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    Clinical Trial Results:
    Nivolumab and AVD in early-stage unfavorable classical Hodgkin lymphoma - A GHSG randomized, multicenter phase II trial

    Summary
    EudraCT number
    		 2016-002626-37
    Trial protocol
    		 DE  
    Global end of trial date
    20 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2023
    First version publication date
    07 Jul 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Uni-Koeln-2854
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03004833
    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, German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    Trial Coordination Center, German Hodgkin Study Group (GHSG), 0049 22147888200, 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
    03 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate efficacy of the 2 experimental strategies in patients with early-stage unfavorable cHL. Secondary objectives were to describe safety, long-term efficacy and feasibility of both strategies.
    Protection of trial subjects
    Written informed consent before study entry, frequent IDMC monitoring, central response evaluation
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Apr 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 110
    Worldwide total number of subjects
    110
    EEA total number of subjects
    110
    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)
    110
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 19 Apr 2017 and 30 Oct 2018, 110 patients were enrolled in 28 trial sites in Germany.

    Pre-assignment
    Screening details
    		 Main entry criteria were histologically proven first diagnosis of classical Hodgkin lymphoma (cHL), no previous treatment for cHL, age at enrollment 18-60 years, clinical stage I or II with risk factors.

    Period 1
    Period 1 title
    Enrollment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Concomitant therapy
    Arm description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Arm title
    		 Sequential therapy
    Arm description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Number of subjects in period 1
    		Concomitant therapy Sequential therapy
    Started
    55
    55
    Completed
    55
    54
    Not completed
    0
    1
         Disconfirmation of diagnosis
    -
    1
    Period 2
    Period 2 title
    Full analysis set
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Concomitant therapy
    Arm description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Arm title
    		 Sequential therapy
    Arm description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Patients with disconfirmed cHL diagnosis were excluded from all analyses are not reported in the baseline period.
    Number of subjects in period 2 [2]
    		Concomitant therapy Sequential therapy
    Started
    55
    54
    Completed
    51
    50
    Not completed
    4
    4
         False risk-group allocation
    -
    1
         Adverse event, non-fatal
    3
    2
         Participant's wish
    1
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients with disconfirmed cHL diagnosis were excluded from all analyses are not reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Concomitant therapy
    Reporting group description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).

    Reporting group title
    Sequential therapy
    Reporting group description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).

    Reporting group values
    		 Concomitant therapy Sequential therapy Total
    Number of subjects
    		 55 54 109
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 55 54 109
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 26 (18 to 57) 27 (18 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 32 33 65
        Male
    		 23 21 44
    ECOG performance status
    Units: Subjects
        ECOG=0
    		 42 41 83
        ECOG=1
    		 13 13 26
    Histologic subtype
    Units: Subjects
        NS cHL
    		 33 36 69
        MC cHL
    		 6 7 13
        LR cHL
    		 2 1 3
        cHL unspecified
    		 13 10 23
        Unknown
    		 1 0 1
    Ann Arbor Stage
    Units: Subjects
        IA
    		 3 1 4
        IB
    		 0 1 1
        IIA
    		 41 41 82
        IIB
    		 11 11 22
    Risk factor large mediastinal mass
    Units: Subjects
        Yes
    		 7 15 22
        No
    		 48 39 87
    Risk factor extranodal disease
    Units: Subjects
        Yes
    		 8 6 14
        No
    		 47 48 95
    Risk factor elevated ESR
    Units: Subjects
        Yes
    		 25 27 52
        No
    		 30 27 57
    Risk factor 3 or more nodal areas involved
    Units: Subjects
        Yes
    		 39 36 75
        No
    		 16 18 34

    End points

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    End points reporting groups
    Reporting group title
    Concomitant therapy
    Reporting group description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).

    Reporting group title
    Sequential therapy
    Reporting group description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).
    Reporting group title
    Concomitant therapy
    Reporting group description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).

    Reporting group title
    Sequential therapy
    Reporting group description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT).

