Clinical trial NCT03151304
Conditions: Myelodysplastic Syndromes
Keywords: MDS
Sponsor: Helsinn Healthcare SA
Start date: 2017-06-01; Completion date: 2020-12-01
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with azacitidine in patients with IPSS-R high and very high risk myelodysplastic syndrome (MDS) who are previously untreated with hypomethylating agents (HMAs). Enrollment in this study will be limited to high/very high risk MDS because this group represents the highest unmet need, with median survival of less than 18 months.

Stage 1a will be conducted as an open-label single arm in up to 40 subjects to assess if this regimen with a lower pracinostat dose results in a discontinuation rate that meets a predefined threshold and in efficacy that justifies expansion of enrollment into Stage 1b.

A discontinuation rate of approximately ≤10% in Stage 1a, a rate comparable to that observed with azacitidine alone in study MEI-003 (NCT01873703), supports expansion into Stage 1b.

Stage 1b will be conducted as expansion of stage 1a. Approximately 20 additional subjects will be enrolled. Study drugs should be continued until disease progression or intolerable toxicity. It is important to note that the median time to achieving a response with azacitidine alone is 4 to 5 months. Furthermore, the median time to achieving a Complete Response (CR) in study MEI-003 (NCT01873703) was 4 cycles. Therefore, early (\<6 months) discontinuation of trial therapy for 'no response' should be avoided. The Medical Monitor should be contacted prior to discontinuing a subject from the study to discuss the rationale for discontinuation.

Detailed description:

Arms: arm 1: open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles.

In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression.

Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules:

* Schedule 1 - daily therapy on Days 1 through 7
* Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle
Interventions: intervention 1: Pracinostat intervention 2: Azacitidine
Intervention descriptions: intervention 1: 45 mg capsule intervention 2: SC or IV injection

Protocol documents:
Prot_000.pdf: 
MEI Pharma, Inc. 
Clinical Study Protocol 
Pracinostat 
MEI-011 
 
Amendment 2: 25 June 2018 
CONFIDENTIAL 
Page 1 of 70 
 
TITLE  
A Two-Stage, Open-Label, Phase 2 Study of Pracinostat and 
Azacitidine in Patients with IPSS-R High and Very High Risk 
Myelodysplastic Syndromes Previously Untreated with 
Hypomethylating Agents 
 
Protocol Number: 
MEI-011 
Drug Development Phase: 
2 
IND Number: 
79597 
Sponsor and IND Holder: 
Helsinn Healthcare 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 (0) 91 985 2121 
Fax: 
+41 (0) 91 993 2122 
Delegated to Conduct the Study: 
MEI Pharma, Inc. 
3611 Valley Centre Drive, Suite 500 San Diego, CA 
92130, USA 
Phone: +1 (858) 369-7100 
Fax: 
+1 (858) 369-7101 
Coordinating Investigator: 
Ehab Atallah, MD 
Associate Professor of Medicine 
Division of Hematology/Oncology 
Medical College of Wisconsin and Froedtert Hospital 
9200 Wisconsin Avenue, Milwaukee, WI 53226 
eatallah@mcw.edu 
 
Medical Monitor: 
David Ramies, MD 
Mobile: +1 (925) 285 6640 
Phone: +1 (858) 792 6300 
Fax: 
+1 (858) 369 7254 
dramies@meipharma.com 
Amendment 2: 
25 June 2018 
 
 
 
CONFIDENTIAL 
Information and data in this document are privileged and confidential. No person is authorized 
to make any part of this document public without written permission from MEI Pharma, Inc. 
 
 




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Clinical Study Protocol 
Pracinostat 
MEI-011 
 
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INVESTIGATOR SIGNATURE PAGE 
A Two-Stage, Open-Label, Phase 2 Study of Pracinostat and 
Azacitidine in Patients with IPSS-R High and Very High Risk 
Myelodysplastic Syndromes Previously Untreated with 
Hypomethylating Agents 
 
MEI-011 
Amendment 2: 25 June 2018  
 
Investigator Agreement 
 
I have read, understand, and agree to conduct the study in accordance with the current protocol, 
and will:  
• Personally supervise the conduct of this study. 
• Conduct the study in accordance with International Council on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) E6 and applicable regulatory requirements. 
• Comply with the procedures for data recording and reporting as required by regulatory 
authorities and the Sponsor. 
• Permit monitoring, auditing, and inspection of study records as required by ICH GCP. 
• Retain essential clinical study documents as required by ICH GCP and the Sponsor. 
 
 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
 
Principal Investigator Name (Print) 
 


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Pracinostat 
MEI-011 
 
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SYNOPSIS 
TITLE 
A Two-Stage, Open-Label, Phase 2 Study of Pracinostat and Azacitidine in Patients with IPSS-R High 
and Very High Risk Myelodysplastic Syndromes Previously Untreated with Hypomethylating Agents 
PROTOCOL NUMBER 
MEI-011 
PHASE 
Phase 2 
STUDY DURATION 
The total duration of the study is planned to be approximately 36 months: 24 months for enrollment 
and 12 months for follow-up until the primary study analysis. 
PATIENT POPULATION 
Subjects with high and very high risk myelodysplastic syndromes (MDS) according to the Revised 
International Prognostic Scoring System (IPSS-R) (Greenberg 2012).  CMML 1 and 2 subjects will 
also be included. 
NUMBER OF SUBJECTS AND STUDY CENTERS 
This multicenter study will be conducted at approximately 25 sites. 
Approximately 60 efficacy evaluable subjects will be enrolled in an open-label design in 2 stages 
(inclusive of Stage 1 and Stage 1 expansion [Stage 1b]): 
Stage 1: Approximately 40 subjects 
Stage 1 expansion (Stage 1b): Approximately 20 additional subjects to achieve a total of 
approximately 60 efficacy evaluable subjects for the entire study 
PRIMARY OBJECTIVES 
• Define the safety and tolerability of pracinostat plus azacitidine in high/very high risk MDS 
• Determine the overall response rate (ORR), defined as complete remission (CR) and partial 
remission (PR), of pracinostat plus azacitidine in high/very high-risk MDS 
SECONDARY OBJECTIVES 
Evaluate the following endpoints in patients with high/very high-risk MDS administered pracinostat 
plus azacitidine: 
• Complete response (CR) rate 
• Overall hematologic improvement (HI) rate 
• Clinical benefit rate, defined as rate of CR + PR + HI + Marrow CR 
• Rate of cytogenetic complete response/remission 
• Duration of response (DoR) 
• Rate of leukemic transformation 
• Event-free survival (EFS) 
• Progression-free survival (PFS) 
• Overall survival (OS)  


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MEI-011 
 
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BACKGROUND 
Higher risk MDS (high and very high risk in the IPSS-R classification) is a serious medical condition, 
with a median survival of only 0.8 years in very high-risk disease and 1.6 years in high-risk disease 
(Greenberg 2012).  The only curative therapy is allogeneic stem cell transplantation (SCT), however 
most patients with MDS are not candidates for SCT given their typically advanced age, comorbidities, 
and lack of a suitable donor.  Standard therapy with hypomethylating agents (HMAs) in 
intermediate-2/high-risk MDS provides modest responses, though azacitidine has been shown to 
improve survival when compared to conventional care regimens (Fenaux 2009).  Patients who do not 
respond to HMAs or progress after therapy with HMAs have a very poor outcome, with a median 
survival of less than one year (Prebet 2011).  Approaches to improving the treatment effect of 
hypomethylating therapy are clearly indicated.  
Abnormal epigenetic silencing of important regulatory genes has been described in cancer, including 
MDS and acute myeloid leukemia (AML).  The reduction of acetylation status of histones is one 
mechanism for this silencing.  Inhibitors of histone deacetylases (HDACs) have been extensively 
studied in both hematologic and solid tumors.  Histone deacetylases are enzymes involved in the 
remodeling of chromatin, and therefore, have a key role in the epigenetic regulation of gene expression.   
Pracinostat, a potent, oral, pan-HDAC inhibitor was shown to have modest single-agent activity in 
myeloid malignancies.  Synergistic interactions have been observed with multiple cytotoxic 
and targeted anti-cancer therapeutics; notably, the combination index with azacitidine ranged from 
0.44 to 0.55.  The maximum tolerated dose of single-agent pracinostat based on chronic administration 
was established at 60 mg every other day, 3 days each week for 3 weeks, followed by 1 week of rest, in 
28-day cycles. 
STUDY RATIONALE 
A pilot study of pracinostat (60 mg, 3 alternate days each week for 3 consecutive weeks) administered 
in combination with azacitidine (75 mg/m2 intravenously [IV] daily × 7 days) in 28-day cycles 
conducted in 10 patients with advanced MDS showed an encouraging overall response rate 
and cytogenetic responses.  Pracinostat dose was reduced or treatment interrupted as clinically 
indicated to improve tolerability and maintain patients on therapy (Abaza 2017). 
In the subsequent placebo-controlled Phase 2 study (MEI-003) conducted in 102 patients with 
higher-risk MDS, pracinostat (60 mg, 3 alternate days each week for 3 weeks) in combination with 
azacitidine (75 mg/m2 for 7 days) in 28-day cycles failed to increase the CR rate, PFS, and OS 
compared to azacitidine + placebo (Garcia-Manero 2017).  In that study, 26% of subjects in the 
pracinostat group discontinued study drugs in the first 3 cycles of therapy (by approximately Day 84) 
for reasons other than progressive disease or stem cell transplant compared to 10% of patients 
randomized to the placebo group.  The most common cause for early discontinuations in the pracinostat 
group was adverse events (AEs), primarily fatigue and myelosuppression.  Furthermore, in the 
intermediate-2 risk group, 14/30 patients (47%) randomized to pracinostat discontinued the study due 
to AEs or withdrawal of consent at any time in the study compared to 4/33 patients (12%) randomized 
to placebo, whereas in the high-risk group the rate of discontinuation due to AEs or withdrawal of 
consent was similar in the pracinostat group (27%) and placebo group (22%).  In a post-hoc analysis, 
the subset of subjects who received at least 4 cycles of pracinostat/azacitidine and began Cycle 5 had a 
trend for better PFS and OS (hazard ratio [HR] = 0.67) compared to the control group.  This suggests 
the lack of efficacy in the intent-to-treat (ITT) population may be due to early discontinuations and 
insufficient exposure to pracinostat/azacitidine. 
This study will evaluate a regimen consisting of a lower dose of pracinostat in combination with the 
standard dose of azacitidine to determine if the rate of early discontinuation can be reduced, thereby 
improving efficacy. 


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DOSE SELECTION 
This study will investigate a pracinostat dose of 45 mg, 25% lower than the dose used in 
Study MEI-003.  Pracinostat will be administered at 45 mg, 3 days each week (e.g., Monday, 
Wednesday, Friday) for 3 weeks, followed by 1 week of rest, with azacitidine at the standard dose of 
75 mg/m2 for 7 days of each 28-day cycle.   
The rationale for selecting a pracinostat daily dose of 45 mg for this regimen include: 
• The dose of 45 mg has been used in prior Phase 2 studies in MDS and AML as the step-down 
dose level for subjects who did not tolerate the starting dose of 60 mg. 
• In prior studies in MDS and AML, approximately 50% of subjects who achieved an objective 
response and received pracinostat for more than one year had their dose reduced from 60 mg to 
45 mg, indicating this dose is efficacious and well tolerated. 
• A dose of 40 mg was shown to induce a 2-fold increase in histone 3 acetylation (acH3) in 
17 subjects with solid tumors, a level comparable to that achieved with a dose ≥ 60 mg but 
significantly higher than achieved with a dose of 20 mg, suggesting that a dose of 45 mg may be 
sufficient for full pharmacodynamic effects. 
• A dose of 45 mg results in plasma concentrations greater than HDAC C1 inhibitory constant (Ki) 
for approximately 24 hours, suggesting adequate HDAC inhibition at this dose. 
STUDY DESIGN 
This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with 
azacitidine in patients with IPSS-R high and very high-risk MDS who are previously untreated with 
HMAs.  Enrollment in this study will be limited to high/very high-risk MDS because this group 
represents the highest unmet need, with median survival of less than 18 months.  Recognizing that 
additional safety and efficacy of pracinostat plus azacitidine is desirable before evaluating the treatment 
regimen in a placebo-controlled environment, the protocol is being amended to become a 2-stage 
open-label study comprising Stage 1 and Stage 1 expansion (Stage 1b).  
Stage 1 will be conducted as an open-label single arm in approximately 40 evaluable subjects to assess 
if this regimen with a lower pracinostat dose results in a discontinuation rate that meets a predefined 
threshold and the observed efficacy justifies expansion to Stage 1b. 
A discontinuation rate of approximately ≤ 10% in Stage 1, a rate comparable to that observed with 
azacitidine alone in Study MEI-003, would support expansion to Stage 1b.  Stage 1b will be conducted 
as an open-label, single-arm to achieve a total enrollment of approximately 60 efficacy evaluable 
subjects, inclusive of Stage 1 and Stage 1b enrollment. 
Study drugs should be continued until disease progression or intolerable toxicity.  It is important to 
note that the median time to achieving a response with azacitidine alone is 4 to 5 months.  Furthermore, 
the median time to achieving a CR in study MEI-003 was 4 cycles.  Therefore, early (< 6 months) 
discontinuation of study therapy for ‘no response’ should be avoided.  The Medical Monitor should be 
contacted prior to discontinuing study drugs in a subject to discuss the rationale for discontinuation. 
After discontinuing study drugs, subjects will be followed every 3 months (± 1month) until death or 
study termination to collect information on disease status (i.e., improvement of disease response or 
disease progression), start of non-protocol therapies (e.g., stem cell transplant or an MDS-directed 
therapy) and survival. 


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Pracinostat 
MEI-011 
 
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CONFIDENTIAL 
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The primary study analysis will be performed approximately 12 months after the last subject is enrolled 
in the study.  The study duration is anticipated to be approximately 36 months: 24 months for 
enrollment and 12 months of follow-up until the primary analysis.  At the completion of the primary 
analysis, the Sponsor will decide whether to terminate the study or continue study drug dosing in 
ongoing subjects. 
STUDY DRUGS, DOSES, AND MODES OF ADMINISTRATION 
Pracinostat: 45 mg administered orally 3 days each week (e.g., Monday, Wednesday, Friday) for 
3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. 
In later cycles (i.e., after Cycle 4), 45 mg pracinostat can be reduced to orally 3 days each 
week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity 
such as fatigue, gastrointestinal toxicity, or myelosuppression. 
Azacitidine: All subjects will receive a standard regimen of azacitidine at 75 mg/m2 for 7 days of each 
28-day cycle.  Administration will occur by subcutaneous (SC) injection, or intravenous 
(IV) infusion if SC injections are not tolerated, on one of two schedules: 
• Schedule 1 – daily therapy on Days 1 through 7 
• Schedule 2 – 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive 
days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the 
first two days of the next week (Days 8 and 9) of each 28-day cycle. 
Subjects may be treated on either azacitidine schedule, however the preference is to have 
subjects stay on the same schedule during their participation in the study. 
Azacitidine should be given at approximately the same time each day. 
In the presence of toxicity, azacitidine dose reduction in Cycle 2 and subsequent cycles 
will be performed according to the azacitidine product labeling recommendations or local 
standards of care. 
SUBJECT POPULATION 
Inclusion Criteria 
To be eligible for study participation, subjects must meet the following inclusion criteria: 
1. Female or male subjects ≥ 18 years-of-age.  
2. Histologically or cytologically documented diagnosis of MDS according to the World Health 
Organization (WHO) classification (Vardiman 2009, Arber 2016; Appendix B) with  < 20% bone 
marrow blasts by morphology and a peripheral white blood cell (WBC) count of < 20,000/µL 
• If WBC ≥ 20,000/µL, cytoreduction with hydroxyurea is permitted prior to enrollment. 
• CMML-1 and CMML-2 subtypes are eligible for study participation. 
3. Classified as high or very high risk according to the Revised International Prognostic Scoring 
System (IPSS-R) risk category (Appendix C).  CMML-1 and CMML-2 subtypes will be considered 
high-risk MDS and will not require IPSS-R scoring. 
4. Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to planned first study treatment 
(Cycle 1 Day 1). 
5. Clinical indication for treatment with azacitidine. 


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6. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth factors, 
or immunosuppressive therapy is allowed). 
a. Subjects who require the start of an HMA (e.g., azacitidine) due to progressing MDS may 
receive up to 1 cycle of azacitidine within 30 days prior to planned first dose (Cycle 1 Day 1).  
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
8. Adequate organ function as evidenced by: 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the upper 
limit of normal (ULN). 
• Total bilirubin ≤ 1.5 × ULN or total bilirubin of ≤ 2 mg/dL, whichever is higher.  Total 
bilirubin < 3 x ULN for patients with Gilbert-Meulengracht Syndrome. 
• Serum creatinine < 1.5 x ULN, or creatinine clearance > 40 mL/min according to 
institutional standards (actual body weight should be used to calculate creatinine 
clearance).  
• QTcF interval ≤ 450 msec using the mean of triplicate electrocardiograms (ECGs).  
9. Female subjects of childbearing potential and male subjects with female partners of childbearing 
potential are required to use two forms of acceptable contraception, including one barrier method, 
during their participation in the study and for 30 days following last dose.  Female subjects of 
childbearing potential must not be breastfeeding, or planning to breastfeed, and must have 
a negative pregnancy test ≤ 7 days before first study drug administration.  Male subjects must also 
refrain from donating sperm during their participation in the study.   
10. Voluntary written informed consent before performance of any study-related procedure not part of 
normal medical care. 
11. Have the willingness and ability to understand the nature of this study and to comply with the study 
and follow-up procedures. 
Exclusion Criteria 
Exclude subjects from this study if they do not fulfill the inclusion criteria, or if any of the following 
criteria are observed: 
1. Bone marrow blasts ≥ 20%, indicating a diagnosis of acute myeloid leukemia (AML). 
2. Received any of the following within the specified time frame prior to administration of study 
medication: 
• Any investigational agent within 14 days or 5 half-lives prior to enrollment, whichever is 
longer. 
• Hydroxyurea within 48 hours prior to first day of study treatment. 
• Hematopoietic growth factors:  erythropoietin, granulocyte colony stimulating factor 
(G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), 
or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to 
study enrollment. 
• Major surgery within 28 days prior to first study treatment. 


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3. Subjects who have not recovered from side effects of previous therapy. 
4. Cardiopulmonary function criteria: 
• Current unstable arrhythmia requiring treatment. 
• History of symptomatic congestive heart failure (New York Heart Association [NYHA] 
Class III or IV). 
• History of myocardial infarction, pulmonary embolism or cerebrovascular accident 
within 6 months of enrollment. 
• Current unstable angina. 
5. Prior treatment for MDS with the HDAC inhibitors Zolinza (vorinostat), Belenodaq (belinostat), 
Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant 
action as an HDAC inhibitor. 
6. Clinical evidence of central nervous system involvement. 
7. Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, 
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting 
absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis). 
8. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C. 
9. Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could, 
in the Investigator’s opinion, potentially interfere with participation in this study. 
10. Presence of a malignant disease within the last 12 months, with the exception of adequately treated 
in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin cancer, 
or malignancies treated with curative intent and no evidence of active disease in prior 12 months 
and felt to be low risk for recurrence.  Other malignancies may be considered after consultation 
with the Medical Monitor. 
11. An unwillingness or inability (including breastfeeding women, prohibited concomitant 
medications, uncontrolled infections, psychological, familial, sociological, or geographical 
conditions) to comply with study and/or follow-up procedures as outlined in the protocol. 
12. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol. 
13. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, chewing 
tobacco, or nicotine gum is permitted).  Subjects who stopped smoking at least 8 days prior to first 
pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study. 


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CRITERIA FOR EVALUATION 
Safety 
Safety will be assessed by AEs (graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] v4.03), laboratory safety tests including complete blood 
count (CBC) and serum chemistry, physical examination, vital signs, ECOG performance status, and 
12-lead ECG. 
Efficacy 
Efficacy will be evaluated by Investigator assessments based on hematological and cytogenetic 
examination of peripheral blood and bone marrow aspirates and biopsy, as well as transfusions 
administered, using the revised International Working Group (IWG) response criteria for MDS 
(Cheson 2006). If deemed necessary during the conduct of the study, central verification of efficacy 
assessments will be performed by independent reviewers. 
CYTOGENETIC AND MOLECULAR TESTING 
Classical cytogenetics shall be required on BMBx and aspiration at screening, and subsequent 
assessments as indicated.  Cytogenetics are performed as standard of care to classify the subject’s MDS 
in the corresponding IPSS-R risk category and to determine cytogenetic remission/response. 
Fluorescence in situ hybridization (FISH) and molecular tests (e.g., polymerase chain reaction) may be 
conducted as per institutional standard of care but are not required.  If performed, the results should be 
documented in the case report form (CRF). 
STATISTICAL METHODOLOGY 
Sample Size 
Approximately 60 subjects evaluable for efficacy will be enrolled, including approximately 
40 evaluable subjects in Stage 1 and the remaining subjects in Stage 1b.  Non-evaluable subjects will 
be replaced. 
Sample size calculation for Stage 1 
The goal of Stage 1 is to establish a pracinostat/azacitidine regimen with a discontinuation rate of 
approximately up to 10% in the first 3 cycles of therapy, a rate comparable to that observed in the 
azacitidine/placebo group in study MEI-003. The 95% confidence interval (CI) approach is utilized 
to estimate the sample size in Stage 1.  The number of subjects to be enrolled is calculated such 
that the lower bound of the 95% CI of the discontinuation rate will be no more than 12% below the 
point estimate of 22.5%, the mid-point between the discontinuation rates in the azacitidine/placebo 
(10%) and azacitidine/pracinostat (32%) groups, respectively, in study MEI-003. 
With a sample size of 40 subjects, the study will be stopped if ≥ 9 subjects (22.5%, 95% CI: 10.8% 
– 38.4%) discontinue in the first 3 cycles.  Under this scenario, the lower bound of the 95% CI is 
> 10 % (above the pre-specified desired goal) and the upper bound of the 95% CI is > 32% (higher 
than the discontinuation rate in study MEI-003). 
It is also possible to conclude that the desired threshold of a discontinuation rate of ≤ 10% has been 
achieved with fewer than 40 subjects treated in Stage 1.  For example, if 4 discontinuations are 
observed in the first 32 subjects, the lower and upper bounds of the 95% CI around the observed 
discontinuation rate of 12.5% (4 of 32) are 3.5% and 29.0%, lower than reported with 
azacitidine/placebo and azacitidine/pracinostat, respectively, in study MEI-003.  This would justify 
expanding enrollment in Stage 1b of the study after only 32 subjects have been treated for 
≥ 3 cycles.  
The Independent Data Monitoring Committee (IDMC), in coordination with the Sponsor, will 
determine when to open Stage 1b enrollment.  


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Total sample size calculation  
Approximately 60 subjects evaluable for efficacy will be enrolled in the study: approximately 40 in 
Stage 1 and 20 in Stage 1b.  An ORR of 40% in subjects with high/very high-risk MDS treated 
with pracinostat plus azacitidine will be considered a clinically meaningful improvement compared 
to a historical ORR of 25% with azacitidine alone in this subject population.  With a sample size of 
60 subjects, the lower limit of the 95% CI of an observed ORR of 40% is 27.6%, higher than the 
ORR anticipated with azacitidine alone, and will support continued evaluation of this treatment 
regimen in a larger study.  
Statistical Analysis 
All analyses will be descriptive.  Binomial variables will be presented as frequency and 95% CI.  
Continuous variables will be presented as median, mean, range, and 95% CI.  Time-to-event 
endpoints will be analyzed by the method of Kaplan-Meier.  Comparisons between subject subsets 
will be exploratory. 
Primary and exploratory analyses will be performed as described in detail in the study Statistical 
Analysis Plan. 


