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

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ClinicalTrials.gov Identifier: NCT03151408

Recruitment Status : Terminated (The IDMC recommended to stop the study prematurely due to a lack of efficacy.)

First Posted : May 12, 2017

Results First Posted : March 10, 2022

Last Update Posted : March 10, 2022

Sponsor:

Collaborator:

Clinipace Worldwide

Information provided by (Responsible Party):

Helsinn Healthcare SA

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Acute Myeloid Leukemia
Interventions	Drug: Pracinostat Drug: Placebos Drug: Azacitidine
Enrollment	406

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 Details

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...	1 capsule orally, once a day, 3 tim...
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 ^[1]	203 ^[1]
Treated	201	201
Completed	0	0
Not Completed	203	203
Reason Not Completed
Adverse Event	24	23
Death	46	26
Physician Decision	13	19
Withdrawal by Subject	16	20
Progressive disease	45	61
non-compliance by patient	1	0
other reasons	56	52
randomized and not treated	2	2
[1] Screened patients

Baseline Characteristics

Arm/Group Title		Pracinostat Plus AZA	Placebo Plus AZA	Total
Arm/Group Description		60 mg capsule orally, once a day, 3...	1 capsule orally, once a day, 3 tim...	Total of all reporting groups
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 Number of Baseline Participants		203	203	406
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	203 participants	203 participants	406 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	7 3.4%	5 2.5%	12 3.0%
	>=65 years	196 96.6%	198 97.5%	394 97.0%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	203 participants	203 participants	406 participants
		75.4 (5.48)	75.1 (5.91)	75.3 (5.69)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	203 participants	203 participants	406 participants
	Female	87 42.9%	87 42.9%	174 42.9%
	Male	116 57.1%	116 57.1%	232 57.1%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	203 participants	203 participants	406 participants
	American Indian or Alaska Native	0 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 0.0%	1 0.5%	1 0.2%
	Black or African American	2 1.0%	4 2.0%	6 1.5%
	White	149 73.4%	140 69.0%	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 Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 participants
Australia		34 16.7%	29 14.3%	63 15.5%
Argentina		3 1.5%	2 1.0%	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 3.0%	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 3.0%	11 5.4%	17 4.2%
United States		12 5.9%	18 8.9%	30 7.4%
Austria		4 2.0%	6 3.0%	10 2.5%
Height Mean (Standard Deviation) Unit of measure: Cm
	Number Analyzed	203 participants	203 participants	406 participants
		165.1 (10.23)	165.7 (8.96)	165.4 (9.61)
Smoking Habits Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	203 participants	203 participants	406 participants
	Non-smoker	130 64.0%	121 59.6%	251 61.8%
	Ex-smoker	73 36.0%	79 38.9%	152 37.4%
	Current smoker	0 0.0%	3 1.5%	3 0.7%
Cytogenetic Risk Category (central Lab results) ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 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%
		[1] Measure Description: Favorable: inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary aberrations; t(8;21) lacking del (9q) or lacking complex karyotypes. Intermediate: Normal, +8, +6, -Y, del(12p) Unfavorable: del(5q)/-5, -7/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities) Unknown: All other abnormalities
Cytogenetic Risk Category (local or central Lab results used for randomization) ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 participants
Intermediate		136 67.0%	135 66.5%	271 66.7%
unfavorable		67 33.0%	68 33.5%	135 33.3%
		[1] Measure Description: Favorable: inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary aberrations; t(8;21) lacking del (9q) or lacking complex karyotypes. Intermediate: Normal, +8, +6, -Y, del(12p) Unfavorable: del(5q)/-5, -7/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities) Unknown: All other abnormalities
ECOG PS (used for randomization) ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 participants
Grade 0-1		113 55.7%	114 56.2%	227 55.9%
Grade 2		90 44.3%	89 43.8%	179 44.1%
		[1] Measure Description: Grade and Descriptions 0 - Fully active, able to carry on all pre-disease performance without restriction. - 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). - Ambulatory and capable of all selfcare, but unable to carry out any work activities; and about more than 50% of waking hours. - Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. - Completely disabled; cannot carry on any selfcare; totally confined to bed or chair - Dead
ECOG PS (at cycle 1 Day 1) ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 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 0.0%	1 0.5%	1 0.2%
Missing		4 2.0%	4 2.0%	8 2.0%
		[1] Measure Description: Grade and Descriptions 0 - Fully active, able to carry on all pre-disease performance without restriction. - 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). - Ambulatory and capable of all selfcare, but unable to carry out any work activities; and about more than 50% of waking hours. - Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. - Completely disabled; cannot carry on any selfcare; totally confined to bed or chair - Dead
Renal impairment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	203 participants	203 participants	406 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.
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Median (95% Confidence Interval) Unit of Measure: days
	303 (209 to 400)	303 (248 to 346)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8275
	Comments	P-value stratified by cytogenetic risk factor and ECOG performance status
	Method	Log Rank
	Comments	[Not Specified]