    Subject analysis set title
    Efficacy analysis set - Concomitant therapy
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy analysis set (EAS) consists of all patients from the full analysis set who are evaluable for the primary efficacy endpoint. Patients are not evaluable for the primary endpoint and therefore excluded from the EAS in the following cases: • Major protocol deviation (< 3 full cycles of AVD or < 4 doses of nivolumab or administration of any non-protocol therapy) for reasons other than progressive disease or inadequate response • There is evidence that the patient is not qualified for the trial, based on data obtained before study entry (e.g., histology, staging, case history or previous treatment) • Change of treatment group at any time

    Subject analysis set title
    Efficacy analysis set - sequential therapy
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy analysis set (EAS) consists of all patients from the full analysis set who are evaluable for the primary efficacy endpoint. Patients are not evaluable for the primary endpoint and therefore excluded from the EAS in the following cases: • Major protocol deviation (< 3 full cycles of AVD or < 4 doses of nivolumab or administration of any non-protocol therapy) for reasons other than progressive disease or inadequate response • There is evidence that the patient is not qualified for the trial, based on data obtained before study entry (e.g., histology, staging, case history or previous treatment)

    Primary: Complete remission rate

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    End point title
    		 Complete remission rate [1]
    End point description
    The complete remission (CR) rate was defined as the proportion of patients showing a complete tumor response in the centrally reviewed final restaging after completion of protocol treatment including IS-RT. A complete remission has been attained if one of the following conditions was met: • Complete radiologic response with regress of all residual masses to ≤ 1.5 cm in the largest diameter in absence of signs of active lymphoma • Complete metabolic response (score 1-3) with or without residual masses in absence of clinical signs of active lymphoma • No signs of active lymphoma and CR already achieved in an earlier restaging
    End point type
    Primary
    End point timeframe
    Response was measured at the final restaging after completion of protocol treatment including IS-RT.
    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 is a phase-2 trial with 2 regimens to be evaluated independently. There is no arm comparison but 2 single-arm analyses, which cannot be entered in the system. Analyses were as follows: The null hypothesis “CR rate<=80%” was tested against a one-sided alternative via a one-sided 97.5% CI per arm. The lower confidence limits were 79% for concomitant and 84% for sequential therapy, respectively. Thus, the 80% benchmark was narrowly missed in the concomitant and met in the sequential group.
    End point values
    		 Efficacy analysis set - Concomitant therapy Efficacy analysis set - sequential therapy
    Number of subjects analysed
    51 [2]
    50 [3]
    Units: patients
        CR
    46
    47
        Non-CR
    5
    3
    Notes
    [2] - Reasons for exclusion from primary endpoint analysis were AEs (n=3) and participant's wish (n=1)
    [3] - Reasons for exclusion were AEs (n=2), false risk-group allocation (n=1) and participant's wish (n=1
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival is defined as time between the date of randomization and the date of first progression, relapse, or death or, in cases of continuing response, the date of the last documented follow-up.
    End point type
    Secondary
    End point timeframe
    3-year progression-free survival will be reported
    End point values
    		 Concomitant therapy Sequential therapy
    Number of subjects analysed
    55
    54
    Units: percent
        number (confidence interval 95%)
    100 (100 to 100)
    98 (95 to 100)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival is defined as time between the date of randomization and the date of death. If the patient is alive at the time of analysis, overall survival will be censored on the date of the last documented information on survival status.
    End point type
    Secondary
    End point timeframe
    Overall survival after 3 years will be reported
    End point values
    		 Concomitant therapy Sequential therapy
    Number of subjects analysed
    55
    54
    Units: percent
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All events up to 30 days after end of treatment had to be reported. Events that occured later than 30 days after the end of treatment had to be reported if causality was rated at least as “possible”.
    Adverse event reporting additional description
    AEs were assessed on the therapy administration CRFs. SAEs were additionally assessed on specific forms. SAEs may thus be reported twice; non-serious AEs might contain SAEs; non-serious and SAEs might not add up to a total number of AEs. All AEs of CTCAE grade >=1 will be reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Concomitant therapy
    Reporting group description
    		 Concomitant therapy with Nivolumab and AVD (N-AVD) on day 1 and 15 of each 28-day cycle for 4 cycles,followed by consolidating 30 Gy involved-site radiotherapy (IS-RT)

    Reporting group title
    Sequential therapy
    Reporting group description
    		 Sequential therapy starting with 4 infusions of nivolumab in 14-day intervals followed by two 28-day cycles N-AVD and two 28-day cycles AVD, followed by consolidating 30 Gy involved-site radiotherapy (IS-RT)

