Clinical trial NCT02159872
Conditions: Leukemia
Keywords: Leukemia Myelodysplastic Syndrome MDS Omacetaxine Synribo Homoharringtonine
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-05-18; Completion date: 2020-04-14
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is learn if omacetaxine can help to control myelodysplastic syndrome (MDS). The safety of this drug will also be studied.

This is an investigational study. Omacetaxine is FDA approved and commercially available for the treatment of chronic myelogenous leukemia (CML). It is investigational to use omacetaxine in patients with MDS. The study doctor can explain how the study drug is designed to work.

Up to 80 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

Each cycle will be 4-7 weeks, depending on how well the disease responds to the study drug.

If you are found to be eligible to take part in this study, you will receive omacetaxine as an injection under your skin 2 times each day, about 12 hours apart, on Days 1-3 of every 28-day study cycle.

You will receive instructions on how to give these injections to yourself. You will be given a Research Drug Diary to record the drug you take each day. You must bring the Research Drug Diary and any unused drug with you to each study visit. You will also be told how to properly store the drugs.

Depending on how the disease responds to the study drugs, the number of days you receive your injections may stay the same, increase, or decrease. Your doctor will discuss this with you.

During Cycle 1, if the doctor thinks it is needed, you will be given hydroxyurea by mouth to decrease the risk of side effects. You may ask the study staff for information about how the drug is given and its risks.

Study Visits:

At the beginning of every cycle, you will have a physical exam before your dose of study drug.

Every week (+/- 2 days), blood (about 2-3 teaspoons) will be drawn for routine tests. If the disease appears to get better, this blood will only be drawn every 2-4 weeks while you are still receiving the study drugs.

If you live far from the clinic, this blood can be drawn at a clinic close to your home, and the results will be reported to the study doctor.

If the study doctor thinks it is needed, you may have an additional bone marrow aspirate at any time during the study to check the status of the disease and for cytogenetic testing.

Length of Study:

You may continue taking the study drug for up to 24 cycles of treatment. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Follow-Up:

You will have follow-up visits at the clinic every 3-6 months for up to 5 years after you stop taking the study drug. You will be asked about your health and any new drugs you may be taking. If you cannot come to the clinic, you will be called by the study staff and asked about your health. These calls should last about 5-10 minutes.

Every 4-8 weeks after your last dose of study drug, blood (about 2-3 teaspoons) will be drawn for routine tests.

Arms: arm 1: Omacetaxine 1.25 mg/m2 subcutaneously every 12 hours on Days 1-3 of every 28-day study cycle. Participant may continue taking the study drug for up to 24 cycles of treatment.
Interventions: intervention 1: Omacetaxine
Intervention descriptions: intervention 1: 1.25 mg/m2 subcutaneously every 12 hours on Days 1-3 of every 28-day study cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher 
Risk Myelodysplastic Syndrome (MDS) post Hypomethylating Agent (HMA) 
Failure 
2013-0870
Core Protocol Information
Short Title 
Omacetaxine in Patients with Intermediate-1 and Higher 
Risk MDS post HMA Failure
Study Chair: 
Elias Jabbour
Additional Contact:
Jhinelle L. Graham
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-4764
Unit:
0428
Full Title: 
A Phase II Study of Omacetaxine (OM) in Patients with 
Intermediate-1 and Higher Risk Myelodysplastic Syndrome 
(MDS) post Hypomethylating Agent (HMA) Failure 
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 08/05/2018
Version:
08
Document Status:
Saved as "Final"
Submitted by:
Vicky H. Zoeller--9/11/2017 12:24:33 PM
OPR Action:
Accepted by:  Margaret Okoloise -- 9/14/2017 12:09:50 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


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A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 
and Higher Risk Myelodysplastic Syndrome (MDS) post 
Hypomethylating Agent (HMA) Failure  
 


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Table of Contents 
 
1.0 
Objectives .................................................................................................. 3 
2.0 
Background ............................................................................................... 3 
3.0 
Drug Descriptions ...................................................................................... 8 
4.0 
Study Design and Eligibility ....................................................................... 9 
4.2 
Patient eligibility ..................................................................................... 910 
5.0 
Treatment Plan .................................................................................... 1112 
6.0 
Pretreatment Evaluation .......................................................................... 16 
7.0 
Evaluation During Study ...................................................................... 1617 
8.0 
Criteria for Response ............................................................................... 17 
9.0 
Criteria for Removal from the Study ........................................................ 19  
10.0.  Regulatory and Reporting Requirements ................................................ 19 
11.0 
Statistical Considerations ........................................................................ 22  
12.0 
References .............................................................................................. 27  
 


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A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher 
Risk Myelodysplastic Syndrome (MDS) post Hypomethylating Agent (HMA) 
Failure  
 
1.0 
Objectives 
 
1.1 
Primary Objectives: 
a. To assess overall survival and  
b. To assess overall response rate (ORR) 
 
1.2 
Secondary objectives 
a. 
To assess duration of response 
b. 
To assess relapse-free survival  
c. 
To assess the safety profile 
2.0 
Background 
 
2.1 
Myelodysplastic Syndromes  
 
The standard of care for patients with intermediate-1 and above myelodysplastic 
syndrome (MDS) is a hypomethylating agent, either decitabine or azacitidine.1-2 
Although these agents are effective and result in clinical improvement in over 60% of 
patients, it is now accepted that a large majority of patients will lose response. Median 
number of cycles with this class of agents in front line MDS is 8 months. It is now  
established that the prognosis of patients that fail a hypomethylating agent is very poor. 
MD Anderson (MDACC) was the first to report that the median survival of such patients 
is less than 5 months.3 Results confirmed now by multiple centers.4 Of importance, the 
mechanisms of resistance are not understood. At the present time, there is no drug 
approved for patients that have failed this class of agents and because of the very poor 
prognosis of these patients there is an urgent need for an active and safe compound.  