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TABLE OF CONTENTS 
TITLE .................................................................................................................................1 
PROTOCOL SIGNATURE PAGE ..................................................................................2 
INVESTIGATOR SIGNATURE PAGE..........................................................................3 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS ................................................................................................12 
LIST OF TABLES ...........................................................................................................14 
LIST OF ABBREVIATIONS .........................................................................................15 
1 
INTRODUCTION ....................................................................................................18 
1.1 
Background ..........................................................................................................18 
1.2 
Pracinostat ............................................................................................................18 
1.3 
Preclinical Pharmacology ....................................................................................18 
1.4 
Clinical Experience ..............................................................................................18 
1.5 
Rationale for the Study ........................................................................................19 
1.6 
Rationale for Pracinostat Dose Selection ...........................................................21 
1.7 
Rationale for Patient Population ........................................................................21 
2 
STUDY OBJECTIVES ............................................................................................21 
2.1 
Primary Objectives ..............................................................................................21 
2.2 
Secondary Objectives...........................................................................................22 
3 
STUDY DESIGN ......................................................................................................22 
3.1 
Treatment Plan.....................................................................................................23 
3.1.1 
Pracinostat ......................................................................................................23 
3.1.2 
Azacitidine ......................................................................................................24 
4 
SUBJECT POPULATION AND DISCONTINUATION CRITERIA ................24 
4.1 
Inclusion Criteria .................................................................................................24 
4.2 
Exclusion Criteria ................................................................................................25 
4.3 
Discontinuation from Study Treatment .............................................................27 
5 
STUDY PROCEDURES AND ASSESSMENTS ...................................................27 
5.1 
Screening ...............................................................................................................28 
5.2 
Study Treatment ..................................................................................................29 
5.2.1 
Day 1, All Cycles ............................................................................................29 
5.2.2 
Days 2–9, All Cycles .......................................................................................30 
5.2.3 
Day 15 and Day 22 (Cycles 1 and 2 only) .....................................................30 
5.2.4 
Response Assessments ...................................................................................30 
5.3 
End of Treatment .................................................................................................32 
5.4 
Follow-up ..............................................................................................................32 
5.5 
End of Study .........................................................................................................32 
5.6 
Cytogenetic and Molecular Studies ....................................................................33 
6 
SAFETY .....................................................................................................................33 
6.1 
Adverse Events .....................................................................................................33 
6.1.1 
Definitions of Adverse Events .......................................................................33 
6.1.2 
Recording and Reporting of Adverse Events ..............................................33 
6.1.3 
Handling of Adverse Events ..........................................................................34 
6.2 
Serious Adverse Events .......................................................................................35 
6.2.1 
Definitions of Serious Adverse Events .........................................................35 
6.2.2 
Serious Adverse Event Reporting by Investigators ....................................36 


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6.2.3 
Sponsor Serious Adverse Event Reporting Requirements ........................37 
6.3 
Recording of Adverse Events and Serious Adverse Events .............................37 
6.3.1 
Diagnosis versus Signs and Symptoms .........................................................37 
6.3.2 
Persistent or Recurrent Adverse Events ......................................................37 
6.3.3 
Abnormal Laboratory Values .......................................................................37 
6.3.4 
Deaths ..............................................................................................................37 
6.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ............................38 
6.3.6 
Preexisting Medical Condition ......................................................................38 
6.3.7 
New Cancers ...................................................................................................38 
6.4 
Adverse Events of Special Interest .....................................................................38 
6.4.1 
QTc Prolongation ...........................................................................................39 
6.4.2 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ......................39 
6.4.3 
Pracinostat Overdose .....................................................................................39 
6.5 
Study Drug Dose Modifications ..........................................................................40 
6.5.1 
Dose Modification or Interruption for Non-Hematologic Toxicity ...........40 
6.5.2 
Dosage Adjustments of Study Drugs ............................................................41 
7 
STUDY DRUG ..........................................................................................................41 
7.1 
Study Drug ............................................................................................................41 
7.1.1 
Study Drug Labeling, Packaging, and Supply ............................................41 
7.1.2 
Preparation and Administration of Study Drug .........................................41 
7.1.3 
Accountability of Study Drug .......................................................................42 
7.1.4 
Precautions and Risks Associated with the Study Drug.............................42 
7.2 
Azacitidine ............................................................................................................43 
7.2.1 
Azacitidine Labeling, Packaging, and Supply .............................................43 
7.2.2 
Preparation and Administration of Azacitidine ..........................................43 
7.2.3 
Precautions and Risks Associated with Azacitidine ...................................44 
8 
CONCOMITANT MEDICATIONS .......................................................................44 
8.1 
Permitted Concomitant Medications .................................................................44 
8.2 
Prohibited Concomitant Medications ................................................................44 
8.3 
Medications/Agents Affecting Metabolism via Cytochrome P450 ..................45 
9 
STATISTICAL PLAN..............................................................................................45 
9.1 
Sample Size ...........................................................................................................45 
9.1.1 
Sample Size Calculation for Stage 1 .............................................................45 
9.1.2 
Total Sample Size Calculation ......................................................................46 
9.2 
Analysis Populations ............................................................................................47 
9.3 
Statistical Analysis ...............................................................................................47 
9.3.1 
Efficacy Analysis Endpoints..........................................................................47 
9.3.2 
Safety Analysis Endpoints .............................................................................48 
9.4 
Independent Data Monitoring Committee ........................................................49 
10 ETHICS .....................................................................................................................49 
10.1 
Informed Consent ................................................................................................49 
10.2 
Institutional Review Board (IRB)/Ethics Committee (EC) ..............................50 
10.3 
Confidentiality ......................................................................................................50 
10.3.1 
Subject Confidentiality ..................................................................................50 
11 ADMINISTRATIVE CONSIDERATIONS ...........................................................51 
11.1 
Study Termination ...............................................................................................51 


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11.2 
Study Documentation and Storage .....................................................................51 
11.3 
Data Collection .....................................................................................................53 
11.4 
Study Monitoring, Auditing, and Inspections ...................................................53 
11.5 
Quality Assurance and Quality Control ............................................................53 
11.6 
Disclosure and Publication Policy ......................................................................54 
12  REFERENCES .........................................................................................................55 
APPENDIX A 
SCHEDULE OF EVENTS ................................................................57 
APPENDIX B: 
WORLD HEALTH ORDER (WHO) CLASSIFICATIONS 
OF MDS ..............................................................................................60 
APPENDIX C: 
REVISED INTERNATIONAL PROGNOSTIC SCORING 
SYSTEM (IPSS-R) FOR MDS .........................................................61 
APPENDIX D: 
INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA AND MODIFIED IWG RESPONSE CRITERIA  
FOR HEMATOLOGICAL IMPROVEMENT ...............................63 
APPENDIX E: 
ECOG PERFORMANCE STATUS CRITERIA ............................65 
APPENDIX F: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION OF CARDIAC DISEASE ..............................66 
APPENDIX G:  GUIDELINES FOR WOMEN OF CHILDBEARING 
POTENTIAL AND FERTILE MALE SUBJECTS........................67 
APPENDIX H:  DRUGS THAT PROLONG THE QT INTERVAL AND/OR 
INDUCE TORSADES DE POINTES ..............................................69 
APPENDIX I: 
SUBSTRATES OF CYP1A2, CYP2B6 AND CYP3A4 ..................70 
 
LIST OF TABLES 
Table 1 
Pracinostat Dose Level Modifications ....................................................41 
Table 2 
Lower Bound of the 95% Confidence Interval for a Range of Overall 
Response Rate ...........................................................................................46 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol: 
Abbreviation  
Explanation 
acH3 
histone 3 acetylation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
BMBx 
bone marrow biopsy 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMML 
chronic myelomonocytic leukemia 
CO2  
carbon dioxide  
CR 
complete response/remission 
CRi 
complete response/remission with incomplete blood count recovery 
CRF 
case report form 
DoR 
duration of response  
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EFS 
event free survival 
FDA 
US Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
G-CSF 
granulocyte colony stimulating factor  
GM-CSF 
granulocyte macrophage colony stimulation factor 
HDAC 
histone deacetylase 
HI 
hematological improvement 
HI-E 
hematologic improvement on the erythrocytic lineage 
HIPAA 
Health Insurance Portability and Accountability Act 


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Abbreviation  
Explanation 
HMA 
hypomethylating agent 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IPSS 
International Prognostic Scoring System 
IPSS-R 
International Prognostic Score System Revised 
IRB 
Institutional Review Board 
ISF 
investigator site file 
ITT 
intent-to-treat population 
IV 
intravenous(ly) 
IWG 
International Working Group 
Ki 
inhibitory constant 
LDH 
lactate dehydrogenase 
MDS 
myelodysplastic syndrome 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PHI 
protected health information 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SCT 
stem cell transplantation 
SD 
stable disease 
SOP 
standard operating procedure 
SSF 
site study file 
ULN 
upper limit of normal 
US 
United States 


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Abbreviation  
Explanation 
TEAE 
treatment emergent adverse event 
WBC 
white blood cell 
WHO 
World Health Organization 


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1 INTRODUCTION 
1.1 
Background 
Abnormal epigenetic silencing of important regulatory genes has been described in various 
cancers, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) 
(Jones 2007).  The reduction of acetylation status of histones is one mechanism for this silencing.  
Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin, 
and therefore, have a key role in the epigenetic regulation of gene expression.  Inhibitors of 
HDACs have been extensively studied in both hematologic and solid tumors.  Four HDAC 
inhibitors have been approved to date by the US Food and Drug Administration (FDA) for the 
treatment of T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. 
1.2 
Pracinostat 
Pracinostat is a rationally-designed, potent, oral, pan-HDAC (including Class I, II, and IV 
isoforms) inhibitor with pharmacokinetic (PK) properties allowing every other day dosing.  
The half-maximal inhibitory concentration (IC50), across a broad range of human cancers in 
in vitro cytotoxicity assays, ranged from 0.1 to 1.5 μM, with the lowest values noted in leukemia 
and lymphoma cell lines.  Synergistic interactions have been observed with multiple cytotoxic 
and targeted anti-cancer therapeutics; notably the combination index with azacitidine ranged 
from 0.44 to 0.55. 
1.3 
Preclinical Pharmacology 
Results from pharmacology studies showed that pracinostat inhibits predominantly Class I and II 
HDACs (inhibitory constant [Ki] = 16 to 240 nM).  It effectively inhibits acetylation of histones 
and various other target proteins in a variety of human tumor cell lines at the same 
concentrations as it inhibits proliferation and promotes apoptosis (IC50 = 0.1 to 1.5 μM).  
Lymphomas and tumors of hematological origin show the highest sensitivity. 
The antitumor activity of orally administered pracinostat has been demonstrated in several 
xenograft mouse models of solid and hematological malignancies including colorectal cancer, 
ovarian cancer, prostate cancer, AML, and B cell lymphoma.  As observed in the in vitro cell 
studies, hematological malignancies are most sensitive to the anti-tumor effects of pracinostat. 
1.4 
Clinical Experience 
Pracinostat has been evaluated, either as a single agent or in combination with hypomethylating 
agents (HMAs), in over 430 patients with solid tumors and hematologic malignancies in multiple 
Phase 1 and Phase 2 clinical studies.  In the initial studies, pracinostat was administered as 
a single agent and was found to be generally well-tolerated at doses up to 60 mg given 3 days 
each week (e.g., Monday, Wednesday, Friday) for 3 weeks on an every-4-week schedule.  
The most common manageable side effects often associated with drugs of this class, including 
pracinostat, are fatigue, gastrointestinal (GI) effects (nausea, vomiting, diarrhea), 
and myelosuppression.  Please see the Investigator’s Brochure (IB) for further information on 


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clinical studies conducted to date, adverse events (AEs) associated with pracinostat, and efficacy 
results. 
Single-agent pracinostat has demonstrated modest activity in patients with advanced hematologic 
disorders.  In a Phase 1 dose escalation study in 44 patients with various hematologic 
malignancies, pracinostat was evaluated at doses ranging from 20 to 120 mg administered orally 
every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle.  The maximum 
tolerated dose (MTD) was declared as 120 mg; due to dose reduction after multiple cycles of 
treatment, the recommended Phase 2 dose was determined to be 100 mg (Abaza 2017).  Of 
25 patients with AML enrolled in the study, one achieved a complete response/remission (CR) 
lasting 206 days, one achieved a partial response (PR) lasting 362 days, and four achieved stable 
disease (SD) for > 2 cycles.  Three of 14 patients with intermediate or high-risk MDS achieved 
SD for 72 to 134 days. 
A Phase 2 clinical study of oral pracinostat (60 mg every other day for 3 weeks per month) 
showed activity in 22 heavily pre-treated subjects with intermediate or high-risk myelofibrosis.  
Eight (36%) subjects experienced clinical benefit, with 6 (27%) experiencing reductions in 
splenomegaly (median 3 cm, range 1–4 cm) (Quintás-Cardama 2012a). 
Because synergistic epigenetic effects were shown between HDAC inhibitors and HMAs, 
all subsequent studies have evaluated pracinostat in combination with the HMAs azacitidine 
and decitabine in myeloid malignancies AML, MDS, and myelofibrosis.  Information on the 
evaluation of pracinostat in combination with HMAs in MDS is summarized in Section 1.5. 
An open-label Phase 2 study evaluated pracinostat plus azacitidine in 50 patients ≥ 65 years of 
age with previously untreated AML and unfit to receive intensive induction chemotherapy 
(Study MEI-004).  Pracinostat was administered orally at 60 mg every other day, 3 days a week 
for 3 weeks of each 4-week cycle in combination with azacitidine 75 mg/m2 for 7 days of each 
cycle (Garcia-Manero 2017).  The median age was 75 years (range 66 – 84 years); the Eastern 
Cooperative Oncology Group (ECOG) performance status was 0 – 1 in 84% and 2 in 16%; 
66% had de novo AML and 34% had secondary AML; and the median bone marrow blasts was 
40% (range 20 – 89%).  The median number of treatment cycles was 6.5 (range 1 – 24+). 
Non-hematologic AEs grade ≥ 3 reported in > 5% of patients were fatigue 34%; anorexia 10%, 
cellulitis, pneumonia, asthenia, and sepsis in 8%; and urinary tract infection, nausea, back pain, 
hypoxia, hyponatremia, and syncope in 6%.  The 30-day and 60-day mortality rates were 2% 
and 10%.  Complete response was achieved in 21 patients (42%) and a CR with incomplete 
blood recovery (CRi) in 2 (4%).  With a median follow-up of 21 months, the median overall 
survival (OS) was 19.1 months (95% confidence interval [CI], 10.0 – 26.52), and the 1-year and 
2-year OS were 62% and 45%, respectively.  These results compare favorably to historical data 
with single agent azacitidine in comparable populations and serve as the basis for conducting a 
Phase 3 study in patients with untreated AML unfit to receive intensive induction chemotherapy. 
1.5 
Rationale for the Study 
Higher risk MDS in the Revised International Prognostic Scoring System (IPSS-R) classification 
is a serious medical condition, with a median survival of only 0.8 years in very high-risk disease 
and 1.6 years in high-risk disease.  The only curative therapy is allogeneic stem cell 


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transplantation (SCT), however the vast majority of patients with MDS are not candidates for 
SCT given their typically advanced age, comorbidities, and lack of a suitable donor.  Standard 
therapy with HMAs in intermediate-2 or high-risk MDS provides modest responses, though 
azacitidine has been shown to improve survival when compared to conventional care regimens 
(Fenaux 2009).  Patients who do not respond to HMAs or progress after a response to HMAs 
have a very poor outcome, with median survival of less than one year (Prebet 2011).  
Approaches to improving the treatment effect of hypomethylating therapy are clearly indicated. 
A pilot Phase 2 clinical study of pracinostat in combination with azacitidine was conducted in 
10 subjects with advanced MDS and showed a CR + CRi rate of 78% and a cytogenetic complete 
response/remission of 56% (Abaza 2017).  In this study, pracinostat was administered at 60 mg, 
on 3 alternate days each week for 3 consecutive weeks in combination with azacitidine 
(75 mg/m2 intravenously [IV] or subcutaneously [SC] daily × 7 days).  Pracinostat dose was 
reduced or treatment interrupted as clinically indicated to improve tolerability and maintain 
patients on therapy. 
These positive findings led to the conduct of a placebo-controlled Phase 2 study (MEI-003) in 
102 subjects with higher-risk MDS administered pracinostat (60 mg, 3 alternate days each week 
for 3 weeks) or placebo in combination with azacitidine (75 mg/m2 for 7 days) in 28-day cycles 
(Garcia-Manero 2017).  The median age was 69 years (range 26–90 years), 67% of subjects had 
IPSS intermediate-2 risk MDS and 33% had high-risk MDS.  The rate of CR by Cycle 6, the 
study’s primary endpoint, was 18% (9/51) in the pracinostat group compared to 33% (17/51) in 
the placebo group (p = 0.07).  The cytogenetic response rate in the pracinostat group was 
42% (14/33) compared to 55% (17/31) in the placebo group (p = 0.14).  Hematologic 
improvement was 35% (15/43) and 55% (24/44) in the pracinostat and placebo groups, 
respectively (p = 0.51).  Median duration of response (DoR) was 12 months and 9 months in the 
pracinostat and placebo groups, respectively (hazard ratio [HR] = 0.64, 95% CI 0.23 – 1.79).  
With a median duration of follow-up of 15 months, the median OS in the pracinostat and placebo 
group was 16 and 19 months, respectively (HR = 1.21, 95% CI, 0.65 – 2.23).  The median event-
free survival (EFS) was 9 months in both groups (HR = 0.82, 95% CI 0.46 – 1.46) and the 1-year 
OS was 60% in both groups.   
In that study, 26% of subjects in the pracinostat group discontinued study drugs in the first 
3 cycles of therapy (by Day 84) for reasons other than progressive disease (PD) or SCT as 
compared to 10% of subjects randomized to the placebo group.  The most common cause for 
early discontinuations in the pracinostat group was AEs; primarily fatigue and myelosuppression.  
Furthermore, in the intermediate-2 risk group, 14/30 subjects (47%) randomized to pracinostat 
discontinued the study due to AEs or withdrawal of consent at any time in the study compared to 
4/33 subjects (12%) randomized to placebo, whereas in the high-risk group, the discontinuation 
rate due to adverse events/withdrawal was comparable in the 2 treatment arms; 27% in 
pracinostat versus 22% in placebo. 
In a post-hoc analysis, the subset of subjects who received at least 4 cycles of pracinostat 
+ azacitidine and began Cycle 5 had a trend for better progression-free survival (PFS) and OS 
(HR = 0.67) compared to the control group.  This suggests the lack of efficacy in the 
intent-to-treat (ITT) population may be due to early discontinuations and insufficient exposure to 
pracinostat.  This is further supported by the data from Study MEI-004 in elderly AML where 


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the discontinuation rate was lower (8% in the first 2 cycles) resulting in substantial treatment 
efficacy, with a CR rate of 42% and a median survival of 19.1 months (Garcia-Manero 2016).  
Therefore, this current study will evaluate a regimen consisting of a lower dose of pracinostat in 
combination with the standard dose of azacitidine to determine if the rate of early discontinuation 
can be reduced, thereby improving efficacy.  
1.6 
Rationale for Pracinostat Dose Selection 
This study will investigate a pracinostat dose of 45 mg, 25% lower than the dose used in 
Study MEI-003.  The rationale for selecting a pracinostat daily dose of 45 mg for this regimen 
include: 
• The dose of 45 mg has been used in prior Phase 2 studies in MDS and AML as the 
step-down dose level for subjects who did not tolerate the starting dose of 60 mg. 
• In prior studies in MDS and AML, approximately 50% of subjects who achieved an 
objective response and received pracinostat for more than one year had their daily dose 
reduced from 60 mg to 45 mg, indicating this dose is efficacious and well tolerated. 
• A dose of 40 mg was shown to induce a 2-fold increase in histone 3 acetylation (acH3) in 
17 subjects with solid tumors, a level comparable to that achieved with a dose ≥ 60 mg but 
significantly higher than achieved with a dose of 20 mg, suggesting that a dose of 45 mg 
may be sufficient for full pharmacodynamic effects. 
• A dose of 45 mg results in plasma concentrations greater than HDAC C1 Ki for 
approximately 24 hours, suggesting adequate HDAC inhibition at this dose (data on file). 
1.7 
Rationale for Patient Population 
The study will enroll only patients with high and very high-risk MDS by IPSS-R because this is 
a patient subset with the shortest overall survival and the most significant unmet need.  
Furthermore, in Study MEI-003, patients with high-risk MDS randomized to pracinostat plus 
azacitidine had a discontinuation rate similar to that observed with azacitidine plus placebo, 
whereas patients with intermediate-2 MDS had a higher discontinuation rate in the 
pracinostat + azacitidine group, suggesting a different level of tolerability to treatment toxicities. 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are to: 
• Define the safety and tolerability of pracinostat plus azacitidine in high/very high-risk 
MDS 
• Determine the overall response rate (ORR), defined as complete remission (CR) and 
partial remission (PR), of pracinostat plus azacitidine in high/very high-risk MDS 


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2.2 
Secondary Objectives 
Evaluate the following endpoints in patients with high/very high-risk MDS administered 
pracinostat plus azacitidine: 
• CR rate 
• Overall hematologic improvement (HI) rate 
• Clinical benefit rate, defined as rate of CR + PR + HI + Marrow CR 
• Rate of cytogenetic CR 
• DoR 
• Rate of leukemic transformation  
• EFS 
• PFS 
• OS 
3 STUDY DESIGN 
This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with 
azacitidine in patients with IPSS-R high and very high-risk MDS who are previously untreated 
with HMAs.  Enrollment in this study will be limited to high/very high-risk MDS because this 
group represents the highest unmet need, with median survival of less than 18 months.  
Recognizing that additional safety and efficacy of pracinostat plus azacitidine is desirable before 
evaluating the treatment regimen in a placebo-controlled environment, the protocol is being 
amended to become a 2-stage open-label study comprising Stage 1 and Stage 1 expansion 
(Stage 1b). 
Stage 1 will be conducted as an open-label single arm in approximately 40 evaluable subjects to 
assess if the pracinostat dose regimen results in a discontinuation rate that meets a predefined 
threshold, and the observed efficacy justifies expansion of enrollment in Stage 1b. 
A discontinuation rate of approximately ≤ 10% in Stage 1, a rate comparable to that observed 
with azacitidine alone in Study MEI-003, would support expansion to Stage 1b.  Stage 1b will be 
conducted as an open-label arm to achieve a total enrollment of approximately 60 subjects 
evaluable for efficacy, inclusive of Stage 1 and Stage 1b enrollment. 
Study drugs should be continued until disease progression or intolerable toxicity.  It is important 
to note that the median time to achieving a response with azacitidine alone is 4 to 5 months.  
Therefore, early (< 6 months) discontinuation of study therapy for ‘no response’ should be 
avoided.  The Medical Monitor should be contacted by the Investigator prior to discontinuing 
study drugs in a subject from the study to discuss the rationale for discontinuation. 
After discontinuing study drugs, subjects will be followed every 3 months (± 1 month) until 
death or study termination to collect information on disease status (i.e., improvement of disease 