2.Secondary Outcome


Title	Morphologic Complete Remission (CR) Rate
Description	The CR rate is the proportion of patients who achieve a morphologic CR...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Measure Type: Count of Participants Unit of Measure: Participants
	24 11.8%	35 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1244
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

3.Secondary Outcome


Title	Complete Remission Without Minimal Residual Disease (CRmrd) Rate
Description	proportion of patients who achieve a CR without minimal residual disea...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Measure Type: Count of Participants Unit of Measure: Participants
	12 5.9%	20 9.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1430
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

4.Secondary Outcome


Title	Cytogenetic Complete Remission (CRc) Rate
Description	The CRc rate is the proportion of patients who achieve a reversion to ...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	80	64
Measure Type: Count of Participants Unit of Measure: Participants
	7 8.8%	8 12.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9977
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

5.Secondary Outcome


Title	Transfusion Independence (TI)
Description	Transfusion independence rate is defined as the proportion of patients...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Measure Type: Count of Participants Unit of Measure: Participants
	81 39.9%	81 39.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9959
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

6.Other Pre-specified Outcome


Title	Composite Complete Remission (cCR) Rate
Description	Composite complete remission (cCR) rate is the proportion of patients ...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Measure Type: Count of Participants Unit of Measure: Participants
	73 36.0%	64 31.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3502
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

7.Other Pre-specified Outcome


Title	Duration of Composite Complete Remission
Description	Duration of cCR response is the time from first cCR until documented r...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	73	64
Median (95% Confidence Interval) Unit of Measure: days
	576 ^[1] (276 to NA)	319 (170 to 744)

[1]

The upper confidence limit for median cannot be estimated (and it was reported as NA) as the curve that represents the upper confidence limits for the survivor function lies above 0.50. The LogLog transformation was used for computing the confidence interval

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0502
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

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 (functio...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Mean (Standard Deviation) Unit of Measure: score on a scale
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 r...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Median (95% Confidence Interval) Unit of Measure: days
	291 (217 to 429)	190 (155 to 319)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4656
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

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 da...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Median (95% Confidence Interval) Unit of Measure: days
	217 (126 to 257)	220 (182 to 271)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7063
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

11.Other Pre-specified Outcome


Title	Duration of Morphologic CR
Description	Duration of morphologic CR is defined as the time from the date of ach...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	24	35
Median (95% Confidence Interval) Unit of Measure: days
	NA ^[1] (352 to NA)	319 (119 to 744)

[1]

Median was not reachable due to low number of patients with events (CR) therefore the upper limit is not computable

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0592
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

12.Other Pre-specified Outcome


Title	Time to CR
Description	Time to CR is defined as the time from the date of randomization until...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Median (95% Confidence Interval) Unit of Measure: days
	NA ^[1] (NA to NA)	361 ^[2] (311 to NA)

[1]

Time to CR was censored at the date of the last assessment of patient status excluding CR in case no CR occurred by time of analysis. The number of subjects reaching CR was lower than 50%, then neither the median nor the confidence interval were computable

[2]

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3835
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

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 pa...
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...	1 capsule orally, once a day, 3 tim...
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
Overall Number of Participants Analyzed	203	203
Measure Type: Number Unit of Measure: number of patients
	14	16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pracinostat Plus AZA, Placebo Plus AZA
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7099
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

