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    Clinical Trial Results:
    A phase I study of Human Pharmacokinetics and Safety of ORY-1001, and LSD1 inhibitor, in relapsed or refractory acute leukaemia (AL)

    Summary
    EudraCT number
    2013-002447-29
    Trial protocol
    ES   GB  
    Global end of trial date
    01 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jun 2020
    First version publication date
    26 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL01-ORY-1001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Oryzon Genomics S.A
    Sponsor organisation address
    c/Sant Ferran 74, Cornella de LLobregat, Spain, 08940
    Public contact
    Sonia Gutierrez, Oryzon Genomics S.A., +34 935151313, sgutierrez@oryzon.com
    Scientific contact
    Roger Bullock, Oryzon Genomics S.A., +34 935151313, rbullock@oryzon.com
    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
    01 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety (haematological and non-haematological toxicities) and tolerability of ORY-1001 in patients with relapsed/refractory AL. The secondary objectives were to: - Characterise the PK of orally administered ORY-1001 in patients with relapsed/refractory AL - Characterise the PD of orally administered ORY-1001 in patients with relapsed/refractory AL. - Assess remission rate (CR/CRi, PR) of ORY-1001 in patients with relapsed/refractory AL, particularly in those with rMLL gene, TAL1/LMO overexpression or Notch1 activation, as the drug shows more benefit in vitro or in animal models of AL.
    Protection of trial subjects
    A Safety Monitoring Committee was responsible for the decisions related with dose escalation. Additionally, the committee was responsible for decisions of stopping the trial in case of unacceptable toxicities. The committee was formed by representatives of the sponsor and the investigators from all participating sites and reviewed safety data on an ongoing basis.
    Background therapy
    As previously mentioned, relapsed/refractory AL has very poor prognosis, the only curative strategy is hematopoietic allotransplant but up to 50% of patients won’t be suitable candidates for this procedure (not achieving CR/CRi, early relapse, and unacceptable co-morbidity index) or will relapse after this procedure. Relapse has been associated with the inability of current treatment to eradicate leukemic stem cells. Investigation of new therapeutic drugs is imperative. ORY-1001 has demonstrated to be safe and effective to treat AL in animal models, and it seems that rMLL AL, TAL1 or LMO complex over-expressing or Notch1 activated AL and promyelocytic leukaemia, may particularly benefit from this drug
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Scientific research
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    France: 10
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    17
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was performed in 10 sites: Spain(5), UK(2), France(3). 43 pats were screened: 1 was screening failure and 1 died prior to treatment. 41 pats received study medication: 27 pats entered in dose escalation cohorts, 12 completed the study and 15 discontinued. 14 pats entered in the expansion cohort: 3 completed the study and 11 discontinued

    Pre-assignment
    Screening details
    Patients aged 16 and above , must have relapsed or refractory AL (excluding promyelocytic leukaemia) considered by the investigator ineligible for intensive chemotherapy regimen at that time and must have ECOG Performance Status (PS) of 0-2 .

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    COHORT 1 - ORY 1001 - 5 μg/m2/d
    Arm description
    Cohort 1 - ORY 1001 - 5 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-days cycles.

    Arm title
    COHORT 2 - ORY 1001 - 15 μg/m2/d
    Arm description
    Cohort 2 - ORY 1001 - 15 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-days cycles.

    Arm title
    COHORT 3 - ORY 1001 - 30 μg/m2/d
    Arm description
    Cohort 3 - ORY 1001 - 30 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-days cycles.

    Arm title
    COHORT 4 - ORY 1001 - 45 μg/m2/d
    Arm description
    Cohort 4 - ORY 1001 - 45 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-day cycles.

    Arm title
    COHORT 5 - ORY 1001 - 60 μg/m2/d
    Arm description
    Cohort 5 - ORY 1001 - 60 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-day cycles.

    Arm title
    COHORT 6 - ORY 1001 - 80 μg/m2/d
    Arm description
    Cohort 6 - ORY 1001 - 80 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-day cycles.

    Arm title
    COHORT 7- ORY 1001 - 140 μg/m2/d
    Arm description
    Cohort 7 - ORY 1001 - 140 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest for 4 blocks during 28-days cycles.

    Arm title
    COHORT 8 - ORY 1001 - 220 μg/m2/d
    Arm description
    Cohort 8 - ORY 1001 - 220 μg/m2/d
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest for 4 blocks during 28-days cycles.