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response or disease progression), start of non-protocol therapies (e.g., stem cell transplant or an 
MDS-directed therapy) and survival. 
The primary study analysis will be performed approximately 12 months after the last subject is 
enrolled in the study.  The study duration is anticipated to be approximately 36 months: 
24 months for enrollment and 12 months of follow-up until the primary analysis.  At the 
completion of the primary analysis, the Sponsor will decide whether to terminate the study or 
continue study drug dosing in ongoing subjects. 
It is anticipated that subject participation in the study will be for a median of approximately 
10 cycles in the group receiving pracinostat + azacitidine.  
3.1 
Treatment Plan 
3.1.1 
Pracinostat 
Pracinostat is supplied as 45-mg capsules and is self-administered orally (by the subject) once 
per day, 3 days each week for 3 weeks, followed by 1 week of rest, except on Day 1 of Cycle 1, 
when the study medication is to be administered at the clinic.  Treatment cycles are repeated 
every 28 days, unless delayed due to toxicity. 
Pracinostat is to be taken in the morning on an empty stomach or after a light meal with a full 
glass of water at approximately the same time each of the 3 days weekly (e.g., Monday, 
Wednesday, Friday).  Subjects should be instructed to swallow the capsules whole and to not 
chew or crush them.  Pracinostat is to be taken before administration of azacitidine.  If vomiting 
occurs, no attempt should be made to replace the vomited dose.  Pracinostat should not be taken 
with grapefruit, grapefruit juice, or Seville oranges (see Section 8.2). 
The dosing interval between two consecutive doses of pracinostat should be approximately 
48 hours.  For example, if a subject forgets to take the dose before noon, it should be withheld 
that day and restarted the next day to ensure approximately 48 hours between each dose.  As an 
additional example, if a subject misses a dose on Monday, the dose can be restarted on Tuesday, 
and the other doses would be taken on Thursday and Saturday. 
Study medication compliance will be assessed by capsule counts on Day 1 of each cycle.  
The research staff are to count and document the amount of pracinostat taken and returned by the 
subject. 
In later cycles (i.e., after Cycle 4), 45-mg pracinostat can be dose reduced to orally 3 days each 
week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as 
fatigue, GI toxicity, or myelosuppression.  Discuss with the Medical Monitor before decreasing 
pracinostat dosing from 3 to 2 weeks per cycle. 
Subjects who are smokers are prohibited from smoking while receiving pracinostat because 
smoking induces cytochrome CYP1A2 and reduces pracinostat plasma concentrations by 
approximately 60% (see IB for information on the effect of smoking on pracinostat PK in 
Study MEI-006 in healthy volunteers).  The effect on CYP1A2 is due to inhaled hydrocarbons 


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(including vaporizing e-cigarettes).  As such, chewing tobacco and nicotine gum or patches are 
allowed.  Subjects should be asked at site visits about any use of tobacco products.  
3.1.2 
Azacitidine 
All subjects will receive a standard regimen of azacitidine at 75 mg/m2 for 7 days of each 28-day 
cycle.  Administration will occur by SC injection, or IV infusion if SC injections are not 
tolerated, on one of two schedules: 
• Schedule 1 – daily therapy on Days 1 through 7 
• Schedule 2 – 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive 
 
days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine 
 
dosing the first two days of the next week (Days 8 and 9) of each 28-day 
 
cycle.  
Azacitidine should be given at approximately the same time each day.  Each Investigator will 
declare preference as to which schedule is preferred for a subject and use that preference 
throughout the study.  Please contact the Medical Monitor if a change in schedule is required. 
The total dose will be calculated based on the subject’s actual weight on Cycle 1 Day 1 (or up to 
7 days before).  The dose should be recalculated if the subject’s weight changes by ≥ 10% during 
the study.  Sites may follow their institutional guidance for assessing the weight used for dosing.  
In the presence of toxicity, azacitidine dose reduction in Cycle 2 and subsequent cycles will be 
performed according to the azacitidine product labeling recommendations or local standards of 
care. 
4 SUBJECT POPULATION AND DISCONTINUATION CRITERIA 
4.1 
Inclusion Criteria 
To be eligible for study participation, subjects must meet the following inclusion criteria: 
1. Female or male subjects ≥ 18 years-of-age.  
2. Histologically or cytologically documented diagnosis of MDS according to the World Health 
Organization (WHO) classification (Vardiman 2009, Arber 2016; Appendix B) with < 20% 
bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of 
< 20,000/µL. 
• If WBC ≥ 20,000/µL, cytoreduction with hydroxyurea is permitted prior to enrollment.   
• CMML-1 and CMML-2 subtypes are eligible for study participation. 
3. Classified as high or very high risk according to the Revised International Prognostic Scoring 
System (IPSS-R) risk category (Appendix C).  CMML-1 and CMML-2 subtypes will be 
considered high-risk MDS and will not require IPSS-R scoring.  
4. Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to planned first study 
treatment. 


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5. Clinical indication for treatment with azacitidine. 
6. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth 
factors, or immunosuppressive therapy is allowed). 
• Subjects who require start of an HMA (e.g., azacitidine) due to progressing MDS may 
receive up to 1 cycle of azacitidine within 30 days prior to Cycle 1 Day 1.  
7. ECOG performance status of 0, 1, or 2. 
8. Adequate organ function as evidenced by: 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the upper 
limit of normal (ULN). 
• 
Total bilirubin ≤ 1.5 × ULN or total bilirubin of ≤ 2 mg/dL, whichever is higher.  Total 
bilirubin < 3 x ULN for patients with Gilbert-Meulengracht Syndrome. 
• Serum creatinine < 1.5 x ULN, or creatinine clearance > 40 mL/min according to 
institutional standards (actual body weight should be used to calculate creatinine 
clearance). 
• QTcF interval ≤ 450 msec using the mean of triplicate electrocardiograms (ECGs). 
9. Female subjects of childbearing potential and male subjects with female partners of 
childbearing potential are required to use two forms of acceptable contraception, including 
one barrier method, during their participation in the study and for 30 days following last 
dose.  Female subjects of childbearing potential must not be breastfeeding, or planning to 
breastfeed, and must have a negative pregnancy test ≤ 7 days before first study drug 
administration.  Male subjects must also refrain from donating sperm during their 
participation in the study.  
10. Voluntary written informed consent before performance of any study-related procedure not 
part of normal medical care. 
11. Have the willingness and ability to understand the nature of this study and to comply with the 
study and follow-up procedures. 
4.2 
Exclusion Criteria 
Exclude subjects from this study if they do not fulfill the inclusion criteria, or if any of the 
following criteria are observed: 
1. Bone marrow blasts ≥ 20%, indicating a diagnosis of AML. 
2. Received any of the following within the specified time frame prior to administration of 
study medication: 
• Any investigational agent within 14 days or 5 half-lives prior to enrollment, whichever is 
longer. 


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• Hydroxyurea within 48 hours prior to first day of study treatment. 
• Hematopoietic growth factors:  erythropoietin, granulocyte colony stimulating factor 
(G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), 
or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to study 
enrollment. 
• Major surgery within 28 days prior to first study treatment. 
3. Subjects who have not recovered from side effects of previous therapy. 
4. Cardiopulmonary function criteria: 
• Current unstable arrhythmia requiring treatment. 
• History of symptomatic congestive heart failure (New York Heart Association [NYHA] 
Class III or IV). 
• History of myocardial infarction, pulmonary embolism or cerebrovascular accident 
within 6 months of enrollment. 
• Current unstable angina. 
5. Prior treatment for MDS with the HDAC inhibitors Zolinza (vorinostat), Belenodaq 
(belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipeptide), or investigational 
agent with significant action as an HDAC inhibitor. 
6. Clinical evidence of central nervous system involvement. 
7. Subjects with GI tract disease causing the inability to take oral medication, malabsorption 
syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, 
uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis). 
8. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or 
C. 
9. Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that 
could, in the Investigator’s opinion, potentially interfere with participation in this study. 
10. Presence of a malignant disease within the last 12 months, with the exception of adequately 
treated in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin 
cancer, or malignancies treated with curative intent and no evidence of active disease in prior 
12 months and felt to be low risk for recurrence.  Other malignancies may be considered after 
consultation with the Medical Monitor. 
11. An unwillingness or inability (including breastfeeding women, prohibited concomitant 
medications, uncontrolled infections, psychological, familial, sociological, or geographical 
conditions) to comply with study and/or follow-up procedures as outlined in the protocol. 


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12. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol. 
13. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, 
chewing tobacco, or nicotine gum is permitted).  Subjects who stopped smoking at least 
8 days prior to first pracinostat dosing can be enrolled, provided they refrain from smoking 
during the whole study. 
4.3 
Discontinuation from Study Treatment 
The Medical Monitor should be contacted prior to discontinuation of study treatment. 
Subjects will be discontinued from study treatment for any of the following reasons: 
• Documented disease progression or relapse after CR/PR by the International Working 
Group (IWG) criteria (see Section 5.2.4).  Because subjects with MDS receiving HMAs 
may require more than 6 cycles of therapy to achieve a response (median 4 to 5 cycles), 
discontinuation due to “lack of response” in the first 6 cycles of therapy must be avoided. 
• Decision to proceed to intensive therapy and stem cell transplant. 
• Irreversible or intolerable toxicity or abnormal and clinically significant laboratory values 
thought to be related to drug toxicity and not manageable by supportive approaches 
and/or study drug dose reduction or interruption. 
• Pregnancy. 
• Subject request to withdraw from treatment or from the study. 
• Conditions requiring therapeutic intervention not permitted by the protocol. 
• Lost to follow-up. 
• Non-compliance with study treatment or study-related assessments that compromise the 
proper evaluation of the patient’s safety. 
• Early study termination by the Sponsor, the Sponsor’s designee, or regulatory authorities. 
After discontinuation from protocol treatment, subjects must be followed for AEs for 30 calendar 
days after their last dose of study medication.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the Investigator, these AEs are 
not likely to improve because of the underlying disease.   
All subjects who have Grade 3 or 4 laboratory abnormalities (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) at the time of discontinuation 
must be followed until the laboratory values have returned to Grade 1 or 2, unless it is, in the 
opinion of the Investigator, not likely that these values will improve. 
5 STUDY PROCEDURES AND ASSESSMENTS  
See the Schedule of Assessments (Appendix A) for a complete list of all study procedures 
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5.1 
Screening 
The Screening visit should occur ≤ 14 days prior to first study treatment.  Physical examinations 
and serum chemistries on Day 1 do not need to be repeated if performed within 7 days prior to 
Day 1.   
The following procedures and assessments will be performed during screening: 
• Written informed consent must be obtained prior to initiating any other study-required 
procedure.  Some tests performed prior to obtaining informed consent (e.g., bone marrow 
biopsy) may not need to be repeated for this study as long as they were performed within 
the allowed window described in this protocol.  This window allows subjects to not 
unnecessarily repeat tests and impose an undue burden to them.  
• Determine eligibility including IPSS-R score for enrollment.  
 Note: IPSS score for subjects enrolled under Amendment 2 will also be calculated for 
comparison with historical data, however IPSS will not be used to determine 
eligibility (Appendix C).  
• Medical history, including recent smoking history. 
• Transfusion history for 8 weeks prior to first study drug administration. 
• Physical examination. 
• Vital signs, including height, weight, blood pressure, resting heart rate, and oral 
temperature. 
• ECOG performance status determination (see Appendix E). 
• Baseline signs and symptoms. 
• AE/toxicity assessment. 
• Concomitant medication review. 
• 12-lead ECG in triplicate, approximately once every 2 to 5 minutes to calculate the QTcF 
interval. 
• Two complete blood counts (CBCs) with differential and blasts ≥ 7 days apart within 
1 month prior to first study drug administration; the second CBC may be obtained on 
Cycle 1 Day 1 prior to first study drug administration.  For this study, a CBC will consist 
of, at a minimum, WBC count with differential, absolute neutrophil count (ANC), 
lymphocyte count, red blood cell (RBC) count and indices, hemoglobin, hematocrit, 
platelets, and blast count where applicable. 


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• Serum chemistry:  glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT, total 
bilirubin, total protein, albumin, and lactate dehydrogenase (LDH). 
• Serum pregnancy test for women of child-bearing potential (must be performed within 
7 days of first study treatment). 
• Bone marrow biopsy and aspiration within 28 days prior to planned first study treatment. 
5.2 
Study Treatment 
Study visits should occur on a 28-day schedule. A -4 day to +7-day window is allowable for each 
clinic visit to accommodate subject request, holidays, weekends, inclement weather, or other 
unforeseen circumstances. 
Pracinostat is to be taken in the morning on an empty stomach or following a light meal once a 
day on Days 1, 3, and 5 (Week 1); Days 8, 10, and 12 (Week 2); and Days 15, 17, and 19 
(Week 3); with a week of rest during Week 4.  Pracinostat will be administered in the clinic on 
Day 1 of Cycle 1, and subjects may self-administer at home on all other days.  Pracinostat is to 
be taken before azacitidine.  Missed doses of pracinostat should not be made up (refer to 
Section 3.1.1).  To monitor pracinostat dosing, subjects will be given a dosing diary card to track 
medication compliance. 
5.2.1 
Day 1, All Cycles 
The following procedures and assessments will be performed on Day 1: 
• Update of transfusion history for 8 weeks prior to first study drug administration on 
Cycle 1 Day 1 only 
• Physical examination 
• Vital signs 
• Smoking assessment (for subjects enrolled under Amendment 1)  
• ECOG performance status determination 
• AE assessment 
• Concomitant medication review 
• 12-lead ECG performed in triplicate approximately once every 5 to 10 minutes to 
calculate the QTcF interval.  On Day 1 of Cycle 1, ECGs will be obtained pre-dose, 
pracinostat will be taken, and azacitidine will be administered.  Ninety minutes 
(± 15 minutes) post-pracinostat dosing, triplicate ECGs will be repeated.  Beyond 
Cycle 1, non-triplicate ECGs will be performed as clinically indicated. 


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• Administer pracinostat. 
• CBC with differential and blasts. 
• Serum chemistry:  glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, 
ALP, AST, ALT, total bilirubin, total protein, albumin, and LDH. 
• Dispense study medication.  Following Cycle 1, study medication compliance will be 
assessed on Day 1 of each cycle. 
• Azacitidine administration. 
• Response assessments (after Cycle 2 and Cycle 6; see Section 5.2.4). 
5.2.2 
Days 2–9, All Cycles 
• AE assessment on each day of azacitidine administration. 
• Azacitidine administration (see Section 3.1.2). 
5.2.3 
Day 15 and Day 22 (Cycles 1 and 2 only) 
• Vital signs. 
• Smoking assessment (for subjects enrolled under Amendment 1). 
• AE assessment. 
• Concomitant medication review (Day 22 only). 
• CBC with differential and blasts.  A manual differential is preferred but is not required at 
these visits. 
• Serum chemistry:  glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, 
ALP, AST, ALT, total bilirubin, total protein, albumin, and LDH. 
5.2.4 
Response Assessments 
To assess hematologic response, CBC with differential including blast cell counts will be 
obtained every Cycle Day 1 (-4 days to +7 days), and when response assessments 
and confirmations are scheduled to be performed (Appendix A). 
A BMBx and aspirate to assess cellularity, blast percentage, morphology (dysplasia), and 
cytogenetics (if abnormal at baseline), as well as a CBC with differential will be required at the 
end of Cycles 2 and 6, with evidence of disease progression, with evidence of hematologic CR 
which may occur after Cycle 6, and prior to transplant if the subject becomes a candidate for 
transplant.  Once a marrow CR is documented, there is no need to repeat a BMBx unless 
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Ideally, transplant will be after the conclusion of ≥ 4 cycles of therapy.  The following 
assessments are to be performed, and the Medical Monitor is to be advised of the results prior to 
discontinuing treatment for transplant: 
• Bone marrow biopsy and aspiration (classic cytogenetics, fluorescence in-situ 
hybridization [FISH], and molecular studies, if done at baseline).* 
• CBC with differential and blasts. 
* 
FISH and molecular studies are not required by protocol, but results should be collected in the electronic data 
capture (EDC) system if performed as per local practice.  
Transfusions in the 8 weeks prior to starting study drugs and while on study and hematopoietic 
growth factor use will also be captured to assess efficacy. 
Local (i.e., Investigator) assessments of response will be utilized for the primary efficacy 
analyses, employing the IWG standardized response criteria for evaluating clinically significant 
responses in MDS (Cheson 2006).  These criteria measure alterations in the natural history of 
disease, hematologic improvement, cytogenetic response, and improvement in health-related 
quality of life.  Diagnosis of MDS according to the WHO classifications are presented in 
Appendix B. 
The IWG Response Criteria for MDS are presented in Appendix D.  The response categories are 
as follows: 
• CR 
•  PR 
• Marrow CR 
• HI 
• Stable Disease 
• Failure 
• Relapse after CR or PR 
• Cytogenetic Response 
• Disease Progression 
• Survival 
A CBC with differential will be required for confirmation of CR or PR 8 weeks following the 
initial report of response. 


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Modified IWG response criteria are presented in Appendix D. 
5.3 
End of Treatment 
End of Treatment evaluations are required no less than 7 days and no more than 30 days after 
treatment ends, or prior to starting new treatment if urgent treatment is required due to disease 
progression. 
The following assessments will be performed: 
• Smoking assessment (for subjects enrolled under Amendment 1). 
• ECOG performance status determination. 
• AE assessment. 
• Concomitant medication review. 
• Bone marrow biopsy and aspirate must be performed if a subject discontinues due to 
disease progression without clear evidence of progression by peripheral blood counts, due 
to an AE, or prior to bone marrow transplant.  This is required if a BMBx and aspirate 
have not been obtained within 56 days prior to study discontinuation.  Bone marrow 
cytogenetics will be performed if the subject discontinues the study in CR to confirm a 
cytogenetic CR (unless cytogenetic CR has been confirmed in previous marrow 
assessments). 
• CBC with differential and blasts count. 
• Serum chemistry:  glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, 
ALP, AST, ALT, total bilirubin, total protein, albumin, and LDH. 
• Study medication compliance assessment (if applicable). 
5.4 
Follow-up 
After subjects discontinue study drug, they will be followed every 3 months (± 1 month) until 
death or study termination to collect information on progression, any new treatments, and 
survival (e.g., date and cause of death).  With suspicion of disease progression, a CBC (including 
3-part differential, platelets, and blasts) may be performed (optional).  Subjects may be contacted 
during outpatient visits or by telephone.   
5.5 
End of Study 
The end of this study occurs when the Sponsor terminates the study when sufficient subject 
follow-up has been obtained, anticipated to occur approximately 12-months after follow-up of 
the last subject enrolled plus the time to complete End of Treatment evaluations.   The Sponsor 
or designee reserves the right to temporarily suspend or terminate the study at any time for 
reasons including, but not limited to, safety issues or ethical reasons. 


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5.6 
Cytogenetic and Molecular Studies 
Classical cytogenetics shall be required with BMBx and aspirate, and peripheral blood samples 
taken as part of the standard of care.  Fluorescence in situ hybridization (FISH) and molecular 
tests (e.g., polymerase chain reaction) may be conducted as per standard of care but are not 
required.  If FISH or molecular tests are performed as part of the patient’s local standard of care, 
the data should be documented in the case report form (CRF). 
6 SAFETY  
Safety assessments will consist of monitoring and recording protocol-defined AEs and serious 
AEs (SAEs), measurement of protocol-specified hematology, clinical chemistry, measurement of 
protocol-specified vital signs, and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study medication. 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) or ethics committee (EC) according to the policies of the responsible 
IRB/EC. 
6.1 
Adverse Events 
6.1.1 
Definitions of Adverse Events 
An AE is the development of an undesirable medical condition, or the deterioration of 
a preexisting medical condition following or during exposure to a medicinal product, whether 
or not considered causally related to the product. 
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory 
findings). 
6.1.2 
Recording and Reporting of Adverse Events 
All AEs regardless of seriousness or relationship to pracinostat or azacitidine, from the start of 
study drug treatment until 30 calendar days after discontinuation or completion of treatment as 
defined by the clinical study for that subject, are to be recorded in the CRF.  The Investigator 
will provide an opinion as to the relationship of the AE to the study drug treatment (i.e., the 
event is related or unrelated to study medication administration). 
All AEs should be documented.  A description of the event, including date of onset 
and resolution, any relevant SAE outcome criteria, any action taken (e.g., changes to study 
treatment), and outcome, should be provided along with the Investigator’s assessment of 
causality (i.e., the relationship to the study treatment[s]).  For an AE to be a suspected 
treatment-related event there should be at least a reasonable possibility of a causal relationship 
between the protocol treatment and the AE.  Adverse events will be graded according to the NCI 
CTCAE v4.03, and changes will be documented. 


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To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES: There is a plausible temporal relationship between the onset of the AE and administration 
of the study treatment, and the AE cannot be readily explained by the subject’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern 
of response to the study treatment; and/or the AE abates or resolves upon discontinuation 
of the study treatment or dose reduction and, if applicable, reappears upon re-challenge. 
NO: Evidence exists that the AE has an etiology other than the study treatment (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to study treatment administration 
(e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected AEs are those that are listed or characterized in the current version of the pracinostat 
IB. 
If the AE is serious, it should be reported immediately; refer to Section 6.2.2 for SAE reporting 
requirements and contact information.  Other untoward events occurring in the framework of a 
clinical study are also to be recorded as AEs (i.e., AEs that occur prior to assignment of study 
treatment and after the signing of the informed consent form (ICF), that are related to a protocol-
mandated intervention, including invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE. 
Laboratory results or test findings will be reported as an AE if the test result requires an 
adjustment in the study medication(s) or discontinuation of treatment; and/ or test findings 
require additional testing or surgical intervention; a test result or finding is associated with 
accompanying symptoms; or a test result is considered to be an AE by the Investigator. 
6.1.3 
Handling of Adverse Events 
All AEs should be followed until resolution or stabilization.  Subjects must be followed for AEs 
for 30 calendar days after discontinuation or completion of research study-specific treatment 
(e.g., chemotherapy, radiation, oral medications, targeted therapy, and surgery) or until the 
initiation of new therapy for MDS.  All new AEs occurring during this period must be reported 
and followed until resolution unless, in the opinion of the Investigator, the AE or laboratory 
abnormality/ies are not likely to improve because of the underlying disease. 
All adverse events occurring from signing of informed consent to 30 calendar days after 
completion or discontinuation of protocol-specific treatment, are to be recorded on the 
appropriate eCRF section.   
Once > 30 days have elapsed, only AEs, SAEs, or deaths assessed by the Investigator as 
treatment-related are to be reported. 


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6.2 
Serious Adverse Events 
The Investigator is responsible for recognizing and reporting SAEs as outlined in this section.  
It is the Sponsor or designee’s responsibility to report relevant SAEs to the applicable local, 
national, or international regulatory bodies. 
6.2.1 
Definitions of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that:  
• results in death 
• is immediately life-threatening 
• requires at least a 24-hour inpatient hospitalization or prolongation of existing 
hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect. 
The definition of SAE also includes any important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the previous definition.  These should also usually be 
considered serious.  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 development of drug dependency or drug abuse.   
“Disease progression” or “relapse from remission” as such, should not be reported as an SAE.  
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
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Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as an SAE.   
6.2.2 
Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs and SAEs. 
Adverse events classified by the treating Investigator as serious require expeditious handling 
and reporting in order to comply with regulatory requirements.  Serious AEs may occur at any 
time from the start of study treatment through the 30-day follow-up period after the last study 
treatment.  All SAEs, regardless of causality, must be reported within 24 hours of when the 
Investigator is first informed of the event and followed until resolution (with autopsy report, if 
applicable).  Serious AEs that occur prior to assignment of study treatment, that are related to a 
protocol-mandated intervention, including invasive procedures such as biopsies, are to be 
reported. 
All SAEs, regardless of causality, must be entered in the eCRF and supporting documentation 
(i.e., hospital records, autopsy reports) must be reported to: 
 
 
Clinipace Worldwide 
 
Fax:     (919) 573-9526 
 
Email:  MEI16011.safety@clinipace.com 
 
MEI Pharma – Medical Monitor 
Phone:  primary (David Ramies, MD): (925) 285-6640;  
             back-up (Richard Ghalie, MD): (619) 990-1153 
Deaths and other SAEs occurring > 30 calendar days after last study treatment that are deemed 
related (causality = YES) to pracinostat must be reported as SAEs within 24 hours of when the 
Investigator is first informed of the event.  Whenever possible, an autopsy report should be 
collected. 
Deaths occurring > 30 calendar days after last study treatment and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but should be collected as 
part of the study data. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported as soon as it is available.  Refer to the study reference manual for detailed SAE 
reporting guidelines.   


