An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia

• Sponsor: Helsinn Healthcare SA (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03151408
• Collaborator: Clinipace Worldwide (Industry)
• Enrollment: 406
• Locations: 138
• Arms: 2
• Actual Duration (Months): 37.9
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase III, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (AZA) as background therapy in patients ≥ 18 years of age with newly diagnosed acute myeloid leukemia (AML), excluding acute promyelocytic leukemia and cytogenetic low-risk AML, who are unfit to receive intensive remission induction chemotherapy due to age ≥ 75 years or comorbidities. Patients will be randomized in a 1:1 ratio to one of two groups: Group A (experimental group) to receive pracinostat plus AZA and Group B (control group) to receive placebo plus AZA. Randomization will be stratified by cytogenetic risk category (intermediate vs. unfavorable-risk, according to SWOG Cytogenetic Risk Category Definitions) and ECOG performance status (0-1 vs. 2). Treatments will be administered based on 28-day cycles, with pracinostat/placebo administered orally once every other day, 3 times a week for 3 weeks, followed by one week of no treatment and AZA administered for 7 days of each cycle. Study treatment should continue until there is documented disease progression, relapse from complete remission (CR), or non-manageable toxicity. A minimum of 6 cycles may be required to achieve a complete remission. Once permanently discontinued from study treatment, patients will enter the Long-term Follow-up phase of the study and will be followed for assessment of disease progression, if applicable, and survival every 3 months (±1 month) until death. The end of this study is defined when 390 events (deaths) have occurred and the study is unblinded for final overall survival analysis. Patients who are receiving study treatment at the end of the study may have the opportunity to continue to receive the study drugs to which they were randomized to (Post- Study Observation Period), until the Sponsor informs the Investigators of the appropriate course of action based on the study results. The Post-Study Observation Period is defined as the period starting from the end of the study for a maximum of 12 months.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Pracinostat; Drug: Placebos; Drug: Azacitidine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 406 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double-Blind, Placebo-Controlled, Multicenter, Randomized Study Of Pracinostat In Combination With Azacitidine In Patients ≥18 Years With Newly Diagnosed Acute Myeloid Leukemia Unfit For Standard Induction Chemotherapy
• Actual Study Start Date: Jun 23, 2017
• Actual Primary Completion Date: Aug 20, 2020
• Actual Study Completion Date: Aug 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pracinostat plus AZA 60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.	Drug: Pracinostat; 60 mg capsule; Other Names: SB939 ; Drug: Azacitidine; SC or IV injection; Other Names: AZA
Placebo Comparator: Placebo plus AZA 1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.	Drug: Placebos; capsule; Drug: Azacitidine; SC or IV injection; Other Names: AZA

Outcome Measures

Primary Outcome Measures

1. Overall Survival [826 days]

   OS measures the time from randomization to death due to any cause.

Secondary Outcome Measures

1. Morphologic Complete Remission (CR) Rate [744 days]

   The CR rate is the proportion of patients who achieve a morphologic CR according to the response criteria <5% blasts in a bone marrow aspirate sample with spicules There should be no blasts with Auer rods No EMD Absolute Neutrophil Count (ANC) ≥1,000/μL Platelet count of ≥100,000/μL Patient must be independent of transfusions (for at least 1week before each assessment)

2. Complete Remission Without Minimal Residual Disease (CRmrd) Rate [826 days]

   proportion of patients who achieve a CR without minimal residual disease by multicolor flow cytometry according to the following criteria Morphologic CR Minimal Residual Disease (MRD) by MFC negative

3. Cytogenetic Complete Remission (CRc) Rate [826 days]

   The CRc rate is the proportion of patients who achieve a reversion to a normal karyotype at CR within the study period. This endpoint applies only to patients with abnormal cytogenetic at enrollment according to the following criterion Morphologic CR plus reversion to a normal karyotype (defined as no clonal abnormalities detected in a minimum of 20 mitotic cells)

4. Transfusion Independence (TI) [826 days]

   Transfusion independence rate is defined as the proportion of patients who show eight weeks or over without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion during study period

Other Outcome Measures

1. Composite Complete Remission (cCR) Rate [744 days]

   Composite complete remission (cCR) rate is the proportion of patients who achieve either a disease response of CR, CRi or MLFS (i.e., cCR = CR + CRi + MLFS) within the study period, according to the response criteria

2. Duration of Composite Complete Remission [744 days]

   Duration of cCR response is the time from first cCR until documented relapse (the definition of relapse from CR will be applied) or death. Duration of cCR is only defined for patients who achieve a cCR

3. Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30) [from baseline up to 660 days]

   QLQ-C30 is made of multi-item scales and single-item measures (functional and symptom scales, a global health status/QoL scale and single items). Item range is the difference between possible max and min response to individual items of the scale; most items take values from 1 to 4 (range=3). Global health status takes values from 1 to 7 (range = 6). For statistical analysis purpose, single-item and scale values were all standardized (according to linear transformation described in Scoring Manual) to obtain scores ranging 0-100. An high scale score represents an higher response level. Thus an high score for a functional scale represents an high/healthy level of functioning, an high score for the global health status/QoL represents a high QoL, an high score for a symptom scale/item represents an high level of symptomatology/problems.