    Arm title
    EXPANSION COHORT - ORY1001 -140 μg/m2/d
    Arm description
    Extension Cohort, 140 μg/m2/d, as agreed by SMC
    Arm type
    Experimental

    Investigational medicinal product name
    ORY1001
    Investigational medicinal product code
    Other name
    Iadademstat
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    ORY-1001 for oral intake once daily during 5 consecutive days with 2 days of rest during 28-days cycles.

    Number of subjects in period 1
    COHORT 1 - ORY 1001 - 5 μg/m2/d COHORT 2 - ORY 1001 - 15 μg/m2/d COHORT 3 - ORY 1001 - 30 μg/m2/d COHORT 4 - ORY 1001 - 45 μg/m2/d COHORT 5 - ORY 1001 - 60 μg/m2/d COHORT 6 - ORY 1001 - 80 μg/m2/d COHORT 7- ORY 1001 - 140 μg/m2/d COHORT 8 - ORY 1001 - 220 μg/m2/d EXPANSION COHORT - ORY1001 -140 μg/m2/d
    Started
    3
    3
    3
    3
    4
    3
    3
    5
    14
    Completed
    2
    2
    3
    1
    1
    1
    1
    1
    3
    Not completed
    1
    1
    0
    2
    3
    2
    2
    4
    11
         INTERCURRENT ILLNES
    -
    -
    -
    -
    -
    1
    -
    -
    -
         DEATH DUE TO SEPSIS
    -
    -
    -
    -
    1
    -
    -
    -
    -
         DEPRESSED LEVEL OF CONSCIUSNESS
    -
    -
    -
    -
    1
    -
    -
    -
    -
         UNACEPTABLE TOXICITY
    -
    -
    -
    -
    -
    -
    -
    1
    -
         DEATH
    -
    1
    -
    -
    -
    -
    2
    1
    2
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    -
    1
    1
         DISEASE PROGRESSION
    1
    -
    -
    2
    1
    1
    -
    1
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    COHORT 1 - ORY 1001 - 5 μg/m2/d
    Reporting group description
    Cohort 1 - ORY 1001 - 5 μg/m2/d

    Reporting group title
    COHORT 2 - ORY 1001 - 15 μg/m2/d
    Reporting group description
    Cohort 2 - ORY 1001 - 15 μg/m2/d

    Reporting group title
    COHORT 3 - ORY 1001 - 30 μg/m2/d
    Reporting group description
    Cohort 3 - ORY 1001 - 30 μg/m2/d

    Reporting group title
    COHORT 4 - ORY 1001 - 45 μg/m2/d
    Reporting group description
    Cohort 4 - ORY 1001 - 45 μg/m2/d

    Reporting group title
    COHORT 5 - ORY 1001 - 60 μg/m2/d
    Reporting group description
    Cohort 5 - ORY 1001 - 60 μg/m2/d

    Reporting group title
    COHORT 6 - ORY 1001 - 80 μg/m2/d
    Reporting group description
    Cohort 6 - ORY 1001 - 80 μg/m2/d

    Reporting group title
    COHORT 7- ORY 1001 - 140 μg/m2/d
    Reporting group description
    Cohort 7 - ORY 1001 - 140 μg/m2/d

    Reporting group title
    COHORT 8 - ORY 1001 - 220 μg/m2/d
    Reporting group description
    Cohort 8 - ORY 1001 - 220 μg/m2/d

    Reporting group title
    EXPANSION COHORT - ORY1001 -140 μg/m2/d
    Reporting group description
    Extension Cohort, 140 μg/m2/d, as agreed by SMC

    Reporting group values
    COHORT 1 - ORY 1001 - 5 μg/m2/d COHORT 2 - ORY 1001 - 15 μg/m2/d COHORT 3 - ORY 1001 - 30 μg/m2/d COHORT 4 - ORY 1001 - 45 μg/m2/d COHORT 5 - ORY 1001 - 60 μg/m2/d COHORT 6 - ORY 1001 - 80 μg/m2/d COHORT 7- ORY 1001 - 140 μg/m2/d COHORT 8 - ORY 1001 - 220 μg/m2/d EXPANSION COHORT - ORY1001 -140 μg/m2/d Total
    Number of subjects
    3 3 3 3 4 3 3 5 14 41
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    0 3 1 1 1 0 2 1 8 17
        From 65-84 years
    3 0 2 2 3 3 1 4 6 24
    Gender categorical
    Units: Subjects
        Female
    0 0 1 2 2 1 1 1 5 13
        Male
    3 3 2 1 2 2 2 4 9 28
    Subject analysis sets

    Subject analysis set title
    Safety analysis (SA) set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received any amount of ORY-1001 were included in the data summaries for safety (Safety Population).