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A number of agents have been used in the treatment of these patients. These include 
high dose chemotherapy, clofarabine, sapacitabine but have not been formally tested in 
this indication.3 A phase III study of ON1910 (rigorsetib) has been completed and 
results are expected in 2014. Of interest, the FDA allowed a concept of modest 
improvement in survival (from 4 to 6 months) in the design of this trial. 
 
We believe that agents with potential in this context of hypomethylating failure MDS 
cannot be very cytotoxic and allow for gradual responses and stabilization of the 
disease resulting in prolonged survival. This is important because early responses 
associated with significant cytopenias have been associated with short survival, an 
example being cloretazine.5 Based on our experience with omacetaxine (OMA) in CML 
and more recently in AML,6-8 we believe that OMA has the potential to have significant 
activity in this context without excess toxicity.. 
 
2.2 
Omacetaxine (OM) in Myeloid Malignancies 
 
OM is a semisynthetic version of a plant alkaloid extracted from Cephalotaxus fortunei, 
a species of evergreen tree that is indigenous to China. It is available in China for the 
treatment of hematological malignancies. OM mechanisms of action include protein 
synthesis inhibition 9 and induction of differentiation10 and apoptosis. 10-12-14 Recent 
studies indicate OM is affecting histone deacetylase and is also a potent angiogenesis 
inhibitor. OM has shown activity in AML and other hematologic cancers, including acute 
promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and MDS. 13-22 Studies 
from China reported high response rates in patients with leukemia. Trials in the U.S. 
have shown significant activity as well. In a Phase I-II trial, Warrell et al. treated 49 
patients with refractory AML with OM, 5 or 7 mg/m2 daily for 7 days and 5 mg/m2 daily 
for 9 days (25-49 mg/m2 per course), in a continuous infusion schedule. 23 Dose 
escalation beyond 5 mg/m2 daily resulted in frequent interruption of OM infusion 
because of hypotension. Hypotensive episodes occurred in approximately 30% of 
patients; myalgias occurred in 20% of patients and hyperglycemia in 57% of patients (it 


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was severe in 23%). A schedule of 5 mg/m2 daily for 9 days was judged reasonable. Of 
28 evaluable patients with AML who were treated with cumulative doses of 45-49 mg/m2, 
7 (25%) achieved a CR. At lower dose levels, none of nine patients achieved a CR.24 
The recommended dose schedule of OM was 5 mg/m2 daily for 9 days. 
 
Two additional studies of OM in AML showed similar results with CR rates of 20% - 30%. 
25 Stewart et al. did not obtain any CRs in 20 patients with advanced AML who were 
treated with OM, 3.5 mg/m2, on Day 1 and 6 mg/m2 daily × 7, on Days 2-8.26  
In their study, Kantarjian et al. 20 investigated OM in a lower dose, longer infusion 
schedule of 2.5-3 mg/m2 by continuous infusion daily for 14-21 days in patients with 
refractory-recurrent acute leukemia in an attempt to demonstrate efficacy without 
hypotensive events.  While the response rate was low in this AML refractory group of 
patients, the longer infusion lower daily dose schedule averted cardiovascular toxicity. 
The summary Phase I-II trials of OM conducted at the Memorial Sloan-Kettering Cancer 
Center, New York Medical College, and the Eastern Cooperative Oncology Group 
included 117 patients with refractory AML treated at doses of 5-7 mg/m2 daily by 
continuous infusion. Among 91 evaluable patients, 14 achieved a CR (15%) and 1 
achieved a partial response. 23, 25-26 
In the New York Medical College studies, Feldman et al. 27 used OM, 5 mg/m2, by 
continuous infusion daily for 9 days in patients with refractory-recurrent acute leukemia 
or blastic phase CML. Sixty-six patients were treated; their median age was 41 years. 
CRs were achieved in 7 of 43 patients (16%) with recurrent AML, in none of 11 patients 
with AML that primarily was resistant to anthracycline-cytarabine combinations, and in 2 
of 3 patients whose disease was resistant to low-dose cytarabine. Side effects included 
significant hypotensive events, fluid retention, weight gain (29%), and hyperglycemia 
(63%).27 Other studies have also demonstrated the activity of OM in AML.28-30 
 
Studies with subcutaneous dose schedules of omacetaxine in AML established its 
safety and efficacy.  Dose ranges of 0.5-5 mg/m2 daily for 9 days were used.  The 


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regimen was myelosuppressive.31 In the MD Anderson experience doses of more than 
2.5 mg/m2 SQ daily for longer than 5 day exposures were associated with significant 
myelosuppression. 
 
