dose of 
omacetaxine to allow the patient to enter follow-up.
f For women of childbearing potential. Repeat as clinically indicated.


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g On the day of or within 3 days prior to start of the treatment cycle. Review results prior to initiating a treatment cycle.
h Body surface area will be calculated during cycles 1 through 3 of study drug treatment.
i Measure vital signs (HR, BP, RR, T) within 30 minutes prior to administration of omacetaxine and 20 minutes post-dose (±5 min) on day 1 of each treatment 
cycle. If the patient has hypotension (systolic blood pressure <90 mm Hg), vital signs should be taken and recorded more frequently, until the patient has 
stabilized. (In the case of outpatient injections, sometimes points may be omitted if logistically not possible, eg, the time point occurs over the weekend.)
j Chest x-ray may be omitted if a prior study, such as a CT of the chest, is completed within 30 days of first dose of omacetaxine. A screening bone marrow or 
ECG is required only if a prior one has not been performed within 30 days of first dose of omacetaxine.
k Prior to the first 3 cycles (cycles 1 through 3) whether induction or maintenance. It may be omitted at cycle 1 if one was done within 30 days prior to the first 
dose of omacetaxine on day 1 of cycle 1). In other countries, ECGs may be done before and after every omacetaxine cycle, or as directed.
l Electrocardiogram after completion of day 14 of treatment, induction cycle 1, if the patient is available for this exam.
m Complete blood counts (±2 days) to include hematocrit, hemoglobin, RBC, WBC, differential, platelet count.
n During cycles 1 through 5 serum chem 7 (sodium, chloride, CO2 content, creatinine, BUN or urea, glucose, and potassium) will be performed on days 7 (±2), 
14 (±2), and 21 (±2). Studies may be obtained at a local laboratory, with results transmitted to the study investigational center in a timely manner as they 
become available.
o Full serum chemistry and hematology to be performed every 2 weeks (±2 days) after cycle 5.
p Full serum chemistry to be performed at screening and after cycle 5. During cycles 1 through 5, chem 7 (sodium, chloride, CO2 content, creatinine, BUN or 
urea, glucose, and potassium) is to be performed.
q Bone marrow exam with cytogenetic analysis to be performed by the G-banding technique. Marrow specimens will be examined on direct short-term (24-hour) 
cultures; at least 20 metaphases are to be analyzed. May be omitted at screening if bone marrow and cytogenetic analysis have been done in the preceding 
30 days and the patient had not received antileukemic therapy during this period (other than palliative therapy, eg, hydroxyurea). After 12 months on study, and 
once a complete cytogenetic response has been confirmed, may substitute chromosome banding analysis with FISH on blood cells.
r For the convenience of all patients, these studies may be scheduled prior to the next scheduled omacetaxine treatment cycle. Additional studies may be 
conducted earlier than a scheduled 3-month interval if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
s Obtain bone marrow cytogenetic study to confirm a cytogenetic response.
t Obtain BCR-ABL quantitative transcript levels by quantitative PCR analysis of peripheral blood. BCR-ABL transcripts will be detected by real-time 
quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis on peripheral blood. After a patient achieves a confirmed complete cytogenetic 
response, this test should be performed every 6 months unless clinically indicated to do it more often.
u May be omitted if performed within 14 days before the first dose of omacetaxine.
v During the study it is only requested if the patient failed to respond or progressed.
w Except for day 1 of cycle 1 of induction.
x Obtain survival and progression-free survival defined as the time interval from date of first dose to date of death from any cause, or 12 months after last 
treatment cycle whichever occurs first. The patient is requested to be monitored even if the patient is withdrawn from the planned omacetaxine treatment or 
received other anticancer treatment.
HR=heart rate; RR=respiratory rate; BP=blood pressure; T=temperature; RBC=red blood cell; WBC=white blood cell; BUN=blood urea nitrogen; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; PCR=polymerase chain reaction; CML=chronic myeloid leukemia, CO2=carbon 
dioxide, FISH=florescence in situ hybridization.


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Table 3:
Pharmacokinetic Sampling Schedule, Phase 1, Cycle 1 Induction, Days 1 
Through 17
Day
Omacetaxine dose per daya
Times for blood plasma draws
1
Dose 1
–20 min, 15 (±5 min), 30 (±5 min), and 
45 (±5 min) minutes and, 1 hr (±5 min), 
2 hr (±10 min), 4 hr (±10 min), 8 to 12 hr (±15 min)
No Dose 2
NA
2
No Dose 1
24 hr (±1 hr)
No Dose 2
NA
3
No Dose 1
48 hr (±1 hr)
No Dose 2
NA
4
Dose 1
72 hr (±1 hr) (prior to dose 1 on day 4)
Dose 2
NA
5-9
Dose 1 and Dose 2
NA
10 or 11 or 12b
Dose 1
Predose
<1 hr after dose 1
1 to 12 hr after dose 1 
Dose 2
NA
13 or 14 or 15 or 16 or 17c
Dose 1 and Dose 2
Either predose 1 or predose 2
a To accommodate the pharmacokinetic objective of the study, during cycle 1, 1 dose is given in the morning of 
day 1, no dose 2 on day 1, no doses are given on day 2 or day 3.
b Pharmacokinetic samples to be drawn once, either on day 10 or 11 or 12. Day 10 or 11 or 12, <1 hr sample and 1-
12 hr sample should be drawn at least 30 minutes apart.
c Pharmacokinetic samples to be drawn once, either on day 13, or 14, or 15, or 16 or 17.
min=minutes; hr=hour; NA=not applicable.
Note: Exact volume of drug injected, actual time of dosing, and sample collection time will be recorded.
Table 4:
Pharmacokinetic Sampling Schedule, Phase 1 (Cycles 2 and 3) and Phase 2 
(Cycles 1, 2, and 3)
Cycle 1, 2, 3
Omacetaxine dose 
Times for blood plasma draws
Day 1a
Dose 1
Dose 2
<1 hr after dose 1
1 to 12 hr after dose 1
NA
After day 1 during week 1b
Dose 1 and Dose 2
One sample either predose 1 or predose 2
Any day during week 2 b
Dose 1 and Dose 2
One sample either predose 1 or predose 2
a Phase 2 only for cycles 1 to 3, and Phase 1 for cycles 2 and 3. The dosing is as prescribed either 14 days bid or 
7 days bid if in maintenance, or as per the investigator if the patients had dose delays or reductions after cycle 1. 
Exact volume injected of drug, actual time of dosing and sample collection will be recorded.
b Day 10 or 11 or 12, <1 hr sample and 1-12 hr sample should be drawn at least 30 minutes apart.
bid=twice daily; hr=hour; NA=not applicable.


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3.11.1.
Procedures for Screening and Enrollment
A signed and dated informed consent form will be obtained before screening procedures 
commence. Evaluations obtained as part of routine medical care and performed during the 
screening period may be used in place of the protocol-specific evaluations. In addition, 
disease-specific assessments performed within a specified time frame before informed consent 
may be used for the study. Patients will acknowledge and agree to the possible use of this 
information for the study by giving informed consent. 
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
permanent identification number such that all patients from each investigational center are given 
consecutive identification numbers in successive order of inclusion. The first 2 digits of the 
screening number will be the number assigned to the country where the investigational center is 
located, the next 3 digits will be the designated investigator center number, and the last 3 digits 
will be assigned at the investigator center (eg, if the number assigned to the country is 01, the 
3rd patient screened at center 5 would be given the number of 01005003).
During the enrolment period of the study, once the investigator has confirmed that the patient 
meets all eligibility criteria and has obtained patient informed consent, the investigational center 
staff must first register the patient with the sponsor or its designee, in order to enroll the patient 
in the study. Study reference materials for the patient registration procedure will be provided 
separately to each study center upon initiation of the study. Confirmation of patient enrollment 
will be sent to the investigator following receipt and review of the registration.
A patient who is screened but not enrolled, eg, because entry criteria were not met or enrollment 
did not occur within the specified time, may be considered for screening again if, eg, there is a 
change in the patient’s medical background or a modification of study entry criteria. 
Consultation with the sponsor or designee must occur first. The patient will sign a new informed 
consent and a new patient number will be assigned.
The following activities and evaluations will be performed up to 7 days prior to administration of 
the first dose of study drug, unless otherwise specified, in order to determine if a patient meets 
the eligibility criteria:

written informed consent (must be obtained prior to screening evaluations)

review inclusion/exclusion criteria 

review medical history

review medication history

perform physical examination 

measure height and weight and calculate body surface area

perform vital signs measurements (temperature, heart rate, respiratory rate, systolic
and diastolic blood pressures)


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
perform clinical laboratory tests, as follows:

hematology

full serum chemistry

urinalysis

bone marrow aspiration and cytogenetics, if not performed within 30 days before 
the first dose of omacetaxine

pregnancy test (urine or serum) for women of childbearing potential

determination of the types of BCR-ABL transcripts and BCR-ABL transcript 
peripheral blood levels by quantitative reverse transcription PCR (PCR) locally 
performed (Appendix B)

quantitative BCR-ABL kinase domain mutation analysis of peripheral blood 
sample locally performed if not available within 14 days before first dose of 
omacetaxine (Appendix B)

documentation of all other measures of disease and disease symptoms
(eg, extramedullary disease)

ECG, unless one was performed within the preceding 30 days. Prior to study entry, 
any other ECG abnormalities noted at screening other than myocardial infarction 
within the previous 12 weeks and felt by the investigator not to be medically relevant, 
must be documented as such.

chest x-ray unless one was performed within the preceding 30 days

ECOG performance status (Appendix C)
3.11.2.
Procedures During Study Drug Treatment (Induction and Maintenance)
In addition to the procedures specified in this section, data obtained from any unscheduled 
procedures and during any unscheduled visits will be collected on the appropriate CRF. 
3.11.2.1.
Procedures for Day 1 of Each Treatment Cycle 
The following assessments will be performed on day 1, or within 3 days before day 1 of each 
treatment cycle, unless otherwise specified:

physical examination (for cycle 1 may be omitted if done at screening within 7 days 
of dosing)

weight at each cycle (height at screening)


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
collect calculated BSA from investigational center (cycle 1 to cycle 3 only)

ECG prior to cycles 1 through 3 only (for cycle 1, it may be omitted if one was done 
within 30 days prior to the first dose of omacetaxine on day 1 of cycle 1)

vital signs (temperature, heart rate, respiratory rate, systolic and diastolic blood 
pressure) within 30 minutes before omacetaxine and 20 minutes post-injection 
(±5 min) on day 1 of each treatment cycle
Note: If the patient has hypotension (systolic blood pressure <90 mm Hg), vital signs 
should be taken and recorded more frequently, until the patient has stabilized. If no 
significant variations are observed during the first cycle, vital signs will be checked 
preceding each new treatment cycle.

ECOG performance status 

hematology (Appendix D)

serum chemistry 7 (sodium, chloride, carbon dioxide [CO2] content, creatinine, blood 
urea nitrogen (BUN) or urea, blood glucose, and potassium only) (Appendix D)

documentation of all other measures of disease and disease symptoms

drug accountability including review of completed patient diaries (except for day 1 
when the dose will be recorded at the investigational center)

adverse event inquiry

concomitant medication inquiry

Review of updated patient diaries and inquiries on compliance of omacetaxine 
administration. Please refer to the Patient Instructions on Subcutaneous Injection and 
Diary Completion for further details.
3.11.2.2.
Pharmacokinetic Procedures, Phase 1, Cycle 1 Only
Blood sampling for pharmacokinetic analysis will be obtained from all patients in Phase 1 during 
cycle 1 of induction, as follows (see Table 3):

On days 1 through 4 as follows:

20 minutes prior to, 15 (±5 min), 30 (±5 min), and 45(±5 min) minutes and 
1 (±5 min), 2 (±10 min), 4 (±10 min), 8 to 12 (±15 min), 24 (±1 hr), 48 (±1 hr), 
and 72 (±1 hr) hours (predose 1 on day 4) after administration of the first dose of 
omacetaxine

On day 10 or 11 or 12, as follows:


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
predose, within (<) 1 hour after dose 1, and 1 to 12 hours after dose 1

<1 hr sample and 1-12 hr sample should be drawn at least 30 minutes apart.

One sample on day 13, 14, 15, 16, or 17 as follows:

either predose 1 or predose 2
3.11.2.3.
Pharmacokinetic Procedures, Phase 1, Cycles 2 and 3 and Phase 2, Cycles 1 
Through 3
Blood samples (2.5 mL) will be obtained in Phase 1 on day 1 of cycles 2 and 3 as follows (see 
Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
Blood samples (2.5 mL) will be obtained in Phase 2 on day 1 of cycles 1, 2 and 3 as follows (see 
Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
On Day 10 or 11 or 12, the <1 hr sample and 1-12 hr sample should be drawn at least 30 minutes 
apart.
3.11.2.4.
Procedures During Cycles 1 Through 5 of Treatment (Days 7 [±2], 14 [±2], 
21 [±2])
The following assessments will be performed on days 7±2, 14±2, and 21±2 of the first 5 cycles 
of treatment, unless otherwise specified:

hematology

serum chemistry 7 (sodium, chloride, CO2 content, creatinine, BUN or urea, blood 
glucose, and potassium only)

ECG (after completion of day 14 of treatment in cycle 1, if the patient is available)


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
adverse event inquiry

concomitant medication inquiry

drug accountability including review of completed patient diaries
Tests may be obtained at a local laboratory, with results transmitted to the study investigational 
center in a timely manner (especially if needed before administration of omacetaxine or to 
follow-up an adverse event).
3.11.2.5.
Procedures After Cycle 5 of Treatment 
The following assessments will be performed on day 14 (±2 days) (versus weekly) for all 
treatment cycles after cycle 5.

hematology

full serum chemistry (Appendix D)

adverse event inquiry

concomitant medication inquiry

review of updated patient diaries and inquiries on compliance of omacetaxine 
administration
3.11.2.6.
Procedures During Study Drug Treatment–Every 3 Months (ie, every 3 cycles)
on Study–All Patients
The following studies will be obtained every 3 months (ie, every 3 cycles) while on study, in all 
patients, unless otherwise specified:

bone marrow aspiration and cytogenetics every 3 months
Performance of bone marrow procedures for these patients should be based on the 
need to demonstrate continued cytogenetic response and clinical circumstances 
(ie, may not be needed if clinical disease progression is documented). Cytogenetic 
response evaluation will be based on standard cytogenetic analysis (at least 
20 metaphases are to be analyzed).

measure BCR-ABL transcript levels by real-time, PCR of peripheral blood 

quantitative BCR-ABL kinase domain mutation analysis of peripheral blood sample, 
locally performed, if a patient failed to respond or progressed after treatment with 
omacetaxine (follow-up of BCR-ABL mutations) (Appendix B)

ECG (may be performed more frequently as clinically indicated or as required by 
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
drug accountability

adverse event inquiry

concomitant medication inquiry

review of updated patient diaries and inquiries on compliance of omacetaxine 
administration
For patient convenience, these studies may be scheduled to be obtained prior to the next 
scheduled omacetaxine treatment cycle.
Note: Any or all of the above studies may be conducted earlier than a scheduled 3-month interval 
if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
3.11.2.7.
Confirmation of Complete Hematologic Response or Major or Complete 
Cytogenetic Response (Induction or Maintenance)
In patients achieving a CHR or major cytogenetic response (either complete or partial 
cytogenetic response, up to 35% Ph+ metaphases) during the induction phase, the response will 
be confirmed by a repeat CBC, bone marrow aspiration (for patients with a hematologic 
response), cytogenetics of the bone marrow aspirate (for patients with a cytogenetic response), 
and BCR-ABL transcript levels by quantitative reverse transcription-polymerase chain reaction 
(RT-PCR) of peripheral blood, at the intervals specified below. For patient convenience, 
confirmatory studies may be scheduled to be done prior to the next scheduled omacetaxine
treatment cycle (rather than exactly at 4 or 8 weeks, as specified below, after the initial 
response). 

chronic phase CML: Confirm the response at least 8 weeks after the initial 
documentation of the response, ie, at least 8 weeks after the patient first meets the 
clinical and laboratory criteria for a response, as defined in Appendix A.

accelerated phase CML: Confirm the response at least 4 weeks after the initial 
documentation of the response, ie, at least 4 weeks after the patient first meets the 
clinical and laboratory criteria for a response, as defined in Appendix A.
If the CBC, bone marrow aspiration, and/or cytogenetic results do not confirm the clinical 
response and the patient is already on maintenance treatment cycles, the patient may revert back 
to induction cycles (ie, 14 days omacetaxine treatment) or the highest dose tolerated previously, 
if clinically indicated.
3.11.3.
Procedures After Study Drug Treatment
3.11.3.1.
End-of-Treatment Visit
The following procedures will be performed at the end-of-treatment visit, 28 days (+2 days) after 
the last dose of study drug, unless otherwise specified:


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
physical examination

weight

vital signs (temperature, heart rate, respiratory rate, systolic and diastolic blood 
pressure)

laboratory studies (Appendix D)

hematology

serum chemistry

bone marrow aspiration (or biopsy) if indicated ± cytogenetics (for confirmation of 
response)

ECG

BCR-ABL transcript levels by quantitative PCR of peripheral blood at local
laboratory (Appendix B) 

other measures of disease and disease symptoms, eg, extramedullary disease

ECOG performance status

drug accountability including review of completed patient diaries

adverse event inquiry

concomitant medication inquiry
For patients who complete the study, or for those who withdraw prematurely from the study, 
final evaluations will be performed 28 days (+2 days) after the last dose of study drug. Patients 
who withdraw prematurely may have their end-of-treatment visit earlier than 28 days after the 
last dose of omacetaxine. Patients with ongoing adverse events or clinically significant abnormal 
laboratory test results (as interpreted by the investigator) will be monitored as described in 
Section 7.1.2 and Section 7.3, respectively.
If a patient withdraws from the study during the treatment period, the reason must be determined 
and recorded on the patient’s CRF (see Section 4.3). Patients who withdraw prematurely from 
treatment with omacetaxine (planned period of up to 12 cycles) are still required to enter the 
follow-up period unless they withdraw consent. For patients who withdraw consent, every 
attempt will be made to determine the reason.
3.11.3.2.
Follow-up
Patients will be monitored every 3 months (±7 days) for progression (if the patient had not 
progressed at the time of the end-of-treatment visit) and survival for 1 year after the last dose of 


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omacetaxine, death, or lost to follow-up, whichever comes first, regardless of patients receiving 
other anticancer treatment. If the patient is receiving other anticancer treatment, the type of 
treatment and the dates of treatment will be reported on the CRF. The first follow-up visit will be 
in person and the rest of the follow-up visits may be done by telephone screening.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Changes to inclusion and exclusion criteria are indicated below and detailed in Section 17.
4.1.
Patient Inclusion Criteria
Patients may be included in the study only if they meet all of the following criteria:
a.
The patient has a confirmed diagnosis of Philadelphia chromosome (Ph) positive 
chronic myelogenous leukemia in either CP or AP. Accelerated phase will be defined 
as disease having 1 of the following: ≥15% to <30% blasts in peripheral blood or 
bone marrow; ≥30% blasts + promyelocytes in peripheral blood or bone marrow;
≥20% basophils in peripheral blood or bone marrow; platelet count <100x109/L 
unrelated to therapy; or clonal evolution.
b. The patient has either failed, demonstrated intolerance, or a combination of prior 
failure and intolerance, to prior treatments with at least 2 tyrosine kinase inhibitors 
(TKI's). Failure of TKI treatment may either be primary (never achieved a response) 
or secondary resistance (loss of response).

TKI treatment failure will be defined as 1 of the following:

no CHR by 12 weeks (whether lost or never achieved)

no partial cytogenetic response by 24 weeks (ie, 1 to 35% Ph-positive) 
(whether lost or never achieved)

no major cytogenetic response by 52 weeks (ie, ≤35% Ph-positive) (whether 
lost or never achieved)

progressive leukocytosis, defined as increasing white blood cell (WBC) count 
on at least 2 consecutive evaluations, at least 2 weeks apart and doubling from 
the nadir to ≥20000/µL or absolute increase in WBC by ≥50000/µL above the 
post-treatment nadir

Intolerance to TKI therapy will be defined as 1 of the following:

grade 3 to 4 nonhematologic toxicity that does not resolve with adequate 
intervention

grade 4 hematologic toxicity lasting more than 7 days, or a documented 
inability to sustain the TKI therapy because of recurrent grade 3 or 4 
hematologic toxicity with re-initiation of the same therapy

any grade 2 or greater toxicity that is unacceptable to the patient

Patients with a known T315I mutation must have been treated and failed 
ponatinib (prior to the entry into this study; this would not apply in a country 
where ponatinib has not been approved or where patients otherwise would not 
have access to this medication) unless medically contraindicated by the treating 
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c.
Patients must have completed all previous anticancer therapy for at least 2 weeks 
prior to the first planned dose of omacetaxine, except as noted below, and must have 
fully recovered from side effects of a previous therapy. 

In patients with rapidly proliferating disease, hydroxyurea may be administered 
before study entry, if clinically indicated, to control disease. In such cases, CHR
must be sustained for at least 4 weeks for accelerated CML, and at least 8 weeks 
for chronic phase CML, following the discontinuation of hydroxyurea, to be 
considered as a CHR. 

Patients may receive anagrelide for up to 28 days (in countries where the product 
is registered). Leukapheresis is allowed up to 24 hours prior to the first treatment 
cycle with omacetaxine.
d. Patients must have adequate hepatic and renal function as evidenced by bilirubin 
2.0 times the upper limit of the normal range (ULN) or lower, ALT and asparate 
aminotransferase (AST) 3 times the ULN or lower, serum creatinine 1.5 times the 
ULN or lower. Patients with nonclinically significant elevations of bilirubin up to 
5.0 g/dL (85500 µmol/L) due to known or suspected Gilbert’s disease are eligible; 
this must be documented on the medical history page of the CRF.
e.
Patients must have an ECOG performance status of 0 to 2. 
f.
Patients are men or women at least 18 years of age.
g. Patients must be able and willing to provide written informed consent prior to any 
study related procedure. (In the event that the patient is re-screened for study 
participation or if a protocol amendment alters the care of an ongoing patient, a new 
informed consent form must be signed.)
h. Patients must be able to comply with the requirements of the entire study. 
i.
The patient must take precautions to not become pregnant or produce offspring. 
Women must be of non-childbearing potential (surgically sterile or postmenopausal 
for at least 12 months, confirmed by follicle-stimulating hormone [FSH] >40 IU/L) or 
agree to use a medically accepted method of contraception for the duration of the 
study and 90 days after treatment. Men must be surgically sterile or agree to use a 
medically accepted method of contraception for the duration of the study and 90 days 
after treatment. Acceptable methods of contraception include abstinence, barrier 
method with spermicide (excluding cervical cap and sponge), intrauterine device 
(IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in 
conjunction with a barrier method. 
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria:


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a.
The patient has NYHA class III or IV heart disease, active ischemia, or any other 
uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac 
arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.
b. The patient has had a myocardial infarction in the previous 12 weeks. (Prior to study 
entry, any other electrocardiogram [ECG] abnormalities noted at screening other than 
myocardial infarction within the previous 12 weeks and felt by the investigator not to 
be medically relevant, must be documented as such.)
c.
The patient has received radiotherapy within 30 days prior to the start of study drug, 
or has not recovered from the acute toxicities associated with prior approved therapies 
including investigational drugs.
d. The patient has another concurrent illness that would preclude study conduct and 
assessment, including, but not limited to, another active malignancy (excluding 
squamous or basal cell skin cancer and in situ cervical cancer), uncontrolled medical 
conditions, uncontrolled and active infection (considered opportunistic, life 
threatening, or clinically significant), uncontrolled risk of bleeding, or uncontrolled 
diabetes mellitus.
e.
The patient underwent autologous or allogeneic stem cell transplant within 60 days 
prior to receiving the first dose of omacetaxine and has any evidence of ongoing graft 
versus host disease (GVHD), or GVHD requiring immunosuppressive therapy.
f.
The patient has a human leukocyte antigen (HLA)-matched donor and is eligible for 
allogeneic transplantation for CML treatment.
g. The patient has known positive human immunodeficiency virus (HIV) or known 
active human t-cell lymphotropic virus (HTLV) I/II disease, whether on treatment or 
not.
h. The patient has known active hepatitis B or C. The determination of active hepatitis B 
or C is left to the investigator.
i.
The patient is pregnant or lactating (any women becoming pregnant during the study 
will be withdrawn from the study).
j.
The patient has any medical or psychiatric condition, which may compromise the 
ability to give written informed consent or to comply with the study protocol. 
k. The patient has lymphoid Ph+ blast crisis or blast phase CML. 
l.
The patient participated in another clinical investigation within 30 days of enrollment 
or is receiving another investigational agent, unless discussed with the sponsor.
m. The patient received omacetaxine or has a history of hypersensitivity.
n. The patient has a known hypersensitivity to mannitol.


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o. The patient has a hemoglobin value, which is, in the opinion of the investigator, not 
adequate given the pharmacokinetic blood draw requirements of the Phase 1 portion 
of the study.
p. The patient has undergone major surgery within 14 days prior to starting 
omacetaxine, or who has not recovered from side effects of such procedure.
4.3.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.3.4), or other reasons concerning the health or well-being of the 
patient, or in the case of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.6, 5.4, and 7.1.7. 
Should a patient decide to withdraw after administration of study drug, or should the investigator
decide to withdraw the patient, all efforts will be made to complete and report the observations 
up to the time of withdrawal as thoroughly as possible. A complete final evaluation at the time of 
the patient’s withdrawal should be made and an explanation given of why the patient is 
withdrawing or being withdrawn from the study.
The reason for and date of withdrawal from study drug treatment and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed onto 
the CRF. If a patient withdraws consent, every attempt will be made to determine the reason. If 
the reason for withdrawal is an adverse event or a clinically significant abnormal laboratory test 
result, monitoring will be continued at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
specific event or test result(s) must be recorded on the source documentation and transcribed 
onto the CRF.


