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    Clinical Trial Results:
    HD-R3i - A prospective, randomized, placebo-controlled, international, multicenter phase I/II trial of RAD001 (everolimus) in combination with DHAP as induction therapy in patients with relapsed or refractory Hodgkin Lymphoma

    Summary
    EudraCT number
    2010-021086-73
    Trial protocol
    DE  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Apr 2020
    First version publication date
    09 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1443
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01453504
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus Magnus-Platz, Köln, Germany, 50923
    Public contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 221478 88 200, ghsg@uk-koeln.de
    Scientific contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 221478 88 200, ghsg@uk-koeln.de
    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 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I: To identify the recommended phase-II dose of RAD001 in combination with DHAP (Ever-DHAP) Phase II: To demonstrate the efficacy of Ever-DHAP as induction therapy
    Protection of trial subjects
    Written informed consent prior to study entry; IDMC monitoring; Phase I: 3+3 design with recruitment pause after completion of each dose level; start of phase II only after approval of ethics committee following review of phase I results.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    73
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between 13Aug2012 and 24Jan2014, 14 patients were enrolled into phase I according to a modified 3+3 design. Enrollment for phase II started on 04Jul2014, with randomization between verum and placebo. Due to slow recruitment, the placebo arm was closed after 9 patients, and enrollment to verum continued up to a total of 50 patients on 07Mar2018.

    Pre-assignment
    Screening details
    Main inclusion criteria: Histologically confirmed first relapse of HL, HL refractory to first-line treatment or multiple relapse without prior HDCT/SCT; Age 18-60 years; ECOG<=2; normal organ function. Main exclusion criteria: Relevant concurrent disease; pregnancy or lactation.

    Period 1
    Period 1 title
    Phase I and II (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Phase I was not randomized; patients received Ever-DHAP with everolimus on different dose levels according to a modified 3+3 design. Phase II started randomized between Ever-DHAP and Placebo-DHAP. After enrollment of 9 patients per arm, the placebo arm was closed and all subsequent patients were enrolled into the verum arm without randomization or blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase I, 2.5 mg
    Arm description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 2.5 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg everolimus administered on days 1-14 of each cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Arm title
    Phase I, 5 mg
    Arm description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 5 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg everolimus administered on days 1-14 of each cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Arm title
    Phase I, 7.5 mg
    Arm description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 7.5 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    7.5 mg everolimus administered on days 1-14 of each cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Arm title
    Phase I, 10 mg
    Arm description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg everolimus administered on days 1-14 of each cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Arm title
    Phase II, Ever-DHAP
    Arm description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg everolimus administered on days 1-14 of each cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Arm title
    Phase II, Plac-DHAP
    Arm description
    Two cycles of DHAP chemotherapy in 14-day intevals with placebo
    Arm type
    Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg dexamethasone administered on days 1-4 of each cycle

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg cytarabine per m² BSA administered every 12 hours on day 2 of each cycle

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg cisplatin per m² BSA administered on day 1 of each cycle over 24 hours

    Number of subjects in period 1
    Phase I, 2.5 mg Phase I, 5 mg Phase I, 7.5 mg Phase I, 10 mg Phase II, Ever-DHAP Phase II, Plac-DHAP
    Started
    3
    3
    5
    3
    50
    9
    Start of treatment
    3
    3
    5
    3
    48
    9
    Completed
    3
    3
    3
    3
    45
    9
    Not completed
    0
    0
    2
    0
    5
    0
         Adverse event, non-fatal
    -
    -
    2
    -
    3
    -
         HL diagnosis disconfirmed
    -
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I, 2.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 2.5 mg

    Reporting group title
    Phase I, 5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 5 mg

    Reporting group title
    Phase I, 7.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 7.5 mg

    Reporting group title
    Phase I, 10 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Reporting group title
    Phase II, Ever-DHAP
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Reporting group title
    Phase II, Plac-DHAP
    Reporting group description
    Two cycles of DHAP chemotherapy in 14-day intevals with placebo