2.3 
Myelodysplastic Syndrome (MDS) 
 
Twenty-eight patients with MDS or MDS evolved into AML were treated with OM 5 
mg/m2/daily by continuous intravenous infusion for 9 days.22 Their median age was 67 
years. Seven patients achieved CR, and 1 had a PR, for an overall response rate of 
28%. Complete response occurred in 3 of 15 patients with MDS and in 4 of 13 patients 
with MDS that evolved to AML. Median duration of remission was 7 months. In this 
study group, induction death was high (13 of 28 patients), mainly because of 
myelosuppression-related infections. Myelosuppression was prolonged and severe, but 
other toxicities were mild. 22 The dose schedule of OM used in this study of elderly 
patients was effective but toxic. Lower dose schedules of OM may demonstrate similar 
efficacy and lower toxicity in MDS. 
 
2.4 
Human toxicology 
 
In the early trials of brief OM infusions (10-360 minute infusion daily for 1-10 days), 
delayed hypotension and reflex tachycardia were the dose-limiting and dose-dependent 
toxic effects of the drug. 24, 32-35 These effects were most prominent at doses above 3 
mg/m2 and appeared approximately 4-6 hours after bolus drug administration. 
Subsequent studies using lower dose longer infusion schedules resulted in complete 
elimination of the cardiovascular problems.  
 
Administration of OM by continuous intravenous infusion schedules in Phase I-II studies 
has resulted in a dramatic decrease in the incidence of cardiovascular complications 
with an increased antiproliferative effect producing prolonged granulocytopenia and 
thrombocytopenia.23 In a Phase I-II study of refractory AML dose of 2.5 mg/m2 daily for 
15 to 21 days (n = 13) or 3.0 mg/m2 daily for 15 days (n =18).20 Cardiovascular 


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complications were minimal, consisting of asymptomatic hypotension (drop of systolic 
blood pressure by 20 mm Hg) in one patient and supraventricular arrhythmias in two 
patients. While hypotension is still observed when OM is administered by continuous 
infusion, temporary interruption of dosing and/or fluid administration is usually 
successful in reversing this side effect. When OM was given by continuous IV infusion, 
hypotension appeared within 24-48 hours after starting treatment. With continuous 
infusion schedules, myelotoxicity becomes the dose-limiting toxicity.24,32-35 
Hyperglycemia, associated with increased plasma insulin levels, has been observed in 
adult patients treated with OM. Patients receiving OM therapy by continuous infusion, 
particularly at doses >5 mg/m2, as well as diabetics and patients concurrently receiving 
asparaginase and/or prednisone should have their blood glucose levels routinely 
monitored. Therapy with insulin may be required; however, the effect is usually mild and 
reversible following completion of OM therapy. 
 
2.6 
Justification for study treatment plan 
 
This study is a simple phase II study assessing the efficacy of OM in patients with MDS.. 
OM will be administered via subcutaneous injection at a dose of 1.25 mg/m2 twice daily 
for 3 consecutive days every 28 days. This dosage route and schedule have been used 
in previous clinical studies both as a single agent and in combination with other 
therapies. Although many early studies administered OM using both bolus IV and 
continuous infusion, the subcutaneous route of administration is being used to provide 
better convenience to patients to allow administration at home. We have recently 
reported our experience using OM for 3 days in combination with low-dose cytarabine. 
This combination was found to be safe and effective in inducting an objective response 
rate of 50% (CR rate of 30%) with a median survival of 9.3 months.6  
 
The pharmacokinetics and safety of this route has been evaluated in a dose escalation 
study in patients with AML. Dose dependent Cmax and AUC were observed, and an 
MTD of 5 mg/m2/d for 9 days was reported. Based on these data and results as well as 
safety and efficacy data from previous studies, the dose of 1.25 mg/m2 was selected as 


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it was associated with the greatest number of responses and had an acceptable safety 
profile.  
2.7 
Summary of risk and benefits 
 
The safety profile of OM has been well documented in many clinical studies. The 
principal toxicities associated with subcutaneous OM have been myelosuppression, 
diarrhea, fatigue, nausea, fever, and infection which are not unexpected in patients with 
MDS.36 There will be ongoing safety monitoring during the study and SAE and AE data 
will be reviewed in conjunction with the other safety measures. 
 
3.0 
Drug Descriptions 
3.1 
OM 
 
OM is a cephalotaxine ester. It is an alkaloid derived from the plant Cephalotaxus 
fortunei. Cephalotaxines have the empirical composition C18H21NO4 and contain a 
methylenedioxypheno group, a secondary hydroxyl group, double bond and a vinyl 
methoxyl group. A variety of esters of cephalotaxine are known and the two which have 
been investigated clinically are harringtonine, ester-2 and homoharringtonine, ester-3. 
Homoharringtonine differs from harringtonine in having a methylene group inserted in 
the side chain. Homoharringtonine can be totally synthesized. OM is commercially 
available in China from Hangzhou Minsheng Pharmaceutical Group (Hangzhou, China) 
for the treatment of hematological malignancies. There are no known drug 
incompatibilities. 
 