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5.
TREATMENT OF PATIENTS
5.1.
Study Drugs Administered
In Phase 1, there will be 3 cohorts of approximately 7 patients each. All patients will be given a 
fixed dose of 2.5 mg omacetaxine subcutaneous injection twice daily. The intent is to include, as 
much as possible, an equal number of patients in each BSA cohort. Cohort 1 will include patients 
whose BSA is less than 1.7 m2. Cohort 2 will include patients with a BSA between 1.7 m2 to 
2.0 m2 inclusive. Cohort 3 will include patients with BSA greater than 2.0 m2. 
Following the analysis of pharmacokinetic and preliminary safety and efficacy data from the 
Phase 1 patients reviewed by the independent DMC, a decision will be made whether to continue 
to the Phase 2 portion to further determine safety and efficacy. Refer to Sections 3.1 and 8, for 
further information on study design and pharmacokinetics, respectively.
For both phases (with the exception of cycle 1 of Phase 1 only), patients will receive induction 
cycles of 14 days twice daily treatment followed by 14 days without treatment (1 induction 
cycle) for as long as they adequately recover their blood counts and/or until they achieve 
hematologic response. Patients will then receive maintenance cycles of 7 days twice daily 
treatment followed by 21 days without treatment (1 maintenance cycle) for as long as they 
continue to benefit up to a period of 12 months following the first dose. Dose modifications for 
toxicity are allowed (see Section 5.1.2). If patients are continuing to receive benefit after 
12 months, discussion with the sponsor must take place before continuing study agent 
administration or being given omacetaxine commercially available where omacetaxine is 
approved. Doses should be administered at 12 hour (±2 hour) intervals. Patients who miss 1 day 
of dosing can make up that missed day as long as there is no more than 1 day interruption in 
dosing. That dose can added at the end of that cycle as long as it is continuous.
For cycle 1 of Phase 1 only, patients will receive only 1 dose of omacetaxine on day 1, no doses 
on days 2 and 3, and 2 doses on days 4 through 17 due to the pharmacokinetic objectives of the 
study (see Table 3). Therefore, each patient will be scheduled to receive 29 doses during cycle 1.
In both phases, the first fixed dose (2.5 mg) of cycle 1 will be given as reconstituted by a 
healthcare professional (eg, investigational center pharmacist) in a syringe at the investigational 
center. All doses of study drug will be administered via a prefilled syringe with a fixed dose of 
omacetaxine. Some of these doses may be administered on an outpatient basis or away from the 
investigational center by the patient, health care provider, or caregiver (patient must have been 
carefully trained before subcutaneous administration [see Section 5.1.1]) with a prefilled syringe 
reconstituted by applicable trained study healthcare professionals. The patient will record 
omacetaxine injections on a diary, which will be supplied for this purpose. The patient will 
return to the investigational center to obtain prefilled syringes (as per the expiration date).
Omacetaxine must be reconstituted by a healthcare professional. Proper aseptic technique should 
be used. Avoid contact with the skin. If omacetaxine comes into contact with skin, immediately 
and thoroughly wash affected area with soap and water. 


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Omacetaxine does not contain antimicrobial preservatives. Therefore, care must be taken to 
ensure that the solution for injection is not contaminated during preparation.
Omacetaxine is an antineoplastic product. Caution should be used during handling and 
preparation. 
Information regarding reconstitution, handling, shipping, and disposal of the syringe will be 
provided to the investigational center personnel.
5.1.1.
Training for the Patient or Caregiver
Omacetaxine will be administered by subcutaneous injection twice daily. The first dose of 
cycle 1 will be administered at the investigational center. Subsequent doses (in prefilled 
syringes) may be administered away from the investigational center after training takes place.
For day 1 of each cycle patients come to the investigational center to obtain drug and perform the 
required tests as applicable. If patients have difficulty after they undergo training, and in absence 
of a caregiver, they may be asked to come to the investigational center more often until they 
demonstrate proper technique.
The dose will be prepared in a commercially available 1-mL syringe by a healthcare professional 
and the fixed dose will be constant across all patients. The expiration date and time should be 
checked by the healthcare professional, caregiver, or patient before administration. The syringe 
may be carried in a tray within a container that will maintain the recommended storage
conditions for omacetaxine. The patient will return to the investigational center to obtain 
prefilled syringes (as per the expiration date). Further details of this information will be available 
in a Pharmacy Manual or pharmacy section of the investigator’s file at the investigational center 
including the most current stability data of the reconstituted omacetaxine.
Omacetaxine is to be administered by subcutaneous injection. The injection site should be 
disinfected with an alcohol swab, and allowed to air dry before the injection. The healthcare 
provider, caregiver, or the patient will be instructed to choose 1 of the following anatomical sites 
for the injection: thighs, abdomen, or back of the upper arms. The healthcare provider, caregiver, 
or the patient should select a new site before each injection. Any new injection must be done at 
least 3 cm from a previous injection site. The healthcare provider, caregiver, or the patient will 
be instructed not to inject study drug in areas where the skin have bruises, is sensitive, red, or 
indurated.
The patient and/or caregiver will be carefully trained before the subcutaneous administration.
Retraining as a refresher for investigational centers or patients will take place frequently and at 
least once per year for investigational centers that have active patients, but also as needed if 
issues arise via monitoring of the diaries, or monitoring of the investigational pharmacies. A 
training pamphlet with illustrations of the administration of a subcutaneous injection will be 
made available to the investigational centers and the patients or caregivers. Instructions on how 
to fill out the diary for accurate recording of doses administered will also be made available to 
investigational centers and patients.


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The patient will record omacetaxine injections in a diary, which will be supplied for this purpose. 
The diaries will be requested and reviewed by investigational centers at approximately weekly 
visits or more frequently if a patient has difficulties in the beginning. Further training will also be 
available. Applicable information from the diary will be entered into the clinical database. To 
ensure compliance of the reconstituted doses of omacetaxine and required procedures, outpatient 
nursing services, when needed, may be provided by the sponsor or reimbursed by the sponsor, 
depending on where the patient lives.
5.1.2.
Dose Modifications for Toxicity
5.1.2.1.
Hematologic Toxicity
Omacetaxine treatment cycles may be delayed and/or the number of days of dosing during the 
cycle reduced for hematologic toxicities (eg, neutropenia, thrombocytopenia). 
Complete blood counts should be performed weekly during the first 5 cycles. After the initial 
5 cycles, CBCs should be performed every 2 weeks (±2 days) or as clinically indicated via 
unscheduled but collected data visits. If a patient experiences grade 4 neutropenia (absolute 
neutrophil count [ANC] less than 0.5x109/L) or grade 3 thrombocytopenia (platelet counts less 
than 50x109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 
1.0x109/L and platelet count is greater than or equal to 50x109/L. If the patient should experience 
a delay as just described, in the next cycle, the number of dosing days can be reduced by 2 days.
For example, during induction this would be from 14 days to 12 days; during maintenance, this 
would be from 7 days to 5 days. If subjects tolerate a cycle with a 2-day reduction without any 
problems, then the following cycle, the full cycle can be provided. If more than 2 delays occur 
secondary to grade 4 neutropenia or grade 3 thrombocytopenia with yet another reduction in 2 
more days in either induction or maintenance, consideration of discontinuing study medication 
should be discussed by the treating physician, the designated CRO physician, and the designated 
Sponsor physician.
5.1.2.2.
Nonhematologic Toxicity
Other clinically significant nonhematologic toxicity will be managed on the basis of symptoms. 
Interrupt and/or delay omacetaxine until toxicity is resolved.
Complete blood count monitoring may be changed to every second week as clinically indicated 
during treatment starting with cycle 6.
5.2.
Restrictions
There are no specific restrictions in this study other than those described above and below.
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or procedure a patient has had within 14 days 
before study drug administration or during study drug administration, will be recorded on the 
CRF. During follow-up, any new anticancer treatments will be recorded. Generic or trade name, 


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indication, and dosage will be recorded. The sponsor will encode all therapy and medication 
according to the World Health Organization (WHO) drug dictionary (WHO Drug).
Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the 
platelet count is less than 50000/μL as they may increase the risk of bleeding.
Omacetaxine can induce glucose intolerance. Patients already being treating for diabetes, or 
patients with risk factors for diabetes, must have their blood glucose levels checked frequently.
5.3.1.
Permitted Concomitant Medications
The following concomitant medications are allowed during the study:

For patients with rapidly proliferating disease, hydroxyurea may be administered 
immediately prior to and during the first 2 cycles of treatment, if clinically indicated, 
to control disease. In such cases, CHR must be sustained for at least 4 weeks for 
accelerated phase CML and for at least 8 weeks for chronic phase CML, following 
the discontinuation of hydroxyurea, to be considered as a CHR.

Patients may receive anagrelide for up to 28 days (in countries where the product is 
registered).

Leukapheresis is allowed up to 24 hours prior to the first treatment cycle with 
omacetaxine.

All medications necessary for the treatment of other chronic patient conditions should 
be administered at a stable dose for 30 days prior to the first study drug 
administration and during the course of study treatment. Any major changes need to 
be discussed with the medical monitor.

Premedication with antiemetic therapy will be permitted if clinically indicated. All 
such medications should be noted and recorded on the appropriate case report form.

Hematopoietic growth factors may be used for treatment of febrile neutropenia; they 
may not be used to prophylactically maintain the white blood cell count.

Erythropoietin or darbepoetin alfa may be used and /blood transfusions administered 
at any time for treatment of anemia except 24 hours before a pharmacokinetic blood 
sample is drawn.
These requirements do not exclude the use of appropriate medications for the treatment of 
adverse events and/or intercurrent illness under the direction of the principal investigator. 
5.3.2.
Prohibited Medications
Systemic chemotherapy in the 2 weeks prior to the first study drug administration of 
omacetaxine and during the course of study treatment is prohibited.


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5.4.
Procedures for Monitoring Patient Compliance
Each investigator will be responsible for monitoring patient compliance and assisting the sponsor 
with accurate record keeping of administration of omacetaxine. A check of study drug 
compliance will be performed during each visit after the initial dispensation of study drug, and 
study drug accountability records will be completed. If the investigator or the sponsor determines 
that the patient is not in compliance with the study protocol, the investigator and the sponsor 
should determine whether the patient should be withdrawn. Patients will also be notified of these 
requirements in the informed consent process. The IEC/IRB should be notified.
5.5.
Total Blood Volume
The total blood volume to be withdrawn for any given patient is difficult to accurately predict 
and will depend, among other things, on how long the patient receives study drug, whether there 
are any adverse events leading to unscheduled blood draws, and whether there is any 
hospitalization related to said adverse events. Therefore, the timing and quantity obtained are 
defined in general terms as follows:
Full serum chemistry laboratory tests are scheduled to be performed at screening, every 2 weeks 
(±2 days) after cycle 5, and at the end-of-treatment visit. At each time point, 6 to 7 mL of blood 
will be drawn.
Serum chemistry 7 laboratory tests are scheduled to be performed on day 1 of each cycle, and 
days 7 (±2 days), 14 (±2 days), and 21 (±2 days) of cycles 1 through 5. At each time point, 6 to 
7 mL of blood will be drawn.
Hematology laboratory tests are scheduled to be performed at screening, day 1 of each cycle, 
days 7 (±2 days), 14 (±2 days), and 21 (±2 days) of cycles 1 through 5, day 14 (±2 days) for 
cycles after cycle 5, at confirmation of response, and at the end-of-treatment visit. At each time
point, 4 to 5 mL of blood will be drawn.
BCR-ABL transcript levels are scheduled to be performed at screening, every 3 months (ie, 
every 3 cycles) during the study, at confirmation of response, and at the end-of-treatment visit. 
At each time point, 3 mL of blood will be drawn.
BCR-ABL mutation analysis is to be performed at screening and every 3 months (ie, every 
3 cycles) on study. At each time point 3mL of blood will be drawn.
A serum pregnancy test for all women of childbearing potential may be performed at screening
(a urine pregnancy test is also acceptable); 2 mL of blood will be drawn.
Pharmacokinetic blood samples are scheduled to be performed at 15 time points during cycle 1 
of Phase 1, at 4 time points per cycle during cycles 2 and 3 of Phase 1, and at 4 time points per 
cycle during cycles 1, 2, and 3 of Phase 2. At each time point, 2.5 mL of blood will be drawn.


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As an example and assuming an average number of cycles of 4 per patient, the total blood 
volume for a patient in Phase 1 receiving 4 cycles of treatment would be 233.5 mL to 269.9 mL. 
The total blood volume for a patient in Phase 2 receiving 4 cycles would be 216 mL to 252 mL.


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6.
ASSESSMENT OF EFFICACY
6.1.
Primary Efficacy Variables
The primary efficacy variables and endpoints for this study are as follows: 

For patients with CP CML, the proportion of patients who achieve a major 
cytogenetic response (MCyR: complete cytogenetic response with no Ph+ metastases 
and partial cytogenetic response with up to 35% Ph+ metaphases) at any time during 
the study.

For patients with AP CML, the proportion of patients who achieve a major 
hematologic response (MaHR: complete hematologic response or no evidence of 
leukemia) and/or MCyR at any time during the study.

Final determination of response will be made by the independent DMC, comprised of 
3 physicians who treat patients with CML, are experienced with this type of activity, 
and are not investigators in the study. The method for response review will be 
detailed in the DMC Charter.
Response evaluation criteria are described in Appendix A.
6.2.
Secondary Efficacy Variables
The secondary efficacy variables and endpoints for this study are as follows: 

duration of response 

progression-free survival

overall survival 

molecular response at any time during the study
6.2.1.
Duration of Response
Duration of response is defined for responders as the time interval from the first reported date of 
MCyR or MaHR, as defined above, to the earliest date of objective evidence of disease 
progression (ie, development of accelerated-phase CML), relapse (ie, loss of complete 
hematologic or major cytogenetic response), or death. Patients who have an ongoing response or 
patients who discontinue treatment for reasons other than adverse events, progression, or death 
will have their data censored at the last response assessment date.


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6.2.2.
Progression-Free Survival 
Progression-free survival is defined as the time interval from the date of first dose to the date of 
the earliest objective evidence of disease progression (ie, development of accelerated-phase 
CML), relapse (ie, loss of complete hematologic or major cytogenetic response), or death. 
Patients who do not have disease progression or patients who discontinue treatment for reason 
other than adverse events, progression, or death will have their data censored at the last response 
assessment date.
6.2.3.
Overall Survival 
Overall survival is defined as the time interval from the date of the first dose to the date of death 
from any cause. Patients who do not die at the time of analysis will have their data censored at 
the last known alive date. 
6.2.4.
Molecular Response
Molecular response is defined by the decrease in the amount of BCR-ABL mRNA measured by 
reverse transcriptase polymerase chain reaction (RT-PCR) or by the actual percentage of 
BCR-ABL mRNA transcripts (ratio of BCR-ABL transcript numbers to the number of control 
gene transcripts) (Baccarani et al 2013, Cross et al 2012, Hughes et al 2006) (see Appendix A).


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study staff by evaluating the following:

adverse events (type, frequency, severity, and causality)

clinical laboratory test results (serum chemistry and hematology) at various points in 
the study

vital signs measurements (blood pressure, heart rate, respiratory rate, body 
temperature)

body weight

physical examination (including body weight)

12-lead ECG

concomitant medication usage

ECOG performance status
During the conduct of the study, an independent DMC will review accumulating safety and 
efficacy data on a regular basis (depending on percent of patients enrolled, or as described in the 
DMC charter) to ensure the safety of the study patients and study conduct issues. The DMC will 
also review data (pharmacokinetic, preliminary safety and efficacy) in Phase 1 in order to decide 
if the study is to continue to Phase 2 portion or be terminated.
The DMC will be composed of independent physicians with expertise in the CML therapeutic 
field. The DMC will receive safety and efficacy data, and other ad hoc data requested, as 
described in the charter. They will have the right to recommend discontinuation of the study for 
safety reasons. 
The DMC chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment. 
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form should be recorded and reported as an adverse event. 


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An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during the study will not be considered adverse 
events. 
Accordingly, an adverse event could include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions. (Note: A condition, recorded as pre-existing, 
that is intermittently symptomatic [eg, headache] and which occurs during the study 
should be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or any washout phase of the study

laboratory or diagnostic test abnormalities occurring after the start of the study (ie, 
after screening and once confirmed by repeat testing) that results in the withdrawal of 
the patient from the study, requires medical treatment or further diagnostic work-up, 
or is considered by the study Investigator to be clinically significant. Note: Abnormal 
laboratory test results at the screening visit that preclude a patient from entering the 
study or receiving study treatment are not considered adverse events, but will be 
recorded to monitor data from patients who do not meet screening criteria.

all events of possible drug induced liver injury with hyperbilirubinemia (defined as 
AST or ALT ≥3 times ULN, plus either bilirubin ≥2 times the ULN or International 
Normalized Ratio [INR] >1.5) or Hy's Law events require immediate study treatment 
cessation and reporting as a serious adverse event. 
Disease progression (or progressive disease), including death from disease progression, will not 
be considered an adverse event or a serious adverse event in this study, but will be collected as 
an efficacy variable, unless the outcome is more serious than what would normally be expected 
from the normal course of the disease.


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7.1.2.
Recording and Reporting Adverse Events
For the purpose of adverse event recording, the study period is defined as that time period from 
signature of the informed consent form through the end-of-treatment visit. Additional follow-up 
is without treatment for 12 months after the last treatment cycle or until death.
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed and the serious adverse event must be reported immediately (see 
Section 7.1.5.3.1). The investigator does not need to actively monitor patients for adverse events 
once the study has ended. Serious adverse events occurring to a patient after the treatment of that 
patient has ended should be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must query the patient for adverse 
events by asking an open ended question such as, “Have you had any unusual symptoms or 
medical problems since the last visit? If yes, please describe.” All reported or observed signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings will be recorded collectively 
as a single diagnosis on the CRF and, if it is a serious adverse event, on the Serious Adverse 
Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF. 
The relationship of each adverse event to study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the Investigator, must be recorded 
as described below.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event will be graded according to the NCI CTCAE version 4.0.
Adverse events that are not included in the NCI CTCAE lists will be graded according to the 
NCI CTCAE general guideline for grades as follows:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.


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Grade 2
Moderate; minimal, local intervention, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL), eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL, eg, 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to adverse event.
7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the study drug.

It could readily have been produced by the patient’s 
clinical state, environmental, or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
study drug. 

It does not reappear or worsen when the drug is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug administration cannot 
be ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the study drug.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental, or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the drug, yet a drug relationship
clearly exists.

It follows a known pattern of response to the study
drug.


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7.1.5.
Serious Adverse Events
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

death

a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing 
condition that has not worsened during participation in the study will not be 
considered serious adverse events. 

persistent or significant disability or incapacity (refers to a substantial disruption of 
one's ability to conduct normal life functions)

a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event.
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing condition 
that has not worsened during participation in the study will not be considered serious adverse 
events.
A visit to the hospital emergency room or hospital clinic is not considered inpatient 
hospitalization; however, it could be considered a serious adverse event if medical intervention 
was necessary in order to prevent a serious outcome, or if the patient was hospitalized. Thus, 
observation is not considered a serious adverse event.


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7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the current
Investigator’s Brochure. 
The sponsor’s Global Patient Safety & Pharmacovigilance Department will determine the 
expectedness for all serious adverse events.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the study period (including the protocol-defined follow-up period, described in 
Section 7.1.2), regardless of judged relationship to treatment with the study drug, must be
reported to the sponsor by the investigator. The event must be reported within 24 hours of when 
the investigator learns about it. Completing the serious adverse event form and reporting the 
event must not be delayed, even if not all the information is available. The investigator does not 
need to actively monitor patients for adverse events once the study has ended. Serious adverse 
events occurring to a patient after the treatment of that patient has ended should be reported to 
the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or other 
designated personnel (a contract research organization [CRO] in a country without a Sponsor 
LSO) (contact information is in the Clinical Study Personnel Contact Information section); the 
LSO will forward the report to the sponsor’s Global Patient Safety & Pharmacovigilance 
Department..
The following information should be provided to record the event accurately and completely:

study number C41443/2057

investigator and investigational center identification

patient number

patient initials

onset date and description of adverse event

investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of patient


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
date of first dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was related to study drug)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center within 24 hours of when it becomes 
known to the same address as the initial report.
For all countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) form/
extensible markup language (XML) file to the LSO/CRO for local submission to the regulatory 
authorities and IEC/IRBs and Investigators, according to regulations. The investigator is 
responsible for ensuring that the IEC/IRB is also informed of the event, in accordance with local 
regulations.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.2).


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7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all Investigators participating in 
sponsored clinical studies of omacetaxine and the appropriate regulatory authorities (and 
IEC/IRB, if appropriate).
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following: 

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to omacetaxine
7.1.6.
Protocol-Defined Adverse Events for Expedited Reporting
No protocol defined adverse events for expedited reporting were identified for this study.
7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from omacetaxine and/or the 
study at any time at the discretion of the investigator. If a patient is withdrawn wholly or in part 
because of an adverse event, both the adverse event page and termination page (end-of-treatment 
termination and/or study termination) of the CRF will be completed at that time, especially if the 
patient may not be able to come back for the regularly scheduled end-of-treatment visit.
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the clinical project physician (CPP)/clinical leader (CL) as soon as 
possible of all patients who are being considered for withdrawal due to adverse events. 
Additional reports must be provided when requested.
If a patient is withdrawn from omacetaxine for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event which in the opinion 
of the investigator is not severe enough to warrant discontinuation but which requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be need to take a prohibited medication, not the adverse event.


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7.1.8.
Medical Emergencies
Medical emergencies must be reported to the individual identified in the clinical study personnel 
contact information section of this protocol.
Equipment, supplies, and properly skilled medical personnel must be accessible for an adverse 
event requiring immediate treatment. Any dose of study drug, whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor.
7.1.9.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Pregnancy 
All pregnancies (pregnancies of women participating in the study and partners of men 
participating in the study) that occur during the study, or within 90 days of completion of the 
study, are to be reported immediately to the individual identified in the clinical study personnel 
contact information section of this protocol, and the investigator must provide the LSO/CRO
with the pregnancy form. The process for reporting a pregnancy is the same as that for reporting 
a serious adverse event (see Section 7.1.5.3). 
Any patient becoming pregnant during the study will be withdrawn. All patients (or partners) 
who become pregnant will be monitored to the completion or termination of the pregnancy. If the 
pregnancy continues to term, the outcome (health of the infant up to 8 weeks of age), details of 
birth, and presence or absence of any birth defect, congenital abnormalities, or maternal and 
newborn complications, will be reported to the sponsor. Any complication of pregnancy will be 
reported as an adverse event or serious adverse event, as appropriate.
If the pregnancy does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form.


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7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range allowed for this study for this 
patient population will be interpreted by the investigator as belonging to 1 of the following 
categories:

abnormal but not a clinically significant worsening from baseline

abnormal and a clinically significant worsening from baseline
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up.
Clinical laboratory tests (serum chemistry and hematology) will be performed at screening, prior 
to each treatment cycle, every 7 days (±2 days) during the first 5 cycles, and every 2 weeks 
(±2 days) during later cycles, as clinically indicated, and at the end-of-treatment visit. Urinalysis 
will be performed at screening only. 
Additional serum chemistry and hematology tests will be performed as clinically indicated in the 
case of severe toxicity until toxicity (or follow-up for an adverse event) resolves, returns to the 
baseline value, or grade 1 toxicity. These will be recorded on unscheduled CRF pages.
Additional hematology laboratory tests may be performed (and collected) to follow cytopenia at 
the discretion of the investigator or follow-up of an adverse event such as infection. These will 
be recorded on unscheduled CRF pages.
Clinical laboratory tests will be performed using local laboratories. Specific laboratory tests to be 
performed are listed below.
7.3.1.
Serum Chemistry
The following serum chemistry tests will be performed, unless otherwise specified:

phosphorus

sodium

potassium

chloride

bicarbonate or carbon dioxide

glucose


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
blood urea nitrogen (BUN) or urea

creatinine

uric acid

ALT

AST

total bilirubin

direct bilirubin, if clinically indicated

indirect bilirubin, if clinically indicated
7.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

red blood cell (RBC) count 

platelet count

ANC

white blood cell (WBC) count and differential count

polymorphonuclear leukocytes (neutrophils)

lymphocytes

eosinophils

monocytes

basophils

Other (see Appendix D)
7.3.3.
Urinalysis
Urinalysis, performed only at screening, will include testing for the following:


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
protein

glucose

ketones

blood (hemoglobin)

pH

specific gravity

microscopic, only if clinically indicated 

bacteria

RBCs

WBCs

casts

crystals
7.3.4.
Other Clinical Laboratory Tests
Other clinical laboratory tests will be performed to ensure the safety of the patients, but will not 
be used to assess the safety of the study drug.
Human chorionic gonadotropin (HCG) urine tests or beta HCG (βHCG) serum tests will be 
performed for all women at screening and thereafter, if clinically indicated. Any patient who 
becomes pregnant during the study will be withdrawn. Procedures for reporting the pregnancy 
are provided in Section 7.2. 
7.4.
Vital Signs
Vital signs include the following:

heart rate

respiratory rate

seated blood pressure

body temperature
Before pulse and blood pressure are measured, the patient must be in a supine or 
semi-erect/seated position and resting for at least 5 minutes. (The same position and arm should 


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be used each time vital signs are measured for a given patient.) For any abnormal vital sign 
finding, the measurement should be repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2.
7.5.
Electrocardiography
A 12 lead ECG will be conducted at screening, prior to dosing on day 1 of cycles 1 through 3, 
optionally after completion of treatment on day 14 of cycle 1, every 3 months (ie, every 3 cycles)
during the study, and at the end-of-treatment visit. Prior to study entry, any other ECG 
abnormalities noted at screening other than myocardial infarction within the previous 12 weeks 
and felt by the investigator not to be medically relevant, must be documented as such. In 
countries where required, ECGs will be performed before and after every cycle (±3 days) or 
more frequently as clinically indicated. Any ECG finding that is judged by the investigator as a 
clinically significant change (worsening) compared with a baseline value will be considered an 
adverse event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.6.
Physical Examinations
Physical examinations, including body weight (and height to be obtained at the screening visit 
only) will be performed as in the schedule of events Table 2. Physical examination findings at 
screening will be classified using standard categories as listed on the Medical History CRFs. Any 
physical examination finding that is judged by the investigator as a clinically significant change 
(worsening) compared to a baseline value will be considered an adverse event, recorded on the 
Adverse Event CRF, and monitored as described in Section 7.1.2.
7.7.
Concomitant Therapy or Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.
7.8.
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group (ECOG) performance status will be assessed at screening, 
day 1 of each cycle, and at the end-of-treatment visit.
7.9.
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data
Methods and timing of assessing safety data are discussed in Section 3.11. Procedures for 
recording safety data are discussed in Section 13.1, and methods of analyses are discussed in 
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Furthermore, all adverse events will be reviewed on a periodic basis (eg, scheduled safety 
reviews for omacetaxine) as interim/preliminary safety databases become available (see 
Section 7). 