4. Relapse Free Survival [744 days]

   the time from the date of achievement of CR or CRi until the date of relapse or death from any cause

5. Progressive Free Survival Rate (PFS) [800 days]

   PFS is defined as the time from the date of randomization until the date of relapse (progression), or death from any cause, whichever occurs first.

6. Duration of Morphologic CR [744 days]

   Duration of morphologic CR is defined as the time from the date of achievement of CR until the date of relapse (progression).

7. Time to CR [616 days]

   Time to CR is defined as the time from the date of randomization until the date of CR in the absence of interceding therapies. The analysis set was the ITT set.

8. Morphologic CR Within 6 Cycles Rate [within 6 cycles]

   Morphologic CR within 6 cycles rate is defined as the proportion of patients who achieved CR in the absence of interceding therapies within 6 treatment cycles (i.e., during treatment phase up to Day 1 of Cycle 7 included). Analysis was performed in the ITT set.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patient ≥ 18 years of age with newly diagnosed, histologically or cytologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics

2. Unable to receive intensive chemotherapy regimens at enrollment, based on one of the following:

1. Age ≥ 75 years, or

II. Age < 75 years with at least 1 of the following co-morbidities:

1. An ECOG performance status of 2

2. Clinically significant cardiovascular disease defined as:

1. Left ventricular ejection fraction (LVEF) ≤ 50%, measured within 3 months prior to Day 1 confirmed by ECHO/MUGA ii. Congestive heart failure requiring medical therapy

1. Chronic stable angina requiring medical therapy iv. Prior cerebrovascular accident with sequelae c. Clinically significant pulmonary disease defined as: i. Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected ii. Lung diffusing capacity for carbon monoxide (DLCO) ≤ 65% of expected Confirmed by pulmonary tests. d. Diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, nephropathy, neuropathy, vasculopathy) e. Autoimmune inflammatory conditions (e.g., rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel disease, or similar) requiring chronic disease modifying therapy (e.g., etanercept, adalimumab, infliximab, rituximab, methotrexate, or similar) f. Class III obesity defined as a Body Mass Index (BMI) > 40 kg/m2 g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 115 µmol/L) or creatinine clearance <70 ml/min h. Clinically significant cognitive impairment defined as requiring medical therapy and/or assistance with activities of daily living

1. 20% blasts in bone marrow

2. Peripheral white blood cell (WBC) count 30,000/µL For cyto-reduction, hydroxyurea is allowed during screening and up to Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.

3. ECOG performance status ≤ 2

4. Adequate organ function as evidenced by the following laboratory findings:

5. Total bilirubin ≤ 2 × upper limit of normal (ULN) or < 3 x ULN for patients with Gilbert-Meulengracht Syndrome

6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN

7. Serum creatinine ≤ 1.5 × ULN according to institutional standards or creatinine clearance ≥ 50 mL/min

8. QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 ms on electrocardiogram (ECG) at Screening

9. Male patient who is surgically sterile, or male patient who is willing to agree to remain completely abstinent (refrain from heterosexual intercourse) or who use barrier contraceptive measures and agree to refrain from donating sperm during the entire study treatment period and for 3 months after the last administration of study drug

10. Female patient who is of childbearing potential willing to use adequate contraceptive measures while participating on study, OR willing to completely abstain from heterosexual intercourse during the entire study treatment period

11. Female patient who is of childbearing potential must have a negative serum pregnancy test result within 3 weeks prior to starting study drugs.

12. Willing to provide voluntary written informed consent before performance of any study related procedure not part of normal medical care

13. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria:

1. Able to receive intensive induction chemotherapy

2. AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e. promyelocytic leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or complex karyotypes

3. Presence of an active malignant disease within the last 12 months, with the exception of adequately treated cervical cancer in-situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]). Other malignancies may be considered after consultation with the Medical Monitor

4. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator's opinion, could compromise the patient's safety or put the study outcomes at risk

5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classification

6. Evidence of AML central nervous system (CNS) involvement

7. Previous chemotherapy for AML except for the following, which are allowed:

8. Hydroxyurea for cytoreduction

9. One course of hypomethylating agent therapy (i.e.; up to 7 doses of azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment (Day 1)

10. Use of experimental drugs ≤ 30 days prior to screening

11. Received prior HDAC inhibitor therapy

12. Received prior treatment with a hypomethylating agent, except as allowed in Exclusion Criterion 7.b

13. Known hypersensitivity to any components of pracinostat, azacitidine, or mannitol

14. History of human immunodeficiency virus (HIV) or an active and uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

15. Gastrointestinal (GI) tract disease that causes an inability to take oral medication, malabsorption syndrome, or a requirement for IV alimentation; prior surgical procedures affecting absorption; or uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

16. Any disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of pracinostat and/or AZA, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study

17. Breast-feeding woman

18. current smokers(use of patches, chewing gums and vaping nicotine conaining fluids is permitted). Patients who stopped smoking at least 8 day prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study

19. prohibited concomitant medications

20. uncontrolled infections

21. receive more than 1 prior cycle of HMA or bone marrow transplant for any prior hematological disorder antecedent to AML