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Investigators must report SAEs and follow-up information to their responsible IRB/EC according 
to its policies. 
6.2.3 
Sponsor Serious Adverse Event Reporting Requirements 
The Sponsor or designee is responsible for reporting relevant SAEs to the competent authority, 
other applicable regulatory authorities, and participating Investigators, in accordance with the 
International Council on Harmonisation (ICH) guidelines, FDA regulations, and/or local 
regulatory requirements. 
6.3 
Recording of Adverse Events and Serious Adverse Events 
6.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually unless the AEs constitute components of a recognized 
condition, disease, or syndrome.  If a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE as appropriate.  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  
If a diagnosis is determined subsequent to the reporting of the constellation of symptoms, 
the signs/symptoms should be updated to reflect the diagnosis. 
6.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
time points.  Such events should only be recorded once.  If a persistent AE becomes more severe 
or lessens in severity, it should be recorded separately. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, 
and subsequently recurs.  All recurrent AEs should be recorded. 
6.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value 
or vital sign should be considered additional information that must be collected.  If the laboratory 
abnormality is a sign of a disease or syndrome, only the diagnosis should be recorded. 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study medication(s) or discontinuation of treatment; and/ or laboratory findings 
require additional testing or surgical intervention; a laboratory result or finding is associated with 
accompanying symptoms; or a laboratory result is considered to be an AE by the Investigator. 
6.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease should be recorded in the Death Report CRF.  


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All other on-study deaths, regardless of attribution, will be recorded as an SAE and expeditiously 
reported.   
When recording an SAE with an outcome of death, the event or condition that caused 
or contributed to the fatal outcome should be recorded as the single medical concept.  
6.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of > 24 hours or prolongation of preexisting 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE (see Section 6.2.1). 
6.3.6 
Preexisting Medical Condition 
A preexisting medical condition is one that is present at the start of the study.  Such conditions 
should be recorded as part of the subject’s medical history.  A preexisting medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the study.  When recording such events, it is important to convey the concept that 
the preexisting condition has changed by including applicable descriptors. 
6.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria (see Section 6.2.1).  New primary cancers are those that are not 
the primary reason for the administration of the study treatment and have developed after the 
inclusion of the subject into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered disease progression. 
6.4 
Adverse Events of Special Interest 
Adverse Events of special interest (AESI) are defined as pre-specified AEs, serious and non-
serious, under ongoing monitoring by the Sponsor.   No specific reporting timelines or other 
activities are required by the Investigator in addition to the normal AE reporting practices as 
described in the above sections for the following AESIs:  
• Supraventricular arrhythmias 
• Sepsis, septic shock, Grade ≥ 3 lung infection (pneumonia) 
• Any infection leading to death 
• Grade ≥ 3 anemia, neutropenia, febrile neutropenia, and thrombocytopenia 
• Grade ≥ 3  hemorrhage 


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6.4.1 
QTc Prolongation 
Any QTc prolongation ≥ 500 ms and/or > 60 ms change from baseline, irrespective of the 
relationship to study treatment, must be always reported as an AE (see Section 6.1.2). 
The Investigator or the Investigator’s designee must complete the AE pages of the eCRF with all 
necessary information, and any accompanying source documents (hospital records, ECG report, 
etc.) should be faxed or e-mailed (as PDFs) at the following contacts: 
Clinipace Worldwide 
Fax:     (919) 573-9526 
Email:  MEI16011.safety@clinipace.com 
6.4.2 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Female subjects of child-bearing potential and male subjects (even if surgically sterilized) must: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and for 30 days following last dose, or 
• Agree to completely abstain from heterosexual intercourse. 
• Male subjects must also refrain from donating sperm during their participation in this 
study. 
During the course of the study, all female subjects of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix G) must contact the treating 
Investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating Investigator). 
If an Investigator suspects that a subject may be pregnant after the subject has been receiving 
study medications, study drugs must immediately be withheld until the result of the pregnancy 
test is confirmed.  If a pregnancy is confirmed, study drugs must be immediately 
and permanently stopped, the subject must be discontinued from the study, and the Investigator 
must notify the Sponsor/designee as soon as possible.   
If a subject becomes pregnant while enrolled in the study, the Investigator should expeditiously 
report this event, regardless of whether or not it meets the criteria for expedited reporting.  
Abortions (spontaneous, accidental, or therapeutic) must also be reported.  Refer to Appendix G 
for detailed information on the pregnancy reporting process. 
6.4.3 
Pracinostat Overdose 
There is no specific antidote to pracinostat.  If overdose is suspected, administration of study 
drug should be stopped, and general supportive measures instituted.  The risk of overdose is 
minimized by the standard dose and written dosing instructions for subjects. 
Symptomatic and non-symptomatic overdose (e.g., > 45 mg single dose or > 2 doses in a 
< 48-hour interval) must be collected as part of the study data.  Any accidental or intentional 


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overdose with the study drug that is symptomatic, even if not fulfilling a seriousness criterion, is 
to be reported within 24 hours from first knowledge of the event and following the same process 
described for SAE reporting (see Section 6.2.2). 
6.5 
Study Drug Dose Modifications 
Adverse events and laboratory abnormalities (see Appendix A for details) will be monitored 
throughout the study and toxicities will be graded per NCI CTCAE v4.03.  Appropriate 
supportive care treatment, such as antiemetics or antidiarrheal treatment, will be administered 
according to local standards of care as appropriate, prior to considering study drug dose 
modification or interruption. 
If necessary to manage toxicities, azacitidine dose reduction will be implemented according to its 
package insert or local standards of care.  Pracinostat dose reduction to less than 45 mg is not 
planned in this study.  Of note, there may be overlapping toxicities between azacitidine and 
pracinostat, particularly for myelosuppression, fatigue, nausea, and vomiting.   
6.5.1 
Dose Modification or Interruption for Non-Hematologic Toxicity 
From Cycle 2 onwards in case of Grade ≥ 3 non-hematologic toxicities a dose reduction or, as a 
subsequent option, a dose interruption of both pracinostat and azacitidine is permitted after prior 
discussion with the Medical Monitor.  
Patients with Grade ≥ 3 non-hematologic toxicities may have both study drugs held up to a 
maximum of 4 weeks, or until return to Grade 1 or baseline (whichever comes first).  However, 
in patients who are experiencing a reduction in marrow blasts but have not achieved counts 
< 5%, dose interruptions beyond 28 days are permitted, but require prior discussion with the 
Medical Monitor.  
• If unexplained reductions in serum bicarbonate levels (or CO2 if bicarbonate is not routinely 
measured at the site) to < 20 mmol/L occur, then the azacitidine dose should be reduced by 
50% for all subsequent cycles. 
• If unexplained elevations of urea/BUN or serum creatinine to ≥ 2-fold above baseline values 
and above ULN occur, then the next cycle should be delayed until values return to normal or 
baseline, and the azacitidine dose should be reduced by 50% for all subsequent cycles. 
• When a QT prolongation is observed for the first time, the patient should be followed with 
additional ECGs as determined by the Investigator.  All study drugs should be held until QT 
returns to baseline in patients who develop any of the following, unless there is a clear 
alternative cause for the changes: 
o Sustained (at least two ECG measurements, approximately 30 minutes apart) QTcF that 
is ≥ 500 ms and/or > 60 ms longer than the baseline value. 
o New ECG finding of clinical concern. 


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Study drugs may be resumed, provided that any ECG abnormalities have been resolved, and 
underlying causes have been addressed, the patient remains clinically stable and is appropriately 
monitored.  Clinical judgment should be applied. 
6.5.2 
Dosage Adjustments of Study Drugs 
Subjects will receive one course of therapy during every 28-day cycle.  The Medical Monitor 
will review with the Investigator any decision to reduce or discontinue either of the study drugs 
(pracinostat or azacitidine). 
In the presence of toxicity, azacitidine dose reduction must be implemented according to its 
package insert or local standards of care.  Azacitidine dose reduction is not allowed in Cycle 1 
but may be implemented in Cycle 2, if deemed clinically necessary. 
If after Cycle 4 the subject experiences continued toxicity despite azacitidine dose reduction, 
then the schedule of pracinostat administration may be reduced as presented in Table 1.  Please 
discuss with the Medical Monitor before reducing the dose of pracinostat from 3 to 2 weeks per 
cycle. 
Table 1 
Pracinostat Dose Level Modifications 
Dose Level 
Pracinostat 
Starting Dose 
45 mg administered orally once a day, 3 days each week (e.g., Monday, Wednesday, 
Friday) for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles 
Dose Level -1 
45 mg administered orally once a day, 3 days each week (e.g., Monday, Wednesday, 
Friday) for 2 consecutive weeks, followed by 2 weeks of rest, in 28-day cycles 
7 STUDY DRUG  
7.1 
Study Drug 
Investigational Product 
Dosage Form and Strength 
Pracinostat  
45-mg capsules 
7.1.1 
Study Drug Labeling, Packaging, and Supply 
Pracinostat 45-mg capsules will be supplied by MEI Pharma. 
All study drugs must be kept in a secure place under appropriate storage conditions.  Pracinostat 
capsules should be stored at controlled room temperature, 20 – 25°C (68 – 77°F) with excursions 
allowed between 15 – 30°C (59 – 86°F). 
7.1.2 
Preparation and Administration of Study Drug 
No preparation of pracinostat is necessary. 
Details of pracinostat administration are provided in Section 3.1.1. 


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7.1.3 
Accountability of Study Drug 
The Investigator (or designee) is responsible for accountability of all used and unused study 
medication supplies at the site. 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
All study drug inventories must be made available for inspection by the monitor, the Sponsor 
(or its designees), and regulatory agency inspectors upon request. 
At the end of the study, study drug will be returned to the Sponsor (or designee) or destroyed.  
Study drug must not be destroyed unless prior approval has been granted by the Sponsor or its 
representative. 
7.1.4 
Precautions and Risks Associated with the Study Drug 
Precautions and associated risks with pracinostat 
Hematologic 
Treatment with pracinostat has been associated with cytopenias including 
anemia, thrombocytopenia, and neutropenia.  The incidence of cytopenias may 
increase with increasing doses of pracinostat.  Subjects participating in clinical 
studies of pracinostat should be monitored closely for adverse hematologic 
affects. The effect of dose reduction on the amelioration of cytopenias has not 
been established, however prudent clinical management, including supportive 
care (appropriate use of transfusions and/or hematopoietic growth factors) and 
dose modification or discontinuation should be followed (see Section 6.5). 
Gastrointestinal 
Gastrointestinal disturbances (including nausea, vomiting, and diarrhea) have 
been reported in subjects treated with pracinostat.  Standard antiemetic 
and antidiarrheal medications and appropriate supportive care should be used per 
normal clinical practice in subjects participating in clinical studies of pracinostat.  
Preexisting nausea, vomiting, and diarrhea should be adequately controlled 
before beginning therapy. 
QTc Prolongation/Cardiac 
Asymptomatic QTc interval prolongation has been observed during clinical 
studies of pracinostat.  Subjects with a CTCAE Grade 2 prolonged QTc interval 
during screening will not be permitted to participate in clinical studies of 
pracinostat.  Hypokalemia or hypomagnesemia should be corrected prior to 
pracinostat administration and consideration should be given to monitoring 
potassium and magnesium in symptomatic subjects (e.g., subjects with nausea, 
vomiting, diarrhea, fluid imbalance, or cardiac symptoms).  See the 
Investigator’s Brochure for additional information on QTc prolongation. 
Concomitant medications with a known risk of prolonging the QT interval and/or 
causing Torsades de Pointes are prohibited.  In addition, caution should be taken 
when using concomitant medications with a possible or conditional risk of 
prolonging the QT interval and/or causing Torsades de Pointes; medications with 
a possible or conditional risk may be used at the discretion of the Investigator 
(Appendix H). 


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Precautions and associated risks with pracinostat 
General Signs and Symptoms 
Fatigue has been the most common AE reported in subjects receiving pracinostat 
and has frequently prompted dose reduction in subjects receiving > 60 mg/day.  
Anorexia has also been commonly reported.  Subjects experiencing debilitating 
fatigue or anorexia with weight loss may benefit from dose reduction or 
interruption of pracinostat treatment.  Related SAEs of febrile neutropenia 
fatigue, and pneumonia have been reported.  Disturbances of the GI tract, 
including nausea, vomiting, and diarrhea, have been reported in patients treated 
with pracinostat. In the Phase II study of pracinostat + azacitidine in AML, 
nausea, diarrhea and vomiting were among the most frequently reported 
manifestations of GI toxicity, with most cases graded as 1 or 2.  Standard 
antiemetic and antidiarrheal medications and appropriate supportive care should 
be used per normal clinical practice.  Pre-existing nausea, vomiting, and diarrhea 
should be adequately controlled before starting study drug. 
Please refer to the IB for detailed information on the risks associated with the use of pracinostat. 
7.2 
Azacitidine 
Azacitidine is to be administered in accordance with the terms of its marketing authorization 
and/or in accordance with local standards of care.  Please refer to the approved Prescribing 
Information for detailed information on how to prepare and administer azacitidine. 
7.2.1 
Azacitidine Labeling, Packaging, and Supply 
Where applicable, each site will procure a supply of azacitidine, which is commercially 
available. 
All study medications must be kept in a secure place under appropriate storage conditions.  
Refer to the approved Prescribing Information for azacitidine storage conditions.  The expiration 
date on the label must not be exceeded. 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
7.2.2 
Preparation and Administration of Azacitidine 
Azacitidine is to be prepared and administered in accordance with the terms of its marketing 
authorization or in accordance with local standards of care.  For those sites unable to administer 
azacitidine according to the recommended administration schedule (for 7 consecutive days), a 
5-2-2 administration scheme (5 consecutive days, 2 rest days, and the first 2 days of the 
following week) is acceptable.  Azacitidine should be administered at approximately the same 
time each day.  Each Investigator will declare preference as to which schedule is preferred for a 
subject and use that schedule throughout the study for this subject. 


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7.2.3 
Precautions and Risks Associated with Azacitidine 
Common risks associated with azacitidine administration 
Anemia, neutropenia, and thrombocytopenia  
Perform CBCs prior to each treatment cycle and as needed to 
monitor response and toxicity. 
Hepatotoxicity 
Use with caution in subjects with severe preexisting liver 
impairment. 
Renal abnormalities 
Monitor subjects with renal impairment for toxicity since 
azacitidine and its metabolites are primarily excreted by the 
kidneys. 
Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle. 
Please refer to the approved Prescribing Information for detailed information on the risks 
associated with the use of azacitidine. 
8 CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded from the first study drug administration until 30 days 
after the last study drug administration, or until new treatment for MDS is started. 
8.1 
Permitted Concomitant Medications 
Premedication with antiemetics is allowed according to standard practice guidelines and/or local 
standards of care.  
Prophylaxis with quinolone antibiotics is permitted per local standards of care. 
Caution should be taken in concomitant administration of the following: 
• Fibrinolysis inhibitors 
• Anticoagulant and antiplatelet drugs 
Other medications considered necessary for subject safety and well-being may be given at the 
discretion of the Investigator with the exception of those listed in Section 8.2. 
8.2 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
• No other investigational therapy should be given to subjects. 
• No anticancer agents should be administered to subjects.  If such agents are required, 
the subject must first be withdrawn from the study. 
• HDAC inhibitors (Zolinza [vorinostat], Istodax [romidepsin/depsipeptide]) or valproic 
acid (which has significant action as a HDAC inhibitor). 


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• Medications with a known risk of prolonging the QT interval and/or causing Torsades de 
Pointes. 
• Herbal preparations (e.g., St John’s wort) are not allowed throughout the study.  Subjects 
must discontinue herbal medications at least 7 days prior to the first dose of study 
treatment. 
• Patients should avoid grapefruits, grapefruit juice, and Seville oranges during the study 
since they are known to be inhibitors of CYP3A4. 
• Smoking or vaporizing of tobacco or cannabis-related products is prohibited.  These 
products must be discontinued at least 8 days prior to the first dose of study treatment. 
[Note: Nicotine gum or patches are allowed, as is chewing tobacco].    
• Prophylactic G-CSF may be used only in subjects with a treatment-emergent AE of 
febrile neutropenia while on study, or in subjects with persistent (> 5 days) Grade 4 
neutropenia who are at high risk for development of febrile neutropenia. 
8.3 
Medications/Agents Affecting Metabolism via Cytochrome P450 
Limited clinical information is available on drug interactions for pracinostat.  Pracinostat is a 
substrate of cytochrome P450 1A2 (CYP1A2), cytochrome P450 2C8 (CYP2C8) and 
cytochrome P450 3A4 (CYP3A4).  Caution in use of pracinostat is required with drugs that 
inhibit 3A4 and 2C8 or induce CYP1A2, 2C8 and 3A4 (see Study PRAN-17-14 [Investigator’s 
Brochure]).  Lists of 3A4 and 2C8 inhibitors and 1A2, 2C8 and 3A4 inducers are provided in 
Appendix I. 
Smoking results in CYP1A2 induction and has been shown to decrease pracinostat Cmax and 
AUC by approximately 60%.  Therefore, current smokers are excluded from the study. 
9 STATISTICAL PLAN 
9.1 
Sample Size 
Approximately 60 subjects evaluable for efficacy will be enrolled: approximately 40 in Stage 1 
and 20 in Stage 1b.  Non-evaluable subjects will be replaced. 
9.1.1 
Sample Size Calculation for Stage 1 
The goal of Stage 1 is to establish if this pracinostat + azacitidine regimen achieves 
a discontinuation rate of approximately ≤ 10% in the first 3 cycles of therapy, a rate comparable 
to that achieved in the azacitidine + placebo group in Study MEI-003.  The 95% CI approach is 
utilized to estimate the sample size in Stage 1.  The number of subjects to be enrolled is 
calculated such that the lower bound of the 95% CI of the discontinuation rate will be no more 
than 12% lower than the point estimate of 22.5%, the midpoint between the discontinuation rates 
in the azacitidine + placebo (10%) and azacitidine + pracinostat (32%) groups, respectively, 
in Study MEI-003.  


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With a sample size of 40 subjects, the study will be stopped if ≥ 9 subjects (22.5%, 95% CI: 
10.8–38.4%) discontinue in the first 3 cycles.  Under this scenario, the lower bound of the 95% 
CI is > 10 % (above the pre-specified desired goal) and the upper bound of the 95% CI is > 32% 
(higher than the discontinuation rate in study MEI-003).  
It is also possible to conclude that the desired threshold of a discontinuation rate of ≤ 10% has 
been achieved with fewer than 40 subjects treated in Stage 1.  For example, if 4 discontinuations 
are observed in the first 32 subjects, the lower and upper bounds of the 95% CI around the 
observed discontinuation rate of 12.5% (4 of 32) are 3.5% and 29.0%, lower than reported with 
azacitidine/placebo and azacitidine/pracinostat, respectively, in Study MEI-003.  This would 
justify expanding enrollment to Stage 1b of the study after only 32 subjects have been treated for 
≥ 3 cycles.  
In addition to the discontinuation threshold, an observed ORR of ≥ 20% will be desired to 
support opening Stage 1b of the study because it is expected that azacitidine alone results in an 
ORR of approximately 20% in high/very high-risk MDS. 
The study’s Independent Data Monitoring Committee (IDMC), in coordination with the Sponsor, 
will determine when enrollment in Stage 1 can be concluded, and whether to open enrollment in 
Stage 1b. 
9.1.2 
Total Sample Size Calculation  
This study is intended to provide preliminary efficacy information to serve as a basis for a 
subsequent confirmatory study.  Published studies have reported an ORR of approximately 25% 
(range 20-32%) with azacitidine alone in higher risk MDS (Fenaux 2009, Prebet 2014, 
Sekeres 2014).  An ORR of 40% with pracinostat plus azacitidine will be considered as clinically 
meaningful improvement compared to azacitidine alone.  With a sample of 60 subjects, the lower 
bound of the 95% CI of an observed ORR of 45% is 27.6%, higher than the expected ORR with 
azacitidine alone, and will support continued evaluation of pracinostat plus azacitidine in a larger 
study in higher risk MDS.  Table 2 lists the lower bound of the 95% CI for a range of ORR and 
indicates that a sample of 60 subjects is informative for future development and shows that 
doubling the sample size to 120 subjects will only increase the precision of the 95% CI by 
approximately 4%. 
Table 2 
Lower Bound of the 95% Confidence Interval for a Range of Overall 
Response Rate 
 
Lower Bound 95% CI of ORR 
ORR 
N = 60 
N = 120 
50% 
36.8 
40.7 
45% 
32.1 
35.9 
40% 
27.6 
31.2 
35% 
23.1 
26.5 
30% 
18.9 
22.0 
CI = confidence interval; ORR = overall response rate. 


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9.2 
Analysis Populations 
The primary efficacy analysis will be conducted using the ITT population, which is defined as all 
treated subjects.  Exploratory analyses will be performed for the Per-Protocol population, defined 
as subjects who received at least 2 cycles of therapy and a follow-up bone marrow assessment. 
The Safety population, defined as all subjects who have been treated, will be used for the safety 
analysis.   
9.3 
Statistical Analysis 
All analyses will be descriptive.  Binomial variables will be presented as frequency and 95% CI.  
Continuous variables will be presented as median, mean, range, and 95% CI.  Time-to-event 
endpoints will be analyzed according to the method of Kaplan-Meier.   
Primary and exploratory analyses will be performed as described in detail in the study Statistical 
Analysis Plan. 
9.3.1 
Efficacy Analysis Endpoints 
Efficacy endpoints include: 
• Overall response rate (ORR), defined as the proportion of subjects with confirmed CR 
and PR according to the IWG criteria. 
• Complete remission (CR) rate, defined as the proportion of subjects with confirmed CR 
(i.e., 2 CRs at least 28 days apart) according to the IWG criteria.  Subjects who are not 
evaluable for response for any reason at or before the Cycle 6 response assessment will 
be considered as not achieving CR. 
• Overall HI rate, defined as the proportion of subjects who demonstrate major 
hematologic improvement as defined by the IWG criteria.  Only subjects with pre-
treatment abnormal values will be considered for this endpoint at 8 weeks. 
• Clinical benefit rate (CBR), defined as the proportion of subjects with confirmed CR, PR, 
Marrow CR, and HI.  All patients who achieve hematologic CR, PR, marrow CR, or HI 
on the erythrocytic lineage (HI-E) per modified IWG response criteria will be considered 
responders.  
• Rate of cytogenic complete response/remission, defined as the proportion of subjects with 
confirmed CR by cytogenetic assessment. Complete cytogenetic response is defined per 
modified IWG response criteria. 
• Duration of response (DoR), for subjects who have achieved CR, PR, Marrow CR, 
or HI), defined as the time from the initial determination of response to the time of 
disease progression or death on study, whichever occurs first.  For subjects who are alive 
and have not experienced disease progression on study (prior to receiving 


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subsequent/new treatment or stem cell transplant), duration of response will be censored 
at the day of the last disease assessment. 
• Rate of leukemic transformation, defined as transformation at landmark time points of 
6 months, 12 months, 18 months, and 24 months. 
• Event-free survival (EFS), defined as the time from the first day of study drug 
administration (Day 1) to failure or death from any cause.  Subjects who are alive and 
free from disease progression will be censored at the date of last disease assessment. 
• Progression-free Survival (PFS), defined as the time from the first day of study drug 
administration (Day 1) to disease recurrence or progression as defined by the IWG 
criteria, or death on study.  Subjects who are alive and free from disease progression will 
be censored at the date of last disease assessment. 
• Overall survival (OS), defined as the time from the first day of study drug administration 
(Day 1) to death on study.  Subjects who are alive will be censored at the date of last 
disease evaluation. 
9.3.2 
Safety Analysis Endpoints 
Safety endpoints will include the incidence of treatment-emergent AEs (TEAEs), characterized 
and graded using NCI CTCAE v4.03, and changes in laboratory results, ECG findings, physical 
examinations, vital signs, and ECOG performance status. 
Safety will be assessed through the analysis of the reported incidence of TEAEs, including 
SAEs, dose-limiting toxicities, AEs leading to withdrawal, events of at least CTCAE Version 
4.03 Grade 3 in severity, and AEs related to study drug.  Treatment-emergent AEs are those with 
an onset on or after the initiation of therapy.  Other safety endpoints include laboratory results, 
ECG findings, physical examinations, vital signs, and changes in ECOG performance status.  A 
copy of CTCAE Version 4.03 scoring system may be downloaded from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  
Adverse events will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
coding terms, system organ class, and preferred term for all subjects in the Safety population.  
The AEs will also be tabulated by maximum severity and relationship to study drug where 
applicable.  Other safety endpoints, including laboratory results, vital signs, and shifts in ECG 
findings, will be summarized for all subjects in the Safety population.  AESIs will be presented 
also in specific summary table(s) and listing(s). 
Concomitant medications will be coded using the WHO-Drug Dictionary and they will be listed 
and summarized. 
The rate of discontinuation, defined as the number of subjects who discontinue study drugs prior 
to study completion divided by the number of subjects treated, will be calculated for all subjects 
and for subjects who complete Cycle 3 and Cycle 6. 