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...		1 capsule orally, once a day, 3 tim...
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 (%)		Affected / at Risk (%)
Total	121/203 (59.61%)		128/203 (63.05%)
Serious Adverse Events Serious Adverse Events
	Pracinostat Plus AZA		Placebo Plus AZA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	153/201 (76.12%)		151/201 (75.12%)
Blood and lymphatic system disorders
Febrile neutropenia ^†	60/201 (29.85%)	105	53/201 (26.37%)	79
Anaemia ^†	9/201 (4.48%)	11	9/201 (4.48%)	16
Thrombocytopenia ^†	7/201 (3.48%)	8	5/201 (2.49%)	10
Pancytopenia ^†	5/201 (2.49%)	10	3/201 (1.49%)	5
Neutropenia ^†	1/201 (0.50%)	1	4/201 (1.99%)	4
Cardiac disorders
Atrial fibrillation ^†	5/201 (2.49%)	6	2/201 (1.00%)	2
Gastrointestinal disorders
Vomiting ^†	7/201 (3.48%)	7	2/201 (1.00%)	2
Nausea ^†	6/201 (2.99%)	6	0/201 (0.00%)	0
General disorders
Pyrexia ^†	11/201 (5.47%)	12	15/201 (7.46%)	17
Fatigue ^†	6/201 (2.99%)	7	2/201 (1.00%)	2
Infections and infestations
Pneumonia ^†	25/201 (12.44%)	27	31/201 (15.42%)	37
Sepsis ^†	18/201 (8.96%)	20	15/201 (7.46%)	17
Urinary tract infection ^†	9/201 (4.48%)	16	6/201 (2.99%)	6
Cellulitis ^†	5/201 (2.49%)	5	5/201 (2.49%)	5
Septic shock ^†	5/201 (2.49%)	5	4/201 (1.99%)	4
Lung infection ^†	5/201 (2.49%)	5	3/201 (1.49%)	3
Bacteraemia ^†	5/201 (2.49%)	6	2/201 (1.00%)	2
Neutropenic sepsis ^†	4/201 (1.99%)	6	1/201 (0.50%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications ^†	3/201 (1.49%)	3	6/201 (2.99%)	7
Investigations
Investigations ^†	8/201 (3.98%)	9	3/201 (1.49%)	3
Metabolism and nutrition disorders
Metabolism and nutrition disorders ^†	10/201 (4.98%)	12	5/201 (2.49%)	5
Nervous system disorders
Nervous system disorders ^†	10/201 (4.98%)	11	9/201 (4.48%)	10
Renal and urinary disorders
Renal and urinary disorders ^†	3/201 (1.49%)	3	6/201 (2.99%)	6
Respiratory, thoracic and mediastinal disorders
Epistaxis ^†	5/201 (2.49%)	9	0/201 (0.00%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders ^†	0/201 (0.00%)	0	6/201 (2.99%)	7
Vascular disorders
Vascular disorders ^†	8/201 (3.98%)	8	5/201 (2.49%)	7
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pracinostat Plus AZA		Placebo Plus AZA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/201 (98.01%)		193/201 (96.02%)
Blood and lymphatic system disorders
Anaemia ^†	59/201 (29.35%)	126	69/201 (34.33%)	158
Febrile neutropenia ^†	69/201 (34.33%)	123	61/201 (30.35%)	97
Thrombocytopenia ^†	44/201 (21.89%)	97	41/201 (20.40%)	88
Neutropenia ^†	37/201 (18.41%)	63	32/201 (15.92%)	68
Cardiac disorders
Cardiac disorders ^†	41/201 (20.40%)	59	39/201 (19.40%)	58
Atrial fibrillation ^†	17/201 (8.46%)	23	13/201 (6.47%)	16
Gastrointestinal disorders
Nausea ^†	85/201 (42.29%)	125	79/201 (39.30%)	101
Vomiting ^†	64/201 (31.84%)	96	50/201 (24.88%)	80
Constipation ^†	56/201 (27.86%)	76	60/201 (29.85%)	76
Diarrhoea ^†	54/201 (26.87%)	83	35/201 (17.41%)	52
Abdominal pain ^†	16/201 (7.96%)	18	15/201 (7.46%)	17
Haemorrhoids ^†	16/201 (7.96%)	18	11/201 (5.47%)	13
Proctalgia ^†	10/201 (4.98%)	12	6/201 (2.99%)	7
Mouth ulceration ^†	12/201 (5.97%)	13	5/201 (2.49%)	5
Oral candidiasis ^†	11/201 (5.47%)	13	11/201 (5.47%)	11
General disorders
Pyrexia ^†	43/201 (21.39%)	68	45/201 (22.39%)	76
Fatigue ^†	37/201 (18.41%)	44	38/201 (18.91%)	48