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo clinic hospital	Phoenix	Arizona	United States	85054
2	Arizona Oncology Associates, East Valley Cancer Center	Tempe	Arizona	United States	85284
3	University of Arizona cancer center-north campus	Tucson	Arizona	United States	85724
4	10666 N.Torrey Pines-Scripps Cancer Center	La Jolla	California	United States	92037
5	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093-0698
6	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
7	Saint alphonsus Regional medical center-cancer care center	Boise	Idaho	United States	83706
8	Loyola University Chicago	Maywood	Illinois	United States	60153
9	Universitz of Kansas Cancer Center	Westwood	Kansas	United States	66205
10	Norton Cancer Institute, St. Matthews Campus	Louisville	Kentucky	United States	40207
11	Pontchartrain Cancer Center (Research Location)	Covington	Louisiana	United States	70433
12	Rcca Md Llc	Bethesda	Maryland	United States	20187
13	UMass Memorial medical center-university campus	Worcester	Massachusetts	United States	01655
14	Michigan Center of Medical Research	Farmington Hills	Michigan	United States	48336
15	Michigan State University	Lansing	Michigan	United States	48910
16	Mayo clinic	Rochester	Minnesota	United States	55905
17	Mercy Research	Springfield	Missouri	United States	65804
18	100 Mercy Way	Joplin	Montana	United States	64804
19	Stony Brook University	Stony Brook	New York	United States	11794
20	Duke University Medical Center-2400 Pratt Street	Durham	North Carolina	United States	27710
21	University Hospital Cleveland Medical Center	Cleveland	Ohio	United States	44106
22	Mercy Clinic Oncology & Hematology	Oklahoma City	Oklahoma	United States	73120
23	Oklahoma cancer specialist and research institute	Tulsa	Oklahoma	United States	74146
24	GHS Cancer Institute	Greenville	South Carolina	United States	29615
25	University of Tennessee Medical Center	Knoxville	Tennessee	United States	37920
26	VA North texas Health Care sytem,Dallas VA Medical Center div. Hematology Oncology	Dallas	Texas	United States	75216
27	MD Anderson Cancer Center	Houston	Texas	United States	77030
28	Emily Couric Clinical cancer center	Charlottesville	Virginia	United States	22908
29	Swedish Cancer Institute	Seattle	Washington	United States	98104
30	Thomas Reeve Chauncey	Seattle	Washington	United States	98108
31	Hospital italiano de Buenos Aires	Ciudad Autonoma de Buenos Aire	Buenos Aires	Argentina	C1181ACH
32	Instituto Medico Especializado Alexander Fleming	Ciudad Autonoma de Buenos Aire	Buenos Aires	Argentina	C1426ANZ
33	hospital Italiano la Plata	La Plata	Buenos Aires	Argentina	B1900AXI
34	Sanatorio Britanico SA Paraguay 40, 3P	Rosario	Santa Fe	Argentina	2000
35	sanatorio Allende	Córdoba		Argentina	X5000JHQ
36	H ospi tal Privado de Cordoba	Córdoba		Argentina	X5016KEH
37	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
38	Sunshine coast university hospital	Birtinya	Queensland	Australia	4575
39	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
40	The Northern hospital Pharmacy Department, Ground Floor	Epping	Victoria	Australia	3076
41	Barwon Health, University Hospital Geelong	Geelong	Victoria	Australia	3220
42	Austin Hospital, Clinical Trial Pharmacy	Heidelberg	Victoria	Australia	3084
43	Liverpool hospital	Liverpool		Australia	2170
44	Royal Perth Hospital	Perth		Australia	6000
45	Prince of Wales Hospital	Randwick		Australia	2031
46	Krankenhaus der Elisabethinen Linz GmbH	Linz		Austria	4020
47	Müllner Hauptstrabe 48	Salzburg		Austria	5020
48	General Hospital Hietzing	Vienna		Austria	1130
49	Liga Paranaense de Com bate ao Cancer - Hospital Erasto Gaertner	Curitiba	Paranà	Brazil	81520-060
50	Ce ntro de Pesquisas Hospital Amara l Ca rvalh o	Jau	SP	Brazil	17210-080
51	Centro de Pesquisa Clinica do Hospital Santa Marcelina	São Paulo	SP	Brazil	0827-120
52	Hospital de Cancer de Barretos	Barretos		Brazil	1478-400
53	Hospital Santa Casa de Belo Horizonte -Serviyo de Oncologia Clinica	Belo Horizonte		Brazil	30.150-221
54	Centro de Pesquisas Oncologicas - CEPON	Florianópolis		Brazil	88034-000
55	Hospital de ClÃ-nicas de Porto Alegre	Porto Alegre		Brazil	90035-903
56	Institute Nacional de Cancer Jose de Alencar Gomes da Silva-INCA	Rio De Janeiro		Brazil	20231-050
57	Faculdade de Medicina do ABC - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André		Brazil	09060-870
58	Hospital de Base de Sao Jose do Rio Preto	São José Do Rio Preto		Brazil	15090-000
59	"Fakultni nemocnice Hradec Kralove,	Hradec Králové		Czechia	5oo 05
60	Fakultni nemocnice Olomuc	Olomouc		Czechia	77900
61	Vseobecna fakultni nemocnice	Praha 2		Czechia	I28 08
62	"Fakultni nemocnice Kralovske Vinohrady,	Praha		Czechia	100 34
63	Fakultni nemocnice Kralovske Vinohrady,	Praha		Czechia	10034
64	CHU Amiens Picardie-Site Sud-Service d'Hematologie	Amiens		France	800054
65	L'Hopital privé du Confluent SAS	Nantes		France	44277
66	CHU de Nice, Archet 1 Hospital-Hematology department	Nice		France
67	Hospital saints Louis	Paris		France	75475