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9.4 
Independent Data Monitoring Committee 
An IDMC will be set up for this study to ensure:  
• protection of the subjects 
• the study is conducted according to ethical standards 
• the safety of the study treatments is reviewed independently during the course of the 
study  
The IDMC will meet at intervals that it determines, for the review of data for safety trending; the 
IDMC will recommend continuing, modifying, or stopping the study following each review of 
safety data.  In addition, the IDMC will advise the Sponsor whether to proceed into Stage 1b of 
the study.  
The IDMC will have a consultative role with respect to the Sponsor and/or its representative.  
The Sponsor or its representative will make the final decision regarding the recommendation 
proposed by the committee.  A separate IDMC charter will detail the activities of this committee. 
10 ETHICS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the ICH E6 Tripartite Guideline, applicable government regulations, 
institutional research policies and procedures, and any other local applicable regulatory 
requirements. 
10.1 Informed Consent 
The patient must willingly consent after they have been informed of the procedures to be 
followed, the experimental nature of the treatment, potential benefits, alternatives, side-effects, 
risks and discomforts.  Human protection committee approval of this protocol and consent form 
is required.  Eligible patients who wish to participate in the study will be enrolled. 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study, including 
the procedures to be followed, the experimental nature of the treatment, potential benefits, 
alternatives, side-effects, risks, and discomforts that are relevant to the subject’s decision to 
participate.  Informed consent is documented by means of a written, signed, and dated informed 
consent form. 
The protocol and informed consent form (ICF) will be submitted for approval to the human 
protection committee or equivalent that are responsible for review and approval of the study.  
Each ICF must include all of the relevant elements currently required by the FDA, as well as any 
local county authority, state regulations, and national requirements. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the research study.  Once the essential information has been provided, and the Investigator is 


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confident that the prospective subject understands the implications of participating in this 
research study, the prospective subject will be asked to give consent to participate in the study by 
signing the ICF.  A notation that the subject was given a full explanation of the study, was given 
ample opportunity to ask questions, and a copy of the ICF which includes the subject’s signature 
was given to the subject, must be made in the subject’s medical record. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
subjects, the subject’s consent to continue participation in the study should be obtained. 
10.2 Institutional Review Board (IRB)/Ethics Committee (EC) 
The protocol, ICF, IB, available safety information, subject documents (e.g., study diary), subject 
recruitment procedures (e.g., advertisements), information about payments (i.e., Investigator 
payments), compensation available to the subjects, and documentation evidencing the 
Investigator’s qualifications should be submitted to the IRB/EC for ethical review and approval 
prior to the study start. 
The Investigator, Sponsor, and/or their designees will follow all necessary regulations to ensure 
appropriate, initial, and ongoing IRB/EC review.  The Investigator/Sponsor (as appropriate) must 
submit and, where necessary, obtain approval from the IRB/EC for all subsequent protocol 
amendments and changes to the ICF. 
Safety updates for pracinostat will be prepared by the Sponsor, or its representatives, as required 
for submission to the relevant IRB/EC. 
10.3 Confidentiality 
10.3.1 
Subject Confidentiality 
Confidentiality of subjects’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and subsequent amendments in 
the US and national data protection laws.  HIPAA regulations require that, in order to participate 
in the study, a subject must sign an authorization stating that he or she has been informed of the 
following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, 
and that if the information is disclosed the information may no longer be protected by 
federal or state privacy laws 
• The information collected about the research study will be kept separate from the 
subject’s medical records, but the subject will be able to obtain the research records after 
the conclusion of the study 


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• Whether the authorization contains an expiration date 
• The rights of a research subject to revoke his or her authorization. 
• In the event that a subject revokes authorization to collect or use his or her PHI, the 
Investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of subject authorization.  For subjects that have revoked authorization to 
collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e., that the subject is alive) at the end of their scheduled study period. 
• In compliance with ICH GCP guidelines, it is a requirement that the Investigator 
and institution permit authorized representatives of Sponsor, the regulatory authorities 
and the IRB/EC direct access to review the subject’s original medical records at the site 
for verification of study-related procedures and data. 
• Measures to protect confidentiality include:  
 only a unique study number will identify subjects in the CRF or other documents 
submitted to the Sponsor or its representative.  This information will be used in the 
database for identification. 
 subject names or addresses will not be entered in the CRF. 
 no material bearing a subject’s name will be kept on file by the Sponsor or its 
representative. 
 subjects will be informed of their rights within the ICF.  
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Study Termination 
Study termination is defined as the time when all study treatments, study related-assessments, 
and study data collection are completed.  Upon termination of the study, the Sponsor or designee 
will conduct site closure activities with the Investigator or site staff (as appropriate), in 
accordance with applicable regulations and the study manuals and documents. 
The Sponsor or designee reserves the right to temporarily suspend or terminate the study at any 
time for reasons including, but not limited to, safety issues or ethical reasons.  The Sponsor or 
designee will also promptly inform the relevant regulatory authorities of the 
suspension/termination along with the reasons for such action, when applicable.  Where required 
by applicable regulations, the Investigator or head of the medical institution must inform the 
IRB/EC. 
11.2 Study Documentation and Storage 
The Investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated study duties and should ensure that all persons assisting in the conduct of the study are 
informed of their obligations.  All persons authorized to make entries and/or corrections are to be 


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included on this document.  All entries in the subject’s CRF are to be supported by source 
documentation. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations and activities from which the subject’s CRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Investigator and each study staff member is responsible for maintaining a comprehensive 
and centralized filing system (Site Study File [SSF] or Investigator Site File [ISF]) of all 
study-related (essential) documentation, suitable for inspection at any time by representatives 
from the Sponsor (or its designees) and/or applicable regulatory authorities.  The ISF/SSF must 
consist of those documents that individually or collectively permit evaluation of the conduct of 
the study and the quality of the data produced.  The ISF/SSF should contain, at a minimum, all 
relevant documents and correspondence as outlined in ICH GCP Section 8 and Title 21 of the 
Code of Federal Regulations (21 CFR) Part 312.57, including key documents such as the IB, 
protocol, including amendments, and signed ICFs, copies of completed CRFs, IRB approval 
documents, Financial Disclosure forms, subject identification lists, enrollment logs, delegation of 
authority log, staff qualification documents, laboratory normal ranges, and records relating to the 
study medication, including accountability records.  Drug accountability records should, at a 
minimum, contain information regarding receipt, shipment, and disposition.  Each form of drug 
accountability record, at a minimum, should contain Investigator name, date drug 
shipped/received, date, quantity, and batch/code/ lot number.  In addition, all original source 
documents supporting entries in the CRF must be maintained and readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by the FDA; or, in the event that the marketing application has not 
been approved by the FDA, for no less than 2 years after the last shipment/delivery of the drug 
for investigational use is discontinued and the FDA has been notified of the discontinuation. 
The IRB/EC shall maintain adequate documentation of IRB/EC activities as per 21CFR 
Part 56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by the FDA; or, in the event that the marketing 
application has not been approved by the FDA, for no less than 2 years after the last 
shipment/delivery of the drug for investigational use is discontinued and the FDA has been 
notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating subjects (sufficient information to link records [e.g., CRFs, EDC records, 
and medical records]), all original, signed ICFs, and copies of all CRFs, EDC records, SAE 


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reporting forms, source documents, detailed records of treatment disposition, and related 
essential regulatory documents.  The documents listed above must be retained by the Investigator 
for as long as needed to comply with national and international regulations (generally 2 years 
after discontinuing clinical development or after the last marketing approval).  The Sponsor or its 
representative will notify the Investigator(s)/institutions(s) when the study-related records are no 
longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
or its designee should be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another Investigator, another institution, or to the Sponsor or its 
representative.  The Investigator must obtain from the Sponsor or its representative written 
permission before disposing of any records, even if retention requirements have been met. 
11.3 Data Collection 
The study CRF is the primary data collection instrument for the study.  All CRFs will be 
completed using the English language and should be kept current to enable the Sponsor or its 
representative to review the subjects’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, and subject number will identify 
a subject in the CRF.  If a subject’s name appears on any other document (e.g., laboratory 
report), it must be obliterated on the copy of the document and replaced instead with the subject 
number.  The Investigator will maintain a personal subject identification list (subject numbers 
with corresponding subject identifiers) to enable records to be identified and verified as 
authentic. 
Subject data/information will be kept confidential and will be managed according to applicable 
local, state, and federal regulations. 
All data requested on the CRF must be supported by, and consistent with, the subject’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an ‘unknown’ box is not an option on the CRF, 
a note should be created verifying that the field was “not done” or “unknown”.  For any data 
entry error(s) made, the error(s) must be corrected, and a note explaining the reason for change 
should be provided. 
Once all data for that subject is final, the Investigator will sign and date the subject CRF 
indicating that the data in the CRF has been assessed.  
11.4 Study Monitoring, Auditing, and Inspections 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor, or its designee. 
11.5 Quality Assurance and Quality Control 
Each study site is required to have Standard Operating Procedures (SOPs) to define and ensure 
quality assurance/control processes for study conduct, data generation and collection, recording 


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of data/documentation and reporting according to the protocol, GCP, and any applicable local, 
national, or international regulations. 
11.6 Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, is confidential.  The Sponsor or its representative reserves the 
right to release literature publications based on the results of the study.  Results from the study 
will be published/presented as per the Sponsor or its representative’s publication strategy.  
The financial disclosure information will be provided to the Sponsor or its representative prior to 
study participation from all Investigators and Sub-Investigators who are involved in the study 
and listed on Form FDA-1572. 
The study will be listed on www.clinicaltrials.gov and other registries, as appropriate. 


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12 REFERENCES 
Abaza YM, Kadia TM, Jabbour EJ, et al.  Phase 1 dose escalation multicenter trial of pracinostat 
alone and in combination with azacitidine in patients with advanced hematologic malignancies. 
Cancer. 2017; 123 :4851-4859. 
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20): 2391-2405. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification 
of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 
108(2): 419-425. 
The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994: 253-256. 
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of 
conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a 
randomized, open-label, phase III study. Lancet Oncol. 2009; 10(3): 223-232. 
Garcia-Manero G, Montalban-Bravo G, Berdeja JG, et al. Phase 2, randomized, double-blind 
study of pracinostat in combination with azacitidine in patients with untreated, higher-risk 
myelodysplastic syndromes. Cancer. 2017; 123(6):994-1002. 
Garcia-Manero G, Atallah E, Khaled SK, Arellano M, et al. Phase 2 study of pracinostat and 
azacitidine in older patients with acute myeloid leukemia (AML) not eligible for induction 
chemotherapy: response and long-term survival benefit. Blood. 2016; 128: Abstract 100. 
Greenberg PL, Cox C, LeBeau MM, et al. International Scoring System for Evaluating Prognosis 
in Myelodysplastic Syndromes. Blood. 1997; 6(March 15): 2079-2088. 
Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for 
myelodysplastic syndromes. Blood. 2012; 120(12): 2454-2465. 
Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007; 128(4): 683-692. 
Karnofsky DA, Abelmann WH, Craver LF, et  al. The use of nitrogen mustards in the palliative 
treatment of carcinoma. Cancer 1948; 1: 634-656. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5: 649-655. 
Prebet T, Gore SD, Esterni B, et al.  Outcome of high-risk myelodysplastic syndrome after 
azacitidine treatment failure. J Clin Oncol. 2011; 29: 3322-3327. 
Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without 
entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplastic-


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related changes: Results of the US Leukemia Intergroup Trial E1905.  J Clin Oncol. 2014; 32: 
1242-1248. 
Quintás-Cardama A, Kantarjian H, Estrov Z, et al. Therapy with the histone deacetylase 
inhibitor, pracinostat, for patients with myelofibrosis. Leuk Res. 2012a; 36(9): 1124-1127. 
Ramos F, Fernandez-Ferrero S, Suarez D, et al. Myelodysplastic syndrome: a search for minimal 
diagnostic criteria. Leuk Res. 1999;23: 283-290 
Sekeres MA, Othus M, List AF, et al.  A randomized phase II study of azacitidine combined with 
lenalidomide or with vorinostat vs. azacitidine monotherapy in higher risk myelodysplastic 
syndromes (MDS) and chronic myelomonocytic leukemia (CMML): North American Intergroup 
Study SWOG S1117.  Blood. 2014; 124: LBA-5. 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important 
changes. Blood. 2009; 114: 937-951. 
 


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APPENDIX A 
Schedule of Events 
Assessments/Procedures 
Screeninga 
Treatment Cycles (28 days -4 to + 7 days)b 
 
End of 
Treatme
nt visitq 
Follow-upr 
  Day 
 -14 to 0 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
15p 
Day 
22p 
 
Obtain Informed Consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine eligibilityd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, including recent smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion history for 8 weeks prior to first 
study drug administration 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse  
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Smoking assessmentt 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Baseline signs and symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/toxicity assessmentf 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xo 
Xo 
X 
X 
 
X 
 
Concomitant medication review 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
12-Lead ECG in triplicateg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBCi 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
Serum Chemistryh 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
Serum pregnancy test (if applicable)j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration and biopsyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Assess study medication compliancel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
New Treatments and Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense/administer pracinostatl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
--Azacitidine Administration (1-7)m,n 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
--Azacitidine Administration (5-2-2)m,o 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
Abbreviations:  AE = adverse events; CBC = complete blood count; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group. 
 
 
 


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APPENDIX A 
Schedule of Events (Continued) 
 
End of 
Cycle 2b 
End of 
Cycle 6b 
Evidence of 
Disease Progression 
Evidence of 
Hematologic CR 
Prior to 
Transplant 
Response Evaluations 
 
 
 
 
 
CBCi 
X 
X 
X 
X 
X 
Bone marrow aspiration and biopsyk 
X 
X 
X 
X 
X 
Bone marrow aspirate and peripheral blood sample 
for molecular studiesk 
X 
X 
X 
X 
X 
Abbreviations:  CBC = complete blood count.  
 
a 
Screening visit should occur ≤ 14 days before the first study treatment; the Day 1 physical examination and serum chemistry do not need to be repeated if performed within 
7 days prior to Day 1. 
b 
Study visits should occur on a 28-day schedule.  A -4-day to +7-day window is allowed for each clinic visit to accommodate subject request, due to holidays, weekends, 
inclement weather, or other unforeseen circumstances.  Treatment may also be delayed for up to 4 weeks (1 cycle) for toxicity.  Treatment interruption > 4 weeks must be 
discussed first with the Medical Monitor. 
c 
Written informed consent must be obtained prior to any study-required procedure being initiated. 
d 
Inclusion/exclusion criteria must be met prior to enrollment into the study on Cycle 1 Day 1, including IPSS-R score.  NOTE: IPSS in subjects enrolled under Amendment 2 
should also be calculated for comparison with historical data; however, IPSS will not be used to determine eligibility (Appendix C)  
e 
Vital signs to include height (at Screening visit only), weight, blood pressure, resting heart rate, and oral temperature. 
f 
Monitor for AEs each visit and for 30 days after last dose of drug taken on study. 
g 
12-lead ECG performed in triplicate approximately once every 2 to 5 minutes to calculate the QTcF interval.  On Day 1 of Cycle 1, ECGs will be obtained pre-dose, 
pracinostat will be taken, and azacitidine will be administered.  Ninety minutes (± 15 minutes) post pracinostat dosing, triplicate ECGs will be repeated.  Beyond Cycle 1, 
non-triplicate ECGs will be performed as clinically indicated. 
h 
Serum chemistry: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, total protein, albumin, and lactate dehydrogenase (LDH). 
i 
CBC to be obtained with differential and blasts.  A differential is preferred but is only required at the Screening visit and at the end of Cycles 2 and 6, with evidence of disease 
progression, with evidence of hematologic complete response (CR), and prior to transplant if the subject becomes a candidate for transplant.  Ideally, this will be after the 
conclusion of ≥ 4 cycles of therapy.  CBCs are to be performed at the Screening visit (two CBCs ≥ 7 days apart are required within 1 month prior to first study drug 
administration; the second CBC may be obtained on Cycle 1 Day 1 prior to first study drug administration), on Day 1 of each 28-day cycle, on Day 15 and Day 22 of Cycles 1 
and 2 only, at response evaluations and confirmations, the End of Study visit, and with suspicion of disease progression during follow-up. CBC will consist of, at a minimum, 
WBC count with differential, absolute neutrophil count (ANC), lymphocyte count, red blood cell (RBC) count and indices, hemoglobin, hematocrit, platelets, and blast count 
where applicable.  
j 
Serum β-hCG test for women of childbearing potential must be performed within 7 days of first study treatment; urine pregnancy tests may be performed at other visits if 
necessary. 


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APPENDIX A 
Schedule of Events (Continued) 
k 
Bone marrow biopsy (BMBx) and aspirate must be performed within 28 days prior to planned first study treatment.  For response assessments, BMBx and aspirate, including 
classic cytogenetics, FISH (fluorescence in-situ hybridization), and molecular studies* (if these tests were done at baseline), and slides will be collected.  This will occur at the 
end of Cycles 2 and 6; with evidence of hematologic CR, which may occur after Cycle 6; at the end of study (if more than 56 days after last BM assessment); with evidence of 
disease progression; and prior to transplant if the subject becomes a candidate for transplant.  Ideally, transplant will be after the conclusion of ≥ 4 cycles of therapy.  A CBC 
with differential will be required for confirmation of CR or partial response (PR) 8 weeks following the initial report of response.  Once a marrow CR is documented, there is 
no need to repeat a BMBx unless clinically indicated. 
l 
Pracinostat capsules will be dispensed to the subject at the beginning of each cycle.  The capsules are to be taken before azacitidine administration 3 times each week (e.g., 
Monday, Wednesday, and Friday) for 3 weeks, followed by 1 week of rest; this scheme will be repeated for every 28-day cycle.  Following Cycle 1, study medication 
compliance will also be assessed on Day 1 of each cycle.  Subjects will be administered their study medication at the clinic on Day 1 of Cycle 1 and will self-administer at 
home on all other days (see Section 5.2). 
m 
Azacitidine is to be administered at 75 mg/m2 via subcutaneous (SC) injection or intravenous (IV) infusion 7 days of every 28-day cycle at about the same time on each 
administration day. 
n 
Azacitidine administration:  Days 1 through 7 of every 28-day cycle. 
o 
Azacitidine administration:  Days 1 through 5, and Days 8 and 9 of every 28-day cycle.  Days 6 and 7 will be rest days. 
p 
Only Cycles 1 and 2 have a Day 15 and Day 22 visit. 
q 
End of Study evaluations are required no less than 7 days and no more than 30 days after treatment ends (or prior to starting new treatment, if urgent treatment is required).  
End of Study BMBx and aspirate (including cytogenetics, FISH, and molecular studies*, if done at baseline, and slides) are required to be performed if:  a subject 
discontinues due to disease progression without clear evidence of progression by peripheral blood counts, due to an AE, or prior to BM transplant.  This is required if a BMBx 
and aspirate have not been obtained within 56 days prior to study discontinuation.   
r 
After subjects discontinue study drug, they will be followed every 3 months (±1 month) until death or study termination to collect information on progression, any new 
treatments, and survival (e.g., date and cause of death). With suspicion of disease progression, a CBC (including 3-part differential, platelets, and blasts) may be performed 
(optional).  Subjects may be contacted during outpatient visits or by telephone. 
s 
A BMBx and aspirate as well as a CBC with differential will be required at the end of Cycles 2 and 6, with evidence of disease progression, with evidence of hematologic CR, 
and prior to transplant if the subject becomes a candidate for transplant. 
t 
After the Cycle 3 visits, smoking assessments for subjects enrolled under Amendment 1 will only occur at the Day 1 visit of each cycle. 
 
* FISH and molecular tests should only be performed as part of the patient’s standard of care.  


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APPENDIX B: 
World Health Order (WHO) Classifications of MDS 
Name 
Dysplastic 
Lineages 
Cytopenias* 
Ring Sideroblasts 
as % of Marrow 
Erythroid 
Elements 
BM and PB 
Blasts 
Cytogenetics by 
Conventional 
Karyotype Analysis 
MDS with single lineage 
dysplasia (MDS-SLD) 
1 
1 or 2 
< 15%/< 5%† 
BM < 5%, 
PB < 1%, 
no Auer rods 
Any, unless fulfills 
all criteria for MDS 
with isolated del(5q) 
MDS with multilineage 
dysplasia (MDS-MLD) 
2 or 3 
1-3 
< 15%/< 5%† 
BM < 5%, 
PB < 1%, 
no Auer rods 
Any, unless fulfills 
all criteria for MDS 
with isolated del(5q) 
MDS with ring sideroblasts (MDS-RS) 
 
 
 
 
MDS-RS with single 
lineage dysplasia 
(MDS-RS-SLD) 
1 
1 or 2 
≥ 15%/≥ 5%† 
BM < 5%, 
PB < 1%, 
no Auer rods 
Any, unless fulfills 
all criteria for MDS 
with isolated del(5q) 
MDS-RS with multilineage 
dysplasia (MDS-RS-MLD) 
2 or 3 
1-3 
≥ 15%/≥ 5%† 
BM < 5%, 
PB < 1%, 
no Auer rods 
Any, unless fulfills 
all criteria for MDS 
with isolated del(5q) 
MDS with isolated del(5q) 
1-3 
1-2 
None or any 
BM < 5%, 
PB < 1%, 
no Auer rods 
del(5q) alone or with 
1 additional 
abnormality except 
−7 or del(7q) 
MDS with excess blasts (MDS-EB) 
 
 
 
 
MDS-EB-1 
0-3 
1-3 
None or any 
BM 5–9% 
or PB 2–4%, 
no Auer rods 
Any 
MDS-EB-2 
0-3 
1-3 
None or any 
BM 10–19% 
or PB 5–19% 
or Auer rods 
Any 
MDS, unclassifiable (MDS-U) 
 
 
 
 
with 1% blood blasts 
1-3 
1-3 
None or any 
BM < 5%, 
PB = 1%,‡ 
no Auer rods 
Any 
with single lineage 
dysplasia and pancytopenia 
1 
3 
None or any 
BM < 5%, 
PB < 1%, 
no Auer rods 
Any 
based on defining 
cytogenetic abnormality 
0 
1-3 
< 15%§ 
BM < 5%, 
PB < 1%, 
no Auer rods 
MDS-defining 
abnormality 
Refractory cytopenia of 
childhood 
1-3 
1-3 
None 
BM < 5%, 
PB < 2% 
Any 
Abbreviations:  BM = bone marrow; MDS = myelodysplastic syndrome; PB = peripheral blood. 
* Cytopenias defined as: hemoglobin, < 10 g/dL; platelet count, < 100 × 109/L; and absolute neutrophil count, < 1.8 × 109/L. 
Rarely, MDS may present with mild anemia or thrombocytopenia above these levels. PB monocytes must be < 1 × 109/L. 
† If SF3B1 mutation is present. 
‡ One percent PB blasts must be recorded on at least 2 separate occasions. 
§ Cases with ≥ 15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-RS-SLD. 
Reference:  Vardiman 2009, Arber 2016. 


