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    Clinical Trial Results:
    An open-label Phase Ib/ II, multi-center study of 4SC-202 in Combination with Pembrolizumab in Patients with Unresectable Stage III/Metastatic Stage IV Cutaneous Melanoma primary refractory/non-responding to prior Anti-PD-1 Therapy – The SENSITIZE Study

    Summary
    EudraCT number
    		 2017-001050-33
    Trial protocol
    		 DE   IT  
    Global end of trial date
    02 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2023
    First version publication date
    15 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    4SC-202-2-2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03278665
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    4SC AG
    Sponsor organisation address
    Fraunhoferstr. 22, Planegg-Martinsried, Germany, 82152
    Public contact
    Corporate Communications, 4SC AG, 4SC AG, 0049 897007630, public@4sc.com
    Scientific contact
    Clinical Development, 4SC AG, 4SC AG, 0049 897007630, medical.request@4sc.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
    29 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine safety and tolerability of combination treatment with domatinostat and Pembrolizumab in patients with advanced cutaneous malignant melanoma who are primary refractory or non-responding to anti-PD-1 mono or combination therapy.
    Protection of trial subjects
    The dose escalation phase (Phase Ib) followed a modified “rolling six” design. Cohorts of patients received pre-defined escalating doses of domatinostat in combination with Pembrolizumab. Dose escalation decisions were made by the Safety Review Committee (SRC), considering the safety and tolerability data from the dose limiting toxicity (DLT) period. If 1 of 3 subjects experienced a DLT, the dose level was expanded to at least 6 patients. If the next higher dose level had already been opened after clearance of the first 3 subjects, further enrollment in this next higher dose level was interrupted. The SRC decided depending on the type and nature of the DLT(s) if a dose reduction in ongoing subjects of this next higher dose level was mandatory. If a dose level was considered non-tolerable, the previous dose level was expanded to 6 subjects to determine the MTD. If 2 or more subjects experienced DLTs in a dose levels, enrollment was interrupted and the SRC was convened for an ad-hoc meeting to decide on the further procedures. Toxicity management guidelines were given in the protocol requiring interruption, reduction or discontinuation of domatinostat treatment, depending on the severity of the toxicity. Before the start of a new treatment cycle subjects were assessed including AEs, physical examination, and measurement of hematological and biochemical parameters. Depending on the observed toxicities, treatment was to be interrupted and could only be re-started after the toxicity had resolved. For any events that fulfilled DLT criteria, the dose of domatinostat had to be reduced at re-start. Reduced doses could not be increased for the remainder of the trial. Subjects requiring more than 2 dose reductions had to be discontinued.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2017
    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: 38
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    27
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were enrolled from 9-Nov-2017 to 19-Nov-2020 at 6 centers in Germany and 1 in Italy.

    Pre-assignment
    Screening details
    		 51 subjects were screened, of which 11 subjects were screening failures due to not meeting inclusion criteria (3 subjects) or meeting exclusion criteria (8 subjects).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 100 mg once daily 14+7 (DL1)
    Arm description
    		 100 mg domatinostat once daily treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Domatinostat
    Investigational medicinal product code
    4SC-202
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A once daily oral dose of domatinostat (1 x 100 mg tablet) was taken within 2 hours after a light breakfast in the morning. On study days 1, 2, 14 and 15 of the first cycle and Day 1 of the second cycle the tables were taken after blood samples for PK analysis were drawn and more than 2 hours after having a light breakfast. The tablets were not to be chewed and/or crushed and were swallowed together with about 200 ml of noncarbonated water (e.g. tap water) at room temperature.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Pembrolizumab i.v. once every 3 weeks, administered prior to domatinostat dosing.

    Arm title
    		 200 mg once daily 14+7 (DL2a)
    Arm description
    		 200 mg domatinostat once daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Domatinostat
    Investigational medicinal product code
    4SC-202
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A once daily oral dose of domatinostat (2 x 100 mg tablet) was taken after a fasting period of at least 2 hours. On study days 1, 2, 14 and 15 of the first cycle and Day 1 of the second cycle the tables were taken after blood samples for PK analysis were drawn and after a fasting period of at least 2 hours. The tablets were not to be chewed and/or crushed and were swallowed together with about 200 ml of noncarbonated water (e.g. tap water) at room temperature.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Pembrolizumab i.v. once every 3 weeks, administered prior to domatinostat dosing.

    Arm title
    		 200 mg twice daily 14+7 (DL3)
    Arm description
    		 200 mg domatinostat twice daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Domatinostat
    Investigational medicinal product code
    4SC-202
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A twice daily oral dose of domatinostat (2 x 100 mg tablet twice daily) was taken after a fasting period of at least 2 hours. On study days 1, 2, 14 and 15 of the first cycle and Day 1 of the second cycle the tables were taken after blood samples for PK analysis were drawn and after a fasting period of at least 2 hours. The tablets were not to be chewed and/or crushed and were swallowed together with about 200 ml of noncarbonated water (e.g. tap water) at room temperature.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Pembrolizumab i.v. once every 3 weeks, administered prior to domatinostat dosing.

    Arm title
    		 200 mg once daily 21 days (DL2b)
    Arm description
    		 200 mg domatinostat once daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Domatinostat
    Investigational medicinal product code
    4SC-202
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A once daily oral dose of domatinostat (2 x 100 mg tablet) was taken after a fasting period of at least 2 hours. On study days 1, 2, 14 and 15 of the first cycle and Day 1 of the second cycle the tables were taken after blood samples for PK analysis were drawn and after a fasting period of at least 2 hours. The tablets were not to be chewed and/or crushed and were swallowed together with about 200 ml of noncarbonated water (e.g. tap water) at room temperature.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Pembrolizumab i.v. once every 3 weeks, administered prior to domatinostat dosing.