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8.
ASSESSMENT OF PHARMACOKINETICS
To characterize the pharmacokinetics of omacetaxine, blood samples (2.5 mL) for measurement 
of plasma concentrations of omacetaxine and its 2 known circulating metabolites, 4’-DMHHT
and cephalotaxine, will be obtained (via venipuncture or indwelling catheter) as specified below 
in Section 8.2. The actual time, dose, and volume of omacetaxine administered and actual blood 
collection time will be documented on CRFs.
8.1.
Pharmacokinetic Variables
The following pharmacokinetic parameters for omacetaxine and its metabolites will be 
calculated for each patient, when possible, from plasma concentrations obtained following the 
first dose of omacetaxine in Phase 1: 

maximum observed plasma drug concentration (Cmax) by inspection (without 
interpolation)

time to Cmax, by inspection (tmax)

area under the plasma drug concentration by time curve (AUC) from time 0 to infinity 
(AUC0–∞)

AUC from time 0 to the time of the last measurable drug concentration (AUC0–t)

AUC from time 0 to 12 hours (AUC0–12)

apparent plasma terminal elimination rate constant (λz) and associated terminal 
elimination half-life (t½)

percentage extrapolation calculated as (AUC0-∞-AUC0-t)/(AUC0-∞)x100

apparent plasma clearance (CL/F)

apparent volume of distribution (Vz/F)

predicted accumulation ratio (Rpred) calculated as AUC0–∞/AUC0–12
8.2.
Blood Sampling and Handling
Methods for blood sampling and processing are in the Pharmacokinetics and Laboratory Manual.
8.2.1.
Phase 1 
In Phase 1, to accommodate the pharmacokinetic objective of the study, during cycle 1, 
omacetaxine will be administered by subcutaneous injection as follows: 1 dose will be 
administered in the morning of day 1, no doses will be administered on days 2 or 3, 2 doses will 


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be administered on days 4 through 17. Starting with cycle 2, patients will continue treatment as 
in Section 5.1.
Blood samples (2.5 mL) will be obtained during Phase 1 as follows (see Table 3):

20 minutes prior to and 15 (±5 min), 30 (±5 min), and 45 (±5 min) minutes and 
1 (±5 min), 2 (±10 min), 4 (±10 min), 8 to 12 (±15 min), 24 (±1 hr), 48 (±1 hr), and 
72 (±1 hr) hours (predose 1 on day 4) after administration of the first dose of 
omacetaxine 

on day 10 or 11 or 12, predose, within (<) 1 hour after dose 1, and 1 to 12 hours after 
dose 1

1 sample on day 13, 14, 15, 16, or 17 either predose 1 or predose 2
In addition, blood samples (2.5 mL) will be obtained in Phase 1 on day 1 of cycles 2 and 3 as 
follows (see Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
8.2.2.
Phase 2
Blood samples (2.5 mL) will be obtained in Phase 2 on day 1 of cycles 1, 2, and 3 as follows (see 
Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
8.3.
Shipment of Samples
Procedures for shipment and processing of samples are in the Pharmacokinetics and Laboratory 
Manual.


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9.
STATISTICS
9.1.
Study Design 
This is a Phase 1/Phase 2 open-label, single-group clinical study in patients with CP or AP CML 
who have failed 2 or more TKI therapies to investigate the pharmacokinetics, safety, and efficacy 
of omacetaxine given subcutaneously as fixed doses. 
9.2.
Sample Size and Power Considerations
The sample size for Phase 1 is approximately 21 patients in order to meet the pharmacokinetic 
objectives of the study. These 21 patients will also be counted in the sample size for Phase 2 and 
be part of any Phase 2 analyses.
Phase 2 sample sizes are based on Simon’s 2-stage optimum design. To reject the null hypothesis 
of MCyR rate 2.5% or lower in patients with CP CML at a target 1-sided alpha of 0.025 and beta 
of 0.10 (power of 90%) and assuming that the MCyR rate in the current study will be at least 
16%, in the first stage 16 patients with CP CML will be treated. If 1 or more patients respond, 
then the study will enroll another 29 patients with CP CML for a total of 45 patients. If 4 or more 
of the 45 patients achieve a MCyR, the fixed-dose regimen will be deemed effective in patients 
with CP CML. If the true rate is less than or equal to 2.5%, the probability of stopping after 
stage 1 is 0.667. 
The alternative hypothesis rate is set at 16% because an 18.4% response rate was observed in the 
registration studies (Studies CGX-635-CML-202 and CGX-635-CML-203) in which patients 
received older generations of TKI drugs, and in the current study patients will be more likely to 
have received a newer generation of TKI drugs and more lines of therapy and may be less likely 
to respond to omacetaxine.
To reject the null hypothesis of MCyR rate 2.5% or lower in patients with AP CML at a target 
1-sided alpha of 0.025 and beta of 0.10 (power of 90%), and assuming that the MaHR rate in the 
current study will be at least 12%, in the first stage 40 patients with AP CML will be treated. If 
2 or more patients achieve a MaHR, then the study will enroll another 27 patients with AP CML 
for a total of 67 patients. If 5 or more of the 67 patients respond, then the drug will be deemed to 
be effective in patients with AP CML. If the true rate is 2.5% or lower, the probability of 
stopping after stage 1 is 0.736. The alternative hypothesis rate is set at 12%, lower than the 
observed rate of 14.3 in the above mentioned registration studies for the same reason.
9.3.
Analysis Sets
The set of enrolled patients includes all patients who provide informed consent to participate in 
the study and who meet all inclusion and exclusion criteria, regardless of whether or not a patient
receives any study drug. 
The safety analysis set will include patients who receive 1 or more doses of study drug. 


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The per-protocol analysis set will include patients in the safety analysis set who have at least 
1 response assessment after study drug administration and have been compliant with the study 
protocol. 
The pharmacokinetic analysis set will include all patients who have at least 1 pharmacokinetic 
measurement value after receiving study drug. 
9.4.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data. Patients without response assessment after dosing 
will be considered nonresponders. 
9.5.
Study Population
The set of enrolled patients (see Section 9.3) will be used for all study population summaries 
unless otherwise noted. Summaries will be presented by BSA categories and overall in Phase 1, 
by disease phase (CP CML and AP CML), and overall in Phase 2, as appropriate.
9.5.1.
Patient Disposition
Data from patients who are enrolled, patients enrolled but not treated, patients in the safety,
per-protocol, and pharmacokinetic analysis sets, patients who complete the study, and patients
who withdraw from the study will be summarized using descriptive statistics. Data from patients
who withdraw from the study will also be summarized by reason for withdrawal using 
descriptive statistics.
9.5.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, prior medications, 
and ECG findings will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number [n], mean, standard deviation, standard error, median, minimum, 
and maximum) will be provided. For categorical variables, patient counts and percentages will 
be provided. Categories for missing data will be presented if necessary.
9.6.
Efficacy Analysis
Efficacy variables will be calculated using the safety analysis set and the per-protocol analysis 
set and be displayed by disease phase.
9.6.1.
Primary Variables
The primary efficacy variable for patients with CP CML is the proportion of patients who 
achieve a major cytogenetic response (MCyR: complete cytogenetic response with no Ph+ 
metastases and partial cytogenetic response with up to 35% Ph+ metaphases). The primary 
efficacy variable for patients with AP CML is the proportion of patients who achieve a major 


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hematologic response (MaHR: complete hematologic response or no evidence of leukemia) 
and/or MCyR. 
9.6.2.
Secondary Variables
The secondary efficacy variables are as follows:

duration of response, defined for responders as the time interval from the first 
reported date of MCyR or MaHR, as defined above, to the earliest date of objective 
evidence of disease progression (ie, development of accelerated-phase CML), relapse 
(ie, loss of complete hematologic or major cytogenetic response), or death
Patients who have ongoing response or patients who discontinue treatment for 
reasons other than adverse events, progression, or death will have their data censored 
at the last response assessment date.

progression-free survival, defined as the time interval from the date of the first dose 
to the earliest date of objective evidence of disease progression (ie, development of 
accelerated-phase CML), relapse (ie, loss of complete hematologic or major 
cytogenetic response), or death
Patients who do not have disease progression or patients who discontinue treatment 
for reason other than adverse events, progression, or death will have their data
censored at the last response assessment date.

overall survival, defined as the time interval from the date of first dose to the date of 
death from any cause
Patients who do not die at the time of analysis will have their data censored at the last 
known alive date. 

molecular response, defined by the decrease in the amount of BCR-ABL mRNA 
measured by RT-PCR (reverse transcriptase polymerase chain reaction) or by the 
actual percentage of BCR-ABL mRNA transcripts (ratio of BCR-ABL transcript 
numbers to the number of control gene transcripts) (Baccarani et al 2013; Cross et al
2012, Hughes et al 2006) (see Appendix A).
9.6.3.
Planned Method of Analysis
Response rates by disease phase (CP CML and AP CML) and their 2-sided exact 95% CIs will 
be calculated. The lower limit of the CI will be compared with a prior value of 2.5%. If the lower 
limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold 
required to demonstrate efficacy. When sample size permits, these variables will also be 
compared within a disease phase by age, sex, disease history, and treatment history using a 
logistic regression model. 
For duration of response, time to progression, and overall survival, the Kaplan-Meier method 
will be used to calculate survival rates by disease phase. When sample size permits, these 
variables will also be compared within a disease phase by age, sex, disease history, and treatment 
history using a Cox proportional hazards regression model.


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Molecular responses will be analyzed using descriptive statistics.
Efficacy variables will also be analyzed separately in patients who were treated in Phase 1.
Additional exploratory analyses may be performed to assist in planning future studies.
9.7.
Multiple Comparisons and Multiplicity
There are no multiple comparisons or multiplicity in this study.
9.8.
Safety Variables and Analysis
The safety and tolerability of omacetaxine treatment will be assessed throughout the study by 
evaluating the following:

adverse events (type, frequency, severity, and causality)

clinical laboratory test results (serum chemistry and hematology) at various points in 
the study

vital signs measurements (blood pressure, heart rate, respiratory rate, body 
temperature)

bodyweight

12-lead ECG

concomitant medication usage

ECOG performance status
The safety analysis set will be used for all safety analyses. Safety data will be displayed by 
disease phase and overall.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events (overall 
and by severity), adverse events determined by the investigator to be related to study drug 
treatment (ie, related, not related, or with missing relationship) (overall and by severity), serious 
adverse events, serious treatment-related adverse events, adverse events leading to withdrawal, 
and grade 3 and 4 adverse events. Patient listings of adverse events, serious adverse events, and 
adverse events leading to withdrawal will be presented.
Laboratory values will be graded according to NCI CTCAE version 4.0 criteria. The number and 
percentage of patients with grade 3 or 4 values will be tabulated. Summaries of laboratory values 
for laboratory parameters will be provided. Vital signs abnormalities will be categorized and 
tabulated. Summaries of the vital sign measurements will be provided. Changes in ECOG 


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performance status will be identified as improved, worsened, or stayed the same, and incidences 
of patients with changes will be tabulated.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug.
For continuous variables, descriptive statistics (n, mean, standard deviation, standard error, 
median, minimum, and maximum) will be provided for actual values and changes from baseline 
to each time point. For categorical variables, patient counts and percentages will be provided. 
Descriptive summaries of serious adverse events, patient withdrawals due to adverse events, and 
potentially clinically significant abnormal values (clinical laboratory or vital signs) based on 
predefined criteria will also be provided.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report. 
Safety variables will also be analyzed separately in patients who were treated in Phase 1.
9.9.
Pharmacokinetic Analysis
The pharmacokinetic analysis set will be used for all pharmacokinetic analyses. Pharmacokinetic 
parameters will be summarized by BSA categories and overall using descriptive statistics. All 
plasma concentration data may also be included in population pharmacokinetic analyses to 
further characterize the pharmacokinetics of omacetaxine in the patient populations and to assess 
exposure-response and exposure-safety relationship in patients receiving omacetaxine, if 
appropriate.
9.10.
Planned Interim Analysis
Pharmacokinetic and pharmacodynamic analyses as appropriate will be conducted to monitor 
patients during Phase 1 of the study. As each patient completes cycle 1 in Phase 1, plasma 
concentrations of omacetaxine will be measured. A few patients may be batched. The difference 
between expected and measured pharmacokinetic data will be used to determine if the fixed dose 
strategy is appropriate, or whether alternative strategies are warranted. If differences emerge, 
analyses will be conducted to determine if the deviations can be explained by differences in 
BSA.
Once a total of approximately 21 patients with adequate pharmacokinetic samples are enrolled in 
Phase 1 of the study, pharmacokinetic parameters will be determined. Some patients may be 
replaced. Whether or not there is any correlation between exposure and preliminary efficacy or 
safety will be explored. 
After all patients in Phase 1 have completed cycle 1 of treatment and have pharmacokinetic 
samples analyzed, descriptive statistics will be used to compare pharmacokinetic parameters 
among the 3 cohorts (patients with small, medium, and large BSA). No formal statistical testing 
will be done due to the small sample size. Selected preliminary safety and efficacy data, as 


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appropriate, will also be provided to the DMC to assist with the evaluation of whether the fixed 
dose is appropriate for Phase 2 of the study. 
9.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the complete statistical plan, the clinical study report, or any 
combination of these, as appropriate.


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10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The medical experts, study monitors, auditors, and health authority inspectors (or their agents) 
will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with local requirements.
Each investigator must maintain the original records (ie, source documents) of each patient’s 
data at all times. Examples of source documents are hospital records, office visit records, 
examining physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, 
drug inventory, study drug label records, diary data, protocol required worksheets, and CRFs that 
are used as the source (see Section 3.9).
Each investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.


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11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when necessary to 
address immediate safety concerns to the patients or when the change involves only logistics or 
administration. The investigator and the sponsor will sign the protocol amendment.
11.1.2.
Protocol Deviations
Any significant deviation from the protocol will be considered a protocol violation. Protocol 
violations include nonadherence on the part of the patient, the investigator, or the sponsor to 
protocol-specific inclusion/exclusion criteria, primary objective variable criteria, or GCP 
guidelines; noncompliance to study drug administration; use of prohibited medications; or any 
other deviations that may have an impact on the processes put in place for the care and safety of 
the patients. Protocol violations will be identified and recorded by investigational center
personnel on the CRF. All protocol violations will be reported to the responsible IEC/IRB, as 
required.
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical representative. The decision will be based on ensuring the safety of the patient 
and preserving the integrity of the study. 
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
eligibility criteria was entered into a study, they must immediately inform the sponsor of the 
protocol violation. If such patient has already completed the study or has withdrawn early, no 
action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
Each investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). Each investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study staff, including each 
investigator, and for ensuring they comply with the protocol. Additional information will be 


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made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor.
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines.
The study monitor is the primary association between the sponsor and each investigator. The 
main responsibilities of the study monitors are to visit the investigator before, during, and after 
the study to ensure adherence to the protocol, that all data are correctly and completely recorded 
and reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitors will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, to include specific electronic 
source documentation [see Section 3.9]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification (SDV) flags to the CRF and will ensure that 
all required electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. Each investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication.
11.4.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit.
Each investigator must accept that regulatory authorities and sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines.


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12.
ETHICS
12.1.
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and/or oral information about the study will be provided in a language as 
nontechnical as practical and understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study.
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in writing in a consent form, which 
will be signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the patients. It will also be explained to the patients that the patient is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment.
12.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center
before the IEC/IRB and health authority (where applicable) for the center give written approval 
or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
Each investigator must assure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (eg, initials and identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.


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12.4.
Declaration of the End of the Clinical Study
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed.
12.5.
Registration of the Clinical Study
In accordance with sponsor’s standard procedures, this clinical study will be registered on 
clinical trials registry websites, such as clinicaltrials.gov.


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13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 CFR part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and study-specific training. After they are trained, users will be provided with individual 
system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient screened according to the data source. 
Patient identity should not be discernible from the data provided on the CRF. Data will be 
verified using the data source by the study monitor, and reviewed for consistency by Data 
Management using both automated logical checks and manual review. All data collected will be 
approved by the investigator at the investigational center. This approval acknowledges the 
investigator’s review and acceptance of the data as being complete and accurate. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data), the results will be sent to the investigational center where 
they will be retained but not entered into the CRF unless otherwise specified in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management) for direct entry into the clinical database (see Section 3.9). Laboratory test results 
will not be entered into the CRF unless otherwise noted in the protocol. All data from other 
sources will be available to the investigator(s).
For patients who enter a study but do not meet screening criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality assurance, will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data quality assurance, will be described in a data management 
plan.
Case report forms received will be processed and reviewed for completeness, consistency, and 
the presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 


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accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried.
Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents
13.3.1.
Investigator Responsibilities
All records related to the study (ie, source data, source documents, CRFs [see Section 3.9], data 
results from other sources [see Section 13.1], copies of protocols and protocol amendments, drug 
accountability forms, correspondence, patient identification lists, signed informed consent forms, 
and other essential documents) must be retained until the sponsor notifies the institution, in 
writing, that records may be destroyed.
If the sponsor has not provided written notification of records destruction after 15 years from 
study completion (or earlier in the event of an institution closing), and the institution determines 
the study record retention is unduly burdensome, the institution may submit a written request to 
the sponsor at least 60 days before the planned disposition of the study records. No study 
document or image (eg, scan, radiograph, ECG tracing) should be destroyed without prior 
written agreement between the sponsor and each investigator. Should an investigator wish to 
assign the study records to another party or move them to another location, advance written 
notice will be given to the sponsor.
13.3.2.
Sponsor Responsibilities
The sponsor will be responsible for the processing and quality control of the data. Data 
management and filing will be carried out as described in the sponsor’s SOPs for clinical studies.
If data management and filing of documents for this study are delegated to a contract 
organization, these functions will be carried out as described in the SOPs for clinical studies at 
that organization. These SOPs will be reviewed by the sponsor before the start of data 
management and filing activities. The original CRFs will be archived by the sponsor. 
Center-specific CRFs will be provided to the respective investigational centers for archiving.


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14.
FINANCING AND INSURANCE
A separate financial agreement will be made between the principal investigator and the sponsor 
before the study drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. 
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions.
Excluded from the insurance cover are, inter alia, damages to health and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.


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15.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results.
The sponsor is responsible for preparing a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating 
investigator.
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Uniform Requirements for Manuscripts Submitted to Biomedical Journals” as established by 
the International Committee of Medical Journal Editors (www.ICMJE.org). Authorship will be 
restricted to parties who have editorial or conceptual input to protocol design, collection of data 
and/or analysis, interpretation of data, and manuscript preparation. The publications committee 
established by the sponsor will oversee this process. Additional publications may follow. Policies 
regarding the publication of the study results are defined in the financial agreement.
No patent application(s) based on the results of the study may be made by the investigator nor 
may assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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16.
REFERENCES
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European 
LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 
2013;122(6):872-84.
Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M. Chronic myeloid 
leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of 
Oncology 2012;23 (Supplement 7):vii72-vii77.
Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood 
2012;120(7):1390-7.
Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, et al. Phase 2 study of 
subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML 
with T315I mutation. Blood 2012;120(13):2573-80.
Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular 
response in chronic myeloid leukemia. Leukemia 2012;26(10):2172-5.
Field KM, Kosmider S, Jefford M, Michael M, Jennens R, Green M, et al. Chemotherapy dosing 
strategies in the obese, elderly, and thin patient: Results of a nationwide survey. Journal of 
Oncology Practice 2008;4(3):108-13.
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML 
patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for 
harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain 
mutations and for expressing results. Blood 2006;108(1):28-37.
Mathijssen HJ, DeJong FA, Loos WJ, van der Bol JM, Verweij J, Sparreboom A. Flat-fixed 
dosing versus body surface area-based dosing of anticancer drugs in adults: Does it make a 
difference? The Oncologist 2007;12:913-23.
Nemunaitis J, Mita A, Stephenson J, Mita MM, Sarantopoulos J, Padmanabhan-Iyer S, et al. 
Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients 
with advanced solid and hematologic tumors. Cancer Chemother Pharmacol 2013;71(1):35-41.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 01 Dated 22 April 2015
The primary reasons for this amendment are 1) the French Competent Authority review of the 
sponsor’s regulatory submission, where they required clarification that patients with the T315I
specific mutation should not be enrolled into the 2057 study unless they have failed or were 
intolerant to ponatinib as one of their prior therapies, assuming they are medically fit to receive 
this TKI, 2) risk benefit information added in protocol in response to comment from the Central 
Ethics Committee (CEC) to add risk benefit information, and 3) revised specifics for reporting 
serious adverse events section and updated relationship categories under assessment of safety 
based on new protocol template.
The revisions listed below have been made to the protocol (and protocol synopsis, as 
appropriate) and some are considered substantial by the Teva Authorized Representative. Minor 
editorial changes have also been made to the protocol, but are not listed in the table below.


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Initial wording
Amended or new wording
Reason/Justification for change
Chapter/section concerned:
Header
Clinical Study Protocol
Chapter/section concerned:
Header
Clinical Study Protocol with Amendment 01
Added that this is Amendment 01
Chapter/section concerned:
Title Page
Clinical Study Protocol
Protocol Approval Date:
Chapter/section concerned:
Title Page
Clinical Study Protocol with Amendment 01
Protocol Amendment 01 Approval Date:
Added that this is Amendment 01
Chapter/section concerned:
Title Page, Authorized Representative (Signatory)
 
Teva Pharmaceuticals
Chapter/section concerned:
Title Page, Authorized Representative (Signatory)
 
Teva Pharmaceuticals
Date of copyright changed from 2012 to 2015.
Change in Administration.
Changed date to reflect year the 
protocol was approved.
Chapter/section concerned:
Title Page
This clinical study will be conducted in accordance 
with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Conference on 
Harmonization (ICH); United States (US) Code of 
Federal Regulations (CFR) and European Union (EU) 
Directives (as applicable in the region of the study); 
local country regulations; and the sponsor’s Standard 
Operating Procedures (SOPs). 
This document contains confidential and proprietary 
information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a 
confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc., and its affiliate, 
Cephalon, Inc. (collectively the “Sponsor”). The 
recipient agrees that no information contained herein 
may be published or disclosed without written approval 
from the Sponsor.
Chapter/section concerned:
Title Page
Confidentiality Statement
This clinical study will be conducted in accordance with current 
Good Clinical Practice (GCP) as directed by the provisions of the 
International Conference on Harmonization (ICH); United States 
(US) Code of Federal Regulations (CFR) and European Union 
(EU) Directives (as applicable in the region of the study); local 
country regulations; and the sponsor’s Standard Operating 
Procedures (SOPs). 
This document contains confidential and proprietary information 
(including confidential commercial information pursuant to 
21CFR§20.61) and is a confidential communication of Teva 
Branded Pharmaceutical Products R&D, Inc., and its affiliate, 
Cephalon, Inc. (collectively the “Sponsor”). The recipient agrees 
that no information contained herein may be published or 
disclosed without written approval from the Sponsor.
The words “Confidentiality 
Statement” were missing from the 
title page.