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APPENDIX C: 
Revised International Prognostic Scoring System 
(IPSS-R) for MDS 
Note: IPSS-R scoring is not applicable to CMML-1 and CMML-2 subtypes.  
Sum the scores for each feature: 
 
Score Value 
Prognostic variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Karyotype† 
Very 
Good 
- 
Good 
- 
Intermediate 
Poor 
Very 
Poor 
Marrow blasts (%) 
≤ 2 
- 
> 2 – < 5 
- 
5–10 
> 10 
- 
Hemoglobin (g/dL) 
≥ 10 
- 
8 – < 10 
< 8 
- 
- 
- 
Platelet Count (× 109/L) 
≥ 100 
50 – < 100 
< 50 
- 
- 
- 
- 
Absolute Neutrophil 
Count (× 109/L) 
≥ 0.8 
< 0.8 
- 
- 
- 
- 
- 
† Very Good karyotype = -Y, del(11q);  
Good karyotype = 46XX, 46XY, del(5q), del(12p), del(20q), double including del(5q);  
Intermediate karyotype = del(7q), +8, +19, i(17q), any other single or double independent clones;  
Poor karyotype = -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex with 3 abnormalities;  
Very Poor karyotype = complex with > 3 abnormalities. 
Use the summed scores to determine risk category and prognosis: 
Risk Category 
(% IPSS-R population) 
Overall Score 
Median Survival 
(years) 
Time (years) for 25% of 
Patients to Progress to 
Acute Myeloid Leukemia 
Very Low (19) 
≤ 1.5 
8.8 
Not reached 
Low (38) 
> 1.5 – 3 
5.3 
10.8 
Intermediate (20) 
> 3 – 4.5 
3.0 
3.2 
High (13)* 
> 4.5 – 6 
1.6 
1.4 
Very High (10)* 
> 6 
0.8 
0.73 
* 
Required for eligibility per inclusion criterion #3. (Greenberg 2012) 
 
 


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International Prognostic Scoring System (IPSS) for MDS 
The International Prognostic Scores (IPSS) score will not be used as an inclusion/exclusion 
criterion, however the IPSS will be recorded in all enrolled subjects to facilitate the comparison 
of IPSS scores with prior studies (Greenberg 1997). 
Use the table below to determine the IPSS sum scores. 
IPSS for MDS: Survival and AML Evolution 
 
Score Value 
Prognostic 
Variable 
0 
0.5 
1.0 
1.5 
2.0 
BM Blasts (%) 
< 5 
5 to 10 
— 
11 to 20 
21 to 31 
Karyotypea 
Good 
Intermediate 
Poor 
 
 
Cytopeniasb 
0/1 
2/3 
 
 
 
Scores for risk groups are as follows: Low, 0; INT-1, 0.5 to 1.0; INT-2, 1.5 to 2.0, and High, ≥ 2.5. 
a Good: normal, — Y, del(5q), del(20q); Poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies; 
Intermediate: other abnormalities. 
b Cytopenia is defined as hemoglobin < 10 g/dL, absolute neutrophil count < 1,500/μL, and a platelet count 
< 100,000/μL. 
Source: Greenberg 1997 


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Amendment 2: 25 June 2018 
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APPENDIX D: 
International Working Group (IWG) Response Criteria 
and Modified IWG Response Criteria for 
Hematological Improvement 
Proposed Modified International Working Group Response Criteria for Altering Natural History of MDS 
Category 
Response Criteria (responses must last at least 28 days) 
Complete 
remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted*† 
Peripheral blood‡  
  Hemoglobin ≥ 11 g/dL 
  Platelets ≥ 100 × 109/L  
  Neutrophils ≥ 1.0 × 109/L†  
  Blasts 0% 
Partial remission 
All CR criteria if abnormal before treatment except: 
  Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
  Cellularity and morphology not relevant 
Marrow CR† 
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment†  
Peripheral blood:  if HI responses, they will be noted in addition to marrow CR† 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for > 8 weeks 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, 
increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB 
subtype than pretreatment 
Relapse after CR 
or PR 
At least 1 of the following: 
  Return to pretreatment bone marrow blast percentage 
  Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets 
  Reduction in hemoglobin concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic 
response 
Complete:  Disappearance of the chromosomal abnormality without appearance of new ones  
Partial: At least 50% reduction of the chromosomal abnormality 
Disease 
progression 
For patients with: 
  Less than 5% blasts:  ≥ 50% increase in blasts to > 5% blasts 
  5% – 10% blasts:  ≥ 50% increase to > 10% blasts 
  10% – 20% blasts:  ≥ 50% increase to > 20% blasts 
  20% – 30% blasts:  ≥ 50% increase to > 30% blasts  
Any of the following: 
  At least 50% decrement from maximum remission/response in granulocytes or platelets  
  Reduction in hemoglobin by ≥ 2 g/dL 
  Transfusion dependence 
Survival 
Endpoints: 
  Overall:  death from any cause 
  Event free:  failure or death from any cause 
  PFS:  disease progression or death from MDS 
  DFS:  time to relapse 
  Cause-specific death:  death related to MDS 


MEI Pharma, Inc. 
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Amendment 2: 25 June 2018 
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Page 64 of 70 
Reference:  Cheson 2006. 
Abbreviations:  CR = complete response; DFS = disease-free survival; FAB = French-American-British; MDS = myelodysplastic syndrome; 
PFS = progression-free survival; PR = partial response 
Deletions to IWG response criteria are not shown.  To convert hemoglobin from g/dL to g/L, multiply g/dL by 10. 
* Dysplastic changes should consider the normal range of dysplastic changes (modification) (Ramos et al. 1999) 
† Modification to IWG response criteria. 
‡ In some circumstances, protocol therapy may require the initiation of further treatment (e.g., consolidation, maintenance) before the 
4-week period.  Such patients can be included in the response category into which they fit at the time the therapy is started.  Transient 
cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as long as they recover 
to the improved counts of the previous course. 
 
Modified IWG Response Criteria for Hematological Improvement 
Hematological Improvement* 
Response Criteria (responses must last at least 8 weeks) † 
Erythroid response  
(pretreatment, < 11 g/dL) 
(HI-E) 
Hemoglobin increase by ≥ 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8 weeks compared with the pretreatment 
transfusion number in the previous 8 weeks.  Only RBC transfusions 
given for a hemoglobin of ≤ 9.0 g/dL pretreatment will count in the RBC 
transfusion response evaluation† 
Platelet response  
(pretreatment, < 100 × 109/L) 
(HI-P) 
Absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L 
platelets 
Increase from < 20 × 109/L to > 20 × 109/L and by at least 100%†  
Neutrophil response 
(pretreatment, < 1.0 × 109/L) 
(HI-N) 
At least 100% increase and an absolute increase > 0.5 × 109/L† 
Progression or relapse after HI‡ 
At least 1 of the following: 
• 
At least 50% decrement from maximum response levels in 
granulocytes or platelets 
• 
Reduction in hemoglobin by ≥ 1.5 g/dL 
• 
Transfusion dependence 
Abbreviations:  HI = hematologic improvement; RBC = red blood cell;  
Deletions to the IWG response criteria are not shown. 
To convert hemoglobin levels from g/dL to g/L, multiply g/dL by 10. 
* Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥ 1 week apart (modification). 
† Modification to IWG response criteria. 
‡ In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet responses be 
reported overall as well as by the individual response pattern. 


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Amendment 2: 25 June 2018 
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Page 65 of 70 
APPENDIX E: 
ECOG Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Status Scale 
Score 
Description 
Percent 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, 
no evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
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. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or do normal 
work. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs.  
50 
Requires considerable assistance 
and frequent medical care. 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead 
References:  Oken 1982, Karnofsky 1948. 


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Amendment 2: 25 June 2018 
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APPENDIX F: 
New York Heart Association (NYHA) Classification of 
Cardiac Disease 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Reference:  NYHA 1994. 
 


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APPENDIX G: 
Guidelines for Women of Childbearing Potential 
and Fertile Male Subjects 
Acceptable Contraception Methods: 
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 30 days after stopping 
treatment. 
Highly effective contraception is defined as: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
Sterilization 
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks prior to study entry.  In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment. 
Male Partner Sterilization 
When the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate. 
Use of a combination 
of any two of the following 
(one from a + one from b): 
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or established use of oral, injected, or implanted hormonal methods of 
contraception 
b) Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
Fertile male subjects, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus spermicidal agent during the 
study treatment period and for 30 days after the last dose of study drug, and should not father 
a child during this period. 
Male subjects must also refrain from donating sperm during their participation in the study. 
Unacceptable Contraception Methods:  
Unacceptable contraception methods for women of childbearing potential include: 
• IUD progesterone T 
• Female condom 
• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield 


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Amendment 2: 25 June 2018 
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Page 68 of 70 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported within 
24 hours of learning of its occurrence: refer to the study reference manual for reporting contact 
information.  The pregnancy should be followed up for 3 months after the termination of the 
pregnancy to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on the eCRF and reported by the Investigator.  Pregnancy follow-
up should be recorded and should include an assessment of the possible relationship to the study 
drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not of Childbearing Potential are defined as follows: 
• Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) 
• Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) 
• Women who are > 45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 12 months or who have a follicle 
stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL 
(140 pmol/L) 
• Women who are > 45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year or who have had documented 
evidence of menopause based on FSH > 40 mIU/mL and estradiol < 40 pg/mL prior to 
initiation of hormone-replacement therapy 


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Amendment 2: 25 June 2018 
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Page 69 of 70 
APPENDIX H: 
Drugs that Prolong the QT Interval and/or Induce 
Torsades de Pointes 
Drugs with a Risk of Prolonging the QT Interval and/or Torsades de Pointes  
Amiodarone 
Arsenic trioxide 
Asetemizole 
Azithromycin 
Bepridil 
Chloroquine 
Chlorpromazine 
Cispride 
Citalopram 
Clarithromycin 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Escitalopram 
Flecainide 
Halofantrine 
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine 
Methadone 
Moxifloxacin 
Pentamidine 
Pimozide 
Probucol 
Procainamide 
Quinidine 
Sevoflurane 
Sotalol 
Sparfloxacin 
Terfenadine 
Thioridazine 
Vandetanib 
 
Drugs with a Possible Risk of Prolonging the QT Interval and/or Torsades de Pointes 
Alfuzosin 
Artenimol+piperaquine 
Atazanavir Bedaquiline 
Clozapine 
Dolasetron 
Dronedarone 
Eribulin 
Famotidine 
Felbamate 
Fingolimod 
Foscarnet 
Fosphenytoin 
Gatifloxacin 
Gemifloxacin 
Granisetron 
Iloperidone 
Indapamide 
Isradipine 
Lapatinib 
Levofloxacin 
Lithium 
Mirtazapine 
Moexipril/HCTZ 
Nicardipine 
Nilotnib 
Ofloxacin 
Olanzapine 
Ondansetron 
Oxytocin 
Paliperidone 
Pasireotide 
Perflutren 
Lipid 
Microspheres 
Promethazine 
Quetipine 
Ranolazine 
Risperidone 
Roxithromycin 
Saquinavir 
Sertindole 
Sunitinib 
Tacrolimus 
Tamoxifen 
Telithromycin 
Tizanidine 
Tolterodine 
Vardenafil 
Venlafaxine 
Voriconazole 
Ziprasidone 
 
Drugs with a Conditional Risk of Prolonging the QT Interval and/or Torsades de Pointes  
(Should be used with Investigator discretion) 
Amantadine 
Amisulpride 
Amitriptyline 
Chloral Hydrate 
Ciprofoxacin 
Clomipramine 
Desipramine 
Diphenhydramine 
Doxepin 
Fluconazole 
Fluoxetine 
Galantamine 
Imipramine 
Itraconazole 
Ketoconazole 
Nortriptyline 
Paroxetine 
Protriptyline 
Quinine 
Sulfate 
Ritonavir 
Sertraline 
Solifenacin 
Trazodone 
Trimethoprim-Sulfa 
Trimipramine 
The following website was used as a guide for drugs which may prolong the QT interval: 
https://www.crediblemeds.org.  Medications listed on the website which do not appear in this appendix may be 
used at the discretion of the Investigator. 
 


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Amendment 2: 25 June 2018 
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Page 70 of 70 
APPENDIX I: 
Substrates of CYP1A2, CYP2B6 and CYP3A4  
For the complete list please refer to source: FDA website - Drug Development and Drug 
Interactions:  Table of Substrates, Inhibitors and Inducers (Sep 26th, 2016). 
Examples of CYP1A2 substrates 
 
Sensitive substrates 
Moderate sensitive substrates 
CYP1A2 
alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tasimelteon, theophylline, 
tizanidine 
clozapine, pirfenidone, ramosetron 
Examples of CYP2B6 substrates 
 
Sensitive substrates 
Moderate sensitive substrates 
CYP2B6 
bupropion 
efavirenz 
Examples of CYP3A4 substrates 
 
Sensitive substrates 
Moderate sensitive substrates 
CYP3A4 
alfentanil, avanafil, buspirone, conivaptan, 
darifenacin, darunavir, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatin, midazolam, 
naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus, tipranavir, 
triazolam, vardenafil, budesonide, dasatinib, 
dronedarone, eletriptan, eplerenone, 
felodipine, indinavir, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
alprazolam, aprepitant, atorvastatin, 
colchicine, eliglustat, pimozide, rilpivirine, 
rivaroxaban, tadalafil 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
MEI Pharma, Inc. 
Protocol MEI-011 
                                                                                                               
 
 
Page 1 of 30 
 
   
 
 
DOCUMENT: 
Statistical Analysis Plan 
PROTOCOL: 
MEI-011 
 A Two-Stage, Open-Label Phase 2 Study of Pracinostat and 
Azacitidine in Patients with IPSS-R High and Very High Risk 
Myelodysplastic Syndromes Previously Untreated with 
Hypomethylating Agents  
SAP VERSION: 
3.0 
SAP DATE:  
 28 August 2020 
PROTOCOL DATE: Original:   
14 December 2016 
 
 
 
Amendment 1:  27 January 2017 
 
 
 
Amendment 2:  25 June 2018 
 
 
 
 
 
SPONSOR: 
 
MEI Pharma, Inc. on behalf of Helsinn Healthcare 
PREPARED BY: 
Clinipace Worldwide 
AUTHOR: 
 
Barbara Collins, BSc PhD  
 
 
 
 
Senior Biostatistician, US Biostatistics 
 
 
 
Clinipace Worldwide 
 
 




Statistical Analysis Plan 
 
MEI Pharma, Inc. 
Protocol MEI-011 
                                                                                                               
 
 
Page 3 of 30 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................. 3 
ABBREVIATIONS ..................................................................................................................................... 7 
1 
INTRODUCTION.......................................................................................................................... 8 
2 
STUDY OBJECTIVE(S), TREATMENTS, AND ENDPOINT(S) ............................................ 8 
2.1 
Study Objectives ............................................................................................................................ 8 
2.1.1 
Primary Objectives ........................................................................................................................ 8 
2.1.2 
Secondary Objectives..................................................................................................................... 8 
2.2 
Treatment Groups ......................................................................................................................... 8 
2.3 
Study Endpoints and Evaluations ................................................................................................ 9 
2.3.1 
Primary Endpoints......................................................................................................................... 9 
2.3.2 
Secondary Endpoints ..................................................................................................................... 9 
3 
STUDY DESIGN .......................................................................................................................... 11 
3.1 
Overall Study Design ................................................................................................................... 11 
4 
SAMPLE SIZE CONSIDERATIONS ....................................................................................... 11 
4.1 
Sample Size Determination for Stage 1 ...................................................................................... 11 
4.2 
Total Sample Size Determination ............................................................................................... 11 
5 
ANALYSIS POPULATIONS ..................................................................................................... 12 
5.1 
Safety Population ......................................................................................................................... 12 
5.2 
Intent to Treat (ITT) Population ................................................................................................ 12 
5.3 
Efficacy Evaluable (EE) Population ........................................................................................... 12 
5.3 
Per Protocol (PP) Population ...................................................................................................... 12 
6 
CONSIDERATIONS FOR DATA ANALYSIS ........................................................................ 13 
6.1 
Programming Environment ........................................................................................................ 13 
6.2 
Strata and Covariates .................................................................................................................. 13 
6.3 
Subgroups ..................................................................................................................................... 13 


Statistical Analysis Plan 
 
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6.4 
Multiple Comparisons and Multiplicity ..................................................................................... 13 
6.5 
Significance Level......................................................................................................................... 13 
6.6 
Statistical Notation and Methodology ........................................................................................ 13 
7 
DATA HANDLING METHODS ................................................................................................ 13 
7.1 
Visit Windows .............................................................................................................................. 13 
7.2 
Date Values ................................................................................................................................... 14 
7.3 
Other Missing Values .................................................................................................................. 14 
7.4 
Data Derivations .......................................................................................................................... 14 
8 
STUDY POPULATION .............................................................................................................. 15 
8.1 
Subject Enrollment ...................................................................................................................... 15 
8.2 
Subject Disposition....................................................................................................................... 15 
8.3 
Protocol Deviations ...................................................................................................................... 15 
8.4 
Inclusion/Exclusion Criteria ....................................................................................................... 16 
8.5 
Demographic and Baseline Characteristics ............................................................................... 16 
8.6 
Prior Therapies ............................................................................................................................ 16 
8.6.1 
Prior and Concomitant Transfusion Therapy........................................................................... 16 
8.6.2 
Prior and Concomitant Stem Cell Transplant Therapy ........................................................... 16 
8.6.3 
Prior MDS Therapy ..................................................................................................................... 16 
8.7 
Medical History ............................................................................................................................ 16 
9 
EFFICACY ANALYSIS .............................................................................................................. 17 
9.1 
Primary Endpoint Analysis ......................................................................................................... 18 
9.2 
Secondary Endpoint Analysis ..................................................................................................... 18 
9.2.1 
Clinical Response ......................................................................................................................... 18 
9.2.1.1 Complete Response (CR) rate ..................................................................................................... 19 
9.2.1.2 Overall hematologic improvement (HI) response rate ............................................................. 19 
9.2.1.3 Clinical Benefit rate (CBR) ......................................................................................................... 19 


Statistical Analysis Plan 
 
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Protocol MEI-011 
                                                                                                               
 
 
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9.2.1.4 Cytogenetic Complete Response/Remission rate ...................................................................... 19 
9.2.1.5 Leukemic Transformation rate .................................................................................................. 19 
9.2.2 
Time-to-Event Endpoints ............................................................................................................ 19 
9.2.2.1 Duration of Response (DOR) ...................................................................................................... 19 
9.2.2.2 Event Free Survival (EFS) .......................................................................................................... 20 
9.2.2.3 Progression-Free Survival (PFS) ................................................................................................ 20 
9.2.2.4 Overall Survival (OS) .................................................................................................................. 20 
10 
SAFETY ANALYSIS................................................................................................................... 20 
10.1 
Data Monitoring Committee ....................................................................................................... 21 
10.1 
Adverse Events ............................................................................................................................. 21 
10.3 
Extent of Exposure ....................................................................................................................... 21 
10.4 
Compliance ................................................................................................................................... 22 
10.5 
Prior and Concomitant Medications .......................................................................................... 22 
10.6 
Laboratory Evaluations............................................................................................................... 23 
10.7 
Vital Signs ..................................................................................................................................... 23 
10.8 
Pregnancy Test ............................................................................................................................. 23 
10.9 
Electrocardiograms (ECG) ......................................................................................................... 23 
10.10 Physical Examinations ................................................................................................................. 23 
10.11 ECOG Performance Status ......................................................................................................... 23 
10.12 Bone Marrow Assessment ........................................................................................................... 24 
11 
OTHER ANALYSES ................................................................................................................... 24 
11.1 
Correlative/Pharmacodynamics Analysis .................................................................................. 24 
11.2 
Interim Analysis ........................................................................................................................... 24 
12 
END OF STUDY ANALYSIS ..................................................................................................... 24 
13 
CHANGES FROM PROTOCOLLED ANALYSIS ................................................................. 24 
14 
REFERENCES ............................................................................................................................. 25 


Statistical Analysis Plan 
 
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Page 6 of 30 
 
15 
TABLE OF CONTENTS FOR TABLES, LISTINGS AND FIGURES REFERRED TO 
BUT NOT PRESENTED IN THE TEXT .................................................................................. 25 


Statistical Analysis Plan 
 
MEI Pharma, Inc. 
Protocol MEI-011 
 
 
 
Page 7 of 30 
 
ABBREVIATIONS 
AE  
 
Adverse event 
CFB 
 
Change from baseline 
CR 
 
Complete response/remission 
CRi 
 
Complete remission with incomplete blood count recovery 
CRF 
 
Case Report Form 
CTCAE  
Common Toxicity Criteria for Adverse Events 
DOR 
 
Duration of response 
ECG 
 
Electrocardiogram 
ECOG 
 
Eastern Cooperative Oncology Group 
EFS 
 
Event free survival 
HI 
 
Hematologic improvement   
IPSS-R  
Revised International Prognostic Scoring System   
IWG 
 
International Working Group 
KM 
 
Kaplan-Meier 
MDS 
 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
 
Maximum Tolerated Dose 
ORR 
 
Overall response rate 
OS 
 
Overall survival 
PD 
 
Progressive Disease 
PFS 
 
Progression Free Survival 
PK 
 
Pharmacokinetic 
PP 
 
Per Protocol  
PR 
 
Partial remission 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SCT 
 
Stem Cell Transplant 
SD 
 
Stable disease  
STD 
 
Standard deviation 
TE 
 
Treatment Emergent 
TEAE 
 
Treatment Emergent Adverse Event 
TESAE  
Treatment Emergent Serious Adverse Event  
WHO 
 
World Health Organization 
 
 
 
 


Statistical Analysis Plan 
 
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Protocol MEI-011 
 
 
 
Page 8 of 30 
 
1 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the summary and 
analysis of clinical protocol MEI-011.  Background information is provided for the overall study design 
and objectives.  The reader is referred to the study protocol and electronic case report forms (eCRFs) for 
details of study conduct and data collection.  Pharmacokinetic analyses and reporting are not included in 
this analysis plan. 
2 
STUDY OBJECTIVE(S), TREATMENTS, AND ENDPOINT(S) 
2.1 
Study Objectives 
The purpose of this Phase 2 study is to evaluate the safety, tolerability, and efficacy of pracinostat and 
azacitidine as a combination treatment for subjects with Revised International Prognostic Scoring System 
(IPSS-R) high and very-high risk myelodysplastic syndromes (MDS) [3].  
2.1.1 
Primary Objectives 
The primary objectives of this study are: 
 
 
To define the safety and tolerability of pracinostat plus azacitidine in high/very high risk MDS  
 
To define the rate of overall response rate (ORR), defined as complete remission (CR) and partial 
remission (PR), of pracinostat plus azacitidine in high/very high risk MDS  
2.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
 
Complete response (CR) rate  
 
Overall hematologic improvement (HI) response rate  
 
Clinical benefit rate, defined as rate of CR + PR + HI + Marrow CR  
 
Rate of cytogenetic complete response/remission  
 
Duration of response (DoR)  
 
Rate of leukemic transformation  
 
Duration of event-free survival (EFS)  
 
Duration of progression-free survival (PFS)  
 
Duration of overall survival (OS)  
2.2 
Treatment Groups 
All Stage 1 and Stage 1b subjects will receive pracinostat and azacitidine.  Treatment will be open-label. 


Statistical Analysis Plan 
 
MEI Pharma, Inc. 
Protocol MEI-011 
 
 
 
Page 9 of 30 
 
2.3 
Study Endpoints and Evaluations 
2.3.1 
Primary Endpoints 
 
The primary efficacy endpoint is overall response rate (ORR) – defined as the proportion of subjects with 
confirmed complete response (CR) or partial response (PR) according to IWG criteria [1]. The ORRs will 
be assessed for both stages. 
 
The primary safety endpoint is subject incidence of treatment emergent adverse event (TEAEs). 
 
2.3.2 
Secondary Endpoints 
The secondary efficacy endpoints are: 
 
Complete remission (CR) rate: proportion of subjects with confirmed CR (i.e. 2 CRs at least 28 
days apart) per IWG criteria.  CR is defined as: 
 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines; persistent dysplasia 
will be noted. 
 