68	Haut-Leveque-Service d'hématologie clinique et de thérapie cellular	Pessac		France	33604
69	Centre Hospitalier Lyon Sud	Pierre-Bénite		France	69495
70	Centre Henri Becquerel	Rouen Cedex 1		France	76028
71	Universitatsklinikum Erlangen	Erlangen	Bavaria	Germany	91054
72	Klinikum St. Marien Amberg	Amberg	Bayern	Germany	92224
73	Marien Hospital Herne-Universitätsklinikum der Ruhr-Universität Bochum	Herne	North Rhine-westphalia	Germany	44625
74	Charité-Universitätsmedizin - 1. Campus Mitte	Berlin		Germany	10117
75	Klinikum Chemnitz gGmbH	Chemnitz		Germany	09116
76	SRH Wald-Klinikum Gera GmbH	Gera		Germany	07548
77	Staedtisches krankenhaus kiel	Kiel		Germany	24116
78	Universitaet Mainz	Mainz		Germany	55131
79	university of Pécs	Pécs	Baranya	Hungary	7624
80	Pecsi Egyetem I. Belgy6gyaszati Klinika	Pécs	Baranya	Hungary	H-7624
81	St. Istvan & St. Laszlo Hospital, Deapartment of Hematology and Stem Cell Transplantation	Budapest		Hungary	H-1097
82	University of Debrecen Clinical Center	Debrecen		Hungary	H-4032
83	Somogy Megyei Kaposi Mor Oktato Korhaz, Dep. Of Haematology	Kaposvár		Hungary	7400
84	Szabolcs-Szatmar-Bereg megyei Korhazak es Egyetemi Oktatokorhaz â€" Josa Andras Oktatokorhaz, Hematologiai Osztaly	Nyiregyhaza		Hungary	II-1065
85	Ospedale San Raffaele-U.O. Ematologia e TMO	Milano	Lombardia	Italy	20132
86	Ospedale la Maddalena, UO Oncoematologia e TMO	Palermo	PA	Italy	90146
87	AOU Policlinico Consorziale di Bari	Bari		Italy	70124
88	AOU Policlinico Sant'Orsola-Malpighi	Bologna		Italy	40138
89	Azienda Ospedaliera-Università Careggi	Firenze		Italy	50134
90	Ospedale Policlinico San Martino	Genova		Italy	16132
91	ospedale Vito Fazzi	Lecce		Italy	73100
92	Azienda Ospedaliere Antonio Cardarelli,	Naples		Italy	80131
93	Azienda Ospedaliera Universitaria Federico II	Napoli		Italy	80131
94	Fondazione IRCCS policlinico San Matteo Pavia	Pavia		Italy	27100
95	Fondazione PTV-Policlinico Tor Vergata	Roma		Italy	00133
96	Policlinico Universitario Gemelli	Roma		Italy	00168
97	Azienda Ospedaliera Ordine Mauriziano	Torino		Italy	10128
98	Inje university Busan Paik Hospital	Busan		Korea, Republic of	47392
99	Chonnam National University Hwasun Hospital	Hwasun		Korea, Republic of	58128
100	Gachon University Gil medical center, div hematology	Incheon		Korea, Republic of	21565
101	Seoul National University Hospital, Div.Hematology/Oncology	Seoul		Korea, Republic of	0080
102	Sumsung medical center	Seoul		Korea, Republic of	06351
103	Seoul St.Mary Hospital, div hemato-oncology	Seoul		Korea, Republic of	06591
104	Ulsan University Hospital	Ulsan		Korea, Republic of	44033
105	Examen Sp. Z o.o.,	Poznań		Poland	60-192
106	Specjalistyc:my Szpi tal im. dra Alfreda Sokolowskiego	Wałbrzych		Poland	58-309
107	Uniwersytecki Szpital Kliniczny	Wrocław		Poland	50-556
108	Wojewodzkie Wielospecjalistyczne Centrum onkologii I traumatologii	Łódź		Poland	93-513
109	Spitalul Clinic Filantropia	Craiova	Jud.dolj	Romania	200143
110	Spitalul Clinic Colentina	Bucuresti		Romania	020125
111	clinical hospital Coltea Bld	Bucuresti		Romania	030171
112	Spitalul Universitar de Urgenta Bucuresti	Bucuresti		Romania	050098
113	Oncological Institute "Ion Chiricuta"	Cluj-Napoca		Romania	400015
114	institutu Regional de Oncologie Iasi	Iaşi		Romania	700483
115	Institut Català D'Oncologia (ICO)	Badalona	Barcelona	Spain	08916
116	Hospital San Pedro de Alcantara	Caceres	Extremadura	Spain	10003
117	Hosp.Universitario A Coruña-Hospital Teresa Herrera	A Coruña	Galicia	Spain	15006
118	Hospital Universitario Son Espases	Palma De Mallorca	Isla Baleares	Spain	07120
119	"Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
120	Hospital de La Santa Creu i Sant Pau	Barcelona		Spain	08041
121	Hospital Clinico San Carlos	Madrid		Spain	28040
122	Hospital Universitario la Paz	Madrid		Spain	28046
123	Hospital Univers itario HM Sanchinarro	Madrid		Spain	28050
124	Hospital Uni vcrsitario de Salamanca	Salamanca		Spain	37007
125	Hospital Universitario Virgen del Rocio	Sevilla		Spain	46013
126	Hospital Universitario y Politecnico de La Fe	Valencia		Spain	46026
127	Changhua Christian Hospital	Changhua		Taiwan	50006
128	Hematology and Oncology, Changhwa Christian Hospital	Changhua		Taiwan	500
129	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
130	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung		Taiwan	83301
131	China Medical University Hospita	Taichung		Taiwan	40447
132	Division of Hematology, National Taiwan University Hospital	Taipei		Taiwan	100
133	koo-Foundation Sun Yat-Sen Cancer Center	Taipei		Taiwan	112
134	Royal Devon & Exeter Hospital (Wonford site)	Exeter	Devon	United Kingdom	EX25DW
135	Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool	Lancashire	United Kingdom	FY3 8NR
136	Bradford Teaching Hospitals NHS Foundation trust	Bradford		United Kingdom	BD9 6RJ
137	University Hospitals Coventry and Warwickshire NHS Trust	Coventry		United Kingdom	CV2 2DX
138	Royal Liverpool University Hospital	Liverpool		United Kingdom	L7 8XP