The study medication, OM will be provided to the principal investigator by the supporter, 
Cephalon, Inc.  OM is approved by the FDA for use in the United States.  OM drug 
product is a lyophilized vial containing 3.5 mg OM, 10 mg mannitol in a 10-mL clear 
glass vial, sealed with rubber stopper and aluminum flip-off seal. Drug is stored at 
controlled room temperature, 15ºC to 30ºC. The study drug will be provided as 
individual vials of 3.5 mg OM. 


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OM is administrated by the subcutaneous injection. Each 3.5-mg OM vial must be 
reconstituted with 1.0 mL of 0.9% NaCl (isotonic saline) before subcutaneous injection. 
Constituted OM can be stored at ambient temperature and must be used within 12 
hours. If refrigerated, constituted OM can be stored for up to 6 days and must be used 
within those 6 days.   
 
4.0 
Study Design and Eligibility 
 
4.1 
Study design 
 
This will be a single arm, single center, open label phase II study assessing OM in 
patients with intermediate-1 and higher risk MDS post HMA failure. OM will be 
administered at the dose of 1.25 mg/m2 subcutaneously every 12 hours for 3 days. If 
patient is in the hospital a nurse will administer the treatment. If patient is at home then 
the treatment can be self-administered or administered by a family member. This Phase 
II study will include up to a total of 80 patients.  The primary endpoint of this Phase II 
study is achievement of objective response and overall survival.   Early stopping rules 
will be implemented for low CR rates and survival (please refer to section 11.2) 
 
4.2 
Patient eligibility 
 
4.2.1  Inclusion 
 
1. Age >/= 18 years 
 
2. Diagnosis of MDS confirmed within 10 weeks prior to study entry according to WHO 
criteria. Patients are either not eligible for or choose not to proceed with a stem cell 
transplant. 


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3.  MDS classified as follows: RAEB-1 (5%-9% BM blasts); RAEB-2 (10%-19% BM 
Blasts); CMML (5%-19% BM blasts); RAEB-t (20%-29% BM blasts) AND/OR by IPSS: 
intermediate-1 and high risk patients. 
 
4.  No response, progression, or relapse (according to 2006 IWG criteria) following at 
least 4 cycles of either azactidine or decitabine, which were completed within the 
last 2 years - AND/OR - intolerance to azacitidine or decitabine defined as drug-
related >/= grade 3 hepatic or renal toxicity leading to treatment discontinuation 
during the preceding 2 years. 
 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of </= 2. 
 
6.  Willing to adhere to and comply with all prohibitions and restrictions specified in the 
protocol. 
 
7.  Patient (or patient's legally authorized representative) must have signed an informed 
consent document indicating that the patient understands the purpose of and 
procedures required for the study and is willing to participate in the study.)  
 
4.2.2 Exclusion 
 
1. Uncontrolled intercurrent illness including, but not limited to, symptomatic 
congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. 
 
2. Active infection not adequately responding to appropriate antibiotics (i.e. ongoing 
temperatures of >/= 38 degree Celsius). 
 
3.  Total bilirubin >/= 1.5 mg/dL and not related to hemolysis or Gilbert's disease. 
Patients with total bilirubin >/= 1.5 mg/dL to 3 mg/dL are eligible if at least 75% of 
the bilirubin is indirect. 


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4.  Alanine transaminase (ALT/SGPT) or aspartate transaminase (AST/SGOT) >/= 
2.5 x the upper limit of normal. 
 
5.  Serum creatinine > 1.5 mg/dL. 
 
6.  Female patients who are pregnant or lactating. 
 
7. Patients with reproductive potential who are unwilling to following contraception 
requirements (including condom use for males with sexual partners, and for 
females: prescription oral contraceptives [birth control pills], contraceptive 
injections, intrauterine devices [IUD], double-barrier method [spermicidal jelly or 
foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) 
throughout the study. 
8. Female patients with reproductive potential who do not have a negative urine or 
blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at 
screening. 
 
9. Patients receiving any other concurrent investigational agent or chemotherapy, 
radiotherapy, or immunotherapy. 
10.  Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors 
(eg, G-CSF, GM-CSF, procrit, aranesp, thrombopoietins) is allowed at any time 
prior to or during study if considered to be in the best interest of the patient. 
11. Psychiatric illness or social situation that would limit the patient's ability to comply 
with study requirements. 
 
5.0 
Treatment Plan 
5.1 Treatment Plan 
 


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In this Phase II study 80 patients will be treated with OM for the first 3 days of every 4-7 
week cycle.  The primary endpoint of this study will be efficacy as measured by 
objective response rate and overall survival.  Early stopping rules will be implemented 
for excessive toxicity or lack of efficacy.  Please refer to statistical section 11 for details. 
 
5.2 
General study treatment plan 
 
The intent of the study design is for all patients to receive up to 12 courses. Treatment 
will be continued during the duration of the study unless patients exhibit evidence of 
treatment failure, disease progression, experience an unacceptable toxicity, or the 
investigator determines that discontinuation of treatment is in the best interest of the 
patient. 
 
Patients will be treated with study drugs based on a calculation determined from the 
patient's body surface area (BSA). BSA will be calculated before each cycle and will be 
based on the patient's height (measured at baseline) and weight (measured each cycle) 
and will be adjusted downward to "ideal" weight. 
 