Oedema peripheral ^†	29/201 (14.43%)	42	31/201 (15.42%)	37
Asthenia ^†	24/201 (11.94%)	32	17/201 (8.46%)	19
Infections and infestations
Pneumonia ^†	36/201 (17.91%)	39	44/201 (21.89%)	54
Urinary tract infection ^†	21/201 (10.45%)	29	18/201 (8.96%)	23
Sepsis ^†	18/201 (8.96%)	20	15/201 (7.46%)	17
Upper respiratory tract infection ^†	17/201 (8.46%)	19	7/201 (3.48%)	8
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications ^†	36/201 (17.91%)	65	46/201 (22.89%)	62
Transfusion reaction ^†	10/201 (4.98%)	20	4/201 (1.99%)	6
Fall ^†	10/201 (4.98%)	12	6/201 (2.99%)	6
Investigations
Investigations ^†	74/201 (36.82%)	223	60/201 (29.85%)	108
Platelet count decreased ^†	23/201 (11.44%)	69	7/201 (3.48%)	8
Neutrophil count decreased ^†	16/201 (7.96%)	46	13/201 (6.47%)	18
Weight decreased ^†	24/201 (11.94%)	26	15/201 (7.46%)	15
Metabolism and nutrition disorders
Hypokalaemia ^†	48/201 (23.88%)	80	39/201 (19.40%)	60
Decreased appetite ^†	39/201 (19.40%)	52	31/201 (15.42%)	35
Hypomagnesaemia ^†	20/201 (9.95%)	23	19/201 (9.45%)	38
Hypophosphataemia ^†	17/201 (8.46%)	18	9/201 (4.48%)	10
Hyperglycaemia ^†	12/201 (5.97%)	12	11/201 (5.47%)	11
Hyponatraemia ^†	10/201 (4.98%)	12	7/201 (3.48%)	8
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders ^†	41/201 (20.40%)	79	59/201 (29.35%)	86
Back pain ^†	10/201 (4.98%)	17	23/201 (11.44%)	24
Pain in extremity ^†	12/201 (5.97%)	12	9/201 (4.48%)	9
Nervous system disorders
Nervous system disorders ^†	61/201 (30.35%)	88	62/201 (30.85%)	84
Dizziness ^†	13/201 (6.47%)	14	22/201 (10.95%)	26
Headache ^†	14/201 (6.97%)	20	12/201 (5.97%)	13
Psychiatric disorders
Psychiatric disorders ^†	35/201 (17.41%)	47	40/201 (19.90%)	47
Insomnia ^†	15/201 (7.46%)	18	7/201 (3.48%)	9
Renal and urinary disorders
Renal and urinary disorders ^†	32/201 (15.92%)	46	50/201 (24.88%)	68
Acute kidney injury ^†	13/201 (6.47%)	13	12/201 (5.97%)	14
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders ^†	73/201 (36.32%)	138	85/201 (42.29%)	159
Dyspnoea ^†	15/201 (7.46%)	18	28/201 (13.93%)	29
Epistaxis ^†	20/201 (9.95%)	28	13/201 (6.47%)	18
Cough ^†	17/201 (8.46%)	20	20/201 (9.95%)	23
Pleural effusion ^†	8/201 (3.98%)	9	13/201 (6.47%)	13
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders ^†	56/201 (27.86%)	89	57/201 (28.36%)	100
Rash ^†	12/201 (5.97%)	14	10/201 (4.98%)	11
Vascular disorders
Vascular disorders ^†	54/201 (26.87%)	72	39/201 (19.40%)	50
Hypertension ^†	13/201 (6.47%)	14	15/201 (7.46%)	18
Hypotension ^†	17/201 (8.46%)	20	11/201 (5.47%)	11
Haematoma ^†	10/201 (4.98%)	10	1/201 (0.50%)	1
† Indicates events were collected by systematic assessment

Limitations and 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.

More Information

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Francesco Scarci
Organization:	Helsinn Healthcare SA
Phone:	+41 (0)91 985 1946
EMail:	francesco.scarci@helsinn.com

Layout table for additonal information

Responsible Party:	Helsinn Healthcare SA
ClinicalTrials.gov Identifier:	NCT03151408
Other Study ID Numbers:	PRAN-16-52
First Submitted:	May 5, 2017
First Posted:	May 12, 2017
Results First Submitted:	August 20, 2021
Results First Posted:	March 10, 2022
Last Update Posted:	March 10, 2022

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