Peripheral blood (in the absence of transfusions) 
o Hemoglobin ≥ 11 g/dL  
o Platelets ≥ 100 × 109/L  
o Neutrophils ≥ 1.0 × 109/L  
o Blasts 0%  
 
Overall hematologic improvement (HI) rate: proportion of subjects who demonstrate major 
hematologic improvement per IWG criteria, for at least one criterion.  Only subjects with pre-
treatment abnormal values will be considered for this evaluation at 8 weeks. 
 
Clinical benefit rate (CBR): proportion of subjects with confirmed CR, PR, Marrow CR, or HI.   
All subjects who achieve hematologic CR, PR, marrow CR (with or without HI), or HI without 
marrow CR per IWG will be considered responders. PR is defined as all of the CR criteria if 
abnormal before treatment except bone marrow blasts, which can be decreased by ≥ 50% over 
pretreatment but still > 5%, and cellularity and morphology are not relevant. Marrow CR is 
defined, only in patients with MDS with excess blasts, as: 
o  Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment  
o Peripheral blood: if HI responses, they will be noted in addition to marrow CR  
 
Relapse: after CR or PR, at least one of: 
o Return to pretreatment bone marrow blast percentage  


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o Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets  
o Reduction in hemoglobin concentration by ≥ 1.5 g/dL or transfusion dependence  
 
Cytogenetic complete response/remission rate: proportion of subjects with disappearance of the 
chromosomal abnormality without appearance of new ones, by cytogenetic assessment in the 
subset of subjects with abnormal cytogenetics at baseline.  
 
Duration of response (DOR) will be derived in 2 ways: for subjects who achieve CR or PR 
(primary), and for subjects who achieve CR, PR, marrow CR or HI: time from initial 
determination of response to time of disease progression or death on study, whichever occurs 
first.  For subjects who are alive and have not experienced disease progression on study (prior to 
receiving subsequent/new treatment or stem cell transplant), duration of response will be 
censored at the day of last disease assessment. 
 
Leukemic transformation rate: leukemic transformation at landmark time points of 6, 12, 18, and 
24 months. 
 
Event-free survival (EFS), defined as the time from the first day of study drug administration 
(Day 1) to disease progression, relapse or death from any cause. Subjects who are alive and free 
from disease progression will be censored at the date of last disease assessment . 
 
Progression-free survival (PFS): time from the first day of study drug administration (day 1) to  
progression per IWG criteria, or death on study.  Subjects who are alive and free from disease 
progression will be censored at the date of last disease assessment. 
 
Overall survival (OS): time from the first day of study drug administration (day 1) to death from 
any cause on study.  Subjects who are alive will be censored at the date of last visit or contact 
with the investigator. 
 
Time to Stem Cell Transplant (SCT): time from the first day of study drug administration (day 1) 
to SCT, for subjects with SCT. If no SCT date can be confirmed, SCT date will be imputed as 
study drug discontinuation day.  
For each of DOR, EFS, PFS and OS, in the sensitivity analyses, subjects with no events who stopped 
treatment and received SCT will be censored at the SCT day (either confirmed SCT day, or study drug 
treatment discontinuation day, if no SCT date can be confirmed) even if there were events which occurred 
after the SCT date.   
 
For both stages, the rate of treatment discontinuation in the first 3 cycles of therapy due to 
possibly safety-related reasons will be used as a secondary endpoint to evaluate the safety and 
tolerability. Progressive disease and transplant are reasons to discontinuation related to efficacy, 
therefore these events will be excluded from the analysis. All the other reasons for treatment 
discontinuation will be considered as possibly safety-related, therefore will be included in the 
analysis as events.  
 


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3 
STUDY DESIGN 
3.1 
Overall Study Design 
This study is a two stage Phase 2 trial in subjects with IPSS-R high and very high risk myelodysplastic 
syndromes (MDS) previously untreated with hypomethylating agents. 
 
Stage 1 is an open-label portion in approximately 40 evaluable subjects will be treated with pracinostat 
and azacitidine.  The goal of Stage 1 is to evaluate treatment tolerability – based on whether the 
combination regimen of pracinostat and azacitidine’s  rate of treatment discontinuation due to possibly 
safety reasons in the first 3 cycles of therapy is not significantly higher than 10%, and to determine if the 
observed efficacy justifies expansion of enrollment in Stage 1b based on ORR.  
 
Stage 1b is an open-label expansion to achieve a total enrollment of approximately 60 subjects evaluable 
for efficacy, inclusive of Stage 1 and Stage 1b enrollment.  
4 
SAMPLE SIZE CONSIDERATIONS 
Approximately 60 subjects evaluable for efficacy will be enrolled: approximately 40 in Stage 1 and 20 in 
Stage 1b.  Non-evaluable subjects will be replaced.  
4.1 
Sample Size Determination for Stage 1 
The goal of Stage 1 is to establish if this pracinostat + azacitidine regimen is safe and tolerable, as 
measured by the rate of treatment discontinuation due to possibly safety related reasons in the first 3 
cycles of therapy. An discontinuation rate of 10%, based on that was observed in the azacitidine + 
placebo group in Study MEI-003 will be used as the threshold for safety evaluation. The 95% CI 
approach is utilized to estimate the sample size in Stage 1. A rate of treatment discontinuation of 22.5%, 
the midpoint between the discontinuation rates in the azacitidine + placebo (10%) and azacitidine + 
pracinostat (32%) groups, respectively, in Study MEI-003, is assumed to be the estimated discontinuation 
rate due to possibly safety related reasons. 
 
With a sample size of 40 subjects, the study will be stopped if ≥ 9 subjects (22.5%, 95% CI: 10.8–38.4%) 
discontinue in the first 3 cycles. Under this scenario, the lower bound of the 95% CI is > 10 % (above the 
pre-specified desired goal).  
 
In addition to the discontinuation threshold, the lower bound of 95% CI for an observed ORR of ≥ 25% 
will be desired to support opening Stage 1b of the study because it is expected that azacitidine alone 
results in an ORR of approximately 25% in high/very high-risk MDS. For example, with a sample sizeof 
N=40 and an assumed ORR of 45% for the azacitidine + pracinostat combination regimen, the 95% CI 
using exact method is (29.3%, 61.5%) with the lower bound higher than 20%. 
 
4.2 
Total Sample Size Determination 
This study is intended to provide preliminary efficacy information to serve as a basis for a subsequent 
confirmatory study. Published studies have reported an ORR of approximately 25% (range 20-32%) with 
azacitidine alone at higher risk of MDS ([2], [4], [5]). An ORR of 40% with pracinostat plus azacitidine 
will be considered as clinically meaningful improvement compared to azacitidine alone. With a sample of 


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60 subjects, the lower bound of the 95% CI of an observed ORR of 40% is 27.6%, higher than the 
expected ORR with azacitidine alone, and will support continued evaluation of pracinostat plus 
azacitidine in a larger study in high risk MDS. The table below lists the lower bound of the 95% CI for a 
range of ORR and indicates that a sample of 60 subjects is informative for future development and shows 
that doubling the sample size to 120 subjects will only increase the precision of the 95% CI by 
approximately 4%. 
 
Lower Bound 95% CI of ORR
ORR
N=60
N=120
50%
36.8
40.7
45%
32.1
35.9
40%
27.6
31.2
35%
23.1
26.5
30%
18.8
22.0
 
5 
ANALYSIS POPULATIONS 
5.1 
Safety Population 
The Safety Population is defined as all subjects who have been treated.  The Safety population will be 
used for safety analyses. 
5.2 
Intent to Treat (ITT) Population 
The Intent to Treat (ITT) population is defined as all enrolled subjects and is identical to the Safety 
Population. In this open-label single arm study, subjects who received at least one dose of study drug are 
defined as enrolled. The ITT population will be used for efficacy analyses.  
5.3 
Efficacy Evaluable (EE) Population 
The Efficacy Evaluable (EE) population for endpoints requiring both bone marrow and peripheral blood 
assessments is defined as all subjects who  
 
received at least 2 cycles of therapy and a follow-up bone marrow AND peripheral blood 
assessments 
 
or experienced PD prior to completion of 2 cycles of therapy. 
The Efficacy Evaluable (EE) population for endpoints requiring either bone marrow or peripheral blood 
assessment is defined as all subjects who  
 
received at least 2 cycles of therapy and a follow-up bone marrow OR peripheral blood 
assessments depending on the corresponding endpoints 
or experienced PD prior to completion of 2 cycles of therapy. 
The EE population will be used for key efficacy analyses as supportive analyses. 
5.3 
Per Protocol (PP) Population 
The Per Protocol (PP) population is defined as all treated subjects without major protocol deviations, as 
detailed in section 8.3. The PP population will be used for the primary efficacy analysis.  


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6 
CONSIDERATIONS FOR DATA ANALYSIS 
6.1 
Programming Environment 
All analyses will be conducted using SAS version 9.3 or above. 
6.2 
Strata and Covariates 
There are no planned strata or covariate-adjusted analyses. 
6.3 
Subgroups  
The following analyses will be broken down overall as well as by risk factor (high vs. very high risk 
group by IPSS-R), baseline characteristics (Age: <65 vs 65+, Gender, Bone marrow blasts <5% vs ≥5%) , 
primary vs. secondary MDS (secondary MDS is defined as MDS in patients treated with chemo or 
radiation for a prior malignancy), and undergoing transplant (yes vs no):  
Overall Response 
Clinical Benefit 
Event Free Survival 
Overall Survival   
 
6.4 
Multiple Comparisons and Multiplicity 
There are no planned adjustments for multiple hypothesis testing. 
6.5 
Significance Level 
No formal hypothesis testing is planned. 
6.6 
Statistical Notation and Methodology 
Unless stated otherwise, the term “descriptive statistics” refers to the number of subjects (n), mean, 
median, standard deviation (SD), minimum (min), and maximum (max) for continuous data and 
frequencies (counts and percentages) for categorical data.  Min and max values will be rounded to the 
precision of the original value, means and medians will be rounded to 1 decimal place greater than the 
precision of the original value, and STDs will be rounded to 2 decimal places greater than the precision of 
the original value.  Percentages will be rounded to the nearest whole number (zeros will not be displayed), 
with values of “<1%” and “>99%” shown as necessary for percentages falling near the boundaries.  P-
values will be presented with 3 decimal places of precision, and values less than 0.001 will be presented 
as “<0.001”. 
Unless otherwise noted, all data collected during the study will be included in subject data listings and 
will be sorted by dose cohort, subject number, and date/time within each subject.  
7 
DATA HANDLING METHODS 
7.1 
Visit Windows 
Day 1 will be the date corresponding to the first administration of study drug. 


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The screening assessments and the treatment/post-treatment assessments will be partitioned into the 
following two visit windows: 
 
A screening window, beginning on Day -14 and ending on Day -1. 
 
A treatment window, beginning on Day 1 and ending on the Study Day corresponding with the End 
of Study (EOS) visit. 
Subject visits will be presented according to the nominal visit as obtained upon the eCRF.  All values will 
be included in the subject data listings. 
7.2 
Date Values 
The missing component(s) of incomplete dates (e.g. start and/or stop dates of AE, concomitant 
medication, medical history) will be assumed as the most conservative value possible.  For example, if the 
start date has a missing day value, the first day of the month will be imputed for study day computations, 
etc.  If day is missing for an end date, the last day of the month will be imputed.  If the start date has a 
missing month value, the first month of the year will be imputed for study day computations, etc.  If 
month is missing for an end date, the last month of the year will be imputed.  For determination of 
treatment-emergent status, the start date will be imputed as the date of the first dose of study drug. 
Date imputation will only be used for computational purposes such as treatment-emergent status, etc.  
Actual data values, as they appear in the original eCRFs, will be presented in the subject data listings.
 
 
7.3 
Other Missing Values 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects who have 
been enrolled.  There will be no imputation for missing data. 
7.4 
Data Derivations  
Baseline values will be considered as the last non-missing assessment prior to the first administration of 
either study drug (pracinostat or azacitidine).  Assessments performed prior to Day 1 for all other study 
procedures will be assumed to have been performed prior to administration of either study drug.  Unless 
otherwise specified, change from baseline (CFB) calculations for a treatment window assessment will be 
the applicable treatment window assessment minus the baseline assessment (i.e., CFB = treatment 
window assessment – baseline).  If either the treatment window assessment value or the baseline value 
is/are missing, then CFB will be set to missing. 
For a given date within the screening window, Study Day will be computed as the given date minus Day 
1 (i.e., Study Day = Date – Day 1). 
 
For a given date within the treatment window, Study Day will be computed as the given date minus Day 1 
plus 1 (i.e., Study Day = Date – Day 1 + 1). 
 
Age will be calculated from the date of birth to the date of informed consent. 
      
 
The following will define prior medication use versus concomitant medication use: 
 
Prior: Medication use ended before Day 1; 
 
Concomitant: Medication use (initiation date, or the stop date) is on or after Day 1. 


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8 
STUDY POPULATION 
Unless otherwise stated, all study population analyses will be performed using the ITT Population (see 
Section 5.2). Subjects who are approved by the Medical Monitor, but never dosed are not included in 
listings such as “Demographics” and instead only included in a table of Screen Failures or Subjects 
excluded from analysis populations. Unless otherwise stated, summaries will be summarized in a total 
group. 
8.1 
Subject Enrollment 
Subject enrollment will be summarized as the number and percentage for each analysis population  
overall.  Subjects who were never dosed will not be included in “enrolled”. The denominators for 
calculating percentages will be based on the number of enrolled subjects. 
A summary of the number of subjects who were screen failures along with the reasons for screen failure 
will be provided overall. The number of subjects enrolled but never treated will be provided for the total 
group. 
Enrollment information will be provided in a data listing by subject.   
8.2 
Subject Disposition 
Subject disposition will be presented for the ITT population using descriptive statistics.  The number and 
percentage of subjects who receive at least one dose of study drug (pracinostat or azacitidine), subjects 
who have completed the study versus discontinued from the study, and subjects who discontinued from 
the study with their accompanying reason for discontinuation  summarized for the total group.  The 
denominators for calculating percentages will be based on the number of subjects for the total group. 
Subjects who discontinued prior to dosing will be excluded from the analysis and treated as a screen 
failure. Discontinued subjects will be provided in a data listing by subject. 
8.3 
Protocol Deviations 
Major protocol deviations are defined to be those deviations that could potentially bias either efficacy or 
safety summaries of the study.  Subjects associated with major protocol deviations will be identified and 
documented prior to database lock. 
Major deviations from the clinical protocol may include, but are not limited to: 
 
Informed consent issue 
 
Inclusion/exclusion criteria “other than those pre-planned via a waiver” 
 
Protocol required evaluation not completed  
 
Non-compliance with study drug administration 
 
Received excluded treatment or prohibited medication 
 
Developed withdrawal criteria but not withdrawn 
The number and percentage of subjects with major deviations and the number of deviations will be 
summarized by type of deviation and overall.  Summaries will be provided for the total group.  The 
denominators for calculating percentages will be based on the number of subjects in the ITT population 
for the total group. 
All protocol deviations not classified as major protocol deviations will be classified as minor protocol 
deviations. 


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All protocol deviations will be provided in a data listing by subject.  
8.4 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria deviations will be provided in a data listing by subject. 
8.5 
Demographic and Baseline Characteristics 
Subject demographics at screening include gender; age; race and ethnicity; height; weight; BMI; and 
baseline disease severity (IPSS-R and IPSS overall score and sub-components), and ECOG Performance 
Status, MDS WHO classification [3]. 
Gender, ethnicity, race, and disease history will be summarized as the number and percentage (n, %) of 
subjects within each category for the total group.  Denominators used in the calculation of percentages 
will be based on the number of subjects in the ITT population for the total group. 
Age, weight, height and BMI will each be summarized as a continuous variable using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum) for the total group. 
Demographic characteristics will be provided in a data listing by subject. 
8.6 
Prior Therapies 
8.6.1 
Prior and Concomitant Transfusion Therapy 
Prior and concomitant transfusion therapies will be summarized by product (fresh frozen plasma, packed 
RBCs, platelets, whole blood, plasma, other) and volume used for the total group. 
Transfusion therapies will be reported in a data listing by subject. 
8.6.2 
Prior and Concomitant Stem Cell Transplant Therapy 
Prior and concomitant stem cell transplant therapies will be summarized by type (autologous, allogenic, 
syngeneic, unknown, other) and units provided for the total group. 
Stem cell transplants will be reported in a data listing by subject, including age, diagnosis, IPSS-R and 
IPSS score, best response obtained and number of cycles received for each transplanted subject. 
8.6.3 
Prior MDS Therapy 
Prior MDS therapy will be summarized by therapy class and coded termfor the total group. 
Prior MDS therapy will be reported in a data listing by subject. 
8.7 
Medical History 
Medical history (including smoking history but excluding prior MDS therapies) will be summarized for 
each medical history code with descriptive statistics for the total group.  Denominators for calculating 
percentages will be based on the number of subjects in the analysis population for each dose cohort and 
overall. 
A summary table of smoking assessment will be summarized with descriptive statistics for the total 
group. Under protocol amendment 2, smoking assessment was added at days 1, 15 and 22 of each cycle 


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and the end of treatment visit. Records recorded as “Not Done”, as the visit was prior to this addition, will 
not be included in the summary table. 
A comprehensive data listing of medical history by subject will also be provided.  
9 
EFFICACY ANALYSIS  
 
 
 
The ITT population will be used for summaries and analyses of efficacy described below unless otherwise 
stated.  In addition, the primary efficacy will also be produced for the EE and PP populations. If the PP and 
ITT populations are identical, the PP tables will not be provided. 
 
In this study, efficacy will be assessed by response to treatment with pracinostat and azacitidine.  
Response to treatment will be determined using the IWG criteria for MDS. 
 
A summary of disease response will be provided using frequencies (counts and percentages).  
Denominators for calculating percentages will be based on the number of subjects in the ITT population.  
 
Response to treatment will be provided in a data listing by subject. 
 
 


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9.1 
Primary Endpoint Analysis 
 
Overall response rate 
The primary efficacy endpoint is overall response rate (ORR) defined as complete remission (CR) or partial 
remission (PR) per IWG criteria. The ORR and associated 95% confidence interval will be calculated using 
an exact binomial distribution approach for each of the ITT, EE and PP populations. For the PP population, 
the response rate will also be summarized by treatment schedule. In addition, a waterfall plot of the 
percentage change in blasts will be provided, and a forest plot of the ORR and corresponding 95% 
confidence intervals will be provided for each of the risk factors detailed in section 6.3. 
 
If the ORR is shown to differ between the two treatment schedules, additional tables split by treatment 
schedule may be provided, 
 
9.2 
Secondary Endpoint Analysis 
 
Rate of Discontinuation due to possibly safety reasons 
For both stages, the rate of treatment discontinuation in the first 3 cycles of therapy due to possibly 
safety-related reasons will be used as a secondary endpoint to evaluate the safety and tolerability. The rate 
of subject discontinuation in the first 3 cycles and associated 95% confidence interval will be calculated 
using an exact binomial distribution approach. 
 
Progressive disease and transplant are reasons to discontinuation related to efficacy, therefore these events 
will be excluded from the analysis. All the other reasons for treatment discontinuation will be considered 
as possibly safety-related, therefore will be included in the analysis as events. 
 
 
9.2.1 
Clinical Response 
Clinical response rates will be based on the best response achieved by each patient in the following 
hierarchy: 
CR -> PR -> Marrow CR -> SD -> PD 
The response rate is based on confirmed response, the following rules will be taken into account: 
If a patient has 2 CRs at least 28 days apart, best response is CR; 
If a patient has at least 1 PR followed by 1 CR at least 28 days later, but no subsequent CR (ie the CR is 
not confirmed), best response is PR; 
If a patient has 2 PRs at least 28 days apart, but no subsequent CRs, best response is PR; 
If a patient has at least 1 Marrow CR followed by 1 CR or PR at least 28 days later, but no subsequent CR 
or PR (ie the CR/PR is not confirmed), best response is Marrow CR; 
If a patient has 2 Marrow CRs at least 28 days apart, but no subsequent CRs or PR, best response is 
Marrow CR; 


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If a patient has 2 stable disease (SD) at least 28 days apart, but no subsequent PD, best response is SD. 
9.2.1.1 Complete Response (CR) rate 
Complete Response (CR) rate will be defined as the proportion of subjects with confirmed CR (i.e. 2 CRs 
at least 28 days apart) according to IWG criteria, as defined in section 2.3.2. Subjects achieving IWG 
criteria on bone marrow (≤ 5% myeloblasts with normal maturation of all cell lines), achieving IWG 
criteria on Peripheral blood at next 6 cycles, and confirmed achieving IWG criteria on Peripheral blood 
again with at least 28 days apart will be defined as achieving CR. 
Subjects who are not evaluable for response for any reason will be considered as not achieving CR. The 
response rate and associated 95% confidence interval will be calculated using an exact binomial 
distribution approach for the ITT, EE and PP populations.  
9.2.1.2 Overall hematologic improvement (HI) response rate 
Overall hematologic improvement (HI) response rate will be defined as the proportion of subjects who 
demonstrate confirmed major hematologic improvement as defined by IWG criteria (i.e. 2 HIs at least 8 
weeks apart), for at least one criterion.  Only subjects with pre-treatment abnormal values will be 
considered for this endpoint. The response rate and associated 95%. confidence interval will be calculated 
using an exact binomial distribution approach for the ITT, EE and PP populations. 
9.2.1.3 Clinical Benefit rate (CBR) 
Clinical benefit rate (CBR) will be defined as the proportion of subjects with confirmed CR, PR, marrow 
CR, or HI.  All patients who achieve hematologic CR, PR, marrow CR (with or without HI), or HI 
without marrow CR per modified IWG response criteria will be considered responders. The response rate 
and associated 95%. confidence interval will be calculated using an exact binomial distribution approach 
for the ITT, EE and PP populations. In addition, a forest plot of the ORR and corresponding 95% 
confidence intervals will be provided for each of the risk factors detailed in section 6.3. 
9.2.1.4 Cytogenetic Complete Response/Remission rate 
Cytogenetic complete response/remission rate will be defined as the proportion of subjects with 
disappearance of the chromosomal abnormality without appearance of new ones, by cytogenetic 
assessment in the subset of subjects with abnormal cytogenetics at baseline. The response rate and 
associated 95%. confidence interval will be calculated using an exact binomial distribution approach. 
9.2.1.5 Leukemic Transformation rate 
Leukemic transformation rate will be determined at landmark time-points of 6, 12, 18, and 24 months and 
present the transformation rate and corresponding 95% confidence interval. 
9.2.2 
Time-to-Event Endpoints 
 
9.2.2.1 Duration of Response (DOR) 
Duration of Response (DOR) will be analysed for the patients who achieved CR or PR, and for patients 
who achieved CR, PR, marrow CR or HI separately, and present the median time and associated 95% 


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confidence interval, analyzed by the Kaplan-Meier method. In addition Kaplan-Meier plots will be 
provided. Data will be censored as detailed in section 2.3.2.A sensitivity analysis will be performed 
censoring at the confirmed SCT day, or study drug treatment discontinuation day, if no SCT date can be 
confirmed. This will be analysed for the ITT population, and will present the median time and associated 
95% confidence interval, analyzed by the Kaplan-Meier method. In addition, a Kaplan-Meier plot will be 
provided. These will be repeated for each of the risk factors detailed in section 6.3. 
9.2.2.2 Event Free Survival (EFS) 
Event Free Survival (EFS) will be analysed for the EE population and present the median time and 
associated 95% confidence interval, analyzed by the Kaplan-Meier method. In addition a Kaplan-Meier 
plot will be provided. These will be repeated for each of the risk factors detailed in section 6.3. Data will 
be censored as detailed in section 2.3.2. 
A sensitivity analysis will be performed censoring at the confirmed SCT day, or study drug treatment 
discontinuation day, if no SCT date can be confirmed. This will be analysed for the ITT population, and 
will present the median time and associated 95% confidence interval, analyzed by the Kaplan-Meier 
method. In addition, a Kaplan-Meier plot will be provided. These will be repeated for each of the risk 
factors detailed in section 6.3. 
9.2.2.3 Progression-Free Survival (PFS) 
Progression-Free Survival (PFS) will be analysed for the EE population and will present the median time 
and associated 95% confidence interval, analyzed by the Kaplan-Meier method. In addition a Kaplan-
Meier plot will be provided. Data will be censored as detailed in section 2.3.2. 
A sensitivity analysis will be performed censoring at the confirmed SCT day, or study drug treatment 
discontinuation day, if no SCT date can be confirmed. This will be analysed for the ITT population, and 
will present the median time and associated 95% confidence interval, analyzed by the Kaplan-Meier 
method. In addition, a Kaplan-Meier plot will be provided. These will be repeated for each of the risk 
factors detailed in section 6.3. 
9.2.2.4 Overall Survival (OS) 
Overall Survival (OS) will be analysed for the ITT population, and will present the median time and 
associated 95% confidence interval, analyzed by the Kaplan-Meier method. In addition a Kaplan-Meier 
plot will be provided. These will be repeated for each of the risk factors detailed in section 6.3. Data will 
be censored as detailed in section 2.3.2.  
A sensitivity analysis will be performed censoring at the confirmed SCT day, or study drug treatment 
discontinuation day, if no SCT date can be confirmed. This will be analysed for the ITT population, and 
will present the median time and associated 95% confidence interval, analyzed by the Kaplan-Meier 
method. In addition, a Kaplan-Meier plot will be provided. These will be repeated for each of the risk 
factors detailed in section 6.3. 
10 
SAFETY ANALYSIS 
Unless stated otherwise, all safety analyses will be performed on the Safety Population.   