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Initial wording
Amended or new wording
Reason/Justification for change
Chapter/section concerned:
Chapter/section concerned:
Amendment history page added.
Amendment history page added 
because we have an administrative 
letter and Amendment 01 to add.
Chapter/section concerned:
Investigator Agreement
Chapter/section concerned:
Investigator Agreement
Sponsor’s Authorized Representative changed from 
 
to 
and revised Investigator Agreement page inserted.
Updated to reflect revised protocol 
template and change in 
administration.
Chapter/section concerned:
Coordinating Investigator Agreement
(For studies in the EUropean union)
Chapter/section concerned:
Coordinating Investigator Agreement
(For studies in the EUropean union)
This page was deleted because the new Investigator Agreement 
page replaces the Coordinating Investigator page.
This page was deleted because the 
new Investigator Agreement page 
replaces the Coordinating 
Investigator page.
Chapter/section concerned:
CLINICAL STUDY PERSONNEL CONTACT 
INFORMATION
For protocol and clinical questions, contact:
Teva Pharmaceuticals
For study operational issues, contact the operational 
lead listed below: 
 
 
Teva Pharmaceuticals
 
 
Chapter/section concerned:
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For protocol and clinical questions, contact:
Teva Pharmaceuticals
For study operational issues, contact the operational lead listed 
below: 
 
Teva Pharmaceuticals
 
Change in Administration.
Correction to fax number for 
 
Chapter/section concerned:
Chapter/section concerned:
The protocol was amended as a 


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Initial wording
Amended or new wording
Reason/Justification for change
Clinical Study Protocol Synopsis
Criteria for Inclusion b
Clinical Study Protocol Synopsis
Criteria for Inclusion b
The following text was added as a bullet point under criteria for 
exclusion b:

Patients with a known T315I mutation must have 
been treated and failed ponatinib (prior to the entry 
into this study; this would not apply in a country 
where ponatinib has not been approved or where 
patients otherwise would not have access to this 
medication) unless medically contraindicated by 
the treating study doctor
result of the French Competent 
Authority review of the sponsor’s
regulatory submission, where they 
required clarification that patients 
with this specific mutation should 
not be enrolled into the 2057 study 
unless they have failed or were 
intolerant to ponatinib as one of 
their prior therapies, assuming 
they are medically fit to receive 
this TKI.
Chapter/section concerned:
Clinical Study Protocol Synopsis
Criteria for Exclusion:
b. The patient has had a myocardial infarction in the 
previous 12 weeks.
Chapter/section concerned:
Clinical Study Protocol Synopsis
Criteria for Exclusion:
b. The patient has had a myocardial infarction in the previous 
12 weeks. (Prior to study entry, any other electrocardiogram 
[ECG] abnormalities noted at screening other than myocardial 
infarction within the previous 12 weeks and felt by the 
investigator not to be medically relevant, must be documented as 
such.)
Clarification.
Chapter/section concerned:
Clinical Study Protocol Synopsis
Duration of Patient Participation
The study will consist of up to a 7-day screening 
period, and treatment for up to 12 months depending on 
response and tolerability. Patients will also have an 
end-of-treatment follow-up visit approximately 28 days
after the last dose of omacetaxine.
Chapter/section concerned:
Clinical Study Protocol Synopsis
Duration of Patient Participation
The study will consist of up to a 7-day screening period, and 
treatment for up to 12 months depending on response and 
tolerability. Patients will also have an end-of-treatment follow-up 
visit approximately 28 days (+2 days) after the last dose of 
omacetaxine.
Added +2 days so there is a 
window of 3 days for the visit to 
occur and can cover over a 
weekend or a holiday.
Chapter/section concerned:
Clinical Study Protocol Synopsis
General Design and Methodology:
In both phases, omacetaxine will be administered by 
subcutaneous injection twice daily. For cycle 1, the 
first dose will be administered at the investigational 
center. Subsequent doses (in prefilled syringes) may be 
administered on an outpatient basis after training takes 
place. Patients will be evaluated every 7 days with 
complete blood and platelet counts up to and including 
cycle 5 and every 2 weeks after cycle 5; the number of 
Chapter/section concerned:
Clinical Study Protocol Synopsis
General Design and Methodology:
In both phases, omacetaxine will be administered by subcutaneous 
injection twice daily. For cycle 1, the first dose will be 
administered at the investigational center. Subsequent doses (in 
prefilled syringes) may be administered on an outpatient basis 
after training takes place. Patients will be evaluated every 7 days 
with complete blood and platelet counts up to and including cycle 
5 and every 2 weeks (±2 days) after cycle 5; the number of 
consecutive doses of omacetaxine or intervals between subsequent 
All chemistry and hematology 
tests have a ±2 day window. 
Clarification of every 3 months.
Text added for consistency 
between sections of protocol.


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Initial wording
Amended or new wording
Reason/Justification for change
consecutive doses of omacetaxine or intervals between 
subsequent cycles may be adjusted, as clinically 
indicated. Every 3 months, bone marrow aspiration and 
cytogenetics, BCR-ABL transcript measurements, 
quantitative BCR-ABL kinase domain analysis of 
peripheral blood, and ECGs will be performed.
cycles may be adjusted, as clinically indicated. Every 3 months 
(ie, every 3 cycles), bone marrow aspiration and cytogenetics, 
BCR-ABL transcript measurements, quantitative BCR-ABL 
kinase domain analysis of peripheral blood, and ECGs will be 
performed. Note: After a patient achieves a confirmed complete 
cytogenetic response, RT-PCR BCR-ABL testing should be 
performed every 6 months unless clinically indicated to do it 
more often.
Chapter/section concerned:
Clinical Study Protocol Synopsis
Pharmacokinetics:

1ne sample on day 13, 14, 15, 16, or 17 
either predose 1 or predose 2

1one sample either predose 1 or predose 2 
on any day during wee21 
Chapter/section concerned:
Clinical Study Protocol Synopsis
Pharmacokinetics:

1ne sample on day 13, 14, 15, 16, or 17 either 
predose 1 or predose 2

1one sample either predose 1 or predose 2 on any 
day during wee21 week 2
Correction of typographical errors.
Chapter/section concerned:
List of abbreviations and definitions of terms
Chapter/section concerned:
List of abbreviations and definitions of terms
CEC, Central Ethics Committee Commission of the European 
Communities, abbreviation added.
CO2, carbon dioxide, abbreviation added.
PPD, Pharmaceutical Product Development, LLC, abbreviation 
added.
RR, respiratory rate, abbreviation added.
XML, extensible markup language, abbreviation added.
New abbreviations added.
Chapter/section concerned:
1.1.3 Rationale for the Study
In oncology, the dosage of nearly all cytotoxic drugs is 
based on body-surface area (BSA) of the patient (Field 
et al 2008, Mathijssen et al 2007). However, fixed or 
“flat dosing”, using a single dose for all patients 
regardless of BSA or weight may offer advantages with 
regard to administration errors and patient safety for a 
drug given subcutaneously. To satisfy a postmarketing 
requirement (PMR), the sponsor has been requested to 
conduct a Phase 1/Phase 2 single-group clinical study 
to investigate the pharmacokinetics and preliminary 
safety and efficacy of omacetaxine following a 
fixed-dose administration to patients with CP or AP 
Chapter/section concerned:
1.1.3 Rationale for the Study
In oncology, the dosage of nearly all cytotoxic drugs is based on 
body-surface area (BSA) of the patient (Field et al 2008, 
Mathijssen et al 2007). However, fixed or “flat dosing”, using a 
single dose for all patients regardless of BSA or weight may offer 
advantages with regard to administration dose errors and patient 
safety for a drug given subcutaneously. To satisfy a postmarketing 
requirement (PMR), the sponsor has been requested by FDA to 
conduct a Phase 1/Phase 2 single group open label clinical study 
to investigate the pharmacokinetics and preliminary safety and 
efficacy of omacetaxine following a fixed-dose administration to 
patients with CP or AP CML who have failed 2 or more TKI 
therapies. Therefore, this study was designed for the same patient 
Risk benefit information added in 
protocol in response to comment 
from CEC to add risk benefit 
information.
Editorial changes.


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Initial wording
Amended or new wording
Reason/Justification for change
CML who have failed 2 or more TKI therapies. 
A population pharmacokinetic model was developed 
for omacetaxine using the pharmacokinetic data 
collected in Study CGX-635-205 and it was used to 
predict individual measures of omacetaxine exposure in 
patients enrolled in Studies CGX-635-202 and 
CGX-635-203, respectively. Study CGX-635-205 
assessed pharmacokinetics and safety of subcutaneous 
omacetaxine in patients with advanced cancers, and 
had results recently published (Nemunaitis et al 2013). 
The relationships between these individual exposure 
estimates and efficacy and selected safety endpoints 
were investigated. These exposure-response 
relationships were used to simulate anticipated 
outcomes, with data from the CML registration Studies 
CGX-635-202 and CGX-635-2032, respectively, with 
various fixed treatment regimens. The registration 
studies did not have pharmacokinetics in their study 
design. 
A comparison of fixed-doses between 2 and 3.5 mg, 
without regard to BSA, illustrates that there is potential 
benefit in terms of an increased predicted probability of 
efficacy with a dose of 2.5 mg over a 2-mg dose 
(almost 3-fold increase in the predicted probability of 
major hematologic response [MaHR] and almost 2-fold 
increase in the predicted probability of major cytogenic 
response [MCyR]) (data on file). The 3-mg dose is 
associated with an even greater predicted probability of 
efficacy in both the AP and CP populations. The 
increased risk associated with these doses, in terms of 
the predicted probability of experiencing grade 3 or 
grade 4 thrombocytopenia, over the 2-mg dose, is small 
on the basis of the simulation data, but not fully 
understood due to the limited size of the CGX-635-205 
dataset. 
The 3.5-mg dose, which represents a higher dose than 
any administered in Studies CGX-635-205, 
CGX-635-CML-202, or CGX-635-CML-203, is 
predicted to provide only a small additional 
population for which omacetaxine was approved but with a 
“fixed or flat” dosing approach. If this approach proves safe and 
efficacious as in the registration trials, this would prove to be a 
benefit to patients and healthcare providers to ensure or avoid 
less dosing errors when given subcutaneously and improve 
patient compliance due to improved ease of administration.
Additionally, this study was requested since the 
pharmacokinetics of omacetaxine may or may not be related to 
BSA. A BSA-based dose could result in lower drug 
concentrations and potentially reduced efficacy in patients with 
traditionally lower BSAs, such as women, as women have lower 
body surface areas. Lower exposures may contribute to reported 
observations of a lower response rate in women. Therefore, a 
fixed dose may increase exposure in any patients with low BSA 
and potentially optimize their probability of response. This PMR 
study may assist to optimize the dosing regimen in future trials.
A population pharmacokinetic model was developed for 
omacetaxine using the pharmacokinetic data collected in Study 
CGX-635-205 and it was used to predict individual measures of 
omacetaxine exposure in patients enrolled in Studies 
CGX-635-202 and CGX-635-203, respectively. Study CGX-635-
205 assessed pharmacokinetics and safety of subcutaneous 
omacetaxine in patients with advanced cancers, and had results 
recently published (Nemunaitis et al 2013). The relationships 
between these individual exposure estimates and efficacy and 
selected safety endpoints were investigated. These exposure-
response relationships were used to simulate anticipated 
outcomes, with data from the CML registration Studies CGX-635-
202 and CGX-635-2032, respectively, with various fixed 
treatment regimens. The registration studies did not have 
pharmacokinetics in their study design. 
A comparison of fixed-doses between 2 and 3.5 mg, without 
regard to BSA, illustrates that there is potential benefit in terms of 
an increased predicted probability of efficacy with a dose of 
2.5 mg over a 2 mg dose (almost 3-fold increase in the predicted 
probability of major hematologic response [MaHR] and almost 
2-fold increase in the predicted probability of major cytogenic 
response [MCyR]) (data on file). The 3 mg dose is associated with 
an even greater predicted probability of efficacy in both the AP 


Uncontrolled Study–Chronic Myeloid Leukemia
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Initial wording
Amended or new wording
Reason/Justification for change
improvement in the probability of efficacy and in the 
risk of neutropenia over the 3-mg alternative, and also 
a slightly increased risk of thrombocytopenia over the 
3-mg alternative; and it comes with the added 
uncertainty of being outside the range of previously 
tested doses. Therefore, administration of this dose is 
not recommended.
Because the number of patients in Study CGX-635-205 
was small, the predictions from this population 
pharmacokinetic modeling must be used with caution. 
On the basis of the data currently available, the impact 
of fixed dose on the benefit-risk profile in patients with 
CML who have failed TKI therapy remains unknown. 
For this reason, a fixed dose of 2.5 mg twice daily was 
selected because it approximates to the dose that would 
have been given to a patient of median BSA under the 
current 1.25 mg/m2 twice daily regimen. A sample size 
of approximately 21 patients enrolled in cohorts of 
small, medium, and large BSA is considered sufficient 
to properly characterize the pharmacokinetics of the 2.5 
mg twice daily fixed dose.
and CP populations. The increased risk associated with these 
doses, in terms of the predicted probability of experiencing grade 
3 or grade 4 thrombocytopenia, over the 2 mg dose, is small on the 
basis of the simulation data, but not fully understood due to the 
limited size of the CGX-635-205 dataset. 
The 3.5 mg dose, which represents a higher dose than any 
administered in Studies CGX-635-205, CGX-635-CML-202, or 
CGX-635-CML-203, is predicted to provide only a small 
additional improvement in the probability of efficacy and in the 
risk of neutropenia over the 3 mg alternative, and also a slightly 
increased risk of thrombocytopenia over the 3 mg alternative; and 
it comes with the added uncertainty of being outside the range of 
previously tested doses. Therefore, administration of this dose is 
not recommended.
Because the number of patients in Study CGX-635-205 was small, 
the predictions from this population pharmacokinetic modeling 
must be used with caution. On the basis of the data currently 
available, the impact of fixed dose on the benefit-risk profile in 
patients with CML who have failed TKI therapy remains 
unknown. For this reason, a fixed dose of 2.5 mg twice daily was 
selected because it approximates to the dose that would have been 
given to a patient of median BSA under the current 1.25 mg/m2
twice daily regimen. In the phase 1 portion of the study, a A
sample size of approximately 21 patients enrolled in cohorts of 
small, medium, and large BSA is considered sufficient to properly 
characterize the pharmacokinetics of the 2.5 mg twice daily fixed 
dose.
Chapter/section concerned:
1.3.5 Justification for Study Treatment Plan
The purpose of this current study is to evaluate the 
pharmacokinetics and the preliminary safety and 
efficacy of a fixed-dose regimen of omacetaxine for the 
treatment of patients with CP or AP CML following 
failure of TKI therapy. For this reason the treatment 
plan is the same as that used in the Phase 2 registration 
studies for omacetaxine (Studies CGX-635-CML-202 
and CGX-635-CML-203) with a fixed dose being used 
in place of doses adjusted for BSA. Stopping rules and 
Chapter/section concerned:
1.3.5 Justification for Study Treatment Plan
The purpose of this current study is to evaluate the 
pharmacokinetics and the preliminary safety and efficacy of a 
fixed-dose regimen of omacetaxine (2.5 mg BID sc) for the 
treatment of patients with CP or AP CML following failure of TKI 
therapy. For this reason, the treatment plan is the same as that 
used in the Phase 2 registration studies for omacetaxine (Studies 
CGX-635-CML-202 and CGX-635-CML-203) with a fixed dose 
being used in place of doses adjusted for BSA and with the 
Risk benefit information added in 
protocol in response to comment 
from CEC to add risk benefit 
information.


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Initial wording
Amended or new wording
Reason/Justification for change
an independent DMC that will evaluate safety, 
pharmacokinetics, and efficacy, will be implemented, 
as defined in its charter.
The treatment plan includes recommendations for 
alternative therapies and management of toxicities, 
including hematologic toxicity, if necessary.
precautions to minimize toxicity and improve tolerability as 
described in Section 1.4 called Known and Potential Risks and 
Benefits to Human Patients. As an additional precaution for 
unforeseeable risks, an independent DMC that will evaluate
safety, pharmacokinetics, and efficacy, has been implemented 
from the beginning of the study including the phase 1 portion as
defined in its charter. Stopping rules and an independent DMC 
that will evaluate safety, pharmacokinetics, and efficacy, will be 
implemented, as defined in its charter.
The study treatment plan includes recommendations for
supportive therapies and management of toxicities, including 
hematologic toxicity, if necessary. Refer please, to Section 3 and 
Section 5 of the protocol CEP 41443/2057 for full details. The 
treatment plan includes recommendations for alternative therapies 
and management of toxicities, including hematologic toxicity, if 
necessary.
Chapter/section concerned:
3.1 General Design and Study Schema
The study will consist of up to a 7-day screening 
period, and treatment for up to 12 months, in Phase 1 
and Phase 2 portions, depending on response and 
tolerability. Patients will also have an end-of-treatment 
follow-up visit approximately 28 days after the last 
dose of omacetaxine.
Chapter/section concerned:
3.1 General Design and Study Schema
The study will consist of up to a 7-day screening period, and 
treatment for up to 12 months, in Phase 1 and Phase 2 portions, 
depending on response and tolerability. Patients will also have an 
end-of-treatment follow-up visit approximately 28 days (+2 days)
after the last dose of omacetaxine.
Added +2 days so there is a 
window of 3 days for the visit to 
occur and can cover over a 
weekend or a holiday.
Chapter/section concerned:
3.1 General Design and Study Schema
Phase 1 and Phase 2: Omacetaxine will be 
administered by subcutaneous injection twice daily. For 
cycle 1, the first dose will be administered at the 
investigational center. Subsequent doses (in prefilled 
syringes) may be administered on an outpatient basis 
after training takes place. See Section 5.1.1 regarding 
training for the patient or caregiver for administration 
of omacetaxine. 
Patients will be evaluated every 7 days with complete 
blood and platelet counts up to and including cycle 5, 
and every 2 weeks after cycle 5 (see Section 3.11.2.5); 
the number of consecutive doses of omacetaxine or 
intervals between subsequent cycles may be adjusted, 
Chapter/section concerned:
3.1 General Design and Study Schema
Phase 1 and Phase 2: Omacetaxine will be administered by 
subcutaneous injection twice daily. For cycle 1, the first dose will 
be administered at the investigational center. Subsequent doses (in 
prefilled syringes) may be administered on an outpatient basis 
after training takes place. See Section 5.1.1 regarding training for 
the patient or caregiver for administration of omacetaxine. 
Patients will be evaluated every 7 days with complete blood and 
platelet counts up to and including cycle 5, and every 2 weeks (±2 
days) after cycle 5 (see Section 3.11.2.5); the number of 
consecutive doses of omacetaxine or intervals between subsequent 
cycles may be adjusted, as clinically indicated, according to 
guidelines provided in Section 5.1.2.
The following tests will be performed every 3 months (ie, every 3 
All chemistry and hematology 
tests have a ±2 day window. 
Clarification of every 3 months.
Added text about 12 months for 
consistency between sections.
Clarification of BCR-ABL testing 
so that it is more specific.


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Initial wording
Amended or new wording
Reason/Justification for change
as clinically indicated, according to guidelines provided 
in Section 5.1.2.
The following tests will be performed every 3 months 
while on study, for all patients:

bone marrow aspiration and cytogenetics 
every 3 months
If patients show other clinical signs of disease 
progression they may not need to undergo a 
bone marrow evaluation. The treatment cycle 
following a bone marrow procedure for the 
long-term responders may begin up to 7 (±3) 
days after the bone marrow procedure. 
Cytogenetic response evaluation will be based 
on standard cytogenetic analysis (at least 20 
metaphases are to be analyzed). 
Note: After a patient achieves a confirmed 
cytogenetic response, bone marrow aspiration 
with cytogenetics will be performed every 
12 months or as often as clinically indicated. 
At this stage, chromosome banding analysis of 
marrow cell metaphases (with at least 20 
metaphases analyzed) can be substituted by 
florescence in situ hybridization (FISH) on 
blood cells once a complete cytogenetic 
response has been confirmed (Baccarani et al 
2013, SYNRIBO prescribing information).

measure BCR-ABL transcript levels by real-
time, quantitative polymerase chain reaction 
(PCR) of peripheral blood performed locally
Note: After a patient achieves a confirmed 
complete cytogenetic response, this test should 
be performed every 6 months unless clinically 
indicated to do it more often (Appendix A).
cycles) while on study, for all patients:

bone marrow aspiration and cytogenetics every 3 months
If patients show other clinical signs of disease 
progression they may not need to undergo a bone marrow 
evaluation. The treatment cycle following a bone marrow 
procedure for the long-term responders may begin up to 
7 (±3) days after the bone marrow procedure. 
Cytogenetic response evaluation will be based on 
standard cytogenetic analysis (at least 20 metaphases are 
to be analyzed). 
Note: After a patient achieves a confirmed cytogenetic 
response, bone marrow aspiration with cytogenetics will 
be performed every 12 months or as often as clinically 
indicated. At this stage, after the patient has been on 
study for at least 12 months, chromosome banding 
analysis of marrow cell metaphases (with at least 20 
metaphases analyzed) can be substituted by florescence 
in situ hybridization (FISH) on blood cells once a 
complete cytogenetic response has been confirmed 
(Baccarani et al 2013, SYNRIBO prescribing 
information).

measure BCR-ABL transcript levels by real-time, 
quantitative polymerase chain reaction (PCR) of 
peripheral blood performed locally
Note: After a patient achieves a confirmed complete 
cytogenetic response, this test RT-PCR BCR-ABL 
testing should be performed every 6 months unless 
clinically indicated to do it more often (Appendix A).
Chapter/section concerned:
3.2.2 Secondary Efficacy Measures and Endpoints

molecular response by site (peripheral 
transcript of BCR-ABL) (Appendix A)
assessed every 3 months 
Chapter/section concerned:
3.2.2 Secondary Efficacy Measures and Endpoints

molecular response by site (peripheral transcript of 
BCR-ABL) (Appendix A Appendix B) assessed every 3 
months (ie, every 3 cycles)
Clarification of every 3 months.
Correction of Appendix.
Chapter/section concerned:
Chapter/section concerned:
Correction to vial size.


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Initial wording
Amended or new wording
Reason/Justification for change
3.4.1 Investigational Product and Dosage
The investigational drug for this study is omacetaxine 
mepesuccinate. Omacetaxine drug product is a 
lyophilized vial containing 3.5 mg omacetaxine and 10 
mg mannitol in a 10-mL clear glass vial, sealed with 
rubber stopper and aluminum flip-off seal. 
Investigational centers will be given vials of 3.5 mg 
omacetaxine. Omacetaxine will be reconstituted by a 
healthcare professional.
3.4.1 Investigational Product and Dosage
The investigational drug for this study is omacetaxine 
mepesuccinate. Omacetaxine drug product is a lyophilized vial 
containing 3.5 mg omacetaxine and 10 mg mannitol in an 810-mL 
clear glass vial, sealed with rubber stopper and aluminum flip-off 
seal. Investigational centers will be given vials of 3.5 mg 
omacetaxine. Omacetaxine will be reconstituted by a healthcare 
professional.
Chapter/section concerned:
3.5 Duration of Patient Participation
The study will consist of up to a 7-day screening 
period, and treatment for up to 12 months depending on 
response and tolerability. Patients will also have an 
end-of-treatment follow-up visit approximately 28 days
after the last dose of omacetaxine.
Chapter/section concerned:
3.5 Duration of Patient Participation
The study will consist of up to a 7-day screening period, and 
treatment for up to 12 months depending on response and 
tolerability. Patients will also have an end-of-treatment follow-up 
visit approximately 28 days (+2 days) after the last dose of 
omacetaxine.
Added +2 days so there is a 
window of 3 days for the visit to 
occur and can cover over a 
weekend or a holiday.
Chapter/section concerned:
3.7.1 Study Drug Storage and Security
Table 1: Time to Administration After Reconstitution
Within 24 hours of reconstitution
Chapter/section concerned:
3.7.1 Study Drug Storage and Security
Table 1: Time to Administration After Reconstitution
Within 24 hours 6 days (144 hours) of reconstitution
Revised storage duration.
Chapter/section concerned:
3.7.2 Study Drug Accountability
For every cycle, the first dose will be reconstituted by 
the healthcare professional and administered at the 
investigational center.
Chapter/section concerned:
3.7.2 Study Drug Accountability
For every cycle, the first dose will be reconstituted by the 
healthcare professional and administered at the investigational 
center. For the first cycle, the first dose will be reconstituted by 
the healthcare professional and administered at the 
investigational center. For any additional cycles, the first dose 
may be administered at the investigational center by a healthcare 
professional, self-administered at home by the patient, or 
administered by the Sponsor selected home care agency 
professional at the home of the patient.
Added information that is optional 
for the patient to have their first 
dose of cycles after C1 to be 
administered in the clinic, 
regardless of whether it is by a 
healthcare professional or self-
administered by the patient.
Clarification that additional cycles 
after the first dose may be 
administered at home.
Chapter/section concerned:
3.10 Time Schedule
The study is expected to start enrolling in 
approximately the second quarter of 2014 and be 
completed enrollment approximately in 2016. The 
study is planned to be conducted at approximately 40 
Chapter/section concerned:
3.10 Time Schedule
The study is expected to start enrolling in approximately the 
second quarter of 2014 and be completed enrollment 
approximately in 2016. The study is planned to be conducted at 
approximately 24 40 study centers in North America, Europe, and 
Correction to number of study 
centers and countries where study 
will be conducted.