"Patients will be instructed to self-administer OM at home and return unused intact drug 
syringes to be disposed of by the study staff or dropped off to the Investigational 
Pharmacy. Patients will be given a Research Medication Diary to record the medication 
taken each day. Patients will be instructed to bring the diary and any unused intact 
medication syringes with them to all study visits. Any unused drug will be disposed of 
per institutional standard practice.  
 
 
5.3 
Dose modifications: 
 
Patients will receive their OM treatment every 4-7 weeks: 
a. 
OM 1.25 mg/m2 SQ every 12 hours (+/- 3 hours) for 3 days.  
 


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Courses will be repeated every 4-7 weeks.  Subsequent courses can be given with 
modified schedules as detailed below:   
 
a. 
Stable or improved MDS with grade 2 or less toxicity:  use same dose 
schedule as previous course. 
b. 
MDS not improved with grade 2 or less toxicity, increase dose schedule to 4 
days of OM if needed. 
c. 
MDS stable/improved or not improved with grade 3-4 toxicity, give 
subsequent course with 2 days of OM if clinically indicated; otherwise may 
take patient off study. 
d. 
Other modifications in the dose schedule based on response and toxicity of 
individual patient are allowed if in the patient best interest, after discussion 
with principal investigator.  
e. 
Missed doses will not be made up. 
 
In addition, any drug-related, non-hematologic toxicity experienced by a patient should 
return to ≤ grade 2 or the baseline grade before the patient continues treatment. 
 
Other dose modifications may be permitted if in the patient’s best interest after 
discussion with the Principal Investigator.  Up to a total of 12 courses.  Additional 
chemotherapy courses may be given if felt to be in the patient’s best interest for an 
additional total of 12 courses (total 24 courses).  
 
5.4 
Supportive measures during treatment 
 
Supportive care measures will be according to institutional and Leukemia Department 
guidelines. 
 
5.5 
Management of toxicities and dose modifications 
 
5.5.1 At all cycles 


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All dose delays, reductions, and modifications for hematologic and non-hematologic 
toxicities will be assessed according to Sections 5.5.2 and 5.5.3. 
 
5.5.2 Hematologic (blood/bone marrow) toxicity 
 
No dose reductions, delays, or modifications are required for hematologic toxicities 
during the first cycle. It is assumed that low counts at diagnosis are due to involvement 
by the disease process and require therapy for improvement. Likewise, patients with 
persistent disease who are considered for more therapy can be expected not to have a 
recovery of their hematologic parameter and thus, no dose reductions, delays, or 
modifications are required for hematologic toxicities unless it is considered to do so in 
the best interest of the patient and after discussion with the Principal investigator.   
 
5.5.3 Non-hematologic toxicity 
 
If grade 2 toxicity occurs during any course of therapy, and it is unresponsive to optimal 
treatment and is possibly related to OM treatment, OM treatment may be withheld after 
the onset of an event until the AE has returned to baseline or ≤ grade 1. If the AE has 
returned to baseline or ≤ grade 1 within the 3 days of the first course or subsequent 
cycles, treatment may resume at the same dose, but missed doses will not be made up. 
 
If grade 3 or greater toxicity occurs during any course of therapy, and it is unresponsive 
to optimal treatment and is possibly related to OM treatment, OM treatment may be 
withheld after the onset of an event until the AE has returned to baseline or ≤ grade 1. If 
the AE has returned to baseline or ≤ grade 1 within the 3 days of the first course or 
subsequent courses, treatment may resume but at a reduced OM subcutaneous dose of 
1.0 mg/m2 twice daily for the remainder of that cycle only. Missed doses will not be 
made up. In subsequent cycles of therapy, the dose of OM will be the original dose, but 
the number of consecutive days of OM treatments should then be reduced by 1 day for 
all subsequent treatment cycles.  


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If persistent grade 2 toxicity occurs after completion of a cycle of therapy (i.e., after day 
3 of each course), and it is unresponsive to optimal treatment and is possibly related to 
OM treatment, OM treatment may be delayed up to 21 days after the onset of an event 
or until the AE has returned to baseline or ≤ grade 1. Then administer 100% of the 
planned dose. If toxicity persists longer than 21 days or recurs, the dose may be 
delayed and the number of consecutive days of OM treatments should then be reduced 
by 1 day for all subsequent treatment cycles.  
 
If grade ≥3 toxicity occurs after completion of the OM treatment (i.e., after day 3 of each 
course) and it is suspected that OM played a role in toxicity, the next scheduled cycle of 
OM therapy should be withheld until toxicity returns to grade 0 or 1 or to baseline. The 
dose of OM will then remain the same, but the treatments may then be reduced by 1 
day for all subsequent treatment cycles. Additional repeat dose reduction of 1 day will 
be made if toxicity recurs or persists. The number of consecutive days of OM may be 
reduced and the intervals between cycles may be shortened or increased, if clinically 
indicated. Missed doses of OM will not be made up. 
 
Dose modifications different from those stated in the protocol will be decided jointly by 
the principal investigator and the treating physician. 
 
Adverse events which are moderate to severe in intensity and which are assessed as 
possibly or probably related to study drug, may result in the termination of study 
treatment in the affected study patient. 
 
Such termination should be reviewed with the principal investigator at the earliest 
possible time. Following review with the principal investigator, the study patient may be 
permanently withdrawn from the study depending upon the nature and severity of the 
event. 
 