    Serious adverse events
    		 Concomitant therapy Sequential therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 55 (38.18%)
    15 / 54 (27.78%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Vascular disorders
    Additional description: Includes Pulmonary embolism, Vena cava thrombosis
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    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: Includes Mucosal inflammation, Pyrexia, General physical health deterioration, Non-cardiac chest pain
         subjects affected / exposed
    6 / 55 (10.91%)
    3 / 54 (5.56%)
         occurrences causally related to treatment / all
    9 / 9
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (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: Includes Pneumothorax, Tonsillitis, Upper respiratory tract infection
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    Additional description: Includes Meningitis, Polyneuropathy
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    Additional description: Includes Febrile neutropenia, Neutropenia
         subjects affected / exposed
    7 / 55 (12.73%)
    4 / 54 (7.41%)
         occurrences causally related to treatment / all
    7 / 7
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: Includes Abdominal pain, Diarrhoea, Dysphagia, Enterocolitis, Gastritis, Gastroenteritis, Nausea, Pancreatitis, Vomiting
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 54 (7.41%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
    Additional description: Includes AI hepatitis, Hepatitis
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 54 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    Additional description: Includes Pruritus, Rash
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urogenital disorder
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         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
    Arthralgia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
    Additional description: Includes Infection, Febrile infection
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Concomitant therapy Sequential therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 55 (98.18%)
    53 / 54 (98.15%)
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
         occurrences all number
    1
    2
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    23 / 55 (41.82%)
    18 / 54 (33.33%)
         occurrences all number
    48
    34
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 55 (90.91%)
    45 / 54 (83.33%)
         occurrences all number
    148
    165
    Thrombocytopenia
         subjects affected / exposed
    11 / 55 (20.00%)
    11 / 54 (20.37%)
         occurrences all number
    18
    27
    Leukopenia
         subjects affected / exposed
    49 / 55 (89.09%)
    46 / 54 (85.19%)
         occurrences all number
    144
    160
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 55 (10.91%)
    11 / 54 (20.37%)
         occurrences all number
    6
    16
    Allergy
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 54 (3.70%)
         occurrences all number
    3
    2
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    12 / 55 (21.82%)
    21 / 54 (38.89%)
         occurrences all number
    23
    39
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    41 / 55 (74.55%)
    37 / 54 (68.52%)
         occurrences all number
    97
    87
    Mucositis
         subjects affected / exposed
    14 / 55 (25.45%)
    19 / 54 (35.19%)
         occurrences all number
    24
    36
    Gastrointestinal disorders
         subjects affected / exposed
    28 / 55 (50.91%)
    19 / 54 (35.19%)
         occurrences all number
    43
    41
    Dysphagia
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 54 (7.41%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    12 / 55 (21.82%)
    13 / 54 (24.07%)
         occurrences all number
    15
    17
    Hepatobiliary disorders
    Hepatobiliary disorder
         subjects affected / exposed
    27 / 55 (49.09%)
    28 / 54 (51.85%)
         occurrences all number
    48
    66
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    23 / 55 (41.82%)
    31 / 54 (57.41%)
         occurrences all number
    42
    65
    Renal and urinary disorders
    Urogenital disorder
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 54 (7.41%)
         occurrences all number
    4
    7
    Renal disorder
         subjects affected / exposed
    4 / 55 (7.27%)
    2 / 54 (3.70%)
         occurrences all number
    5
    3
    Infections and infestations
    Infection
         subjects affected / exposed
    25 / 55 (45.45%)
    23 / 54 (42.59%)
         occurrences all number
    34
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2017
    Within the framework of the Amendment, updates due to a new version of the IB and editorial / organizational changes were implemented.
    11 Dec 2017
    Within the framework of this amendment, a mandatory antiphlogistic and antiemetic concomitant medication and additional measures to increase safety of trial participants were established and editorial changes implemented.
    20 Sep 2018
    Within the framework of the Amendment, updates due to a new version of the IB and editorial / organizational changes were implemented.

    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/32352505
    http://www.ncbi.nlm.nih.gov/pubmed/36508302
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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