Clinical Trial Results:
A randomized phase II multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in UNFIT (i.e. HCT-CI ≥ 3) AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) patients aged >=66 years. A study in the frame of the masterprotocol of parallel randomized phase II studies in UNFIT-older AML/high-risk MDS patients.

Trial information Top of page
Trial identification
Sponsor protocol code	HO135
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Other trial identifiers	METC UMCG: 2015.550, Nederlands Trialregister: NTR6017, CCMO dossiernr: NL55164.042.15
Sponsors
Sponsor organisation name	HOVON
Sponsor organisation address	Dr. Molewaterplein 40, Rotterdam, Netherlands,
Public contact	HOVON Data Center, HOVON, hdc@erasmusmc.nl
Scientific contact	HOVON Data Center, HOVON, hdc@erasmusmc.nl
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	18 Feb 2020
Is this the analysis of the primary completion data?	Yes
Primary completion date	17 Feb 2020
Global end of trial reached?	Yes
Global end of trial date	10 Jul 2024
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	- To assess in a randomized comparison the effect of ibrutinib added to 10-day decitabine treatment on the cumulative CR/CRi rate after 3 cycles.
Protection of trial subjects	Monitoring and Insurance
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	07 Sep 2016
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Netherlands: 85
Country: Number of subjects enrolled	Belgium: 13
Country: Number of subjects enrolled	Lithuania: 10
Country: Number of subjects enrolled	Switzerland: 40
Worldwide total number of subjects	148
EEA total number of subjects	108
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	0
From 65 to 84 years	144
85 years and over	4

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	All subjects gave written informed consent and were screened according to the inclusion- and exclusion criteria
Period 1
Period 1 title	Overall period
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Experimental
Arm description	-
Arm type	Experimental
Investigational medicinal product name	decitabine
Investigational medicinal product code
Other name	DACOGEN
Pharmaceutical forms	Powder for solution for injection
Routes of administration	Intravenous use
Dosage and administration details	The 5-Day dosing regimen is defined as 20 mg/m2 DACOGEN administered as a 1 hour IV infusion for 5 consecutive days every 4weeks. The 3-Day dosing regimen is defined as 15 mg/m2 DACOGEN administered as a 3 hour IV infusion every 8 hours for 3 consecutive days every 6 weeks
Investigational medicinal product name	Ibrutinib
Investigational medicinal product code
Other name	IMBRUVICA
Pharmaceutical forms	Capsule, hard, Tablet
Routes of administration	Oral use
Dosage and administration details	The recommended dose of ibrutinib for MCL or MZL is 560 mg orally once daily until disease progression or no longer tolerated by the subject.
Arm title	Control
Arm description	Standard of care; Decatibine
Arm type	Active comparator
Investigational medicinal product name	decitabine
Investigational medicinal product code
Other name	DACOGEN
Pharmaceutical forms	Powder for solution for injection
Routes of administration	Intravenous use
Dosage and administration details	The 5-Day dosing regimen is defined as 20 mg/m2 DACOGEN administered as a 1 hour IV infusion for 5 consecutive days every 4weeks. The 3-Day dosing regimen is defined as 15 mg/m2 DACOGEN administered as a 3 hour IV infusion every 8 hours for 3 consecutive days every 6 weeks
Number of subjects in period 1 Experimental Control Started 74 74 Completed 0 0 Not completed 74 74      Adverse reactions 14 7      Other 7 11      At patient's request 13 6      Lack of efficacy 40 50

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall period
Reporting group description	-
Reporting group values Overall period Total Number of subjects 148 148 Age categorical Previously untreated adults who were >=66 years old and not considered eligible for intensive chemotherapy, with a cytopathologically confirmed diagnosis of AML or with higher risk MDS (Revised International Prognostic Scoring System score .4.5), a World Health Organization (WHO) performance status #2, and written informed consent, were eligible. Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 0 0     Adults (18-64 years) 0 0     From 65-84 years 144 144     85 years and over 4 4 Age continuous Units: years     median (full range (min-max)) 76 (66 to 89) - Gender categorical Units: Subjects     Female 56 56     Male 92 92