Sponsors and Collaborators

• Helsinn Healthcare SA
• Clinipace Worldwide

Investigators

• Study Chair: Guillermo Garcia-Manero, MD, MD Anderson

Study Documents (Full-Text)

• Study Protocol - Dec 16, 2019
• Statistical Analysis Plan - Nov 11, 2020

More Information

Publications

None provided.

• Responsible Party: Helsinn Healthcare SA
• ClinicalTrials.gov Identifier: NCT03151408
• Other Study ID Numbers: PRAN-16-52
• First Posted: May 12, 2017
• Last Update Posted: Mar 10, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Helsinn Healthcare SA: AML
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Azacitidine

Study Results

Participant Flow

Recruitment Details	Approx. 130 sites worldwide (planned), 116 sites where patients were randomized. Date of 1st patient screened: 12 Jul 2017 and Date of last patient completed: 08 Aug 2020 A total of 725 patients were screened. Of these, 319 were considered screening failures, so a total of 406 patients were randomized
Pre-assignment Detail	Based on request of the IDMC, the interim analysis was actually done on 30Jun2020 when 232/390 events occurred in the study, The study was stopped for futility.

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Period Title: Overall Study
STARTED	203	203
Treated	201	201
COMPLETED	0	0
NOT COMPLETED	203	203

Baseline Characteristics

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA	Total
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection	Total of all reporting groups
Overall Participants	203	203	406
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 3.4%	5 2.5%	12 3%
>=65 years	196 96.6%	198 97.5%	394 97%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75.4 (5.48)	75.1 (5.91)	75.3 (5.69)
Sex: Female, Male (Count of Participants)
Female	87 42.9%	87 42.9%	174 42.9%
Male	116 57.1%	116 57.1%	232 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.5%	1 0.2%
Asian	27 13.3%	26 12.8%	53 13.1%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.5%	1 0.2%
Black or African American	2 1%	4 2%	6 1.5%
White	149 73.4%	140 69%	289 71.2%
More than one race	3 1.5%	3 1.5%	6 1.5%
Unknown or Not Reported	22 10.8%	28 13.8%	50 12.3%
Region of Enrollment (Count of Participants)
Australia	34 16.7%	29 14.3%	63 15.5%
Argentina	3 1.5%	2 1%	5 1.2%
Brazil	10 4.9%	15 7.4%	25 6.2%
Czechia	10 4.9%	8 3.9%	18 4.4%
France	8 3.9%	10 4.9%	18 4.4%
Germany	5 2.5%	6 3%	11 2.7%
Hungary	12 5.9%	14 6.9%	26 6.4%
Italy	19 9.4%	11 5.4%	30 7.4%
Poland	21 10.3%	13 6.4%	34 8.4%
South Korea	8 3.9%	7 3.4%	15 3.7%
Romania	10 4.9%	7 3.4%	17 4.2%
Spain	24 11.8%	28 13.8%	52 12.8%
Taiwan	17 8.4%	18 8.9%	35 8.6%
United Kingdom	6 3%	11 5.4%	17 4.2%
United States	12 5.9%	18 8.9%	30 7.4%
Austria	4 2%	6 3%	10 2.5%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	165.1 (10.23)	165.7 (8.96)	165.4 (9.61)
Smoking Habits (Count of Participants)
Non-smoker	130 64%	121 59.6%	251 61.8%
Ex-smoker	73 36%	79 38.9%	152 37.4%
Current smoker	0 0%	3 1.5%	3 0.7%
Cytogenetic Risk Category (central Lab results) (Count of Participants)
Intermediate	109 53.7%	107 52.7%	216 53.2%
Unfavorable	51 25.1%	60 29.6%	111 27.3%
Missing	43 21.2%	36 17.7%	79 19.5%
Cytogenetic Risk Category (local or central Lab results used for randomization) (Count of Participants)
Intermediate	136 67%	135 66.5%	271 66.7%
unfavorable	67 33%	68 33.5%	135 33.3%
ECOG PS (used for randomization) (Count of Participants)
Grade 0-1	113 55.7%	114 56.2%	227 55.9%
Grade 2	90 44.3%	89 43.8%	179 44.1%
ECOG PS (at cycle 1 Day 1) (Count of Participants)
Grade 0-1	114 56.2%	110 54.2%	224 55.2%
Grade 2	85 41.9%	88 43.3%	173 42.6%
Grade 3	0 0%	1 0.5%	1 0.2%
Missing	4 2%	4 2%	8 2%
Renal impairment (Count of Participants)
Normal or high: ≥ 90 mL/mg/1.73 m2	24 11.8%	28 13.8%	52 12.8%
Mildly decreased: 60-89 mL/mg/1.73 m2	118 58.1%	102 50.2%	220 54.2%
Mildly to moderately decreased: 45-59 mL/mg/1.73 m2	39 19.2%	41 20.2%	80 19.7%
Moderately to severely decreased: 30-44 mL/mg/1.73 m2	18 8.9%	28 13.8%	46 11.3%
Severely decreased: 15-29 mL/mg/1.73 m2	1 0.5%	1 0.5%	2 0.5%
Missing	3 1.5%	3 1.5%	6 1.5%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	OS measures the time from randomization to death due to any cause.
Time Frame	826 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Median (95% Confidence Interval) [days]	303	303