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Initial wording
Amended or new wording
Reason/Justification for change
study centers in North America and the EU.
Asia and the EU.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Header
Omacetaxine induction or maintenance treatment
28-day cycles (up to 12 cycles total)
Chapter/section concerned:
3.11 Study Procedures
Table 2, Header
Omacetaxine induction or maintenance treatment
28-day cycles (±1 day)(up to 12 cycles total)
Added window of ±1 day
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
bFollow-up every 3 months; the first visit will be in 
person but the rest may be by telephone contact.
Follow-up will continue until patient's death or 12 
months after the last treatment cycle, whichever occurs 
first. Follow-up is required even if a patient is 
withdrawn from treatment with omacetaxine.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
bFollow-up visits every 3 months (±7 days); the first visit will be 
in person but the rest may be by telephone contact. Follow-up will 
continue until patient's death, is lost to follow-up, or until 12 
months after the last treatment cycle, whichever occurs first, 
regardless of receiving other anticancer treatment. Follow-up is 
required even if a patient is withdrawn from treatment with 
omacetaxine.
Added window of ±7 days for 
follow-up visits.
Added text for consistency 
between sections
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
eIf a patient completes treatment with omacetaxine or is 
withdrawn from treatment, assessments will be 
performed at an end-of-treatment visit 28 days after the 
last dose of study drug. If the patient is withdrawn from 
treatment, an end-of-treatment visit may occur before 
28 days after the last dose of omacetaxine to allow the 
patient to enter follow-up.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
eIf a patient completes treatment with omacetaxine or is 
withdrawn from treatment, assessments will be performed at an 
end-of-treatment visit 28 days (+2 days) after the last dose of 
study drug. If the patient is withdrawn from treatment, an end-of-
treatment visit may occur before 28 days after the last dose of 
omacetaxine to allow the patient to enter follow-up.
Added +2 days so there is a 
window of 3 days for the visit to 
occur and can cover over a 
weekend or a holiday.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
iMeasure vital signs (HR, BP, temperature) within 30 
minutes prior to administration of omacetaxine and 20 
minutes after administration on day 1 of each treatment 
cycle.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
iMeasure vital signs (HR, BP, RR, temperature T) within 30 
minutes prior to administration of omacetaxine and 20 minutes 
post-dose (±5 min) after administration on day 1 of each treatment 
cycle.
Added RR and window of ±5 min 
post dose for vital signs.
Changed temperature to T 
abbreviation for consistency.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
j May be omitted if prior study available within 
preceding 30 days. 
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
j May be omitted if prior study available within preceding 30 
days. Chest x-ray may be omitted if a prior study, such as a CT 
of the chest, is completed within 30 days of first dose of 
Revised for clarity.


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Initial wording
Amended or new wording
Reason/Justification for change
omacetaxine. A screening bone marrow or ECG is required only 
if a prior one has not been performed within 30 days of first dose 
of omacetaxine.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
k Prior to the first 3 cycles (cycles 1 through 3) whether 
induction or maintenance. It may be omitted at cycle 1 
if one was done within 30 days prior to the first dose of 
omacetaxine on day 1 of cycle 1). In other countries, 
electrocardiograms may be done before and after every 
omacetaxine cycle, or as directed.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
k Prior to the first 3 cycles (cycles 1 through 3) whether induction 
or maintenance. It may be omitted at cycle 1 if one was done 
within 30 days prior to the first dose of omacetaxine on day 1 of 
cycle 1). In other countries, electrocardiograms ECGs may be 
done before and after every omacetaxine cycle, or as directed.
Abbreviation for ECG added.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
mComplete blood counts to include hematocrit, 
hemoglobin, RBC, WBC, differential, platelet count.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
mComplete blood counts (±2 days) to include hematocrit, 
hemoglobin, RBC, WBC, differential, platelet count.
Added window of ±2 days for 
hematology.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
oFull serum chemistry and hematology to be performed 
every 2 weeks after cycle 5.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
oFull serum chemistry and hematology to be performed every 2 
weeks (±2 days) after cycle 5.
All chemistry and hematology 
tests have a ±2 day window.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
p Full serum chemistry to be performed at screening 
and after cycle 5. During cycles 1 through 5, chem 7 
(sodium, chloride, CO2, creatinine, BUN or urea, 
glucose, and potassium) is to be performed.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
p Full serum chemistry to be performed at screening and after 
cycle 5. During cycles 1 through 5, chem 7 (sodium, chloride, 
CO2 content, creatinine, BUN or urea, glucose, and potassium) is 
to be performed.
Added for consistency within the 
protocol.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
qBone marrow exam with cytogenetic analysis to be 
performed by the G-banding technique. Marrow 
specimens will be examined on direct short-term (24-
hour) cultures; at least 20 metaphases are to be 
analyzed. May be omitted at screening if bone marrow 
and cytogenetic analysis have been done in the 
preceding 30 days and the patient had not received 
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
qBone marrow exam with cytogenetic analysis to be performed by 
the G-banding technique. Marrow specimens will be examined on 
direct short-term (24-hour) cultures; at least 20 metaphases are to 
be analyzed. May be omitted at screening if bone marrow and 
cytogenetic analysis have been done in the preceding 30 days and 
the patient had not received antileukemic therapy during this 
period (other than palliative therapy, eg, hydroxyurea). After 12
Added for consistency with 
section 3.1


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Initial wording
Amended or new wording
Reason/Justification for change
antileukemic therapy during this period (other than 
palliative therapy, eg, hydroxyurea).
months on study, and once a complete cytogenetic response has 
been confirmed, may substitute chromosome banding analysis 
with FISH on blood cells.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
t Obtain BCR-ABL quantitative transcript levels by 
quantitative PCR analysis of peripheral blood. 
BCR-ABL transcripts will be detected by real-time 
quantitative reverse transcription-polymerase chain 
reaction (RT-PCR) analysis on peripheral blood. 
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
t Obtain BCR-ABL quantitative transcript levels by quantitative 
PCR analysis of peripheral blood. BCR-ABL transcripts will be 
detected by real-time quantitative reverse transcription-
polymerase chain reaction (RT-PCR) analysis on peripheral blood. 
After a patient achieves a confirmed complete cytogenetic 
response, this test should be performed every 6 months unless 
clinically indicated to do it more often.
Added for consistency within the 
protocol.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
HR=heart rate; RR=respiratory rate; BP=blood 
pressure; T=temperature; RBC=red blood cell; 
WBC=white blood cell; BUN=blood urea nitrogen; 
ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; PCR=polymerase chain reaction; 
CML=chronic myeloid leukemia.
Chapter/section concerned:
3.11 Study Procedures
Table 2, Footnotes
HR=heart rate; RR=respiratory rate; BP=blood pressure; 
T=temperature; RBC=red blood cell; WBC=white blood cell;
BUN=blood urea nitrogen; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; PCR=polymerase 
chain reaction; CML=chronic myeloid leukemia., CO2=carbon 
dioxide, FISH=florescence in situ hybridization.
Added abbreviations used in table.
Chapter/section concerned:
3.11 Study Procedures
Table 3, Footnotes
bPharmacokinetic samples to be drawn once, either on 
day 10 or day 11 or day 12.
Chapter/section concerned:
3.11 Study Procedures
Table 3, Footnotes
bPharmacokinetic samples to be drawn once, either on day 10 or 
day 11 or day 12. Day 10 or 11 or 12, <1 hr sample and 1-12 hr 
sample should be drawn at least 30 minutes apart.
To clarify samples should be 
drawn with sufficient time 
between each collection on Day 
10 or 11 or 12.
Editorial change for consistency.
Chapter/section concerned:
3.11 Study Procedures
Table 4, Footnotes
After day 1 during week 1
Any day during week 2
Chapter/section concerned:
3.11 Study Procedures
Table 4, Footnotes
Footnote b was added
After day 1 during week 1b
Any day during week 2 b
b Day 10 or 11 or 12, <1 hr sample and 1-12 hr sample should be 
drawn at least 30 minutes apart.
To clarify samples should be 
drawn with sufficient time 
between each collection on Day 
10 or 11 or 12.
Chapter/section concerned:
3.11 Study Procedures
Table 4, Footnotes
Chapter/section concerned:
3.11 Study Procedures
Table 4, Footnotes
Deleted abbreviation that wasn’t 
used and added new abbreviation.


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Initial wording
Amended or new wording
Reason/Justification for change
min=minutes; hr=hour; NA=not applicable.
min=minutes bid=twice daily; hr=hour; NA=not applicable.
Chapter/section concerned:
3.11.1 Procedures for Screening and Enrollment

ECG, unless one was performed within 
the preceding 30 days. 
Chapter/section concerned:
3.11 Procedures for Screening and Enrollment

ECG, unless one was performed within the 
preceding 30 days. Prior to study entry, any other 
ECG abnormalities noted at screening other than 
myocardial infarction within the previous 12 weeks 
and felt by the investigator not to be medically 
relevant, must be documented as such.
Clarification
Chapter/section concerned:
3.11.2.1 Procedures for Day 1 of Each Treatment Cycle

vital signs (temperature, heart rate, 
respiratory rate, systolic and diastolic 
blood pressure) within 30 minutes before 
omacetaxine and 20 minutes 
post-injection on day 1 of each treatment 
cycle

serum chemistry 7 (sodium, chloride, CO2
content, creatinine, blood urea nitrogen 
(BUN) or urea, blood glucose, and 
potassium only) (Appendix D)
Chapter/section concerned:
3.11.2.1 Procedures for Day 1 of Each Treatment Cycle

vital signs (temperature, heart rate, respiratory rate, 
systolic and diastolic blood pressure) within 30 
minutes before omacetaxine and 20 minutes 
post-injection (±5 min) on day 1 of each treatment 
cycle

serum chemistry 7 (sodium, chloride, carbon dioxide 
[CO2] content, creatinine, blood urea nitrogen 
(BUN) or urea, blood glucose, and potassium only)
(Appendix D)

Review of updated patient diaries and inquiries on 
compliance of omacetaxine administration. Please 
refer to the Patient Instructions on Subcutaneous 
Injection and Diary Completion for further details.
Added window of ±5 min post 
dose for vital signs.
Added definition for CO2 
abbreviation.
Added information about review 
of patient diaries and compliance 
for consistency between protocol 
sections.
Chapter/section concerned:
3.11.2.2 Pharmacokinetic Procedures, Phase 1, Cycle 1 
Only

On day 10 or 11 or 12, as follows:

predose, within (<) 1 hour after dose 
1, and 1 to 12 hours after dose 1
Chapter/section concerned:
3.11.2.2 Pharmacokinetic Procedures, Phase 1, Cycle 1 Only

On day 10 or 11 or 12, as follows:

predose, within (<) 1 hour after dose 1, and 1 to 
12 hours after dose 1

<1 hr sample and 1-12 hr sample should be 
drawn at least 30 minutes apart.
To clarify samples should be 
drawn with sufficient time 
between each collection on Day 
10 or 11 or 12.
Chapter/section concerned:
3.11.2.3 Pharmacokinetic Procedures, Phase 1, Cycles 
2 and 3 and Phase 2, Cycles 1 Through 3
Blood samples (2.5 mL) will be obtained in Phase 1 on 
day 1 of cycles 2 and 3 as follows (see Table 4):

within (<) 1 hour after dose 1
Chapter/section concerned:
3.11.2.3 Pharmacokinetic Procedures, Phase 1, Cycles 2 and 3 and 
Phase 2, Cycles 1 Through 3
Blood samples (2.5 mL) will be obtained in Phase 1 on day 1 of 
cycles 2 and 3 as follows (see Table 4):

within (<) 1 hour after dose 1
Correction of typo, “e” deleted.
To clarify samples should be 
drawn with sufficient time 
between each collection on Day 
10 or 11 or 12.


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Amended or new wording
Reason/Justification for change

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on 
any day after day 1 during week 1

1e sample either predose 1 or predose 2 
on any day during week 2
Blood samples (2.5 mL) will be obtained in Phase 2 on 
day 1 of cycles 1, 2 and 3 as follows (see Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on 
any day after day 1 during week 1

1 sample either predose 1 or predose 2 on 
any day during week 2

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day 
after day 1 during week 1

1e sample either predose 1 or predose 2 on any day 
during week 2
Blood samples (2.5 mL) will be obtained in Phase 2 on day 1 of 
cycles 1, 2 and 3 as follows (see Table 4):

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day 
after day 1 during week 1

1 sample either predose 1 or predose 2 on any day 
during week 2
On Day 10 or 11 or 12, the <1 hr sample and 1-12 hr sample 
should be drawn at least 30 minutes apart.
Chapter/section concerned:
3.11.2.5 Procedures After Cycle 5 of Treatment
The following assessments will be performed on 
day 14 (versus weekly) for all treatment cycles after 
cycle 5.

review of completed patient diaries and 
inquiries on compliance of omacetaxine 
administration and supplies needed (ie, 
spill kits, gloves, or biohazard containers)
Chapter/section concerned:
3.11.2.5 Procedures After Cycle 5 of Treatment
The following assessments will be performed on day 14 (±2 days)
(versus weekly) for all treatment cycles after cycle 5.

review of completed patient diaries and inquiries on 
compliance of omacetaxine administration and 
supplies needed (ie, spill kits, gloves, or biohazard 
containers) review of updated patient diaries and 
inquiries on compliance of omacetaxine 
administration
All chemistry and hematology 
tests have a ±2 day window. 
Revised text about patient diaries 
and compliance for consistency 
between sections.
Chapter/section concerned:
3.11.2.6 Procedures During Study Drug Treatment–
Every 3 Months on Study–All Patients
The following studies will be obtained every 3 months 
while on study, in all patients, unless otherwise 
specified:
Chapter/section concerned:
3.11.2.6 Procedures During Study Drug Treatment–Every 3 
Months (ie, every 3 cycles) on Study–All Patients
The following studies will be obtained every 3 months (ie, every 3 
cycles) while on study, in all patients, unless otherwise specified:

drug accountability

adverse event inquiry

concomitant medication inquiry

review of updated patient diaries and inquiries on 
compliance of omacetaxine administration
Clarification of every 3 months.
Additional text added for 
consistency.


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Initial wording
Amended or new wording
Reason/Justification for change
Chapter/section concerned:
3.11.3.1 End-of-Treatment Visit
The following procedures will be performed at the 
end-of-treatment visit, 28 days after the last dose of 
study drug, unless otherwise specified:

BCR-ABL transcript levels by 
quantitative PCR of peripheral blood at 
local laboratory (Appendix B) – may be 
omitted if prior study within 14 days 
For patients who complete the study, or for those who 
withdraw prematurely from the study, final evaluations
will be performed 28 days after the last dose of study 
drug.
Chapter/section concerned:
3.11.3.1 End-of-Treatment Visit
The following procedures will be performed at the 
end-of-treatment visit, 28 days (+2 days) after the last dose of 
study drug, unless otherwise specified:

BCR-ABL transcript levels by quantitative PCR of 
peripheral blood at local laboratory (Appendix B) 
may be omitted if prior study within 14 days
For patients who complete the study, or for those who withdraw 
prematurely from the study, final evaluations will be performed 
28 days (+2 days) after the last dose of study drug.
Added +2 days so there is a 
window of 3 days for the visit to 
occur and can cover over a 
weekend or a holiday.
Correction of text; statement 
applied only to the screening 
BCR-ABL test
Chapter/section concerned:
3.11.3.2 Follow-up
Patients will be monitored every 3 months for 
progression (if the patient had not progressed at the 
time of the end-of-treatment visit) and survival for 1 
year after the last dose of omacetaxine, death, or lost to 
follow-up, whichever comes first, regardless of patients 
receiving other anticancer treatment.
Chapter/section concerned:
3.11.3.2 Follow-up
Patients will be monitored every 3 months (±7 days) for 
progression (if the patient had not progressed at the time of the 
end-of-treatment visit) and survival for 1 year after the last dose of 
omacetaxine, death, or lost to follow-up, whichever comes first, 
regardless of patients receiving other anticancer treatment.
Added window of ±7 days for 
follow-up visits.
Chapter/section concerned:
4. Selection and Withdrawal of Patients
Chapter/section concerned:
4. Selection and Withdrawal of Patients
Changes to inclusion and exclusion criteria are indicated below 
and detailed in Section 17.
Added sentence that inclusion and 
exclusion criteria changed.
Chapter/section concerned:
4.1 Patient Inclusion Criteria
Chapter/section concerned:
4.1 Patient Inclusion Criteria
Addition of inclusion criterion under b:

Patients with a known T315I mutation must have 
been treated and failed ponatinib (prior to the entry 
into this study; this would not apply in a country 
where ponatinib has not been approved or where 
patients otherwise would not have access to this 
medication) unless medically contraindicated by 
the treating study doctor.
The protocol was amended as a 
result of the French Competent 
Authority review of the sponsor’s
regulatory submission, where they 
required clarification that patients 
with this specific mutation should 
not be enrolled into the 2057 study 
unless they have failed or were 
intolerant to ponatinib as one of 
their prior therapies, assuming 
they are medically fit to receive 
this TKI.
Chapter/section concerned:
4.2 Patient Exclusion Criteria
Chapter/section concerned:
4.2 Patient Exclusion Criteria
Clarification and text revised for 
consistency between sections of 


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Reason/Justification for change
b. The patient has had a myocardial infarction in the 
previous 12 weeks. (Prior to study entry, ECG 
abnormalities at screening must be documented by the 
investigator as not medically relevant.)
l. The patient participated in another clinical 
investigation within 30 days of enrollment or is 
receiving another investigational agent.
b. The patient has had a myocardial infarction in the previous 
12 weeks. (Prior to study entry, ECG abnormalities at screening 
must be documented by the investigator as not medically relevant.
Prior to study entry, any other electrocardiogram [ECG] 
abnormalities noted at screening other than myocardial 
infarction within the previous 12 weeks and felt by the 
investigator not to be medically relevant, must be documented as 
such.)
l. The patient participated in another clinical investigation within 
30 days of enrollment or is receiving another investigational 
agent, unless discussed with the sponsor.
the protocol.
Clarification.
Chapter/section concerned:
5.1 Study Drugs Administered
For both phases (with the exception of cycle 1 of Phase 
1 only), patients will receive induction cycles of 14 
days twice daily treatment followed by 14 days without 
treatment (1 induction cycle) for as long as they 
adequately recover their blood counts and/or until they 
achieve hematologic response. Patients will then 
receive maintenance cycles of 7 days twice daily 
treatment followed by 21 days without treatment 
(1 maintenance cycle) for as long as they continue to 
benefit up to a period of 12 months following the first 
dose. Dose modifications for toxicity are allowed (see 
Section 5.1.2). If patients are continuing to receive 
benefit after 12 months, discussion with the sponsor 
must take place before continuing study agent 
administration or being given omacetaxine 
commercially available where omacetaxine is 
approved. Doses should be administered at 12 hour 
(±2 hour) intervals.
For cycle 1 of Phase 1 only, patients will receive only 1 
dose of omacetaxine on day 1, no doses on days 2 and 
3, and 2 doses on days 14 through 17 due to the 
pharmacokinetic objectives of the study (see Table 3).
Chapter/section concerned:
5.1 Study Drugs Administered
For both phases (with the exception of cycle 1 of Phase 1 only), 
patients will receive induction cycles of 14 days twice daily 
treatment followed by 14 days without treatment (1 induction 
cycle) for as long as they adequately recover their blood counts 
and/or until they achieve hematologic response. Patients will then 
receive maintenance cycles of 7 days twice daily treatment 
followed by 21 days without treatment (1 maintenance cycle) for 
as long as they continue to benefit up to a period of 12 months 
following the first dose. Dose modifications for toxicity are 
allowed (see Section 5.1.2). If patients are continuing to receive 
benefit after 12 months, discussion with the sponsor must take 
place before continuing study agent administration or being given 
omacetaxine commercially available where omacetaxine is 
approved. Doses should be administered at 12 hour (±2 hour) 
intervals. Patients who miss 1 day of dosing can make up that 
missed day as long as there is no more than 1 day interruption in 
dosing. That dose can added at the end of that cycle as long as it 
is continuous.
For cycle 1 of Phase 1 only, patients will receive only 1 dose of 
omacetaxine on day 1, no doses on days 2 and 3, and 2 doses on 
days 14 4 through 17 due to the pharmacokinetic objectives of the 
study (see Table 3). Therefore, eEach patient will be scheduled 
to receive 29 doses during cycle 1.
Clarification and Typographical 
clarification of day 14. Correction 
from Protocol Amendment Letter 
10 June 2014.
Chapter/section concerned:
5.1.2. Dose Modifications for Toxicity
Chapter/section concerned:
5.1.2. Dose Modifications for Toxicity
All chemistry and hematology 
tests have a ±2 day window.


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Initial wording
Amended or new wording
Reason/Justification for change
5.1.2.1. Hematologic Toxicity
Omacetaxine treatment cycles may be delayed and/or 
the number of days of dosing during the cycle reduced 
for hematologic toxicities (eg, neutropenia, 
thrombocytopenia). 
Complete blood counts should be performed weekly 
during the first 5 cycles. After the initial 5 cycles, 
CBCs should be performed every 2 weeks or as 
clinically indicated via unscheduled but collected data 
visits. If a patient experiences grade 4 neutropenia 
(absolute neutrophil count [ANC] less than 0.5x109/L) 
or grade 3 thrombocytopenia (platelet counts less than 
50x109/L) during a cycle, delay starting the next cycle 
until ANC is greater than or equal to 1.0x109/L and 
platelet count is greater than or equal to 50x109/L. 
Also, for the next cycle, reduce the number of dosing 
days by 2 days (eg, to 12 or 5 days).
5.1.2.1. Hematologic Toxicity
Omacetaxine treatment cycles may be delayed and/or the number 
of days of dosing during the cycle reduced for hematologic 
toxicities (eg, neutropenia, thrombocytopenia). 
Complete blood counts should be performed weekly during the 
first 5 cycles. After the initial 5 cycles, CBCs should be performed 
every 2 weeks (±2 days) or as clinically indicated via unscheduled 
but collected data visits. If a patient experiences grade 4 
neutropenia (absolute neutrophil count [ANC] less than 
0.5x109/L) or grade 3 thrombocytopenia (platelet counts less than 
50x109/L) during a cycle, delay starting the next cycle until ANC 
is greater than or equal to 1.0x109/L and platelet count is greater 
than or equal to 50x109/L. Also, for the next cycle, reduce the 
number of dosing days by 2 days (eg, to 12 or 5 days). If the 
patient should experience a delay as just described, in the next 
cycle, the number of dosing days can be reduced by 2 days.
For example, during induction this would be from 14 days to 
12 days; during maintenance, this would be from 7 days to 5 
days. If subjects tolerate a cycle with a 2-day reduction 
without any problems, then the following cycle, the full cycle 
can be provided. If more than 2 delays occur secondary to 
grade 4 neutropenia or grade 3 thrombocytopenia with yet 
another reduction in 2 more days in either induction or 
maintenance, consideration of discontinuing study medication 
should be discussed by the treating physician, the designated 
CRO physician, and the designated Sponsor physician.
Added for clarification.
Chapter/section concerned:
5.5 Total Blood Volume
The total blood volume to be withdrawn for any given 
patient is difficult to accurately predict and will 
depend, among other things, on how long the patient 
receives study drug, whether there are any adverse 
events leading to unscheduled blood draws, and 
whether there is any hospitalization related to said 
adverse events. Therefore, the timing and quantity 
obtained are defined in general terms as follows:
Full serum chemistry laboratory tests are scheduled to 
be performed at screening, every 2 weeks after cycle 5, 
and at the end-of-treatment visit. At each time point, 6 
Chapter/section concerned:
5.5 Total Blood Volume
The total blood volume to be withdrawn for any given patient is 
difficult to accurately predict and will depend, among other things, 
on how long the patient receives study drug, whether there are any 
adverse events leading to unscheduled blood draws, and whether 
there is any hospitalization related to said adverse events. 
Therefore, the timing and quantity obtained are defined in general 
terms as follows:
Full serum chemistry laboratory tests are scheduled to be 
performed at screening, every 2 weeks (±2 days) after cycle 5, and 
at the end-of-treatment visit. At each time point, 6 to 7 mL of 
blood will be drawn.
All chemistry and hematology 
tests have a ±2 day window.
Clarification of every 3 months.