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Experimental
Reporting group description	-
Reporting group title	Control
Reporting group description	Standard of care; Decatibine

End points Top of page

Primary: Primary endpoint Top of page
End point title	Primary endpoint [1]
End point description
End point type	Primary
End point timeframe	See publication
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: See attached chart/documents for results
End point values Experimental Control Number of subjects analysed 74 74 Units: Whole 74 74
Attachments	Untitled (Filename: HO135_Statistical data section from publication_22MAY2025.pdf) Untitled (Filename: nonsaedata135-22May2025.pdf) Untitled (Filename: saedata135-22May2025.pdf)
No statistical analyses for this end point

Primary: Primary endpoint Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Adverse events will be reported from the first study-related procedure until 30 days following the last dose of any drug from the protocol treatment schedule or until the start of subsequent systemic therapy for the disease under study, if earlier.
Adverse event reporting additional description	Adverse events occurring after 30 days should also be reported if considered at least possibly related to the investigational medicinal product by the local investigator.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	CTCAE
Dictionary version	4
Reporting groups
Reporting group title	Control group
Reporting group description	-
Reporting group title	Experimental group
Reporting group description	Actual number of deaths all causes is 72. Patient died after randomization but before starting treatment.
Serious adverse events Control group Experimental group Total subjects affected by serious adverse events      subjects affected / exposed 59 / 73 (80.82%) 65 / 71 (91.55%)      number of deaths (all causes) 70 71      number of deaths resulting from adverse events Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 6 / 73 (8.22%) 6 / 71 (8.45%)      occurrences causally related to treatment / all 0 / 8 1 / 6      deaths causally related to treatment / all 0 / 2 0 / 3 Vascular disorders Vascular disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 0 / 73 (0.00%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 General disorders and administration site conditions General disorders and administration site conditions Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 5 / 73 (6.85%) 8 / 71 (11.27%)      occurrences causally related to treatment / all 4 / 7 4 / 8      deaths causally related to treatment / all 0 / 0 0 / 2 Immune system disorders Immune system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 0 / 71 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Reproductive system and breast disorders Reproductive system and breast disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 0 / 71 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 6 / 73 (8.22%) 6 / 71 (8.45%)      occurrences causally related to treatment / all 4 / 8 2 / 6      deaths causally related to treatment / all 2 / 4 0 / 0 Psychiatric disorders Psychiatric disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 0 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Investigations Investigations Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 0 / 71 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Injury, poisoning and procedural complications Injury, poisoning and procedural complications Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 2 / 73 (2.74%) 2 / 71 (2.82%)      occurrences causally related to treatment / all 0 / 2 1 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Cardiac disorders Cardiac disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 6 / 73 (8.22%) 6 / 71 (8.45%)      occurrences causally related to treatment / all 2 / 6 4 / 6      deaths causally related to treatment / all 1 / 2 0 / 0 Nervous system disorders Nervous system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 7 / 73 (9.59%) 3 / 71 (4.23%)      occurrences causally related to treatment / all 4 / 8 0 / 3      deaths causally related to treatment / all 0 / 1 0 / 1 Blood and lymphatic system disorders Blood and lymphatic system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 21 / 73 (28.77%) 23 / 71 (32.39%)      occurrences causally related to treatment / all 29 / 32 24 / 30      deaths causally related to treatment / all 0 / 1 0 / 0 Eye disorders Eye disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 1 / 1 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Gastrointestinal disorders Gastrointestinal disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 7 / 73 (9.59%) 4 / 71 (5.63%)      occurrences causally related to treatment / all 1 / 7 2 / 4      deaths causally related to treatment / all 0 / 0 1 / 1 Hepatobiliary disorders Hepatobiliary disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 0 / 71 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 0 / 1 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Renal