    Reporting group values
    Phase I, 2.5 mg Phase I, 5 mg Phase I, 7.5 mg Phase I, 10 mg Phase II, Ever-DHAP Phase II, Plac-DHAP Total
    Number of subjects
    3 3 5 3 50 9 73
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0
        Adults (18-64 years)
    3 3 5 3 50 9 73
        From 65-84 years
    0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    1 0 3 2 17 2 25
        Male
    2 3 2 1 33 7 48

    End points

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    End points reporting groups
    Reporting group title
    Phase I, 2.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 2.5 mg

    Reporting group title
    Phase I, 5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 5 mg

    Reporting group title
    Phase I, 7.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 7.5 mg

    Reporting group title
    Phase I, 10 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Reporting group title
    Phase II, Ever-DHAP
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Reporting group title
    Phase II, Plac-DHAP
    Reporting group description
    Two cycles of DHAP chemotherapy in 14-day intevals with placebo

    Primary: Rate of patients experiencing dose-limiting toxicities

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    End point title
    Rate of patients experiencing dose-limiting toxicities [1] [2]
    End point description
    DLTs were divided into known toxicities of DHAP (category A) and putative toxicities of Ever-DHAP (category B). Initially, only category B toxicities were counted as DLTs. Once a certain toxicity of category A had been reported, this toxicity was henceforth categorized as DLT for all subsequent cases. If it occured again in any patient, it was counted as DLT. Category A) grade III/IV infections; grade III/IV neurotoxicity; grade III/IV ototoxicity; grade III/IV nausea/vomiting despite appropriate antiemetics; grade III/IV nephrotoxicity; neutropenia grade IV for more than 10 days despite GCSF; thrombocytopenia grade IV for more than 5 days. Category B) other non-haematological grade III/IV toxicities with the exception of grade III infections, grade III hyperglycemia and of nausea/vomiting in the absence of appropriate antiemetic therapy; unsuccessful stem cell mobilization (<2 x 106 CD34+ cells/kg) after 2 cycles.
    End point type
    Primary
    End point timeframe
    DLTs were measured during 2 cycles of study treatment in combination with chemotherapy (Ever-DHAP) in phase I.
    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: This was a phase I study with a modified 3+3 design. No dose-limiting toxicities were observed, thus dose escalation was done after 3 patients each and 10 mg of everolimus per day was chosen as recommended phase-II dose. It was decided not to treat additional 3 patients at that dose level because no DLTs had occurred thus far and the probability of observing DLTs in each of these 3 patients (the only scenario that would lead to a change in recommended dose) was low.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Rate of patients experiencing dose-limiting toxicities" was only analyzed in phase I of the study. Thus, it is not reported for phase II patients.
    End point values
    Phase I, 2.5 mg Phase I, 5 mg Phase I, 7.5 mg Phase I, 10 mg
    Number of subjects analysed
    3
    3
    3 [3]
    3
    Units: patients
        Any DLT
    0
    0
    0
    0
        No DLT
    3
    3
    3
    3
    Notes
    [3] - 2 patients excluded from analysis due to treatment termination before end of cycle 2 (both no DLT).
    No statistical analyses for this end point