5.6 
Supportive care 


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Supportive care measures including blood products, infection prophylaxis and growth 
factors will be administered according to institutional and Leukemia Department 
guidelines. 
 
6.0 
Pretreatment Evaluation 
 
History and physical (including weight and blood pressure), CBC with differential and 
platelets, chemistry profile (total bilirubin, serum creatinine, SGPT or SGOT, uric acid, 
LDH, potassium, magnesium, glucose), and an ECG within 14 days of therapy start.   
 
Serum or urine HCG at screening for women of childbearing potential and within 3 days 
prior to treatment start.   
 
Bone marrow aspirate and/or biopsy within 28 days of therapy start. The bone marrow 
evaluation will include immunophenotyping by flow cytometry and cytogenetic studies. 
 
MDS flow panel 
 
7.0 
Evaluation During Study 
Patient will have physical examination prior to each course. In addition: 
1. CBC with differential and platelet counts at least once a week until remission, 
then every 2 to 4 weeks during active treatment, and every 4 to 8 weeks 
thereafter as long as on study. No differential is needed if the WBC is < 1.0 x 
109/L.   
2. Creatinine, bilirubin, ALT or AST once monthly.  


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3. Marrow aspirate to confirm response, to be performed after cycle 2 then every 
2 to 4 cycles until response observed, then as clinically indicated  
4. If pre-treatment MDS Flow Panel was initially abnormal, sequential MDS Flow 
Panel to be performed after cycle 2 then every 2 to 4 cycles until response 
observed, then as clinically indicated if possible. 
5. Conventional cytogenetics to be performed after cycle 2 then every 2 to 4 
cycles until response observed, then as clinically indicated. 
  
The patient may have the laboratory work done by their home physician and the results 
reported to the research nurse for the study. 
 
Patient will be followed for survival at MDACC every 3 to 6 months for up to 5 years 
after completion of active treatment and while still on study.  If the patient is unable to 
return to MD Anderson Cancer Center the follow-up visits may be conducted via 
telephone. 
 
8.0 
Criteria for Response 
The response criteria recommended by the MDS International Working Group. 
Definitions: 
8.1 Complete Response (CR):  
Normalization of the peripheral blood and bone marrow with ≤ 5% bone marrow blasts, 
a peripheral blood granulocyte count ≥(1.0 x 109/ L, and a platelet count ≥ 100 x 109/L).  
8.2 Partial response (PR): 
As above except for the presence of 6-15% marrow blasts, or 50% reduction if <15% at 
start of treatment. 


2013-0870 
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8.3 Hematologic Improvement (HI):  
Meets all criteria for CR except for platelet recovery to ≥100 x 109/L. 
8.4 Marrow CR: 
Blasts ≤ 5% and decrease by ≥ 50% from baseline (baseline blasts should be above 5% 
to be eligible for marrow CR) 
8.5 Clinical benefit:  
Platelets increase by 50% and to above 30 x 109/L untransfused (if lower than that 
pretherapy); or granulocytes increase by 100% and to above 1.0 x 109/L  (if lower than 
that pretherapy); or hemoglobin increase by 1.5 g/dl ; or transfusion independent; or 
splenomegaly reduction by > 50%; or monocytosis reduction by > 50% if pretreatment > 
5 x 109/L. 
 
8.6 
Relapse-free survival (RFS)  
 
 Time from date of response until the date of first objective documentation of 
disease-relapse. 
 
8.7 
Overall survival (OS) 
 
 Time from date of treatment start until date of death due to any cause. 
 
9.0 
Criteria for Removal from the Study 
 
Patients are free to withdraw consent and discontinue participation in the study at any 
time and without prejudice to further treatment. Patients may be discontinued from the 
study for the following reasons: 


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1. 
Patient requests discontinuation. 
2. 
There is unacceptable toxicity (i.e., NCI CTCAE version 4 grade 4 drug-related 
non hematologic toxicity). 
3. 
Patient experiences an NCI CTCAE version 4 >/= grade 3 drug-related non-
hematologic toxicity or clinically significant infection of any grade that is not 
recovered by Day 75 from the onset of the toxicity. 
4. 
Patient experiences a third occurrence of an NCI CTCAE version 4 grade 3 drug-
related non-hematologic toxicity. 
5. 
Patient experiences asymptomatic grade 2 total bilirubin or creatinine 
abnormality that is not recovered by Day 75 from the onset of the toxicity. 
6. 
There is a need for any treatment not allowed by the protocol. 
7. 
Treatment failure or disease relapse. 
8. 
Investigator discretion. 
10.0. Regulatory and Reporting Requirements 
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia 
Specific Adverse Event Recording and Reporting Guidelines. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) most current version will be utilized for adverse 
event reporting. (http://ctep.cancer.gov/reporting/ctc.html).   
 
10.1  Expedited adverse event reporting 
 
Refer to Appendix C for Leukemia-Specific Adverse Event Recording and Reporting 
Guidelines.  
 
These guidelines serve to bring the Department of Leukemia in compliance with the 
institutional policy on Reporting of Serious Adverse Events-definition of expected AE- 


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“All clinical protocols should include a list of the expected and anticipated events or 
hospitalizations relating to the study treatment” and Guideline for Good Clinical Practice 
4.11.1 “All serious adverse events (SAEs) should be reported. 
 