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10.1 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be set up for the study; details are provided in 
the protocol and DMC charter. 
10.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) will be considered as any event occurring after receiving the 
first dose of either study drug until 30 days after the last study drug administration. 
 
Treatment emergent adverse events (TEAE) will be classified into a standardized terminology using the 
Medical Dictionary for Regulatory Activities (MedDRA, version as referenced in the Data Management 
Plan) System Organ Classifications (SOC) and Preferred Terms (PT), and severity classified according to 
CTCAE version 4.03.  All summaries of the incidence of treatment-emergent adverse events will be 
provided using the Safety Population for the total group.  Although a SOC or PT may be reported more 
than once for a subject, each subject will only be counted once in the incidence count for that SOC or PT.  
Summaries of the following types of TEAEs will be provided: 
 
Overall Summary of Treatment Emergent Adverse Events (TEAEs); 
 
Summary of TEAEs by MedDRA SOC, PT and Grade (1 or 2, 3 and above); 
 
Summary of TEAEs related to pracinostat by MedDRA SOC, PT and Grade (1 or 2, 3 and above); 
 
Summary of TEAEs related to azacitidine by MedDRA SOC, PT and Grade (1 or 2, 3 and above); 
 
Summary of TEAEs by PT (in descending order) 
 
Summary of TEAEs leading to discontinuation from the study drug by MedDRA PT, sorted 
alphabetically by SOC and PT. 
 
Summary of Treatment Emergent Serious Adverse Events (TESAEs) by MedDRA PT, sorted 
alphabetically by SOC and PT;  
 
Summary of TESAEs related to pracinostat by MedDRA SOC, PT and Grade (1 or 2, 3 and above); 
 
Summary of TESAEs related to azacitidine by MedDRA SOC, PT and Grade (1 or 2, 3 and above); 
 
Summary of TESAEs by PT (in descending order) 
 
Summary of TEAEs leading to study treatment interruption  
 
Summary of TEAEs leading to azacitidine dose reduction 
These summaries will present the number and percentage of subjects reporting an adverse event for each 
classification level.  The denominators for calculating the percentages will be based on the number of 
exposed subjects in the Safety Population (i.e., study drug was administered) in the total group. 
All adverse events, serious adverse events and deaths, and adverse events leading to discontinuation from 
the study will also be provided in data listings by subject.   
10.3 
Extent of Exposure 
The duration of exposure (days) to study drug (pracinostat or azacitidine) will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) in the total group.  
Duration of exposure will be calculated as the difference between the date of last administration of study 
drug and the date of first administration of study drug plus 1 day. 


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The actual dose taken will be determined from the total number of doses taken (dispensed – returned) and 
the amount of drug per dose. This will be summarized using descriptive statistics for the total group for 
pracinostat dosing, and by scheduled and overall for azacitidine dosing. The number of cycles will be 
summarized using descriptive statistics and also in 3-month categories. 
Exposure data including date, time, and dose of study drug administration at study site visits, diary 
dispense/return dates, and study drug dose modifications will be provided in separate data listings by 
subject. Number (%) of subjects with dose reductions and dose interruptions for both pracinostat and 
azacitidine will be provided. 
10.4 
Compliance 
Treatment compliance will be assessed for each study drug (pracinostat and azacitidine) at each visit for 
which study drug can be determined, by comparing the expected number of daily doses and total dose of 
drug taken with the actual number of daily doses and total dose provided for each.  The expected number 
of daily doses taken will be calculated as the sum of the appropriate number of doses taken and number of 
doses missed entries from the eCRF.  Compliance will be calculated by the formula: 
Percent Compliance (pracinostat) = 100 ∗ Actual # of daily doses taken
Expected # of daily doses taken. 
Percent Compliance (azacitidine) = 100 ∗ 
Actual doses administered
Expected total dose to be taken (
ୢ୭ୱୣ
ୢୟ୷∗ days)
. 
If the number of doses taken is missing on the eCRF, it will be calculated based on the number of 
capsules dispensed and returned from the eCRF drug accountability workflow as total number dispensed 
– total number returned.   If the number of doses missed is missing on the eCRF, it will be calculated 
based on the number of Study Days that have elapsed between the respective visits corresponding to study 
drug dispense and return. 
 
Treatment compliance will be calculated for each subject/cycle and over all cycle for the Safety 
Population.  Compliance values that are less than 0% will be set to 0%.  A summary of treatment 
compliance will be presented using descriptive statistics for the Safety Population. 
 
Compliance data will be presented within a data listing by subject. 
10.5 
Prior and Concomitant Medications 
Medication usage will be coded using the World Health Organization (WHO) Drug Dictionary. 
Medication use will be presented for the Safety Population by WHO Drug 
Anatomical/Therapeutic/Chemical (ATC) category and WHO Drug preferred name.  Medication use 
summaries will be presented for prior medication use (prior to first administration of study drug) and 
concomitant medication use.  Summaries will be provided for the total group.  Medications with partial 
start and/or stop dates, which cannot be definitely categorized as prior or concomitant treatment 
medications will be considered concomitant. 
All summaries will present the number and percentages of subjects using each medication for the total 
group.  The denominators for percentages will be the number of subjects in the analysis population for the 
total group. A summary of the reason for taking medication will also be provided. 
Prior and concomitant medications will be provided in a data listing by subject. 


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10.6 
Laboratory Evaluations 
Absolute and change from baseline values for continuous parameters (analytes) over chemistry and 
hematology tests will be summarized by analyte, assessment, for the total group using descriptive 
statistics (mean, median, SD, minimum, maximum, and number of subjects). In addition, shifts from 
baseline CTCAE toxicity grade to worst on-treatment CTCAE toxicity grade will be presented by panel 
(chemistry and hematology) and analyte for the total group.   
   
Data listings for laboratory parameters will be presented by subject.    
10.7 
Vital Signs 
Vital sign measurements (blood pressure [systolic and diastolic], heart rate, and temperature, as well as 
height and weight) and change from baseline measurements will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum, and number of subjects) for the total group, and will 
also be presented as box plots over time. 
  
10.8 
Pregnancy Test 
Serum pregnancy testing is required within 7 days of first study treatment for females of childbearing 
potential, and urine pregnancy tests may be performed at other visits as deemed necessary.  Results of 
pregnancy tests will be provided in a data listing by subject.  
10.9 
Electrocardiograms (ECG) 
The electrocardiogram (ECG) parameter QTcF interval will be assessed. Descriptive statistics for ECG 
measurements and change from baseline will be presented by assessment for the total group, and will also 
be presented as box plots over time.The triplicate values at each timepoint for a patient will be averaged, 
and the average value will be used in the summaries and plots. 
In addition, the number and proportion of patients obtaining maximum treatment-emergent absolute 
QTcF >450ms and ≤480ms, >480ms and ≤500ms, and >500ms will be presented, along with the number 
and proportion of patients obtaining a maximum treatment-emergent QTcF increase from baseline >30ms 
and ≤60ms, and >60ms.   
10.10 
Physical Examinations 
Physical examination (PE) will be conducted and any findings assessed for clinical significance (CS).  CS 
findings from the Screening PE will be recorded as Medical History; CS findings for all other PEs will be 
captured as AEs. 
 
10.11 
ECOG Performance Status 
The ECOG performance status is a rating scale used to assess how a subject’s is progressing and to assess 
how the disease affects the daily living abilities of the subject.  The score values are 0-5, where 0 
indicates “fully active, able to carry on all pre-disease performance without restriction” and 5 indicates 
subject death. 
 
A summary of ECOG performance status will be provided by visit for the total group using frequencies 
(counts and percentages). 
 


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ECOG performance status will be provided in a data listing by subject. 
10.12 
Bone Marrow Assessment 
Bone marrow assessments (aspiration or biopsy) will be collected at intervals and used to determine 
treatment response.  Bone marrow aspirate/biopsy will be examined for a range of assessments.   
 
A data listing of bone marrow assessments will be presented by subject. 
11 
OTHER ANALYSES 
11.1 
Correlative/Pharmacodynamics Analysis 
No pharmacodynamics analyses are planned. 
11.2 
Interim Analysis 
The data from Stage 1 will be assessed to determine if the discontinuation rate due to possibly safety related 
reasons and preliminary efficacy data support proceeding to Stage 1b, but no formal interim analysis will 
be conducted. 
The primary study analysis will be performed approximately 12 months after the last subject is enrolled in 
the study. At the completion of the primary analysis, the Sponsor will decide whether to terminate the study 
or continue study drug dosing in ongoing subjects.  
11.3 
Pharmacokinetic Analysis 
Not Applicable. 
12 
END OF STUDY ANALYSIS 
The final analysis will be conducted after the last subject discontinues the study or study is terminated by 
sponsor decision, and the resulting clinical database has been cleaned, quality checked, and locked. 
Study database lock and unblinding will follow the applicable Clinipace Worldwide (CPWW) Standard 
Operating Procedures (SOPs).  In brief, the sponsor and CPWW will agree and sign off on the database 
lock and protocol deviations classifications.  After those steps have been completed, both the sponsor and 
CPWW will agree and sign off on the study unblinding form.  Once this form has been finalized, the 
study database export coordinator will transfer the true randomization assignments into CPWW’s 
statistical analysis computing area.   
13 
CHANGES FROM PROTOCOLLED ANALYSIS 
The protocol states that the definition of overall survival is time from the first day of study drug 
administration (day 1) to death from any cause on study.  Subjects who are alive will be censored at the 
date of last disease evaluation. This has been changed to the standardly used definition of time from the 
first day of study drug administration (day 1) to death from any cause on study.  Subjects who are alive 
will be censored at the date of last visit or contact with the investigator. 
The per protocol population has been renamed as the efficacy evaluable population, and an additional 
population, named the per protocol population, has been included in order to perform a sensitivity 
analysis excluding patients with major deviations. 


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14 
REFERENCES 
[1] Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of 
the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006, 108(2): 419-
425.  
 
[2] Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of 
conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, 
open-label, phase III study. Lancet Oncol. 2009; 10(3): 223-232.  
 
[3] Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for 
myelodysplastic syndromes. Blood. 2012; 120(12): 2454-2465. 
 
[4] Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without 
entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplastic-related 
changes: Results of the US Leukemia Intrgroup Trial E1905. J Clin Oncol. 2014; 32: 1242-1248.  
 
[5] Sekeres MA, Othus M, List AF, et al. A randomized phase II study of azacitidine combinmed with 
lenalidomide or with vorinostat vs azacitidine monotherapy in higher risk myelodysplastic syndromes 
(MDS) and chronic myelomonocytic leukemia (CMML): North American Intergroup Study SWOG 
S1117. Blood. 2014; 114: 937-951. 
15 
TABLE OF CONTENTS FOR TABLES, LISTINGS AND FIGURES 
REFERRED TO BUT NOT PRESENTED IN THE TEXT 
 
Table 14.1.1   Summary of Analysis Populations 
Table 14.1.2   Summary of Subject Disposition 
Table 14.1.3   Summary of Demographic Characteristics 
Table 14.1.4   Summary of Major Protocol Deviations 
Table 14.1.5   Summary of Myelodysplastic Disease History 
Table 14.1.6   Summary of Prior and Concomitant Transfusion 
Table 14.1.7   Summary of Stem Cell Transplant Prior/Concomitant 
Table 14.1.8   Summary of Prior Myelodysplastic Syndrome Treatment 
Table 14.1.9   Summary of Medical History 
Table 14.1.10   Summary of Smoking History 
Table 14.1.11.1   Summary of Concomitant Medication 
Table 14.1.11.2   Summary of Prior Medication 


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Table 14.1.12   Summary of Current Procedure 
 
Table 14.2.1.1   Summary of Discontinuation Rate Overall 
Table 14.2.1.2   Summary of Discontinuation Rate by Stage 
Table 14.2.2.1   Summary of Efficacy Responses   
Table 14.2.2.2   Summary of Efficacy Responses  
Table 14.2.2.3   Summary of Efficacy Responses  
Table 14.2.2.4   Summary of Efficacy Responses by Schedule 
Figure 14.2.2.5   Waterfall Plot of Best Overall Response   
Figure 14.2.2.6   Forest Plot of Overall Response by Risk Factor Group 
Figure 14.2.2.7   Forest Plot of Clinical Benefit Rate by Risk Factor Group 
Table 14.2.2.8   Summary of HI Efficacy Responses 
Table 14.2.3   Summary of Leukemic Transformation Rate 
Table 14.2.4.1  Summary of Duration of Response (DOR)  
Figure 14.2.4.2   Kaplan-Meier Plots of Duration of Response (DOR)  
Table 14.2.4.3  Summary of Duration of Response (DOR) – Sensitivity Analysis  
Figure 14.2.4.4   Kaplan-Meier Plots of Duration of Response (DOR) - Sensitivity Analysis 
Table 14.2.4.1  Summary of Duration of CR/PR Response (DOR)  
Figure 14.2.4.2   Kaplan-Meier Plots of Duration of CR/PR Response (DOR)  
Table 14.2.4.3  Summary of Duration of CR/PR Response (DOR) – Sensitivity Analysis  
Figure 14.2.4.4   Kaplan-Meier Plots of Duration of CR/PR Response (DOR) - Sensitivity Analysis 
Table 14.2.5.1  Summary of Event Free Survival (EFS) 
Figure 14.2.5.2   Kaplan-Meier Plots of Event Free Survival (EFS) 
Table 14.2.5.3   Summary of Event Free Survival (EFS) by IPSS-R Risk Factor Group 
Figure 14.2.5.4   Kaplan-Meier Plots of Event Free Survival (EFS) by IPSS-R Risk Factor Group 
Table 14.2.5.5   Summary of Event Free Survival (EFS) by MDS Category 


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Figure 14.2.5.6   Kaplan-Meier Plots of Event Free Survival (EFS) by MDS Category 
Table 14.2.5.7   Summary of Event Free Survival (EFS) by Baseline Characteristics 
Figure 14.2.5.8   Kaplan-Meier Plots of Event Free Survival (EFS) by Baseline Characteristics 
Table 14.2.5.9   Summary of Event Free Survival (EFS) by Stem Cell Transplant 
Figure 14.2.5.10   Kaplan-Meier Plots of Event Free Survival (EFS) by Stem Cell Transplant 
Table 14.2.5.11  Summary of Event Free Survival (EFS) - Sensitivity Analysis 
Figure 14.2.5.12   Kaplan-Meier Plots of Event Free Survival (EFS) - Sensitivity Analysis 
Table 14.2.6.1  Summary of Progression-Free Survival (PFS)  
Figure 14.2.6.2   Kaplan-Meier Plots of Progression-Free Survival (PFS) 
Table 14.2.6.3  Summary of Progression-Free Survival (PFS) – Sensitivity Analysis  
Figure 14.2.6.4   Kaplan-Meier Plots of Progression-Free Survival (PFS) - Sensitivity Analysis 
Table 14.2.7.1  Summary of Overall Survival (OS) 
Figure 14.2.7.2   Kaplan-Meier Plots of Overall Survival (OS)  
Table 14.2.7.3   Summary of Overall Survival (OS) by IPSS-R Risk Factor Group 
Figure 14.2.7.4   Kaplan-Meier Plots of Overall Survival (OS) by IPSS-R Risk Factor Group 
Table 14.2.7.5   Summary of Overall Survival (OS) by MDS Category 
Figure 14.2.7.6   Kaplan-Meier Plots of Overall Survival (OS) by MDS Category 
Table 14.2.7.7   Summary of Overall Survival (OS) by Baseline Characteristics 
Figure 14.2.7.8   Kaplan-Meier Plots of Overall Survival (OS) by Baseline Characteristics  
Table 14.2.7.9   Summary of Overall Survival (OS) by Stem Cell Transplant 
Figure 14.2.7.10   Kaplan-Meier Plots of Overall Survival (OS) by Stem Cell Transplant  
Table 14.2.7.11  Summary of Overall Survival (OS) - Sensitivity Analysis 
Figure 14.2.7.12   Kaplan-Meier Plots of Overall Survival (OS) - Sensitivity Analysis  
Table 14.2.8  Summary of Time to Stem Cell Transplant 
 
Table 14.3.1.1   Summary of Treatment Emergent Adverse Events 


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Table 14.3.1.2   Summary of Treatment Emergent Adverse Events by MEDRA System Organ Class, 
Preferred Term and Grade  
Table 14.3.1.3   Summary of Treatment Emergent Adverse Events Related to Pracinostat by MEDRA 
System Organ Class, Preferred Term and Grade 
Table 14.3.1.4   Summary of Treatment Emergent Adverse Events Related to Azacitidine by MEDRA 
System Organ Class, Preferred Term and Grade 
 
Table 14.3.1.5 Summary of Treatment Emergent Adverse Events Leading to Treatment Discontinuation 
by MEDRA System Organ Class, Preferred Term and Grade 
Table 14.3.1.6 Summary of Treatment Emergent Adverse Events of Special Interest by MEDRA System 
Organ Class, Preferred Term and Grade 
Table 14.3.1.7   Summary of Treatment Emergent Adverse Events by Preferred Term (Descending 
Frequency)  
Table 14.3.1.8   Summary of Treatment Emergent Adverse Events Leading to Study Drug Interruption by 
MEDRA System Organ Class, Preferred Term and Grade  
Table 14.3.1.9   Summary of Treatment Emergent Adverse Events Leading to azacitidine Dose Reduction 
by MEDRA System Organ Class, Preferred Term and Grade 
Table 14.3.2.1   Summary of Serious Treatment Emergent Adverse Events by MedDRA Preferred Term, 
Sorted Alphabetically by System Organ Class and Preferred Term  
Table 14.3.2.2   Summary of Serious Treatment Emergent Adverse Events Related to Pracinostat from the 
Study by MedDRA Preferred Term, Sorted Alphabetically by System Organ Class and Preferred 
Term 
Table 14.3.2.3   Summary of Serious Treatment Emergent Adverse Events Related to Pracinostat from the 
Study by MedDRA Preferred Term, Sorted Alphabetically by System Organ Class and Preferred 
Term 
Table 14.3.2.4   Summary of Serious Treatment Emergent Adverse Events by Preferred Term 
(Descending Frequency) 
Table 14.3.4.1  Summary of Hematology Laboratory Results 
Table 14.3.4.2 Summary of Serum Chemistry Laboratory Results 
Table 14.3.4.3    Summary of Hematology Shifts from Baseline to Worst On-Treatment Toxicity Grade 
Table 14.3.4.4    Summary of Serum Chemistry Shifts from Baseline to Worst On-Treatment Toxicity 
Grade 
Table 14.3.5.1  Summary of Vital Signs 


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Table 14.3.5.2  Plot of Vital Signs Results 
Table 14.3.6.1  Summary of Electrocardiograms (QTcF Intervals) 
Table 14.3.6.2  Summary of Maximum QTcF Intervals 
Table 14.3.6.3  Plot of Electrocardiograms Results 
Table 14.3.7 Summary of ECOG Performance Status 
Table 14.3.8.1  Summary of Extent of Exposure to Pracinostat 
Table 14.3.8.2  Summary of Extent of Exposure to Azacitidine 
Table 14.3.8.3  Summary of Compliance with Pracinostat 
Table 14.3.8.4  Summary of Compliance with Azacitidine 
 
 
Listing 16.2.1.1    Enrollment Information by Subject 
Listing 16.2.1.2    Discontinued Subjects by Subject 
Listing 16.2.2.1    Deviations from the Clinical Protocol by Subject 
Listing 16.2.3.1    Subjects Excluded from Safety Population by Subject 
Listing 16.2.3.2    Subjects Excluded from Intent to Treat Population by Subject 
Listing 16.2.3.3    Subjects Excluded from PK Population by Subject 
Listing 16.2.3.4    Inclusion/Exclusion Criteria Not Met by Subject 
Listing 16.2.4.1    Subject Demographics by Subject 
Listing 16.2.4.2    Prior Transfusion Therapy by Subject 
Listing 16.2.4.3    Prior and Concomitant Stem Cell Transplant Therapy by Subject 
Listing 16.2.4.4    Prior Myelodysplastic Syndrome Treatment by Subject 
Listing 16.2.4.5    Prior Myelodysplastic Radiation by Subject 
Listing 16.2.4.6    Concurrent Procedure by Subject 
Listing 16.2.4.7   Myelodysplastic Syndrome History by Subject 
Listing 16.2.4.8    Smoking History by Subject 
Listing 16.2.4.9    Prior and Concomitant Medications by Subject 
Listing 16.2.5.1    Exposure to Pracinostat by Subject 
Listing 16.2.5.2    Exposure to Azacitidine by Subject 
Listing 16.2.5.3    Compliance with Pracinostat  by Subject 


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Listing 16.2.5.4    Compliance with Azacitidine  by Subject 
Listing 16.2.6.1    Response Assessment by Subject 
Listing 16.2.6.2    Leukemic Transformation (to AML) by Subject 
Listing 16.2.6.3    Time to Disease Progression by Subject 
Listing 16.2.6.4.1    Bone Marrow Assessment by Subject (1) 
Listing 16.2.6.4.2    Bone Marrow Assessment by Subject (2) 
Listing 16.2.6.4.3    Bone Marrow Assessment by Subject (3) 
Listing 16.2.6.4.4    Bone Marrow Assessment by Subject (4) 
Listing 16.2.6.4.5    Bone Marrow Assessment by Subject (5) 
Listing 16.2.6.4.6    Bone Marrow Assessment by Subject (6) 
Listing 16.2.6.5.1    Molecular Markers Testing by Subject (1) 
Listing 16.2.6.5.2    Molecular Markers Testing by Subject (2) 
Listing 16.2.6.5.3    Molecular Markers Testing by Subject (3) 
Listing 16.2.6.6      Peripheral Blood Research Samples by Subject 
Listing 16.2.7.1    Adverse Events by Subject 
Listing 16.2.7.2    Listing of Serious Adverse Events and Deaths by Subject 
Listing 16.2.7.3    Listing of Serious Adverse Events Considered to be Related to Treatment by Subject 
Listing 16.2.7.4    Listing of Adverse Events Leading to Discontinuation from the Study by Subject 
Listing 16.2.7.5 
Listing of Deaths 
Listing 16.2.8.1    Chemistry Results by Subject 
Listing 16.2.8.2    Hematology Results by Subject 
Listing 16.2.8.3    Pregnancy Test Results by Subject 
Listing 16.2.8.4      Cytogenetics (FISH) by Subject 
Listing 16.2.9.1    ECOG Performance Status by Subject