    Primary: Rate of CT-based complete remission after induction

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    End point title
    Rate of CT-based complete remission after induction [4] [5]
    End point description
    Based on the exact binomial distribution, the null hypothesis “CR rate after Ever-DHAP < 21%” was to be tested with an exact single-stage phase-II design, assuming a CR rate after Ever-DHAP of 40% or higher. The Plac-DHAP arm was analyzed descriptively due to the small sample size after early closure.
    End point type
    Primary
    End point timeframe
    Primary endpoint of phase II was the rate of patients with complete remission according to the CT-based final restaging which was to be performed ideally on day 21 of the second (Ever-)DHAP cycle.
    Notes
    [4] - 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: Primary statistical analysis was to test H0 “CR rate after Ever-DHAP < 21%” against a one-sided alternative. It is not possible to enter this single-arm analysis in the system. The observed CR rate of 27% (95% CI 15-42) with Ever-DHAP failed to reach this target and was not significantly superior to the historical benchmark for insufficient efficacy of 21% (p=0.23, exact one-sided binomial test).
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Rate of CT-based complete remission after induction" was only analyzed in phase II of the study. Thus, it is not reported for phase I patients.
    End point values
    Phase II, Ever-DHAP Phase II, Plac-DHAP
    Number of subjects analysed
    45 [6]
    9
    Units: patients
        CR
    12
    2
        Non-CR
    33
    7
    Notes
    [6] - 2 patients dropped out before start of treatment; 3 patients discontinued before restaging
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed from start of treatment until the 28-day follow-up visit or start of a new HL therapy, whichever occured first.
    Adverse event reporting additional description
    Expected AEs of CTCAE grades 3/4 were assessed on the therapy administration CRFs. Unexpected and serious AEs were (additionally) assessed on specific forms. Please note that SAEs may be reported twice (therapy administration and SAE form). Thus, non-serious AEs and SAEs might include duplicate events and do not add up to a total number of AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Phase II, Ever-DHAP
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Reporting group title
    Phase II, Plac-DHAP
    Reporting group description
    Two cycles of DHAP chemotherapy in 14-day intevals with placebo

    Reporting group title
    Phase I, 2.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 2.5 mg

    Reporting group title
    Phase I, 5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 5 mg

    Reporting group title
    Phase I, 7.5 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 7.5 mg

    Reporting group title
    Phase I, 10 mg
    Reporting group description
    Two cycles of Ever-DHAP combination chemotherapy in 14-day intevals with everolimus at a dose of 10 mg

    Serious adverse events
    Phase II, Ever-DHAP Phase II, Plac-DHAP Phase I, 2.5 mg Phase I, 5 mg Phase I, 7.5 mg Phase I, 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 48 (37.50%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    3
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oculogyric crisis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Phase II, Ever-DHAP Phase II, Plac-DHAP Phase I, 2.5 mg Phase I, 5 mg Phase I, 7.5 mg Phase I, 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 48 (89.58%)
    8 / 9 (88.89%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    Cardiac disorders
    Cardiac disorder
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [1]
    1 / 42 (2.38%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [2]
    7 / 42 (16.67%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    9
    1
    0
    0
    2
    0
    Thrombocytopenia
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [3]
    38 / 42 (90.48%)
    7 / 8 (87.50%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    68
    11
    4
    4
    8
    5
    Leukopenia
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [4]
    37 / 42 (88.10%)
    7 / 8 (87.50%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    55
    7
    3
    5
    6
    3
    Nervous system disorders
    Neurotoxicity
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [5]
    0 / 42 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ototoxicity
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Nausea or vomiting
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [6]
    6 / 42 (14.29%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    7
    0
    0
    0
    0
    0
    Mucositis
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [7]
    3 / 42 (7.14%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Gastrointestinal disorder
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [8]
    2 / 42 (4.76%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Skin disorder
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [9]
    1 / 42 (2.38%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Infection
    alternative dictionary used: NCI CTCAE 4.0
    alternative assessment type: Non-systematic
         subjects affected / exposed [10]
    5 / 42 (11.90%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 2 patients enrolled in the phase II Ever-DHAP arm did not receive any study therapy and were thus not exposed to AEs.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2013
    Implementation of current information regarding trial medication and editorial changes
    03 Jun 2014
    Implementation of current information regarding trial medication and editorial changes
    16 Jan 2015
    Implementation of current information regarding trial medication and editorial changes
    06 Oct 2015
    Closure of the placebo arm of the randomized phase II study due to insufficient patient recruitment, replacement of the study drug (everolimus) by commercially available everolimus
    19 Aug 2016
    Update of ICF, editorial changes

    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.
    Although recruitment of the placebo arm did not succeed, conclusions from this phase I/II trial are evident: adding everolimus to time-intensified DHAP is safe and feasible, but does not relevantly improve response to induction therapy.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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