Adverse event is any untoward medical occurrence that may present during treatment 
with a pharmaceutical product but which does not necessarily have a causal 
relationship with this treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
disease or for the modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the 
event would not have happened at all, 2) the event would have occurred later than it 
actually did, or 3) the event would have been less severe. 
 
Adverse Events (AEs) will be evaluated according to current CTC version in each 
protocol.  
 
Expected events during leukemia therapy are: 
1. Myelosuppression related events (due to disease or leukemia therapy) 
a. febrile or infection episodes not requiring management in the intensive 
care unit 
b. epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
c. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, 
leukocytosis 
2. Disease related events 
a. symptoms associated with anemia 


2013-0870 
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i. fatigue 
ii. weakness 
iii. shortness of breath 
b. electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
c. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, 
albumin, uric acid, alkaline phosphatase, glucose) 
d. coagulation abnormalities 
e. disease specific therapy (induction, maintenance, salvage, or stem cell 
therapy) 
f. alopecia 
g. bone,  joint, or muscle pain 
h. liver function test abnormalities associated with infection or disease 
progression 
i. disease progression 
3.  General therapy related events 
a. catheter related events 
b. renal failure related to tumor lysis syndrome or antibiotic/antifungal 
therapy 
c. rash related to antibiotic use 
4. Hospitalization for the management of any of the above expected events 
 
11.0 Statistical Considerations 
 
The proposed study is a single-arm phase II clinical trial study in patients with MDS who 
have failed therapy with hypomethylating agents.  The primary endpoint is to determine 
the overall survival, defined as the time from treatment start to the time of death  A 
maximum of 80 patients will be accrued at a rate of 1 to 5 patients per month (maximum 
accrual period 3.33 years). Additional 12 months of follow-up is planned after the last 
patient is accrued into the trial. It is anticipated that treatment with OM will prolong the 


2013-0870 
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22 
 
 
median OS from 4.2 months, as shown in the current standard therapy, to 6 months. 
The CR, overall survival and toxicity will be monitored during the study, and all data will 
be used to update the prior distributions for toxicity and efficacy parameters. It will be 
postulated that the treatment can achieve a CR rate of 20 percent. 
 
We compare median survival time among patients in this study to historical median 
survival time of 4.2 months.  We assume an exponential distribution of failure in the 
study group and a two-sided significance level of 0.05.  Given one additional year of 
follow up after study recruitment and an accrual rate of 1-5 patients per month, 80 
patients will yield a power of 84% to test for a 1.8 months improvement in median 
survival from 4.2 months.  
 
 
 
11.1 Overall Survival Monitoring 
 
The efficacy endpoint, OS, will be continuously monitored using the Bayesian method 
by Thall et al.37 Let Ts and Te represent the OS times for the historical regimen and the 
experimental regimen OM, respectively. We assume Ts|Ms and Te|Me follow an 
exponential distribution with respective median Ms and Me. Furthermore, we assume 
that the prior for Ms follows an inverse gamma distribution IG (5.0, 16.8) to reflect our 
knowledge of OS in patients treated historically with standard regimen.  This prior 
distribution has a mean of 4.2 months, and a variance of 5.88. The prior for Me is 
assumed to be IG (2.18, 4.94), which has the same mean of 4.2 months and a larger 
variance of 100 to reflect our uncertainty about the median OS of the proposed 
experimental regimen, OM. 
 
The OS will be continuously monitored, and the study will be terminated early if, based 
on the available data, there is less than 5% chance that the median OS in patients 
treated with OM will improve by more than 1.8 months, compared to the historical 
regimen.  The futility stopping rule is as follows: 


2013-0870 
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Pr(Me > Ms+ 1.8 months | data) < 0.05 
 
The operating characteristics of this decision rule are summarized in Table 1 using the 
one-arm TTE software developed by the Department of Biostatistics at M.D. Anderson 
Cancer Center.  
 
 
 
Table 1. Operating characteristics for the design (based on 5000 simulations) 
Scenario 
True Median   
(months) 
Pr(Stopped Early) 
Mean  
No. patients 
Average Trial Duration  
(months) 
1 
2.0 
0.9999 
13 
16.26 
2 
3.0 
0.8882 
32 
22.54 
3  
4.2 
0.2332 
66 
34.00 
4 
5.0 
0.1088 
73 
36.29 
5 
6.0 
0.0478 
77 
37.58 
6 
7.0 
0.0236 
78 
38.05 
 
The monitoring for OS will be carried out through the Clinical Trial Conduct (CTC) 
website (https://biostatistics.mdanderson.org/ClinicalTrialConduct) which is housed on a 
secure server at MDACC and maintained by the MDACC Department of Biostatistics. 
Access to the website will be gained through usernames and passwords provided by 
the MDACC Department of Biostatistics.  Training on the use of the CTC will be 
provided by the biostatistical collaborator of the study, with emphasis on the importance 
of timely updating of follow-up times and recording of events. The monitoring rule for OS 
will be applied continuously when a new patient is enrolled or an existing patient’s data 
is updated.  If the stopping rule is met, an automatic email will be sent out to the study 
PI, RN and the study statistician to keep them informed and the CTC website will not 
allow enrollment of any new patients.  
 