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8275
	Comments	P-value stratified by cytogenetic risk factor and ECOG performance status
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Morphologic Complete Remission (CR) Rate
Description	The CR rate is the proportion of patients who achieve a morphologic CR according to the response criteria <5% blasts in a bone marrow aspirate sample with spicules There should be no blasts with Auer rods No EMD Absolute Neutrophil Count (ANC) ≥1,000/μL Platelet count of ≥100,000/μL Patient must be independent of transfusions (for at least 1week before each assessment)
Time Frame	744 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Count of Participants [Participants]	24 11.8%	35 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1244
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Complete Remission Without Minimal Residual Disease (CRmrd) Rate
Description	proportion of patients who achieve a CR without minimal residual disease by multicolor flow cytometry according to the following criteria Morphologic CR Minimal Residual Disease (MRD) by MFC negative
Time Frame	826 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Count of Participants [Participants]	12 5.9%	20 9.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1430
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Cytogenetic Complete Remission (CRc) Rate
Description	The CRc rate is the proportion of patients who achieve a reversion to a normal karyotype at CR within the study period. This endpoint applies only to patients with abnormal cytogenetic at enrollment according to the following criterion Morphologic CR plus reversion to a normal karyotype (defined as no clonal abnormalities detected in a minimum of 20 mitotic cells)
Time Frame	826 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	80	64
Count of Participants [Participants]	7 3.4%	8 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9977
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Transfusion Independence (TI)
Description	Transfusion independence rate is defined as the proportion of patients who show eight weeks or over without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion during study period
Time Frame	826 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Count of Participants [Participants]	81 39.9%	81 39.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9959
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

6. Other Pre-specified Outcome

Title	Composite Complete Remission (cCR) Rate
Description	Composite complete remission (cCR) rate is the proportion of patients who achieve either a disease response of CR, CRi or MLFS (i.e., cCR = CR + CRi + MLFS) within the study period, according to the response criteria
Time Frame	744 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Count of Participants [Participants]	73 36%	64 31.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3502
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

7. Other Pre-specified Outcome

Title	Duration of Composite Complete Remission
Description	Duration of cCR response is the time from first cCR until documented relapse (the definition of relapse from CR will be applied) or death. Duration of cCR is only defined for patients who achieve a cCR
Time Frame	744 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	73	64
Median (95% Confidence Interval) [days]	576	319

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0502
	Comments
	Method	Log Rank
	Comments

8. Other Pre-specified Outcome

Title	Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30)
Description	QLQ-C30 is made of multi-item scales and single-item measures (functional and symptom scales, a global health status/QoL scale and single items). Item range is the difference between possible max and min response to individual items of the scale; most items take values from 1 to 4 (range=3). Global health status takes values from 1 to 7 (range = 6). For statistical analysis purpose, single-item and scale values were all standardized (according to linear transformation described in Scoring Manual) to obtain scores ranging 0-100. An high scale score represents an higher response level. Thus an high score for a functional scale represents an high/healthy level of functioning, an high score for the global health status/QoL represents a high QoL, an high score for a symptom scale/item represents an high level of symptomatology/problems.
Time Frame	from baseline up to 660 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Global Health Status	-7.040 (31.4458)	-2.303 (28.6611)
Functional Scale - Physical Functioning	-8.937 (32.1163)	-7.018 (25.8512)
Functional Scale - Role Functioning	-6.034 (46.3793)	-2.000 (40.2659)
Symptom Scale - Fatigue	2.107 (34.2928)	4.240 (29.7030)
Symptom Scale - Nausea and Vomiting	5.460 (28.1649)	5.263 (23.2870)
Symptom Scale - Appetite Loss	9.771 (42.8107)	3.509 (40.2150)

9. Other Pre-specified Outcome

Title	Relapse Free Survival
Description	the time from the date of achievement of CR or CRi until the date of relapse or death from any cause
Time Frame	744 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Median (95% Confidence Interval) [days]	291	190