    Subject analysis set title
    Full analysis (FA) set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients who received any amount of ORY-1001 and had protocol evaluations performed in concordance with the time points defined in the protocol, irrespective of whether they completed the schedule or not, were included in data summaries for analysis. Baseline was the date of the first dose of ORY-1001. Patients who had received any amount of ORY-1001, and had any post-baseline efficacy assessment were analysed for efficacy parameters (Treated Population).

    Subject analysis sets values
    Safety analysis (SA) set Full analysis (FA) set
    Number of subjects
    41
    41
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17
    17
        From 65-84 years
    24
    24
    Age continuous
    Units: years
        median (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    13
    13
        Male
    28
    28

    End points

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    End points reporting groups
    Reporting group title
    COHORT 1 - ORY 1001 - 5 μg/m2/d
    Reporting group description
    Cohort 1 - ORY 1001 - 5 μg/m2/d

    Reporting group title
    COHORT 2 - ORY 1001 - 15 μg/m2/d
    Reporting group description
    Cohort 2 - ORY 1001 - 15 μg/m2/d

    Reporting group title
    COHORT 3 - ORY 1001 - 30 μg/m2/d
    Reporting group description
    Cohort 3 - ORY 1001 - 30 μg/m2/d

    Reporting group title
    COHORT 4 - ORY 1001 - 45 μg/m2/d
    Reporting group description
    Cohort 4 - ORY 1001 - 45 μg/m2/d

    Reporting group title
    COHORT 5 - ORY 1001 - 60 μg/m2/d
    Reporting group description
    Cohort 5 - ORY 1001 - 60 μg/m2/d

    Reporting group title
    COHORT 6 - ORY 1001 - 80 μg/m2/d
    Reporting group description
    Cohort 6 - ORY 1001 - 80 μg/m2/d

    Reporting group title
    COHORT 7- ORY 1001 - 140 μg/m2/d
    Reporting group description
    Cohort 7 - ORY 1001 - 140 μg/m2/d

    Reporting group title
    COHORT 8 - ORY 1001 - 220 μg/m2/d
    Reporting group description
    Cohort 8 - ORY 1001 - 220 μg/m2/d

    Reporting group title
    EXPANSION COHORT - ORY1001 -140 μg/m2/d
    Reporting group description
    Extension Cohort, 140 μg/m2/d, as agreed by SMC

    Subject analysis set title
    Safety analysis (SA) set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients who received any amount of ORY-1001 were included in the data summaries for safety (Safety Population).

    Subject analysis set title
    Full analysis (FA) set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients who received any amount of ORY-1001 and had protocol evaluations performed in concordance with the time points defined in the protocol, irrespective of whether they completed the schedule or not, were included in data summaries for analysis. Baseline was the date of the first dose of ORY-1001. Patients who had received any amount of ORY-1001, and had any post-baseline efficacy assessment were analysed for efficacy parameters (Treated Population).

    Primary: Tolerability

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    End point title
    Tolerability
    End point description
    End point type
    Primary
    End point timeframe
    Evaluate the tolerability of ORY-1001 along of cycle of treatment
    End point values
    COHORT 1 - ORY 1001 - 5 μg/m2/d COHORT 2 - ORY 1001 - 15 μg/m2/d COHORT 3 - ORY 1001 - 30 μg/m2/d COHORT 4 - ORY 1001 - 45 μg/m2/d COHORT 5 - ORY 1001 - 60 μg/m2/d COHORT 6 - ORY 1001 - 80 μg/m2/d COHORT 7- ORY 1001 - 140 μg/m2/d COHORT 8 - ORY 1001 - 220 μg/m2/d EXPANSION COHORT - ORY1001 -140 μg/m2/d Full analysis (FA) set
    Number of subjects analysed
    3
    3
    3
    3
    4
    3
    3
    5
    14
    41
    Units: Patients
        Dose limiting toxicities
    0
    0
    0
    0
    0
    0
    0
    2
    0
    2
    Statistical analysis title
    Dose limiting toxicities
    Statistical analysis description
    Escalation has been proceed according to a standard Phase I design in which cohorts of 3-6 patients were treated per dose level (Simon et al., 1997); dose increases had been applied according to a modified Fibonacci scheme (Cohorts 1 to 6) and then by a genuine Fibonacci scheme for Cohorts 7 and 8.
    Comparison groups
    COHORT 1 - ORY 1001 - 5 μg/m2/d v COHORT 2 - ORY 1001 - 15 μg/m2/d v COHORT 3 - ORY 1001 - 30 μg/m2/d v COHORT 4 - ORY 1001 - 45 μg/m2/d v COHORT 5 - ORY 1001 - 60 μg/m2/d v COHORT 6 - ORY 1001 - 80 μg/m2/d v COHORT 7- ORY 1001 - 140 μg/m2/d v COHORT 8 - ORY 1001 - 220 μg/m2/d v EXPANSION COHORT - ORY1001 -140 μg/m2/d
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0
    Method
    NA
    Parameter type
    NA
    Point estimate
    0.5
    Confidence interval
         level
    0%
         sides
    1-sided
         lower limit
    -
         upper limit
    1
    Notes
    [1] - Maximum Tolerated Dose: the highest dose for which no more than 1 of the 6 treated patients exhibits DLT. The Maximum Tolerated Dose and Dose Limiting Toxicities were assessed in a dose escalation cohort, and an extension cohort was treated at the Maximum Tolerated Dose.