11.2.  CR Rate and Toxicity Monitoring 


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Complete response rate and toxicity will be monitored simultaneously using the 
Bayesian approach of Thall, Simon, Estey (1995, 1996) and the extension by Thall 
and Sung (1998).  This regimen of the experimental treatment will be considered 
worthy of further investigation if it elicits an increase in CRR to 20% with acceptable 
toxicity.  A  toxicity rate greater than 30% is considered unacceptable.  Thus, a beta 
(20, 80) and beta (0.4, 1.6) priors were assumed for the standard treatment response 
distribution and experimental treatment response prior distribution, respectively. In 
addition, a beta (30, 70) and beta (0.6, 1.4) priors were assumed for the standard 
treatment toxicity rate and experimental treatment toxicity prior distribution, 
respectively. Interim monitoring rules, assuming the prior distributions, were 
constructed that meet the following two conditions, 
1) 
Pr(S, Toxicity < E, Toxicity | data) > 0.975 and, 
2) 
Pr(E, CR  > S, CR | data) < 0.025 
Where E, Toxicity and E, CRR  are the  toxicity and response rates for the experimental 
treatment, and S, Toxicity  and S, CRR  are the  toxicity and response rates for the 
standard treatment respectively.  The first rule provides for stopping the study if 
excessive toxicity is highly probable (i.e., probability >97.5%) for the experimental 
treatment.  The second condition will stop the study early if the data suggest that it is 
unlikely (i.e., probability < 2.5%) that CR rate of the experimental treatment is 20%. 
Assuming the minimum number of patients is 5, the maximum number of patients is 80 
and the cohort size is 5.  Multc Lean Desktop (version 2.1.0) was used to generate the 
toxicity and futility stopping boundaries and the OC table (Table 4).The monitoring rule 
for the toxicity rate, based on these assumptions and monitoring conditions above is in 
Table 2.  Toxicity is defined as grade 3 or higher drug-related non-hematologic toxicity 
during the first cycle. For example, accrual will cease if 5 patients experience toxicities 
among the first 5 patients treated or if 7 or more patients experience toxicities among 
the first 10 patients. 
Table 2. Stop accrual if the number of toxicities is greater than or equal to indicated (i.e., # patients with toxicities) among the 
number of patients evaluated 


2013-0870 
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25 
 
 
# patients  
evaluated 
# patients  
with toxicities 
 
# patients  
evaluated 
# patients 
with toxicities 
5 
5 
 
45 
22-45 
10 
7-10 
 
50 
24-50 
15 
9-15 
 
55 
26-55 
20 
11-20 
 
60 
28-60 
25 
14-25 
 
65 
30-65 
30 
16-30 
 
70 
32-70 
35 
18-35 
 
75 
34-78 
40 
20-40 
 
80 
Always stop with his many patients 
 
Monitoring the response rate, based on the above assumptions will begin after 5 
patients are treated, on an intent-to-treat basis (Table 3).  For example, accrual will 
cease if 0 patients experience a response in the first 10 patients treated. 
 
Table 3. Stop accrual if the number with CR is less than or equal to indicated (i.e., # patients with CR) among the number of 
patients evaluated 
# patients evaluated  
10-20 
25-30 
35-40 
45 
50-55 
60-65 
70 
75 
# patients  
with CR 
0 
0-1 
0-2 
0-3 
0-4 
0-5 
0-6 
0-7 
 
 
The probability of stopping the study early for low CRRs (i.e., 10%) was higher than 
0.70 when toxicity rates were ranged from 20% to 40%.  Probabilities of stopping early 
for high true toxicity rates (i.e., 40%) were 81% when the true CR rate was 10% and 
45% when true CRR was 20%. 
 
Table 4.  Operating characteristics for simultaneous monitoring response and toxicity rates for patients 
treated 
True 
CRR 
True 
Toxicity 
Rate 
True Probability Vector 
(CRR/Tox, CRR/NoTox, 
NoCRR/Tox, NoCRR/NoTox) 
Probability of 
Stopping 
Average number 
of patients treated 
10% 
20% 
(0.02, 0.08, 0.18, 0.72) 
0.6960 
44 
10% 
30% 
(0.03, 0.07, 0.27, 0.63) 
0.7076 
43 
10% 
40% 
(0.04, 0.06, 0.36, 0.54) 
0.8054 
36 
20% 
20% 
(0.04, 0.16, 0.16, 0.64) 
0.1346 
71 
20% 
30% 
(0.06, 0.14, 0.24, 0.56) 
0.1676 
69 
20% 
40% 
(0.08, 0.12, 0.32, 0.48) 
0.4462 
57 


2013-0870 
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26 
 
 
30% 
20% 
(0.06, 0.24, 0.14, 0.56) 
0.0309 
78 
30% 
30% 
(0.09, 0.21, 0.21, 0.49) 
0.0679 
76 
30% 
40% 
(0.12, 0.18, 0.28, 0.42) 
0.3798 
61 
 
11.3 Analysis method 
 
Safety data will be summarized using frequency and percentage. Complete response 
rates will be estimated along with the 95% credible intervals.  Kaplan--Meier method will 
be used to analyze survival data including overall survival time, response duration and 
relapse free survival time.  The survival medians will be estimated with 95% confidence 
intervals. 
 
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