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to 7 mL of blood will be drawn.
Serum chemistry 7 laboratory tests are scheduled to be 
performed on day 1 of each cycle, and days 7, 14, and 
21 of cycles 1 through 5. At each time point, 6 to 7 mL 
of blood will be drawn.
Hematology laboratory tests are scheduled to be 
performed at screening, day 1 of each cycle, days 7, 14, 
and 21 of cycles 1 through 5, day 14 for cycles after 
cycle 5, at confirmation of response, and at the 
end-of-treatment visit. At each time point, 4 to 5 mL of 
blood will be drawn.
BCR-ABL transcript levels are scheduled to be 
performed at screening, every 3 months during the 
study, at confirmation of response, and at the 
end-of-treatment visit. At each time point, 3 mL of 
blood will be drawn.
BCR-ABL mutation analysis is to be performed at 
screening and every 3 months on study. At each time 
point 3mL of blood will be drawn.
Serum chemistry 7 laboratory tests are scheduled to be performed 
on day 1 of each cycle, and days 7 (±2 days), 14 (±2 days), and 21 
(±2 days) of cycles 1 through 5. At each time point, 6 to 7 mL of 
blood will be drawn.
Hematology laboratory tests are scheduled to be performed at 
screening, day 1 of each cycle, days 7 (±2 days), 14 (±2 days), and 
21 (±2 days) of cycles 1 through 5, day 14 (±2 days) for cycles 
after cycle 5, at confirmation of response, and at the 
end-of-treatment visit. At each time point, 4 to 5 mL of blood will 
be drawn.
BCR-ABL transcript levels are scheduled to be performed at 
screening, every 3 months (ie, every 3 cycles) during the study, at 
confirmation of response, and at the end-of-treatment visit. At 
each time point, 3 mL of blood will be drawn.
BCR-ABL mutation analysis is to be performed at screening and 
every 3 months (ie, every 3 cycles) on study. At each time point 
3mL of blood will be drawn.
Chapter/section concerned:
6.2.4 Molecular Response
Molecular response is defined by the decrease in the 
amount of BCR-ABL mRNA measured by reverse 
transcriptase polymerase chain reaction (RT-PCR) or 
by the actual percentage of BCR-ABL mNRA 
transcripts (ratio of BCR-ABL transcript numbers to 
the number of control gene transcripts) (Baccarani et al 
2013, Cross et al 2012, Hughes et al 2006) (see
Appendix A).
Chapter/section concerned:
6.2.4 Molecular Response
Molecular response is defined by the decrease in the amount of 
BCR-ABL mRNA measured by reverse transcriptase polymerase 
chain reaction (RT-PCR) or by the actual percentage of BCR-ABL 
mNRNA transcripts (ratio of BCR-ABL transcript numbers to the 
number of control gene transcripts) (Baccarani et al 2013, Cross et 
al 2012, Hughes et al 2006) (see Appendix A).
Typo corrected to mRNA.
Chapter/section concerned:
7.1.4 Relationship of an Adverse Event to the Study 
Drug
No reasonable possibility
(not related)
Definition
This category applies to adverse events which, after 
careful consideration, are clearly due to extraneous 
causes (disease, environment, etc) or to adverse events, 
which, after careful medical consideration at the time 
Chapter/section concerned:
7.1.4 Relationship of an Adverse Event to the Study Drug
No reasonable possibility
(not related)
Definition
This category applies to adverse events which that, after careful 
consideration, are clearly due to extraneous causes (disease, 
environment, etc) or to adverse events, which that, after careful 
medical consideration at the time they are evaluated, are judged to 
be unrelated to the study drug.
Updated relationship table based 
on new protocol template 
language for relationship of an 
adverse event to study drug 
categories.


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they are evaluated, are judged to be unrelated to the 
study drug
Clarification
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following 
apply:

It does not follow a reasonable temporal sequence 
from the administration of the test drug.

It could readily have been produced by the 
patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to 
the patient.

It does not follow a known pattern of response to 
the test drug. 

It does not reappear or worsen when the drug is 
re-administered..
Clarification
The relationship of an adverse event may be considered “no 
reasonable possibility” if it is clearly due to extraneous causes or 
if at least 2 of the following apply:

It does not follow a reasonable temporal sequence from the 
administration of the test study drug.

It could readily have been produced by the patient’s clinical 
state, environmental, or toxic factors, or other modes of 
therapy administered to the patient.

It does not follow a known pattern of response to the test
study drug. 

It does not reappear or worsen when the drug is 
re-administered.
Chapter/section concerned:
7.1.4 Relationship of an Adverse Event to the Study 
Drug
Reasonable possibility
(related)
Definition
This category applies to adverse events for which, after 
careful medical consideration at the time they are 
evaluated, a connection with the test drug 
administration cannot be ruled out with certainty.
Clarification
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the drug.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.
Chapter/section concerned:
7.1.4 Relationship of an Adverse Event to the Study Drug
Reasonable possibility
(related)
Definition
This category applies to adverse events for which, after careful 
medical consideration at the time they are evaluated, a connection 
with the test study drug administration cannot be ruled out with 
certainty.
Clarification
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following apply:

It follows a reasonable temporal sequence from 
administration of the study drug.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, environmental, or 
toxic factors, or other modes of therapy administered to the 
patient.

It disappears or decreases on cessation or reduction in dose. 
There are important exceptions when an adverse event does 
Updated relationship table based 
on new protocol template 
language for relationship of an 
adverse event to study drug 
categories.


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
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the drug, yet drug-relatedness 
clearly exists.

It follows a known pattern of response to the test 
drug.
not disappear upon discontinuation of the drug, yet a
drug relatedness relationship clearly exists.

It follows a known pattern of response to the test study drug.
Chapter/section concerned:
7.1.5.3. Reporting a Serious Adverse Event
7.1.5.3.1 Investigator Responsibility
To satisfy regulatory requirements, all serious adverse 
events (as described in Section 7.1.5.1) that occur
during or after the study period (including the protocol 
defined follow up period, described in Section 7.1.2), 
regardless of judged relationship to treatment with the 
study drug, must be reported to the sponsor by the 
investigator. The event must be reported within 24 
hours of when the investigator learns about it or, if the 
event occurs on a weekend or national holiday, on the 
next working day. Completing the serious adverse 
event form and reporting the event must not be 
delayed, even if not all the information is available. 
The investigator does not need to actively monitor 
patients for adverse events once the study has ended. 
Serious adverse events occurring to a patient after the 
treatment of that patient has ended should be reported 
to the sponsor if the investigator becomes aware of 
them.
The serious adverse event form should be sent to the 
local safety officer (LSO) or other designated personnel 
(a contract research organization [CRO] in a country 
without a Sponsor LSO) (contact information is in the
Clinical Study Personnel Contact Information section); 
the LSO will forward the report to the sponsor’s Global 
Patient Safety & Pharmacovigilance Department..
The following information should be provided to 
record the event accurately and completely:

study number C41443/2057
Chapter/section concerned:
7.1.5.3. Reporting a Serious Adverse Event
7.1.5.3.1 Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as 
described in Section 7.1.5.1) that occur during or after the study 
period (including the protocol-defined follow-up period, described 
in Section 7.1.2), regardless of judged relationship to treatment 
with the study drug, must be reported to the sponsor by the 
investigator. The event must be reported within 24 hours of when 
the investigator learns about it. or, if the event occurs on a 
weekend or national holiday, on the next working day.
Completing the serious adverse event form and reporting the event 
must not be delayed, even if not all the information is available. 
The investigator does not need to actively monitor patients for 
adverse events once the study has ended. Serious adverse events 
occurring to a patient after the treatment of that patient has ended 
should be reported to the sponsor if the investigator becomes 
aware of them.
The serious adverse event form should be sent to the local safety 
officer (LSO) or other designated personnel (a contract research 
organization [CRO] in a country without a Sponsor LSO) (contact 
information is in the Clinical Study Personnel Contact Information 
section); the LSO will forward the report to the sponsor’s Global 
Patient Safety & Pharmacovigilance Department..
The following information should be provided to record the event 
accurately and completely:

study number C41443/2057

investigator and investigational center identification

patient number

patient initials
Revised specifics for reporting 
serious adverse events section 
based on new protocol template. 


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Initial wording
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
investigator and investigational center
identification

patient number

patient initials

onset date and description of adverse 
event

investigator’s assessment of the 
relationship of the adverse event to the 
study drug (no reasonable possibility, 
reasonable possibility)
Additional information may include the following:

age and sex of patient

date of first dose of study drug

date and amount of last administered dose 
of study drug

action taken

outcome, if known

severity

concomitant therapy (including doses, 
routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic 
test data 

medical history

results of dechallenge/rechallenge, if 
known

for an adverse event resulting in death: 

cause of death (whether or not the 
death was related to study drug)

autopsy findings (if available)
In the US, the investigator must ensure that the IRB is 
also informed of the event, in accordance with local 
regulations. In the EU, the sponsor or its designee must 
ensure that the IEC is also informed of the event, in 
accordance with local regulations.

onset date and description of adverse event

investigator’s assessment of the relationship of the 
adverse event to the study drug (no reasonable 
possibility, reasonable possibility)
Additional information may include the following:

age and sex of patient

date of first dose of study drug

date and amount of last administered dose of study 
drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant therapy (including doses, routes, and 
regimens) and treatment of the event

pertinent laboratory or other diagnostic test data 

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death: 

cause of death (whether or not the death was 
related to study drug)

autopsy findings (if available)
In the US, the investigator must ensure that the IRB is also 
informed of the event, in accordance with local regulations. In the 
EU, the sponsor or its designee must ensure that the IEC is also 
informed of the event, in accordance with local regulations.
Each report of a serious adverse event will be reviewed and 
evaluated by the investigator and the sponsor to assess the nature 
of the event and the relationship of the event to the study drug, 
study procedures, and to underlying disease. On the basis of this 
assessment, a decision will be made concerning the need for 
further medical intervention.
Additional information (follow-up) about any serious adverse 
event unavailable at the initial reporting should be forwarded by 
the investigational center within 24 hours of when it becomes 
known to the same address as the initial report.


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Each report of a serious adverse event will be reviewed 
and evaluated by the investigator and the sponsor to 
assess the nature of the event and the relationship of the 
event to the study drug, study procedures, and to 
underlying disease. On the basis of this assessment, a 
decision will be made concerning the need for further 
medical intervention. 
Additional information (follow-up) about any serious 
adverse event unavailable at the initial reporting should 
be forwarded by the investigational center within 24 
hours of when it becomes known to the same address 
as the initial report.
For all countries, the sponsor’s Global Patient Safety & 
Pharmacovigilance Department will distribute the 
Council for International Organizations of Medical 
Sciences (CIOMS) form/XML file to the LSO/CRO for 
local submission to the regulatory authorities and 
IEC/IRBs and Investigators, according to regulations.
Note: Although pregnancy is not a serious adverse 
event, the process for reporting a pregnancy is the same 
as that for reporting a serious adverse event, but using 
the pregnancy form (see Section 7.2).
For all countries, the sponsor’s Global Patient Safety & 
Pharmacovigilance Department will distribute the Council for 
International Organizations of Medical Sciences (CIOMS) 
form/extensible markup language (XML) file to the LSO/CRO 
for local submission to the regulatory authorities and IEC/IRBs 
and Investigators, according to regulations. The investigator is 
responsible for ensuring that the IEC/IRB is also informed of 
the event, in accordance with local regulations.
Note: Although pregnancy is not a serious adverse event, the 
process for reporting a pregnancy is the same as that for reporting 
a serious adverse event, but using the pregnancy form (see 
Section 7.2).
Chapter/section concerned:
7.1.5.3. Reporting a Serious Adverse Event
7.1.5.3.2 Sponsor Responsibility
If a serious unexpected adverse event is believed to be 
related to the study drug or study procedures, the 
sponsor will take appropriate steps to notify all 
Investigators participating in sponsored clinical studies 
of omacetaxine and the appropriate regulatory 
authorities. 
In addition to notifying the investigators and regulatory 
authorities, other measures may be required, including 
the following: 
Chapter/section concerned:
7.1.5.3. Reporting a Serious Adverse Event
7.1.5.3.2 Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to 
the study drug or study procedures, the sponsor will take 
appropriate steps to notify all Investigators participating in 
sponsored clinical studies of omacetaxine and the appropriate 
regulatory authorities (and IEC/IRB, if appropriate).
In addition to notifying the investigators and regulatory authorities 
(and IEC/IRB, if appropriate), other measures may be required, 
including the following: 
Revised specifics for reporting 
serious adverse events section 
based on new protocol template.
Chapter/section concerned:
7.3 Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry and 
hematology) will be performed at screening, prior to 
each treatment cycle, every 7 days during the first 5 
Chapter/section concerned:
7.3 Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry and hematology) will 
be performed at screening, prior to each treatment cycle, every 7 
days (±2 days) during the first 5 cycles, and every 2 weeks 
All chemistry and hematology 
tests have a ±2 day window.


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Initial wording
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Reason/Justification for change
cycles, and every 2 weeks during later cycles, as 
clinically indicated, and at the end-of-treatment visit.
(±2 days) during later cycles, as clinically indicated, and at the 
end-of-treatment visit.
Chapter/section concerned:
7.5 Electrocardiography
A 12 lead ECG will be conducted at screening, prior to 
dosing on day 1 of cycles 1 through 3, optionally after 
completion of treatment on day 14 of cycle 1, every 
3 months during the study, and at the end-of-treatment 
visit.
Chapter/section concerned:
7.5 Electrocardiography
A 12 lead ECG will be conducted at screening, prior to dosing on 
day 1 of cycles 1 through 3, optionally after completion of 
treatment on day 14 of cycle 1, every 3 months (ie, every 3 cycles)
during the study, and at the end-of-treatment visit. Prior to study 
entry, any other ECG abnormalities noted at screening other 
than myocardial infarction within the previous 12 weeks and felt 
by the investigator not to be medically relevant, must be 
documented as such.
Clarification of every 3 months.
Text added for clarification and 
consistency between protocol 
sections.
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
A. Complete Hematologic Response (CHR)

CP CML:

WBC<10 x 109/liter

platelets <450 x 109/liter

myelocytes + metamyelocytes <5% 
in blood

no blasts or promyelocytes in 
peripheral blood

<20% basophils in peripheral blood

no extramedullary involvement

response must last at least 8 weeks

AP CML:

ANC ≥1.5 x 109/liter

platelets ≥100 x 109/liter

no blood blasts

bone marrow blasts <5%

no extramedullary disease 

response must last at least 4 weeks

Loss of CHR in CP CML:

WBC >20 x 109/liter

loss of any of the other response 
criteria or progression to accelerated 
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
A. Complete Hematologic Response (CHR)

CP CML:

WBC<10 x 109/liter

platelets <450 x 109/liter

myelocytes + metamyelocytes <5% in blood

no blasts or promyelocytes in peripheral blood

<20% basophils in peripheral blood

no extramedullary involvement

response must last at least 8 weeks

AP CML:

ANC ≥1.5 x 109/liter

platelets ≥100 x 109/liter

no blood blasts

bone marrow blasts <5%

no extramedullary disease 

response must last at least 4 weeks

Loss of CHR in CP CML:

WBC >20 x 109/liter

loss of any of the other response criteria or 
progression to accelerated phase or blast crisis 
or discontinuation due to progressive disease or 
death
Typographical correction. Font 
changed to superscript.


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Initial wording
Amended or new wording
Reason/Justification for change
phase or blast crisis or 
discontinuation due to progressive 
disease or death
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
B. Parial Hematologic Response (PHR)
Same criteria as for CHR but with 1 or more of the 
following being present:

persistence of splenomegaly (although 
with a reduction of ≥50% from 
pretreatment size)

platelets >450 x 109/liter
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
B. Parial Hematologic Response (PHR)
Same criteria as for CHR but with 1 or more of the following 
being present:

persistence of splenomegaly (although with a 
reduction of ≥50% from pretreatment size)

platelets >450 x 109/liter
Typographical correction. Font 
changed to superscript.
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
C. Hematologic Improvement (HI)
Same criteria as CHR except for allowing 
thrombocytopenia lower than 100 x 109/L caused by 
underlying disease and the presence of a few immature 
cells (no blasts or promyelocytes, 5% or fewer 
myelocytes plus metamyelocytes) in the peripheral 
blood.
Chapter/section concerned:
Appendix A. RESPONSE EVALUATION CRITERIA
1.Hematologic Response
C. Hematologic Improvement (HI)
Same criteria as CHR except for allowing thrombocytopenia 
lower than 100 x 109/L caused by underlying disease and the 
presence of a few immature cells (no blasts or promyelocytes, 5% 
or fewer myelocytes plus metamyelocytes) in the peripheral blood.
Typographical correction. Font 
changed to superscript.
Chapter/section concerned:
Appendix D. LABORATORY TESTS
Serum Chemistry

Full Serum Chemistry

uric acid, ALT, AST, total bilirubin, 
blood glucose, BUN or urea, 
potassium, sodium, chloride, CO2 
content (ie bicarbonate), creatinine, 
alkaline phosphatase, phosphorus, 
other
Chapter/section concerned:
Appendix D. LABORATORY TESTS
Serum Chemistry

Full Serum Chemistry

uric acid, ALT, AST, total bilirubin, blood 
glucose, BUN or urea, potassium, sodium, 
chloride, CO2 content (ie bicarbonate), 
creatinine, alkaline phosphatase, phosphorus, 
other
Typographical correction. Font 
changed to subscript.


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17.2.
Administrative Letter Dated 10 June 2014


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APPENDIX A. RESPONSE EVALUATION CRITERIA
1. Hematologic Response
A. Complete Hematologic Response (CHR)

CP CML:

WBC<10 x 109/liter

platelets <450 x 109/liter

myelocytes + metamyelocytes <5% in blood

no blasts or promyelocytes in peripheral blood

<20% basophils in peripheral blood

no extramedullary involvement

response must last at least 8 weeks

AP CML:

ANC ≥1.5 x 109/liter

platelets ≥100 x 109/liter

no blood blasts

bone marrow blasts <5%

no extramedullary disease 

response must last at least 4 weeks

Loss of CHR in CP CML:

WBC >20 x 109/liter

loss of any of the other response criteria or progression to accelerated phase or 
blast crisis or discontinuation due to progressive disease or death
In patients who receive hydroxyurea during the first 2 cycles of treatment, if clinically indicated 
to control disease, CHR must be sustained for ≥4 weeks for AP CML and for ≥8 weeks for CP 
CML following the discontinuation of hydroxyurea to be considered a CHR.


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Treatment-related suppression of peripheral blood counts (PBC) due to continuing maintenance 
courses of omacetaxine therapy will not impact on the requirement for normal peripheral blood 
counts and ANC in calculation of the duration of CHR if it is clear that PBC suppression is 
temporarily due to the prior omacetaxine maintenance treatment course, eg, occurring at the 
expected time for nadir blood counts following a treatment cycle of omacetaxine, and the PBC 
suppression is transient.
B. Partial Hematologic Response (PHR)
Same criteria as for CHR but with 1 or more of the following being present:

persistence of splenomegaly (although with a reduction of ≥50% from pretreatment 
size)

platelets >450 x 109/liter

presence of immature cells in peripheral blood (no blasts or promyelocytes, 5% or 
fewer myelocytes plus metamyelocytes)

5% to 25% blasts in the bone marrow

in patients with EMD pretreatment, there must be a reduction by ≥50% of EMD
C. Hematologic Improvement (HI)
Same criteria as CHR except for allowing thrombocytopenia lower than 100 x 109/L caused by 
underlying disease and the presence of a few immature cells (no blasts or promyelocytes, 5% or 
fewer myelocytes plus metamyelocytes) in the peripheral blood. Patients meeting the CHR with 
thrombocytopenia cased by omacetaxine therapy will be considered to have achieved a CHR.
D. Return to Chronic Phase (RCP) for patients in AP CML

<15% blasts bone marrow and peripheral blood

<30% blasts + promyelocytes in the bone marrow and peripheral blood

<20% basophils in peripheral blood

no extramedullary disease other than spleen and liver
2. Cytogenetic Response

Complete: No Ph-positive metaphases

Partial: 1 to 35% Ph-positive metaphases

Major: 0 to 35% Ph-positive metaphases (complete and partial)


Uncontrolled Study–Chronic Myeloid Leukemia
Clinical Study Protocol with Amendment 01
Study C41443/2057
128

Minor: >35% Ph-positive metaphases

Minimal: >65% to 95% Ph+ cells

None: >95%Ph+ cells

Not Done: <20 metaphases were examined and/or response could not be assigned
A minimum of 20 metaphases should be examined.
Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation; 
thus, unconfirmed CCyR or partial cytogenetic response (PCyR) might have a lesser cytogenetic 
response on a subsequent bone marrow evaluation. A confirmed cytogenetic response is based on 
2 bone marrow cytogenetic evaluations, the latter done at least 1 month after the initial bone 
marrow study.
Cytogenetic response evaluation will be based on standard cytogenetic analysis (at least 
20 metaphases). This condition will always be required for affirmation or complete cytogenetic 
response. However, an assessment of partial response will remain in a sample with 
<20 metaphases when it is immediately preceded or followed by a complete or partial 
cytogenetic response in another sample.
3. No evidence of leukemia (NEL)-CML AP
Morphologic leukemia free state, defined as <5% bone marrow blasts
4. Molecular Response
Molecular response is best assessed according to the International Scale (IS) as the ratio of 
BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control 
transcripts. It is expressed and reported as BCR-ABL1% on a log scale, where 10%, 1%, 0.1%, 
0.01%, 0.0032%, and 0.001% correspond to a decrease of 1, 2, 3, 4, 4.5, and 5 logs, respectively, 
below the standard baseline that was used in the International Randomized Study if Interferon 
Versus ST1571 (IRIS) study (Baccarani et al 2013, Cross et al 2012, Hughes et al 2006).

Major Molecular Response: a BCR-ABL1 expression of ≤0.1%

Other definitions for deep molecular responses and undetectable disease are as described 
in Baccarani et al (2013).


Uncontrolled Study–Chronic Myeloid Leukemia
Clinical Study Protocol with Amendment 01
Study C41443/2057
129
APPENDIX B. MOLECULAR STUDIES
BCR ABL Transcripts Levels and BCR-ABL Mutation Analysis
1. The analysis may be done locally.
2. Type of BCR-ABL transcripts, BCR-ABL transcript levels by quantitative reverse 
transcription PCR (qRT-PCR) and, as indicated in the protocol, BCR-ABL kinase 
mutation analysis of peripheral blood samples will be performed.
3. Please check with your investigational center’s laboratory for volume requirements and 
sample handling.
4. If the investigational center is not able to carry this out at the investigational center, the 
sponsor may assist with arrangements for a central lab to perform these tests. For further 
advice, please contact the CRO or the back-up global clinical operations representative 
found on the first pages of the protocol or refer to the Pharmacokinetics and Laboratory 
Manual.
5. The definition of Molecular Response is found in Appendix A.


Uncontrolled Study–Chronic Myeloid Leukemia
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APPENDIX C. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work).
2
In bed <50% of the time. Ambulatory and capable of all self care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair.
5
Dead


Uncontrolled Study–Chronic Myeloid Leukemia
Clinical Study Protocol with Amendment 01
Study C41443/2057
131
APPENDIX D. LABORATORY TESTS
Hematology

White blood cell, red blood cells, hemoglobin, hematocrit, mean cell volume, mean 
cell hemoglobin, mean cell hemoglobin concentration, mean platelet volume, platelet 
count, neutrophils, ANC, band neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, metamyelocytes, promyelocytes, myelocytes, blasts, other
Serum Chemistry

Full Serum Chemistry

uric acid, ALT, AST, total bilirubin, blood glucose, BUN or urea, potassium, 
sodium, chloride, CO2 content (ie bicarbonate), creatinine, alkaline phosphatase, 
phosphorus, other

direct bilirubin, only if clinically indicated

Serum Chemistry 7

sodium, chloride, CO2 content, creatinine, BUN or urea, blood glucose, and 
potassium only
Special tests

Bone marrow aspiration (or biopsy) and cytogenetics
Urinalysis

specific gravity, pH, glucose, protein, blood, bilirubin, ketones, urobilinogen, nitrite, 
leukocytes, color, appearance, other

SAP_000.pdf: 
Statistical Analysis Plan
An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, 
Safety, and Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed 
Dose in Patients with Chronic Phase or Accelerated Phase Chronic Myeloid Leukemia 
who have Failed 2 or More Tyrosine Kinase Inhibitor Therapies
Study C41443/2057
NCT02078960
Date: 28 March 2018


Statistical Analysis Plan
Study C41443/2057
1
TEVA BRANDED PHARMACEUTICAL PRODUCTS R&D, INC. 
STATISTICAL ANALYSIS PLAN
An Open-Label, Single-Group Clinical Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed Dose in Patients with 
Chronic Phase or Accelerated Phase Chronic Myeloid Leukemia who have Failed 2 or More 
Tyrosine Kinase Inhibitor Therapies
Study C41443/2057 Phase 1/2
Date: 03/28/2018
Version: 1
Prepared by:


Statistical Analysis Plan
Study C41443/2057
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................6
INTRODUCTION ...........................................................................................................................8
1.
STUDY OBJECTIVES ................................................................................................9
2.
STUDY DESIGN .......................................................................................................10
2.1.
General Design and Study Schema.............................................................................10
2.2.
Primary and Secondary Measures and Endpoints ......................................................15
2.2.1.
Primary Efficacy Measures and Endpoints.................................................................15
2.2.2.
Secondary Efficacy Measures and Endpoints.............................................................15
2.2.3.
Safety Measures and Endpoints..................................................................................15
2.2.4.
Pharmacokinetic Measures and Endpoints.................................................................16
2.3.
Sample Size and Power Considerations .....................................................................16
2.4.
Randomization and Blinding......................................................................................17
2.5.
Sequence of Planned Analyses ...................................................................................17
2.5.1.
Interim Analyses.........................................................................................................17
2.5.2.
Final Analyses and Reporting.....................................................................................17
3.
POPULATIONS /ANALYSIS SETS.........................................................................18
3.1.
Enrolled Patients.........................................................................................................18
3.2.
Safety Analysis Set.....................................................................................................18
3.3.
Per-Protocol Analysis Set...........................................................................................18
3.4.
Pharmacokinetic Analysis Set ....................................................................................18
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................19
4.1.
General........................................................................................................................19
4.2.
Specification of Baseline Values................................................................................19
4.3.
Multiple Comparisons and Multiplicity......................................................................19
4.4.
Handling Withdrawals and Missing Data...................................................................19
4.4.1.
Partial Dates................................................................................................................19
4.5.
Study Days and Visit Windows..................................................................................19
5.
STUDY POPULATION.............................................................................................20
5.1.
General........................................................................................................................20
5.2.
Patient Disposition......................................................................................................20
5.3.
Demographics and Baseline Characteristics...............................................................20