    Secondary: Efficacy

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    End point title
    Efficacy
    End point description
    CRi: Morphologic Complete remission but with incomplete blood count recovery Resistant disease (RD): Failure to achieve CR or CRi, or failure to achieve CR, CRi or PR; only includes patients surviving > 7d following completion of initial treatment, with evidence of persistent leukaemia by blood and/or BM examination. Death in aplasia (DA): Deaths occurring > 7d following completion of initial treatment while cytopenic; with an aplastic or hypoplastic BM maintained within 7d of death, without evidence of persistent leukaemia. Death from indeterminate cause (DI) Deaths occurring before completion of therapy, or <7d following its completion; or deaths occurring >7d following completion of initial therapy with no blasts in the blood, but no BM examination available Relapse: BM blasts > 5%; or reappearance of blasts in the blood; or development of extramedullary disease.
    End point type
    Secondary
    End point timeframe
    Bone marrow aspirate had been analyzed on basal and after each cycle (+/-3d)
    End point values
    COHORT 1 - ORY 1001 - 5 μg/m2/d COHORT 2 - ORY 1001 - 15 μg/m2/d COHORT 3 - ORY 1001 - 30 μg/m2/d COHORT 4 - ORY 1001 - 45 μg/m2/d COHORT 5 - ORY 1001 - 60 μg/m2/d COHORT 6 - ORY 1001 - 80 μg/m2/d COHORT 7- ORY 1001 - 140 μg/m2/d COHORT 8 - ORY 1001 - 220 μg/m2/d EXPANSION COHORT - ORY1001 -140 μg/m2/d Full analysis (FA) set
    Number of subjects analysed
    3
    3
    3
    3
    4
    3
    3
    4
    12
    38
    Units: Patients
        CRi
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
        RD
    3
    3
    2
    3
    1
    3
    2
    4
    9
    30
        DA
    0
    0
    0
    0
    2
    0
    1
    0
    2
    5
        DI
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Relapse
    0
    0
    1
    0
    0
    0
    0
    0
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time frame defined as the period from the administration of the first dose of ORY-1001 until the final visit, planned approximately 30 days after receiving the last dose.
    Adverse event reporting additional description
    An AE should preferably be documented in terms of one single medical term (diagnosis). Only when this is not feasible, an AE may be documented in terms of the predominant signs and/or symptoms observed by the investigator or reported by the patient at each study visit. If possible, the terminology should adhere to the one used in CTCA 4.0
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    All patients who received any amount of ORY-1001 were included in the data summaries for safety (Safety Population).