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4656
	Comments
	Method	Log Rank
	Comments

10. Other Pre-specified Outcome

Title	Progressive Free Survival Rate (PFS)
Description	PFS is defined as the time from the date of randomization until the date of relapse (progression), or death from any cause, whichever occurs first.
Time Frame	800 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Median (95% Confidence Interval) [days]	217	220

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7063
	Comments
	Method	Log Rank
	Comments

11. Other Pre-specified Outcome

Title	Duration of Morphologic CR
Description	Duration of morphologic CR is defined as the time from the date of achievement of CR until the date of relapse (progression).
Time Frame	744 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	24	35
Median (95% Confidence Interval) [days]	NA	319

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0592
	Comments
	Method	Log Rank
	Comments

12. Other Pre-specified Outcome

Title	Time to CR
Description	Time to CR is defined as the time from the date of randomization until the date of CR in the absence of interceding therapies. The analysis set was the ITT set.
Time Frame	616 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Median (95% Confidence Interval) [days]	NA	361

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3835
	Comments
	Method	Log Rank
	Comments

13. Other Pre-specified Outcome

Title	Morphologic CR Within 6 Cycles Rate
Description	Morphologic CR within 6 cycles rate is defined as the proportion of patients who achieved CR in the absence of interceding therapies within 6 treatment cycles (i.e., during treatment phase up to Day 1 of Cycle 7 included). Analysis was performed in the ITT set.
Time Frame	within 6 cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pracinostat Plus AZA	Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection	1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
Measure Participants	203	203
Number [number of patients]	14	16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7099
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Time Frame	TEAEs are with onset date/time at or after start date/time of first intake of pracinostat /placebo, or AEs with onset date/time prior to start date/time of first intake of pracinostat/placebo that worsen in severity after start date/time of first intake of pracinostat /placebo, up to end of observation period. Observation period is defined as 30 days after last dose of pracinostat/placebo or start of new therapy for AML whichever occurs first up to 672 days. OS was collected up to 826 days.
Adverse Event Reporting Description	When evaluating all-cause mortality, the population at risk included all the patients randomized (203 patients per each arm) being the mortality linked to the efficacy endpoint. When evaluating Adverse Events, the population at risk included patients who received at least one dose of treatment (201 patients per each arm).
Arm/Group Title	Pracinostat Plus AZA		Placebo Plus AZA
Arm/Group Description	60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Pracinostat: 60 mg capsule Azacitidine: SC or IV injection		1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle. Placebos: capsule Azacitidine: SC or IV injection
All Cause Mortality
	Pracinostat Plus AZA		Placebo Plus AZA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	121/203 (59.6%)		128/203 (63.1%)
Serious Adverse Events
	Pracinostat Plus AZA		Placebo Plus AZA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	153/201 (76.1%)		151/201 (75.1%)
Blood and lymphatic system disorders
Febrile neutropenia	60/201 (29.9%)	105	53/201 (26.4%)	79
Anaemia	9/201 (4.5%)	11	9/201 (4.5%)	16
Thrombocytopenia	7/201 (3.5%)	8	5/201 (2.5%)	10
Pancytopenia	5/201 (2.5%)	10	3/201 (1.5%)	5
Neutropenia	1/201 (0.5%)	1	4/201 (2%)	4
Cardiac disorders
Atrial fibrillation	5/201 (2.5%)	6	2/201 (1%)	2
Gastrointestinal disorders
Vomiting	7/201 (3.5%)	7	2/201 (1%)	2
Nausea	6/201 (3%)	6	0/201 (0%)	0
General disorders
Pyrexia	11/201 (5.5%)	12	15/201 (7.5%)	17
Fatigue	6/201 (3%)	7	2/201 (1%)	2
Infections and infestations
Pneumonia	25/201 (12.4%)	27	31/201 (15.4%)	37
Sepsis	18/201 (9%)	20	15/201 (7.5%)	17
Urinary tract infection	9/201 (4.5%)	16	6/201 (3%)	6
Cellulitis	5/201 (2.5%)	5	5/201 (2.5%)	5
Septic shock	5/201 (2.5%)	5	4/201 (2%)	4
Lung infection	5/201 (2.5%)	5	3/201 (1.5%)	3
Bacteraemia	5/201 (2.5%)	6	2/201 (1%)	2