Statistical Analysis Plan
Study C41443/2057
3
5.4.
Cancer and Glucose History.......................................................................................20
5.5.
Medical History ..........................................................................................................21
5.6.
Prior Leukemia Treatment..........................................................................................21
5.7.
Prior Medications........................................................................................................21
5.8.
Electrocardiography....................................................................................................21
5.9.
Physical Examinations................................................................................................21
5.10.
Protocol Violations.....................................................................................................21
6.
EFFICACY ANALYSIS ............................................................................................22
6.1.
General........................................................................................................................22
6.1.1.
Sub-group Analysis Variables ....................................................................................22
6.2.
Primary Efficacy Variable(s) and Analysis ................................................................22
6.3.
Secondary Efficacy Variables and Analyses ..............................................................22
6.4.
Other Analyses............................................................................................................22
7.
SAFETY ANALYSIS ................................................................................................23
7.1.
General........................................................................................................................23
7.2.
Study Drug Administration.........................................................................................23
7.3.
Adverse Events ...........................................................................................................23
7.4.
Deaths .........................................................................................................................23
7.5.
Clinical Laboratory Tests ...........................................................................................24
7.6.
Vital Signs ..................................................................................................................26
7.7.
Electrocardiography....................................................................................................26
7.8.
ECOG Performance Status .........................................................................................26
7.9.
Physical Examinations................................................................................................27
7.10.
Concomitant Therapy .................................................................................................27
8.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................28
8.1.
Pharmacokinetic Variables.........................................................................................28
8.2.
Blood Sampling ..........................................................................................................28
8.2.1.
Phase 1........................................................................................................................28
8.2.2.
Phase 2........................................................................................................................29
8.3.
Pharmacokinetic Analysis ..........................................................................................29
9.
STATISTICAL SOFTWARE ....................................................................................30
10.
LIST OF SUMMARIES AND LISTINGS.................................................................31
10.1.
Summary Tables .........................................................................................................31


Statistical Analysis Plan
Study C41443/2057
4
10.2.
Individual Patient Data Listings .................................................................................33


Statistical Analysis Plan
Study C41443/2057
5
LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................12
Table 2:
NCI CTCAE v4.0 Severity Criteria for Clinical Laboratory Tests ............................25
Table 3:
Criteria for Clinically Significant Vital Signs ............................................................26


Statistical Analysis Plan
Study C41443/2057
6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AP
Accelerated phase
AUC
area under the plasma drug concentration by time curve
AUC0-∞
area under the plasma drug concentration by time curve from 0 to infinite time
AUC0-t
area under the plasma drug concentration by time curve from 0 to time of the last measurable 
plasma concentration
AUC0-12
area under the plasma drug concentration by time curve from time 0 to the 12-hour time point
BSA
Body Surface Area
CI
Confidence interval 
CL/F
apparent plasma clearance
CRF
Case report forms
Cmax
maximum observed plasma concentration
CML
Chronic myeloid leukemia
CP
Chronic phase
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ICH
International Conference on Harmonization
MaHR
Major hematology response
MCyR
Major cytogenetic response
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NYHA
New York Heart Association
OS
Overall survival
PCR
Polymerase chain reaction
PFS
Progression-free survival
Ph+
Philadelphia chromosome-positive
PK
Pharmacokinetic
PP
Per protocol
Rpred
predicted accumulation ratio
SAP
Statistical Analysis Plan


Statistical Analysis Plan
Study C41443/2057
7
SD
Standard Deviation 
SE
Standard Error
t1/2
apparent terminal elimination half-life
tmax
time to maximum observed plasma drug concentration
TKI
Tyrosine kinase inhibitor
Vz/F
apparent volume of distribution
WBC
White blood cell
WHO
World Health Organization
λz
apparent plasma terminal elimination rate constant 


Statistical Analysis Plan
Study C41443/2057
8
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for TEVA 
Branded Pharmaceuticals Products R&D, Inc. study C41443/2057, (An Open-Label, 
Single-Group Clinical Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of 
Omacetaxine Mepesuccinate Given Subcutaneously as a Fixed Dose in Patients with Chronic 
Phase (CP) or Accelerated Phase (AP) Chronic Myeloid Leukemia (CML) who have Failed 2 or 
More Tyrosine Kinase Inhibitor Therapies), and was written in accordance with SOP-0000930 
(Global Statistical Analysis Plan Preparation, Review and Approval).
This phase 1/2 study is being completed to assess the safety and efficacy of omacetaxine 
mepesuccinate given subcutaneously as a fixed dose in patients with CP or AP CML who have 
failed 2 or more tyrosine kinase inhibitor therapies.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use: E9 Guidance on Statistical 
Principles in Clinical Trials. All work planned and reported for this SAP will follow 
internationally accepted guidelines, published by the American Statistical Association, and the 
Royal Statistical Society, for statistical practice.
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
patient in this study. When differences exist in descriptions or explanations provided in the 
protocol and this SAP, the SAP prevails; the discrepancies will be explained in the CSR. 
Since the study was prematurely terminated during the phase 1 part of the study due to poor 
recruitment, this SAP is adpated to support the abbreviated clinical study report.


Statistical Analysis Plan
Study C41443/2057
9
1.
STUDY OBJECTIVES
The purpose of this study is to investigate the pharmacokinetic and preliminary safety and 
efficacy of omacetaxine treatment following a fixed dose administered subcutaneously in 
patients with CP or AP CML who have failed 2 or more Tyrosine kinase inhibitor (TKI)
therapies. The ultimate goal is to investigate a fixed dose to treat patients with CP and AP CML 
effectively, with no worsening of the safety profile and no loss of efficacy. 
The primary objectives of the study are as follows:

to evaluate the efficacy of omacetaxine when administered subcutaneously as a fixed 
dose in patients with CP CML or AP CML 

to evaluate the safety of omacetaxine when administered subcutaneously as a fixed 
dose in patients with CP CML or AP CML

to characterize the pharmacokinetic profile of omacetaxine in cycle 1 when 
administered subcutaneously as a fixed dose
The secondary objectives of the study are as follows:

to determine the duration of responses

to determine progression-free and overall survival 

to determine molecular response

to determine additional pharmacokinetic parameters after cycle 1

to determine additional parameters, such as the BCR-ABL transcript


Statistical Analysis Plan
Study C41443/2057
10
2.
STUDY DESIGN
2.1.
General Design and Study Schema
This is a Phase 1/Phase 2, open-label, multicenter, single-group clinical study in patients with CP 
or AP CML who have failed 2 or more TKI therapies designed to investigate the 
pharmacokinetic, safety, and efficacy of omacetaxine given subcutaneously as a fixed dose. 
The study will consist of up to a 7-day screening period, and treatment for up to 12 months, in 
Phase 1 and Phase 2 portions, depending on response and tolerability. Patients will also have an 
end-of-treatment follow-up visit approximately 28 days after the last dose of omacetaxine. Each 
patient will be monitored for progression and survival for at least 1 year after their last dose of 
omacetaxine, death, or lost to follow-up, whichever comes first, regardless of patients receiving 
other anticancer treatment. 
Phase 1 portion: In Phase 1, there will be 3 body surface area (BSA) cohorts of approximately 7 
patients each; patients may have either CP or AP CML. All patients will be given a fixed dose of 
2.5 mg omacetaxine subcutaneous injection twice daily. Every effort will be made to include an 
equal number of patients in each BSA cohort. Cohort 1 will include patients whose BSA is less 
than 1.7 m2. Cohort 2 will include patients with a BSA between 1.7 m2 to 2.0 m2 inclusive. 
Cohort 3 will include patients with BSA greater than 2.0 m2. Based on data from previous 
clinical research studies, the range of BSA for patients enrolled in those studies was 1.39 to 2.46 
m2 for CP patients, and 1.34 to 2.31 m2 for AP patients (data on file). Because it is known that 
women usually have a smaller BSA than men, all efforts must be made to include at least 2 men 
in cohort 1 to reduce possible gender bias. After cycle 1, patients will continue to receive 
omacetaxine for 12 months until intolerance or disease progression while safety and efficacy 
parameters are followed.
Phase 2 portion: Following the analysis of pharmacokinetic and preliminary safety and efficacy 
data from the patients in Phase 1, a decision whether or not to continue to Phase 2 will be made. 
If the Phase 1 data indicate that a fixed-dose regimen is not appropriate for subcutaneously
administered omacetaxine, enrollment into the Phase 2 portion will be stopped and the study will 
be terminated. It is anticipated that the analysis of pharmacokinetic and preliminary safety and 
efficacy data from the patients in Phase 1 will take approximately 2 months. Assuming a 
fixed-dose regimen is considered appropriate on the basis of the Phase 1 data, a total of up to 
45 patients with CP CML and a total of up to 67 patients with AP CML will be enrolled in 
Phase 2. 
Phase 1 and Phase 2: Omacetaxine will be administered by subcutaneous injection twice daily. 
For cycle 1, the first dose will be administered at the investigational center. Subsequent doses (in 
prefilled syringes) may be administered on an outpatient basis after training takes place. See 
protocol Section 5.1.1 regarding training for the patient or caregiver for administration of 
omacetaxine. 
Patients will be evaluated every 7 days with complete blood and platelet counts up to and 
including cycle 5, and every 2 weeks after cycle 5; the number of consecutive doses of 
omacetaxine or intervals between subsequent cycles may be adjusted, as clinically indicated, 
according to guidelines provided in protocol Section 5.1.2.


Statistical Analysis Plan
Study C41443/2057
11
See more details in the protocol.
Visit-specific procedures and assessments are outlined in Table 1.


Statistical Analysis Plan
Study C41443/2057
12
Table 1:
Study Procedures and Assessments
Procedures and assessments
Screening
a
Omacetaxine induction or maintenance treatment
28-day cycles (up to 12 cycles total)
Study 
completion 
or
early 
termination
b
Follow-
up
c
Day 1 
induction 
cycles
Day 1 
maintenance 
cycles
Cycles 1 to 5 
(days 7, 14, 
21)
Cycle 6 to end 
of treatment
day 14
Every 
3 months 
on study
d
Confirmation 
of response
e
Informed consent
X
Inclusion/Exclusion criteria
X
Medical history
X
Urine or serum pregnancy test
X
f
Physical exam
X
X
g
Xg
X
Prior medications
X
Height
X
Weight
X
Xg
Xg
X
Calculate body surface area
h
X
X
X
Vital Signs (HR, RR, BP, T)
X
X
i
Xi
X
Chest x-ray
X
j
ECG
Xj
X
k
X
l
X
X
Hematology
m
X
Xg
Xg
X
n
X
o
X
X
Serum chemistry
p
X
Xg
Xg
Xn
Xo
X
Bone marrow aspiration and 
cytogeneticsq
Xj
X
r
X
s
Xq
BCR-ABL quantitative 
transcript levels by PCR
t
X
Xr
X
X
BCR-ABL mutation analysis
X
u
Xrv
Urinalysis
X
Document other measures of 
X
X
X
X


Statistical Analysis Plan
Study C41443/2057
13
Procedures and assessments
Screening
a
Omacetaxine induction or maintenance treatment
28-day cycles (up to 12 cycles total)
Study 
completion 
or
early 
termination
b
Follow-
up
c
Day 1 
induction 
cycles
Day 1 
maintenance 
cycles
Cycles 1 to 5 
(days 7, 14, 
21)
Cycle 6 to end 
of treatment
day 14
Every 
3 months 
on study
d
Confirmation 
of response
e
disease and disease symptoms 
ECOG performance status
X
Xg
Xg
X
Patient diary review
X
w
X
X
X
X
X
Drug accountability
Xw
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
Adverse event inquiry
X
X
X
X
X
X
X
Omacetaxine dosing
Days 1 through 14 during inductionu and days 1 through 7 during maintenance
Survival
x
X
X
X
X
X
X
X
Other anticancer treatment
X
a Screening period is 7 days before first dose of study drug except for bone marrow aspiration, cytogenetics, ECG, and chest x-ray, which may be performed 
within 30 days before start of study drug.
b Follow-up every 3 months; the first visit will be in person but the rest may be by telephone contact. Follow-up will continue until patient's death or 12 months 
after the last treatment cycle, whichever occurs first. Follow-up is required even if a patient is withdrawn from treatment with omacetaxine.
d For patient convenience, these studies may be scheduled to be obtained prior to the next scheduled omacetaxine treatment cycle. Additional studies may be 
conducted earlier than a scheduled 3-month interval if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
e For patients with chronic phase CML, confirm the response at least 8 weeks after the patient first meets the clinical and laboratory criteria for a response. For 
patients with accelerated phase CML, confirm the response at least 4 weeks after the patient first meets the clinical and laboratory criteria for a response. For 
patient convenience, confirmatory studies may be scheduled to be done prior to the next scheduled omacetaxine treatment cycle (rather than exactly at 4 or 
8 weeks after the initial response).
b If a patient completes treatment with omacetaxine or is withdrawn from treatment, assessments will be performed at an end-of-treatment visit 28 days after the 
last dose of study drug. If the patient is withdrawn from treatment, an end-of-treatment visit may occur before 28 days after the last dose of omacetaxine to 
allow the patient to enter follow-up.
f For women of childbearing potential. Repeat as clinically indicated.
g On the day of or within 3 days prior to start of the treatment cycle. Review results prior to initiating a treatment cycle.
h Body surface area will be calculated during cycles 1 through 3 of study drug treatment.
i Measure vital signs (HR, BP, temperature) within 30 minutes prior to administration of omacetaxine and 20 minutes after administration on day 1 of each 
treatment cycle. If the patient has hypotension (systolic blood pressure <90 mm Hg), vital signs should be taken and recorded more frequently, until the patient 
has stabilized. (In the case of outpatient injections, sometimes points may be omitted if logistically not possible, eg, the time point occurs over the weekend.)


Statistical Analysis Plan
Study C41443/2057
14
j May be omitted if prior study available within preceding 30 days.
k Prior to the first 3 cycles (cycles 1 through 3) whether induction or maintenance. It may be omitted at cycle 1 if one was done within 30 days prior to the first 
dose of omacetaxine on day 1 of cycle 1). In other countries, electrocardiograms may be done before and after every omacetaxine cycle, or as directed.
l Electrocardiogram after completion of day 14 of treatment, induction cycle 1, if the patient is available for this exam.
m Complete blood counts to include hematocrit, hemoglobin, RBC, WBC, differential, platelet count.
n During cycles 1 through 5 serum chem 7 (sodium, chloride, CO2 content, creatinine, BUN or urea, glucose, and potassium) will be performed on days 7 (±2), 
14 (±2), and 21 (±2). Studies may be obtained at a local laboratory, with results transmitted to the study investigational center in a timely manner as they 
become available.
o Full serum chemistry and hematology to be performed every 2 weeks after cycle 5.
p Full serum chemistry to be performed at screening and after cycle 5. During cycles 1 through 5, chem 7 (sodium, chloride, CO2, creatinine, BUN or urea, 
glucose, and potassium) is to be performed.
q Bone marrow exam with cytogenetic analysis to be performed by the G-banding technique. Marrow specimens will be examined on direct short-term (24-hour) 
cultures; at least 20 metaphases are to be analyzed. May be omitted at screening if bone marrow and cytogenetic analysis have been done in the preceding 
30 days and the patient had not received antileukemic therapy during this period (other than palliative therapy, eg, hydroxyurea).
r For the convenience of all patients, these studies may be scheduled prior to the next scheduled omacetaxine treatment cycle. Additional studies may be 
conducted earlier than a scheduled 3-month interval if clinically indicated, eg, a rising level of BCR-ABL transcript is observed.
s Obtain bone marrow cytogenetic study to confirm a cytogenetic response.
t Obtain BCR-ABL quantitative transcript levels by quantitative PCR analysis of peripheral blood. BCR-ABL transcripts will be detected by real-time 
quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis on peripheral blood.
u May be omitted if performed within 14 days before the first dose of omacetaxine.
v During the study it is only requested if the patient failed to respond or progressed.
w Except for day 1 of cycle 1 of induction.
x Obtain survival and progression-free survival defined as the time interval from date of first dose to date of death from any cause, or 12 months after last 
treatment cycle whichever occurs first. The patient is requested to be monitored even if the patient is withdrawn from the planned omacetaxine treatment or 
received other anticancer treatment.
HR=heart rate; RR=respiratory rate; BP=blood pressure; T=temperature; RBC=red blood cell; WBC=white blood cell; BUN=blood urea nitrogen; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; PCR=polymerase chain reaction; CML=chronic myeloid leukemia.


Statistical Analysis Plan
Study C41443/2057
15
2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Primary Efficacy Measures and Endpoints
The primary efficacy variable for patients with CP CML is the proportion of patients who 
achieve a major cytogenetic response (MCyR: complete cytogenetic response with no Ph+ 
metaphases and partial cytogenetic response with 1 to 35% Ph+ metaphases).
The primary efficacy variable for patients with AP CML is the proportion of patients who 
achieve a major hematologic response (MaHR: complete hematologic response or no evidence of 
leukemia) and/or MCyR. 
See protocol Appendix A for the measures for response.
2.2.2.
Secondary Efficacy Measures and Endpoints
The secondary efficacy measures and endpoints are as follows:

duration of response, defined for responders as the time interval from the first 
reported date of MCyR or MaHR in patients with AP CML, as defined above, to the 
earliest date of objective evidence of disease progression (ie, development of 
AP-phase CML in patients with CP CML or disease progression as recorded on eCRF 
for patients with AP CML), relapse (ie, loss of complete hematologic response in 
patient with AP CML or major cytogenetic response), death, or treatment 
discontinuation due to toxicity or lack of efficacy 

molecular response by site (peripheral transcript of BCR-ABL) (see protocol 
Appendix A) assessed every 3 months

progression-free survival, defined as the time interval from date of first dose to 
earliest date of objective evidence of disease progression (ie, development of 
AP-phase CML in patients with CP CML or disease progression as recorded on eCRF 
for patients with AP CML), relapse (ie, loss of complete hematologic response in 
patient with AP CML or major cytogenetic response), death, or treatment 
discontinuation due to toxicity or lack of efficacy

overall survival, defined as the time interval from date of first dose to date of death 
from any cause 
2.2.3.
Safety Measures and Endpoints
The safety and tolerability of omacetaxine treatment will be assessed throughout the study by 
evaluating the following safety variables:

adverse events (type, frequency, severity, and causality)

clinical laboratory test results (serum chemistry and hematology) at various points in 
the study

exploratory predictors of toxicity such as myelosuppression to assist with safety 
signals 


Statistical Analysis Plan
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16

vital signs measurements (blood pressure, heart rate, respiratory rate, body 
temperature)

physical examination (including weight)

12-lead electrocardiogram (ECG)

concomitant medication usage
2.2.4.
Pharmacokinetic Measures and Endpoints
The following pharmacokinetic parameters for omacetaxine and its metabolites, 4’-DMHHT and 
cephalotaxine, will be calculated for each patient, when possible, from plasma concentrations 
obtained following the first dose of omacetaxine in Phase 1: 

maximum observed plasma drug concentration (Cmax) by inspection (without 
interpolation)

time to Cmax, by inspection (tmax)

area under the plasma drug concentration by time curve (AUC) from time 0 to infinity 
(AUC0–∞)

AUC from time 0 to the time of the last measurable drug concentration (AUC0–t)

AUC from time 0 to 12 hours (AUC0–12)

apparent plasma terminal elimination rate constant (λz) and associated terminal 
elimination half-life (t½)

percentage extrapolation calculated as (AUC0-∞-AUC0-t)/(AUC0-∞)x100

apparent plasma clearance (CL/F; omacetaxine only)

apparent volume of distribution (Vz/F; omacetaxine only)

predicted accumulation ratio (Rpred) calculated as AUC0–∞/AUC0–12
2.3.
Sample Size and Power Considerations
The sample size for Phase 1 is approximately 21 patients in order to meet the pharmacokinetic 
objectives of the study. These 21 patients will also be counted in the sample size for Phase 2 and 
be part of any Phase 2 analyses.
Phase 2 sample sizes are based on Simon’s 2-stage optimum design. To reject the null hypothesis 
of MCyR rate 2.5% or lower in patients with CP CML at a target 1-sided alpha of 0.025 and beta 
of 0.10 (power of 90%) and assuming that the MCyR rate in the current study will be at least 
16%, in the first stage 16 patients with CP CML will be treated. If 1 or more patients respond, 
then the study will enroll another 29 patients with CP CML for a total of 45 patients. If 4 or more 
of the 45 patients achieve a MCyR, the fixed-dose regimen will be deemed effective in patients 
with CP CML. If the true rate is less than or equal to 2.5%, the probability of stopping after 
stage 1 is 0.667. 
The alternative hypothesis rate is set at 16% because an 18.4% response rate was observed in the 
registration studies (Studies CGX-635-CML-202 and CGX-635-CML-203) in which patients 


Statistical Analysis Plan
Study C41443/2057
17
received older generations of TKI drugs, and in the current study patients will be more likely to 
have received a newer generation of TKI drugs and more lines of therapy and may be less likely 
to respond to omacetaxine.
To reject the null hypothesis of MCyR rate 2.5% or lower in patients with AP CML at a target 
1-sided alpha of 0.025 and beta of 0.10 (power of 90%), and assuming that the MaHR rate in the
current study will be at least 12%, in the first stage 40 patients with AP CML will be treated. If 
2 or more patients achieve a MaHR, then the study will enroll another 27 patients with AP CML 
for a total of 67 patients. If 5 or more of the 67 patients respond, then the drug will be deemed to 
be effective in patients with AP CML. If the true rate is 2.5% or lower, the probability of 
stopping after stage 1 is 0.736. The alternative hypothesis rate is set at 12%, lower than the 
observed rate of 14.3 in the above mentioned registration studies for the same reason.
2.4.
Randomization and Blinding
This is a nonrandomized, open-label study.
2.5.
Sequence of Planned Analyses
2.5.1.
Interim Analyses
Pharmacokinetic and pharmacodynamic analyses as appropriate will be conducted to monitor 
patients during Phase 1 of the study. As each patient completes cycle 1 in Phase 1, plasma 
concentrations of omacetaxine will be measured. A few patients may be batched. The difference 
between expected and measured pharmacokinetic data will be used to determine if the fixed dose 
strategy is appropriate, or whether alternative strategies are warranted. If differences emerge, 
analyses will be conducted to determine if the deviations can be explained by differences in 
BSA. 
Once a total of approximately 21 patients with adequate pharmacokinetic samples are enrolled in 
Phase 1 of the study, pharmacokinetic parameters will be determined. Some patients may be 
replaced. Whether or not there is any correlation between exposure and preliminary efficacy or 
safety will be explored. 
After all patients in Phase 1 have completed cycle 1 of treatment and have pharmacokinetic 
samples analyzed, descriptive statistics will be used to compare pharmacokinetic parameters 
among the 3 cohorts (patients with small, medium, and large BSA). No formal statistical testing
will be done due to the small sample size. Selected preliminary safety and efficacy data, as 
appropriate, will also be provided to the DMC to assist with the evaluation of whether the fixed 
dose is appropriate for Phase 2 of the study.
The analyses identified in Section 10.1 will be performed.
2.5.2.
Final Analyses and Reporting
All final, planned analyses identified in this SAP will be performed only after the last patient has 
completed the study.
Any exploratory analyses completed to support study analyses, which were not identified in this 
SAP, will be documented and reported in appendices to the CSR.


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3.
POPULATIONS /ANALYSIS SETS
3.1.
Enrolled Patients
The set of enrolled patients includes all patients who provide informed consent to participate in 
the study and who meet all inclusion and exclusion criteria, regardless of whether or not a patient 
receives any study drug. 
3.2.
Safety Analysis Set
The safety analysis set will include patients who are enrolled and receive 1 or more doses of 
study drug. 
3.3.
Per-Protocol Analysis Set
Due to study early termination with a very limited number of patients, per-protocol (PP) analysis 
set will be defined but no analyses will be performed on PP analysis set. 
3.4.
Pharmacokinetic Analysis Set
The pharmacokinetic (PK) analysis set will include all patients who have at least 
1 pharmacokinetic measurement value after receiving study drug. 


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19
4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation, standard error 
of the mean, median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages. 
Summaries of clinically significant abnormal values will include all postbaseline values 
(including scheduled, unscheduled, and early termination visits).
Endpoint for analyses and summaries is the last observed postbaseline data.
4.2.
Specification of Baseline Values
Baseline is the last observed data prior to the first dose of study drug.
4.3.
Multiple Comparisons and Multiplicity
There are no multiple comparisons or multiplicity in this study. 
4.4.
Handling Withdrawals and Missing Data
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data. Patients without response assessment after dosing 
will be considered nonresponders.
4.4.1.
Partial Dates 
Dates that have incomplete information, such as only the month and year or just the year, will be 
estimated for the purpose of calculating variables that are dependent on time if necessary.
For partial dates of CML diagnosis, day will be estimated as the first day (01) of the month (if 
month and year of partial date are available) or middle (July 1) of the year (if only year is 
available). 
The imputations for partial dates are only for calculation purpose. Original date variables will not 
be imputed. Listings will list partial dates.
4.5.
Study Days and Visit Windows
For by-visit summaries, if there are multiple assessments at a postbaseline visit then the last non-
missing assessment at that visit will be used for the summary. This includes assessments at the 
scheduled and unscheduled visits.
Study days will be numbered relative to the first day of study drug administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the first dose of study drug, as 
recorded on the study drug diary. Days will be numbered relative to study start (ie, ..., –2, –1, 1, 
2, ...; with day 1 being the start of study drug and day –1 being the day before the start of study 
drug).