    Serious adverse events
    Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 41 (85.37%)
         number of deaths (all causes)
    26
         number of deaths resulting from adverse events
    26
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia cutis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Graft versus host disease in liver
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Pyrexia
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pericarditis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    12 / 41 (29.27%)
         occurrences causally related to treatment / all
    4 / 14
         deaths causally related to treatment / all
    0 / 2
    Leukocytosis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Differentiation syndrome
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    Interstitial lung disease
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 3
    Sepsis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Cellulitis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    Pneumonia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 3
    Anal abscess
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skin infection
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    5
    Haematoma
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Phlebitis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Respiratory failure
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Productive cough
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Pleural effusion
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Rhinorrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    22 / 41 (53.66%)
         occurrences all number
    27
    Thrombocytopenia
         subjects affected / exposed
    8 / 41 (19.51%)
         occurrences all number
    11
    Leukocytosis
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    6
    Neutropenia
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Anaemia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    6
    Headache
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    10
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 41 (39.02%)
         occurrences all number
    24
    Pyrexia
         subjects affected / exposed
    12 / 41 (29.27%)
         occurrences all number
    14
    Oedema peripheral
         subjects affected / exposed
    8 / 41 (19.51%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    9
    Disease progression
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Chest pain
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Mucosal inflammation
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Oedema
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 41 (41.46%)
         occurrences all number
    23
    Constipation
         subjects affected / exposed
    11 / 41 (26.83%)
         occurrences all number
    14
    Nausea
         subjects affected / exposed
    11 / 41 (26.83%)
         occurrences all number
    13
    Vomiting
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    7
    Dry mouth
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Haemorrhoids
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    9
    Pruritus
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Rash maculo-papular
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    11
    Hypokalaemia
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    9
    Hypocalcaemia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Lung infection
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Sepsis
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Oral candidiasis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Oral herpes
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Pneumonia
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2013
    Protocol version 3 date 16 October 2013 was amended to update the times of collection PK/PD samples.
    26 Sep 2014
    Protocol version 7 date 26 September 2014 was amended - to include nucleic acid sequencing on study samples - to modify or to extend dose escalation - to shorten the accrual interval between patients enrolled in a given dose cohort. Patients were included consecutively in each dose level with a minimum time interval of one week to allow for detection of serious and/or unexpected AEs before further patients were treated. -to assess ORY1001 PK parameters in whole blood
    28 Jan 2015
    Protocol version 7.1 date 28 January 2015 .At the request of the Medicines and Healthcare Products Regulatory Authority, UK, a maximum dose of ORY-1001 was included in the protocol. A maximum dose of 580 μg/m2/day was chosen (unless DLT are identified at a lower dose) based on the initial maximal dose (141 μg/m2) corrected by the factor for pre-clinical (dog) to human exposure (< 4.5 X 141 μg/m2=630 μg/m2) and 2 new cohorts, with
    06 Mar 2015
    Protocol version 8.0 date 06 March 2015 The change in maximum dose of ORY-1001 requested by the Medicines and Healthcare Products Regulatory Authority, UK, and included in Protocol version 7.1 date 28 January 2015 was included in the global protocol. -The planned number of sites was increased to include 3 sites in France, and 1 more site in the UK. -The time frame of the study was prolonged; study end was planned for the 2nd quarter 2016. -An interim analysis was planned when the MTD was reached. After the Interim Report the Safety Monitoring Committee decided the priority subtypes of AML to be included in the extension arm, dosing regimen and total number of patients in the extension. For clarification of the definition of the analysis population to be used for the safety analysis the following statement of the protocol was ignored: “Patients who are treated with ORY-1001, but have no follow up for safety, will not be included in safety analyses, because their inclusion would dilute percentages of patients with AEs or laboratory toxicities.“ (see protocol section. 10.6. Procedures for handling missing, unused and spurious data). This was contradictory to the definition of the safety set given in the former sections of the protocol. Instead all patients who received any amount of ORY-1001 were included in data summaries for safety
    12 Oct 2015
    Protocol version 9.0 date 12 October 2015 -PD-LSD1 target engagement analysis was added to the PD assessments to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship and dose response to LSD1 inhibitors in clinical samples. -To improve recruitment, the number of sites was increased to 5 hospitals in Spain, 2 in UK and 3 in France. -Changes to the planned analyses Transfusions can interfere with PK/PD measurements, it was therefore planned that if the patient required a transfusion during the 5 day treatment block, the PK/PD readouts following the transfusion would be recorded but omitted from analysis. This was not done because the PD responses measured over 24 hours on Days 1, 5 and 26 were expected to be relatively independent of these factors. Additional analyses -The Medical Statistics Core Facility at IDIBAPS (Institute d'investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain performed an additional analysis of the peripheral blasts. - A population pharmacokinetic/ pharmacodynamic model was developed to identify and quantify the impact of intrinsic and extrinsic factors on the pharmacokinetics of ORY1001 and to evaluate the relationship between exposure and effect (changes on blasts counts). Marta Valle, PharmD, PhD was responsible for the PKPD modeling and simulation at the Institut de Recerca de l'HSCSP, Hospital de la Santa Creu i Sant Pau, Spain. The complete report is included in Section 16.1.14.

    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
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