Neutropenic sepsis	4/201 (2%)	6	1/201 (0.5%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	3/201 (1.5%)	3	6/201 (3%)	7
Investigations
Investigations	8/201 (4%)	9	3/201 (1.5%)	3
Metabolism and nutrition disorders
Metabolism and nutrition disorders	10/201 (5%)	12	5/201 (2.5%)	5
Nervous system disorders
Nervous system disorders	10/201 (5%)	11	9/201 (4.5%)	10
Renal and urinary disorders
Renal and urinary disorders	3/201 (1.5%)	3	6/201 (3%)	6
Respiratory, thoracic and mediastinal disorders
Epistaxis	5/201 (2.5%)	9	0/201 (0%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	0/201 (0%)	0	6/201 (3%)	7
Vascular disorders
Vascular disorders	8/201 (4%)	8	5/201 (2.5%)	7
Other (Not Including Serious) Adverse Events
	Pracinostat Plus AZA		Placebo Plus AZA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/201 (98%)		193/201 (96%)
Blood and lymphatic system disorders
Anaemia	59/201 (29.4%)	126	69/201 (34.3%)	158
Febrile neutropenia	69/201 (34.3%)	123	61/201 (30.3%)	97
Thrombocytopenia	44/201 (21.9%)	97	41/201 (20.4%)	88
Neutropenia	37/201 (18.4%)	63	32/201 (15.9%)	68
Cardiac disorders
Cardiac disorders	41/201 (20.4%)	59	39/201 (19.4%)	58
Atrial fibrillation	17/201 (8.5%)	23	13/201 (6.5%)	16
Gastrointestinal disorders
Nausea	85/201 (42.3%)	125	79/201 (39.3%)	101
Vomiting	64/201 (31.8%)	96	50/201 (24.9%)	80
Constipation	56/201 (27.9%)	76	60/201 (29.9%)	76
Diarrhoea	54/201 (26.9%)	83	35/201 (17.4%)	52
Abdominal pain	16/201 (8%)	18	15/201 (7.5%)	17
Haemorrhoids	16/201 (8%)	18	11/201 (5.5%)	13
Proctalgia	10/201 (5%)	12	6/201 (3%)	7
Mouth ulceration	12/201 (6%)	13	5/201 (2.5%)	5
Oral candidiasis	11/201 (5.5%)	13	11/201 (5.5%)	11
General disorders
Pyrexia	43/201 (21.4%)	68	45/201 (22.4%)	76
Fatigue	37/201 (18.4%)	44	38/201 (18.9%)	48
Oedema peripheral	29/201 (14.4%)	42	31/201 (15.4%)	37
Asthenia	24/201 (11.9%)	32	17/201 (8.5%)	19
Infections and infestations
Pneumonia	36/201 (17.9%)	39	44/201 (21.9%)	54
Urinary tract infection	21/201 (10.4%)	29	18/201 (9%)	23
Sepsis	18/201 (9%)	20	15/201 (7.5%)	17
Upper respiratory tract infection	17/201 (8.5%)	19	7/201 (3.5%)	8
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	36/201 (17.9%)	65	46/201 (22.9%)	62
Transfusion reaction	10/201 (5%)	20	4/201 (2%)	6
Fall	10/201 (5%)	12	6/201 (3%)	6
Investigations
Investigations	74/201 (36.8%)	223	60/201 (29.9%)	108
Platelet count decreased	23/201 (11.4%)	69	7/201 (3.5%)	8
Neutrophil count decreased	16/201 (8%)	46	13/201 (6.5%)	18
Weight decreased	24/201 (11.9%)	26	15/201 (7.5%)	15
Metabolism and nutrition disorders
Hypokalaemia	48/201 (23.9%)	80	39/201 (19.4%)	60
Decreased appetite	39/201 (19.4%)	52	31/201 (15.4%)	35
Hypomagnesaemia	20/201 (10%)	23	19/201 (9.5%)	38
Hypophosphataemia	17/201 (8.5%)	18	9/201 (4.5%)	10
Hyperglycaemia	12/201 (6%)	12	11/201 (5.5%)	11
Hyponatraemia	10/201 (5%)	12	7/201 (3.5%)	8
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	41/201 (20.4%)	79	59/201 (29.4%)	86
Back pain	10/201 (5%)	17	23/201 (11.4%)	24
Pain in extremity	12/201 (6%)	12	9/201 (4.5%)	9
Nervous system disorders
Nervous system disorders	61/201 (30.3%)	88	62/201 (30.8%)	84
Dizziness	13/201 (6.5%)	14	22/201 (10.9%)	26
Headache	14/201 (7%)	20	12/201 (6%)	13
Psychiatric disorders
Psychiatric disorders	35/201 (17.4%)	47	40/201 (19.9%)	47
Insomnia	15/201 (7.5%)	18	7/201 (3.5%)	9
Renal and urinary disorders
Renal and urinary disorders	32/201 (15.9%)	46	50/201 (24.9%)	68
Acute kidney injury	13/201 (6.5%)	13	12/201 (6%)	14
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	73/201 (36.3%)	138	85/201 (42.3%)	159
Dyspnoea	15/201 (7.5%)	18	28/201 (13.9%)	29
Epistaxis	20/201 (10%)	28	13/201 (6.5%)	18
Cough	17/201 (8.5%)	20	20/201 (10%)	23
Pleural effusion	8/201 (4%)	9	13/201 (6.5%)	13
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	56/201 (27.9%)	89	57/201 (28.4%)	100
Rash	12/201 (6%)	14	10/201 (5%)	11
Vascular disorders
Vascular disorders	54/201 (26.9%)	72	39/201 (19.4%)	50
Hypertension	13/201 (6.5%)	14	15/201 (7.5%)	18
Hypotension	17/201 (8.5%)	20	11/201 (5.5%)	11
Haematoma	10/201 (5%)	10	1/201 (0.5%)	1

Limitations/Caveats

Results of the interim analysis (OS curves crossing at about 300 days) demonstrated futility according to the planned threshold and concluded that it was unlikely to meet the primary endpoint compared to the control group at the final analysis. Based on this outcome, the decision taken was to discontinue the recruitment of patients and terminate the study.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.