and urinary disorders Renal and urinary disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 2 / 73 (2.74%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 1 / 2 1 / 1      deaths causally related to treatment / all 0 / 1 0 / 0 Endocrine disorders Endocrine disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 0 / 73 (0.00%) 1 / 71 (1.41%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 0 / 73 (0.00%) 2 / 71 (2.82%)      occurrences causally related to treatment / all 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Infections and infestations Infections and infestations Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 35 / 73 (47.95%) 35 / 71 (49.30%)      occurrences causally related to treatment / all 32 / 48 22 / 48      deaths causally related to treatment / all 7 / 10 6 / 9
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events Control group Experimental group Total subjects affected by non serious adverse events      subjects affected / exposed 64 / 73 (87.67%) 66 / 71 (92.96%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 1 / 71 (1.41%)      occurrences all number 1 1 Vascular disorders Vascular disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 15 / 73 (20.55%) 12 / 71 (16.90%)      occurrences all number 15 14 Surgical and medical procedures Surgical and medical procedures Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 2 / 73 (2.74%) 0 / 71 (0.00%)      occurrences all number 2 0 General disorders and administration site conditions General disorders and administration site conditions Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 18 / 73 (24.66%) 18 / 71 (25.35%)      occurrences all number 21 24 Immune system disorders Immune system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 2 / 73 (2.74%) 1 / 71 (1.41%)      occurrences all number 2 1 Reproductive system and breast disorders Reproductive system and breast disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 0 / 73 (0.00%) 1 / 71 (1.41%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 10 / 73 (13.70%) 12 / 71 (16.90%)      occurrences all number 12 14 Psychiatric disorders Psychiatric disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 3 / 73 (4.11%) 4 / 71 (5.63%)      occurrences all number 4 6 Investigations Investigations Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 20 / 73 (27.40%) 16 / 71 (22.54%)      occurrences all number 41 27 Injury, poisoning and procedural complications Injury, poisoning and procedural complications Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 5 / 71 (7.04%)      occurrences all number 1 5 Cardiac disorders Cardiac disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 10 / 73 (13.70%) 14 / 71 (19.72%)      occurrences all number 12 17 Nervous system disorders Nervous system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 7 / 73 (9.59%) 9 / 71 (12.68%)      occurrences all number 10 11 Blood and lymphatic system disorders Blood and lymphatic system disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 13 / 73 (17.81%) 18 / 71 (25.35%)      occurrences all number 14 22 Ear and labyrinth disorders Ear and labyrinth disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 1 / 73 (1.37%) 2 / 71 (2.82%)      occurrences all number 1 2 Eye disorders Eye disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 4 / 73 (5.48%) 0 / 71 (0.00%)      occurrences all number 4 0 Gastrointestinal disorders Gastrointestinal disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 24 / 73 (32.88%) 25 / 71 (35.21%)      occurrences all number 33 39 Hepatobiliary disorders Hepatobiliary disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 0 / 73 (0.00%) 2 / 71 (2.82%)      occurrences all number 0 3 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 8 / 73 (10.96%) 14 / 71 (19.72%)      occurrences all number 8 16 Renal and urinary disorders Renal and urinary disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 5 / 73 (6.85%) 6 / 71 (8.45%)      occurrences all number 5 6 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 10 / 73 (13.70%) 4 / 71 (5.63%)      occurrences all number 12 4 Infections and infestations Infections and infestations Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 37 / 73 (50.68%) 34 / 71 (47.89%)      occurrences all number 58 51 Metabolism and nutrition disorders Metabolism and nutrition disorders Additional description: All combined, see non-SAE chart for details      subjects affected / exposed 13 / 73 (17.81%) 16 / 71 (22.54%)      occurrences all number 21 34

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
07 Feb 2017	It involves adding a new centers: Isala Clinic, Zwolle OLVG, Amsterdam Reinier de graaf groep, Delft
22 Apr 2022	It involves a change of investigators in the following hospitals: Meander MC, Amersfoort MUMC, Maastricht Rijnstate, Arnhem
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported
Online references
http://www.ncbi.nlm.nih.gov/pubmed/32915972

More information Top of page