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5.
STUDY POPULATION 
5.1.
General
The set of enrolled patients will be used for all study population summaries unless otherwise 
noted. 
For safety and efficacy analysis, summaries will be presented by BSA cohort and overall.
5.2.
Patient Disposition
Patients screened, patients screened but not enrolled and the reason will be summarized for the 
overall group using patient counts.
Patients enrolled, patients enrolled but not treated, patients in the safety, PP, and PK analysis 
sets, number of cycle treated, patients who completed study treatment, patients who did not 
complete the treatment and reason, patients who completed the study, and patients who withdrew 
from the study and reason will be summarized using descriptive statistics.
The denominator for calculating the percentages will be the number of enrolled patients. 
5.3.
Demographics and Baseline Characteristics
Demographics at baseline will be examined. The continuous variables of patient age, weight, 
height, and BSA will be summarized using descriptive statistics. The categorical variables of age 
group (<65 years, >=65 years), patient sex, race, and ethnicity will be summarized using 
descriptive statistics for each category.
Data will be presented for the enrolled patients.
Baseline characteristics including New York Heart Assiciation (NYHA) function class, Eastern 
Cooperative Oncology Group (ECOG) performance status, liver examination, spleen 
examination, size below left and right costal margin (cm), extramedullary involvement (yes/no), 
and chest X-ray will be summarized using descriptive statistics.
Category for missing data will be provided as necessary.
5.4.
Cancer and Glucose History
Phase of CML at diagnosis, phase of CML at study entry (Chronic Phase vs. Accelerated Phase), 
glucose intolerance (yes/no), and diabetes mellitus (yes /no) will be summarized using 
descriptive statistics. 
If applicable, age at onset of the first CML diagnosis and months since diagnosis of the first 
CML diagnosis to the first dose of study drug will be calculated and summarized using
descriptive statistics.
Age at onset of first CML diagnosis= (date of first CML diagnosis – date of birth +1)/365.25, 
rounded to one decimal place.
Months since diagnosis to the first dose of study drug = (date of first administration of study 
drug – date of first CML diagnosis +1)/30.44, rounded to one decimal place.


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5.5.
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA version 16.1). Patients with a medical history assessment, patients with at least 1 
abnormal finding, and abnormal findings for each system organ class (SOC) will be summarized 
using descriptive statistics. 
5.6.
Prior Leukemia Treatment
Prior leukemia treatment will be coded using the World Health Organization dictionary of 
medical codes (WHO Drug version March 2013). The incidence of prior leukemia treatment will 
be summarized using descriptive statistics by therapeutic class and preferred term. 
Best hematologic response, best cytogenetic response, and best molecular response will be 
summarized using descriptive statistics.
5.7.
Prior Medications
All prior medications will be coded using WHO Drug (version March 2013). The incidence of 
prior medications will be summarized using descriptive statistics by therapeutic class and 
preferred term. Patients are counted only once in each therapeutic class category, and only once 
in each preferred term category. Prior medications will include all medications taken prior to the 
first day of study drug treatment.
Usage of prior hydroxyurea, anagrelide, and leukapheresis will be summarized separately. 
5.8.
Electrocardiography
Electrocardiogram findings (normal, abnormal and clinically significant, and abnormal not 
clinically significant) at baseline will be summarized using descriptive statistics.
5.9.
Physical Examinations
Physical examinations abnormality findings at baseline will be summarized using descriptive 
statistics.
5.10.
Protocol Violations 
Patients with at least 1 protocol violation for each category will be summarized using descriptive 
statistics.


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22
6.
EFFICACY ANALYSIS
6.1.
General
Efficacy analyses will be based on the safety analysis set unless otherwise noted. Efficacy 
analyses will only include the evaluation of response (cytogenetic and hematologic responses by
adjudication or assessed by study sites).
Due to study early termination in Phase 1 portion, efficacy analyses will be performed for Phase 
1 portion of the study only. 
6.1.1.
Sub-group Analysis Variables
No sub-group analyses are performed for efficacy variables due to early termination of the study. 
6.2.
Primary Efficacy Variable(s) and Analysis
Due to study early termination with very limited number of patients, primary efficacy variable 
will be derived by adjudication by the Data Monitoring Committee and will be summarized by 
visit using descriptive statistics.
6.3.
Secondary Efficacy Variables and Analyses
Due to study early termination with very limited number of patients, no secondary efficacy 
variables will be derived and thus no analyses for secondary efficacy variables will be
performed. 
6.4.
Other Analyses
Following post-baseline data will be summarized using descriptive statistics by visit:

Evaluation of response (cytogenetic and hematologic responses assessed by study 
sites);

Liver and spleen examination and extramedullary involvement;

Bone marrow aspiration and cytogenetic.


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7.
SAFETY ANALYSIS
7.1.
General
The safety analysis set will be used for all safety analyses. Summaries will be presented by BSA 
cohort and overall unless specified otherwise. 
7.2.
Study Drug Administration
Duration of treatment, number of days treated (overall and in each cycle), total dose received
(mg, overall and in each cycle), and number of cycle treated per patient will be summarized 
using descriptive statistics. Cycle delay and reason will be summarized by cycle.
Duration of treatment (day) is defined as the time duration from the first dose to the last day of 
treatment (last day of study drug – first day of study drug + 1).
7.3.
Adverse Events
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA version 16.1). The severity of each adverse event will be graded according to the NCI 
CTCAE (version 4.0). Summaries will be presented for all adverse events (overall and by NCI 
CTCAE toxicity grade), adverse events leading to drug withdrawal, adverse events determined 
by the investigator to be treatment-related (overall and by NCI CTCAE toxicity grade), serious 
adverse events, adverse events with NCI CTCAE toxicity grade of 3 or higher and non serious 
adverse events. Adverse events occurring prior to the first day of study drug administration will 
be considered to be “Non Treatment Emergent” adverse events and those occurring on or after 
the first day of study drug administration as “Treatment Emergent” adverse events.
The incidence of adverse events will be summarized using descriptive statistics by system organ 
class and preferred term. Patients are counted only once in each system organ class, and only 
once in each preferred term category. Treatment-related adverse event summaries will include 
adverse events with missing relationship to study drug. For the summaries by NCI CTCAE 
toxicity grade, patients are counted at the greatest severity. Adverse events missing the flag 
indicating serious will be excluded from the summary of serious adverse events but included in 
the summary of non serious adverse events.
Listings for fatal adverse events, serious adverse events, adverse events leading to drug 
withdrawal, adverse events with NCI CTCAE grade of 3 or higher, MedDRA dictionary terms 
for adverse event descriptions, and adverse event preferred terms by patient number will be 
presented.
7.4.
Deaths
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR. 


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24
7.5.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry and hematology) will be performed at screening, each 
cycle in various timepoints, and study completion/early termination.
Selected lab tests will be graded for abnormalities using NCI CTCAE version 4.0. Summary 
statistics for abnormalities of these selected chemistry and hematology laboratory tests will be 
presented for overall (worst value in study), by-cycle (worst value in each cycle), at study 
completion/early termination, and endpoint. For chemistry lab tests with NCI CTCAE grades in 
two directions (Low and High), data will be presented for both low and high for these tests.
Listings for all laboratory data and for NCI CTCAE grade 3 or 4 laboratory data will be 
presented.
The criteria for identifying abnormalities are specified in Table 2. 


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Table 2:
NCI CTCAE v4.0 Severity Criteria for Clinical Laboratory Tests
Chemistry
Grade 1
Grade 2
Grade 3
Grade 4
Albumin (g/l)
<LLN-30
<30 – 20
<20
--
Alk. Phosphatase
>ULN-2.5×ULN
>2.5-5.0×ULN
>5.0-20.0×ULN
>20.0×ULN
AST (SGOT)
>ULN-3.0×ULN
>3.0-5.0×ULN
>5.0-20.0×ULN
>20.0×ULN
ALT (SGPT)
>ULN-3.0×ULN
>3.0-5.0×ULN
>5.0-20.0×ULN
>20.0×ULN
Calcium (mmol/L)
Hypercalcemia (High)
Hypocalcemia  (Low)
>ULN-2.9
--                      
<LLN-2.0
>2.9-3.1
--                 <2.0 
-1.75
>3.1-3.4
--                  
<1.75- 1.5
>3.4         
--                 
<1.5
Glucose (mmol/L )  
Hyperglycemia (High) 
Hypoglycemia (Low)           
>ULN-8.9 
--                <LLN-
3.0
>8.9-13.9 
--                  
<3.0 – 2.2
>13.9-27.8      --      
<2.2 - 1.7
>27.8          --     
<1.7
Potassium(mmol/L) 
Hyperkalemia (High)
Hypokalemia (Low)
>ULN-5.5
--                 <LLN-
3.0
>5.5-6.0
--
NA
>6.0-7.0          --      
<3.0 - 2.5
>7.0            --    
<2.5
Sodium(mmol/L ) 
Hypernatremia (High)
Hyponatremia (Low)  
>ULN-150
--                    
<LLN-130
>150-155
--
NA
>155-160
--                  
<130 - 120
>160 
--                 
<120
Total Bilirubin
>ULN-1.5×ULN
>1.5-3.0×ULN
>3.0-10.0×ULN
>10.0×ULN
Creatinine
>ULN-1.5×ULN
>1.5-3.0×ULN
>3.0-6.0×ULN
>6.0×ULN
Hematology
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin (g/L)
<LLN- 100
<100 – 80
<80 - 65
< 65*
Neutrophils ABS (ANC) 
(×109/L)
<LLN-1.5
<1.5-1.0
<1.0-0.5
<0.5
Platelet count (×109/L)
<LLN-75.0
<75.0-50.0
<50.0 - 25.0
<25.0
WBC count (×109/L)
<LLN-3.0 
<3.0-2.0
<2.0 - 1.0
<1.0
Lymphocytes (ALC) 
(×109/L)
<LLN-0.8
<0.8 - 0.5
<0.5-0.2
<0.2
ULN=upper limit of normal range; LLN = lower limit of normal; Alk. Phosphatase=Alkaline Phosphatase; AST 
(SGOT) =Aspartate Aminotransferase; ALT (SGPT) =Alanine Aminotransferase; ANC=absolute neutrophil count; 
ALC=absolute lymphocyte count; ABS=absolute; WBC=White Blood Cell.
*NCI CTCAE v4.0 does not provide numeric cut-off value for grade 4 hemoglobin. The criterion 
from NCI CTCAE v3.0 is used.
If Neutrophils and Lymphocytes are collected in unit %, the tests will be converted into the value 
in the unit 10E9/L [absolute (ABS): value in % times WBC/100].


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7.6.
Vital Signs
Vital signs will be collected at screening, day 1 of each cycle (30 minutes pre dose and 20 
minutes post dose) and study completion/early termination.
Vital signs values and changes from baseline to each post-baseline assessment and endpoint will 
be summarized using descriptive statistics. The incidence of clinically significant abnormal 
values will be summarized for selected vital signs using descriptive statistics.
Table 3 specifies the criteria for identifying vital signs as clinically significant abnormal. Note 
that in order to be identified as clinically significant abnormal, a value would need to meet both 
conditions below: ie, have a value beyond the criterion value and a change of at least the 
magnitude specified in the change from baseline column.
Table 3:
Criteria for Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15
50 bpm
Decrease of 15
Systolic blood pressure
180 mm Hg
Increase of 20
90 mm Hg
Decrease of 20
Diastolic blood pressure
105 mm Hg
Increase of 15
50 mm Hg
Decrease of 15
Body temperature
≥38.3C
Change of 1.1C
A listing for clinically significant abnormal vital signs will be presented.
7.7.
Electrocardiography 
Electrocardiography (ECG) will be collected at screening, day 1 of cycles 1 to 3 and day 14 of 
cycle 1, every 3 months, and study completion/early termination. Post-baseline assessments will 
be done pre-dose and post dose except for study completion/early termination assessment.
For ECG findings (normal, abnormal and clinically significant, and abnormal not clinically 
significant), shifts from baseline to overall, each post-baseline assessment, and endpoint will be 
summarized using patient counts. For overall, the worst postbaseline finding (the abnormal 
finding if there are both normal and abnormal findings) for the patient will be summarized.
ECG variables results and changes from baseline to each post-baseline assessment and endpoint
will be summarized using descriptive statistics. 
7.8.
ECOG Performance Status
ECOG performance status will be assessed at screening, on day 1 or within 3 days prior to start 
of each treatment cycle, and study completion/early termination.


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Change from baseline to overall (worst value), each post-baseline assessment, and endpoint will 
be summarized using descriptive statistics. Changes will be categorized as ‘improved’, ‘staying 
the same’, and ‘deteriorated’.
7.9.
Physical Examinations
Physical examinations will be performed at screening, on day 1 or within 3 days prior to start of 
each treatment cycle, and study completion/early termination
Shift from baseline to each post-baseline assessment and endpoint will be summarized using 
descriptive statistics.
7.10.
Concomitant Therapy
All concomitant medications will be coded using the WHO Drug. The incidence of concomitant 
medications will be summarized using descriptive statistics by therapeutic class and preferred 
term. Patients are counted only once in each therapeutic class category, and only once in each 
preferred term category. Concomitant medications will include all medications taken while the 
patient takes study drug.
Usage of hydroxyurea, anagrelide, and leukapheresis will be summarized separately.


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8.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
To characterize the pharmacokinetics of omacetaxine, blood samples (2.5 mL) for measurement 
of plasma concentrations of omacetaxine and its 2 known circulating metabolites, 4’-DMHHT 
and cephalotaxine, will be obtained (via venipuncture or indwelling catheter) as specified below 
in Section 8.2. The actual time, dose, and volume of omacetaxine administered and actual blood 
collection time will be documented on CRFs.
8.1.
Pharmacokinetic Variables
The following pharmacokinetic parameters for omacetaxine and its metabolite 4’-DMHHT, will 
be calculated for each patient, when possible, from plasma concentrations obtained following the 
first dose of omacetaxine in Phase 1. Since all measurements of concentration for cephalotaxine 
were zero, none of the pharmacokinetic parameters will be calculated and no summaries will be 
performed for cephalotaxine.

maximum observed plasma drug concentration (Cmax) by inspection (without 
interpolation)

time to Cmax, by inspection (tmax)

area under the plasma drug concentration by time curve (AUC) from time 0 to infinity 
(AUC0–∞)

AUC from time 0 to the time of the last measurable drug concentration (AUC0–t)

apparent plasma terminal elimination rate constant (λz) and associated terminal 
elimination half-life (t½)

percentage extrapolation calculated as (AUC0-∞-AUC0-t)/(AUC0-∞)x100

apparent plasma clearance (CL/F; omacetaxine only)

apparent volume of distribution (Vz/F; omacetaxine only)
8.2.
Blood Sampling
8.2.1.
Phase 1 
In Phase 1, to accommodate the pharmacokinetic objective of the study, during cycle 1, 
omacetaxine will be administered by subcutaneous injection as follows: 1 dose will be 
administered in the morning of day 1, no doses will be administered on days 2 or 3, 2 doses will 
be administered on days 4 through 17. Starting with cycle 2, patients will continue treatment as 
in protocol Section 5.1.
Blood samples (2.5 mL) will be obtained during Phase 1 as follows:

20 minutes prior to and 15 (±5 min), 30 (±5 min), and 45(±5 min) minutes and 
1 (±5 min), 2 (±10 min), 4 (±10 min), 8 to 12 (±15 min), 24 (±1 hr), 48 (±1 hr), and 
72 (±1 hr) hours (predose 1 on day 4) after administration of the first dose of 
omacetaxine 


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
on day 10 or 11 or 12, predose, within (<) 1 hour after dose 1, and 1 to 12 hours after 
dose 1

1 sample on day 13, 14, 15, 16, or 17 either predose 1 or predose 2
In addition, blood samples (2.5 mL) will be obtained in Phase 1 on day 1 of cycles 2 and 3 as 
follows:

within (<) 1 hour after dose 1

1 to 12 hours after dose 1

1 sample either predose 1 or predose 2 on any day after day 1 during week 1

1 sample either predose 1 or predose 2 on any day during week 2
8.2.2.
Phase 2
Due to study early termination in Phase 1, no blood samples were collected for Phase 2.
8.3.
Pharmacokinetic Analysis
The pharmacokinetic analysis set will be used for all pharmacokinetic analyses.
The pharmacokinetic parameter data will be summarized by BSA categories and overall using 
descriptive statistics, including n, mean, standard deviation (SD), standard error (SE), geometric 
mean (if appropriate), coefficient of variation (if appropriate), median, minimum, and maximum.
The plasma concentration data obtained following the first dose (ie, predose through 72 hr 
postdose) will similarly be summarized at each nominal time point.
Listings of all available pharmacokinetic parameter and plasma concentration data will be 
provided.


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9.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.3.


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10.
LIST OF SUMMARIES AND LISTINGS
10.1.
Summary Tables
Summary 
number
Title
Population
15.1
Patient Disposition (for Phase 1)
All Patients
15.2
Demographics
Enrolled Patients
15.3
Baseline Characteristics 
Enrolled Patients
15.4
Cancer History 
Enrolled Patients
15.5
Abnormal Findings in Medical History 
Enrolled Patients
15.6.1.1
Prior Leukemia Treatment by Therapeutic Class and Preferred Term
Enrolled Patients
15.6.1.2
Number of Prior Leukemia Treatment 
Enrolled Patients
15.6.2
Best Response to Prior Leukemia Treatment 
Enrolled Patients
15.7.1
Prior Medications by Therapeutic Class and Preferred Term
Safety Analysis Set
15.7.2
Prior hydroxyurea, Anagrelide, and Leukapheresis Usage by Therapeutic 
Class, and Preferred Term
Safety Analysis Set
15.8
Electrocardiogram Findings at Baseline 
Enrolled Patients
15.9
Abnormal Physical Examination Findings at Baseline 
Enrolled Patients
15.10
Protocol Violations 
Enrolled Patients
15.11
Evaluation of Response (Adjudication) by Visit
Safety Analysis Set
15.12
Evaluation of Hematologic Response (Study Site Evaluation) by Visit
Safety analysis set
15.13
Evaluation of Cytogenetic Response (Study Site Evaluation) by Visit
Safety Analysis Set
15.14
Liver and Spleen Examinations by Visit
Safety analysis set
15.15
Bone Marrow Aspiration and Cytogenetics by Visit
Safety analysis set
15.16
Extramedullary Involvement data by Visit
Safety analysis set
15.17.1
Study Drug Exposure 
Safety Analysis Set
15.17.2
Study Drug Exposure by Cycle
Safety Analysis Set
15.17.3
Study Drug Exposure – Cycle Delay
Safety Analysis Set
15.18.1
Summary of Treatment Emergent Adverse Events
Safety Analysis Set
15.18.2
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term
Safety Analysis Set
15.18.3
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, and Toxicity Grade
Safety Analysis Set
15.18.4
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, and Toxicity Grade – Grade 3 or Higher
Safety Analysis Set
15.18.5
Treatment-Related Treatment Emergent Adverse Events by System Organ 
Safety Analysis Set


Statistical Analysis Plan
Study C41443/2057
32
Summary 
number
Title
Population
Class, and Preferred Term
15.18.6
Treatment-Related Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Toxicity Grade
Safety Analysis Set
15.18.7
Serious Adverse Events by System Organ Class, and Preferred Term
Safety Analysis Set
15.18.8
Adverse Events Leading to Study Drug Withdrawal by System Organ Class 
and Preferred Term
Safety Analysis Set
15.18.9
Non-Serious Treatment Emergent Adverse Events by System Organ Class, 
and Preferred Term
Safety Analysis Set
15.19.1
Overall Worst NCI CTCAE (v4.0) Grades for Selected Hematology 
Laboratory Tests
Safety Analysis Set
15.19.2
NCI CTCAE (v4.0) Grades 3 or 4 for Selected Hematology Laboratory 
Tests by Cycle
Safety Analysis Set
15.20.1
Overall Worst NCI CTCAE (v4.0) Grades for Selected Chemistry 
Laboratory Tests
Safety Analysis Set
15.20.2
NCI CTCAE (v4.0) Grades 3 or 4 for Selected Chemistry Laboratory Tests 
by Cycle
Safety Analysis Set
15.21.1
Vital Signs Values and Changes From Baseline to Each Time Point and 
Endpoint 
Safety Analysis Set
15.21.2
Vital Signs Clinically Significant Abnormal Values 
Safety Analysis Set
15.22.1
Electrocardiogram Findings Shifts from Baseline to Each Time Point and 
Endpoint
Safety Analysis Set
15.22.2
Electrocardiogram Variables Results and Changes From Baseline to Each 
Time Point and Endpoint 
Safety Analysis Set
15.23
ECOG Performance Status Changes From Baseline to Each Visit and 
Endpoint 
Safety Analysis Set
15.24
Physical Examination Findings Shifts From Baseline to Each Visit and 
Endpoint 
Safety Analysis Set
15.25.1
Medications by Therapeutic Class and Preferred Term
Safety Analysis Set
15.26.1
Plasma Concentration at Each Time Point - Omacetaxine
Pharmacokinetic 
Analysis Set
15.26.2
Plasma Concentration at Each Time Point - 4-DMHHT
Pharmacokinetic 
Analysis Set
15.26.3
Plasma Concentration at Each Time Point - Cephalotaxine
Pharmacokinetic 
Analysis Set
15.27.1
Pharmacokinetic Parameters- Omacetaxine
Pharmacokinetic 
Analysis Set
15.27.2
Pharmacokinetic Parameters- 4-DMHHT
Pharmacokinetic 
Analysis Set


Statistical Analysis Plan
Study C41443/2057
33
10.2.
Individual Patient Data Listings
Listing 
Number
Title
Population
16.2.1.01
Patient Disposition 
Enrolled Patients
16.2.1.02
Patients Who Did Not Meet Screening Criteria
16.2.2.01
Protocol Violations 
Enrolled Patients
16.2.4.01
Demographics 
Enrolled Patients
16.2.4.02
Medical History 
Enrolled Patients
16.2.4.03
Cancer History 
Enrolled Patients
16.2.4.04
Glucose History 
Enrolled Patients
16.2.4.05
NYHA Functional Class
Enrolled Patients
16.2.4.06
Chest X-Ray
Enrolled Patients
16.2.4.07
Prior Leukemia Treatment
Enrolled Patients
16.2.4.08
Prior Leukemia Treatment – Assessment Date
Enrolled Patients
16.2.4.09
Prior Hydroxyurea/Anagrelide/Leukapheresis Usage
Enrolled Patients
16.2.5.01
Study Drug Administration (at Study Site)
Safety Analysis Set
16.2.5.02
Study Medication Record (from Patient’s Diary)
Safety Analysis Set
16.2.6.01
Evaluation of Response
Enrolled Patients
16.2.6.02
Evaluation of Response by Study Site
Enrolled Patients
16.2.6.03
Liver Examination
Enrolled Patients
16.2.6.04
Spleen Examination
Enrolled Patients
16.2.6.05
Extramedullary Involvement
Enrolled Patients
16.2.6.06
Bone Marrow Aspiration and Cytogenetics
Enrolled Patients
16.2.6.07
Molecular Biology Data
Enrolled Patients
16.2.6.08
FISH (Fluorescence In Situ Hybridization) for Cytogenetic Analysis
Enrolled Patients
16.2.6.09
Follow-up
Enrolled Patients
16.2.7.01
Adverse Events 
Enrolled Patients
16.2.7.02
Deaths 
Enrolled Patients
16.2.7.03
Serious Adverse Events 
Enrolled Patients
16.2.7.04
Adverse Events Causing Study Drug Withdrawn 
Enrolled Patients
16.2.7.05
Adverse Events with NCI CTCAE Toxicity Grade of 3 or Higher
Enrolled Patients
16.2.7.06
MedDRA Version 16.1 Dictionary Terms For Adverse Event Descriptions
16.2.7.07
Adverse Event Preferred Terms and Patient Number
16.2.8.08
Adverse Events for Patients Who Did Not Meet Screening Criteria
16.2.8.01
Laboratory Reference Ranges


Statistical Analysis Plan
Study C41443/2057
34
Listing 
Number
Title
Population
16.2.8.02
Serum Chemistry Laboratory Tests Results 
Enrolled Patients
16.2.8.03
NCI CTCAE Grade 3 or 4 Serum Chemistry Laboratory Tests Results
Enrolled Patients
16.2.8.04
Hematology Laboratory Tests Results
Enrolled Patients
16.2.8.05
NCI CTCAE Grade 3 or 4 Hematology Laboratory Test Results
Enrolled Patients
16.2.8.06
Urinalysis Laboratory Tests Results 
Enrolled Patients
16.2.8.07
Pregnancy Test Results (Females Only)
Enrolled Patients
16.2.8.08
Treatment Schedule
Enrolled Patients
16.2.8.09
Vital Signs Values 
Enrolled Patients
16.2.8.10
Vital Signs Clinically Significant Abnormal Values 
Enrolled Patients
16.2.8.11
Electrocardiogram Findings 
Enrolled Patients
16.2.8.12
Electrocardiogram Variable Results 
Enrolled Patients
16.2.8.13
Physical Examination Findings 
Enrolled Patients
16.2.8.14
Performance Status (ECOG) 
Enrolled Patients
16.2.8.15
Medications 
Enrolled Patients
16.2.8.16
Hydroxyurea/Anagrelide/Leukapheresis Usage
Enrolled Patients
16.2.8.17
Concomitant Blood and Platelet Transfusion
Enrolled Patients
16.2.8.18
Pharmacokinetic Sample Times – Plasma
Pharmacokinetic
Analysis Set
16.2.8.19
Pharmacokinetic Parameters
Pharmacokinetic
Analysis Set