    Arm title
    		 200 mg twice daily 21 days (DL4)
    Arm description
    		 200 mg domatinostat twice daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Domatinostat
    Investigational medicinal product code
    4SC-202
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A twice daily oral dose of domatinostat (2 x 100 mg tablet twice daily) was taken after a fasting period of at least 2 hours. On study days 1, 2, 14 and 15 of the first cycle and Day 1 of the second cycle the tables were taken after blood samples for PK analysis were drawn and after a fasting period of at least 2 hours. The tablets were not to be chewed and/or crushed and were swallowed together with about 200 ml of noncarbonated water (e.g. tap water) at room temperature.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg/kg Pembrolizumab i.v. once every 3 weeks, administered prior to domatinostat dosing.

    Number of subjects in period 1
    		100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Started
    10
    6
    7
    7
    10
    Completed
    10
    6
    7
    7
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    100 mg once daily 14+7 (DL1)
    Reporting group description
    		 100 mg domatinostat once daily treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 14+7 (DL2a)
    Reporting group description
    		 200 mg domatinostat once daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg twice daily 14+7 (DL3)
    Reporting group description
    		 200 mg domatinostat twice daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 21 days (DL2b)
    Reporting group description
    		 200 mg domatinostat once daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Reporting group title
    200 mg twice daily 21 days (DL4)
    Reporting group description
    		 200 mg domatinostat twice daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Reporting group values
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4) Total
    Number of subjects
    		 10 6 7 7 10 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 7 4 5 3 8 27
        From 65-84 years
    		 3 2 2 4 2 13
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59.0 (23 to 79) 55.0 (30 to 80) 55.0 (29 to 76) 69.0 (46 to 79) 59.5 (46 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 1 2 4 14
        Male
    		 6 3 6 5 6 26

    End points

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    End points reporting groups
    Reporting group title
    100 mg once daily 14+7 (DL1)
    Reporting group description
    		 100 mg domatinostat once daily treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 14+7 (DL2a)
    Reporting group description
    		 200 mg domatinostat once daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg twice daily 14+7 (DL3)
    Reporting group description
    		 200 mg domatinostat twice daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 21 days (DL2b)
    Reporting group description
    		 200 mg domatinostat once daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Reporting group title
    200 mg twice daily 21 days (DL4)
    Reporting group description
    		 200 mg domatinostat twice daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Primary: Number of subjects with treatment-emergent adverse events

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    End point title
    		 Number of subjects with treatment-emergent adverse events [1]
    End point description
    Safety and tolerability of the combination of 4SC-202 and Pembrolizumab will be assessed from adverse events, laboratory tests, vital signs, ECGs, ECOG PS, physical examination and assessment of concomitant medications.
    End point type
    Primary
    End point timeframe
    From treatment start until 20 weeks (±2 weeks) after the last dose of domatinostat or Pembrolizumab, whichever was later.
    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: Only descriptive analysis was done: Continuous variables were summarized using descriptive statistics by reporting the number of non-missing observations, arithmetic mean, standard deviation, median, minimum and maximum. Categorical variables were summarized using frequency tables showing the number and percentage of patients within a particular category.
    End point values
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Number of subjects analysed
    10
    6
    7
    7
    10
    Units: subjects
    10
    6
    7
    7
    10
    No statistical analyses for this end point

    Primary: Number of treatment-emergent adverse events

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    End point title
    		 Number of treatment-emergent adverse events [2]
    End point description
    Safety and tolerability of the combination of 4SC-202 and Pembrolizumab will be assessed from adverse events, laboratory tests, vital signs, ECGs, ECOG PS, physical examination and assessment of concomitant medications.
    End point type
    Primary
    End point timeframe
    From treatment start until 20 weeks (±2 weeks) after the last dose of domatinostat or Pembrolizumab, whichever was later.
    Notes
    [2] - 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: Only descriptive analysis was done: Continuous variables were summarized using descriptive statistics by reporting the number of non-missing observations, arithmetic mean, standard deviation, median, minimum and maximum. Categorical variables were summarized using frequency tables showing the number and percentage of patients within a particular category.
    End point values
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Number of subjects analysed
    10
    6
    7
    7
    10
    Units: adverse events
    109
    93
    173
    103
    177
    No statistical analyses for this end point

    Primary: Number of patients with Dose limiting toxicities (DLTs)

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    End point title
    		 Number of patients with Dose limiting toxicities (DLTs) [3]
    End point description
    Safety and tolerability of the combination of 4SC-202 and Pembrolizumab will be assessed from adverse events, laboratory tests, vital signs, ECGs, ECOG PS, physical examination and assessment of concomitant medications.
    End point type
    Primary
    End point timeframe
    From treatment start to the end of the second cycle with combination therapy (i.e, in the dosing schedules with 7 days off dose, Cycle 1 to Cycle 3; in continuous dosing schedules, Cycle 1 to Cycle 2)
    Notes
    [3] - 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: Only descriptive analysis was done: Continuous variables were summarized using descriptive statistics by reporting the number of non-missing observations, arithmetic mean, standard deviation, median, minimum and maximum. Categorical variables were summarized using frequency tables showing the number and percentage of patients within a particular category.
    End point values
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Number of subjects analysed
    10
    6
    7
    7
    10
    Units: subjects
    1
    1
    1
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of observation for collection of AEs extended from ICF signature until 20 weeks (±2 weeks) after the last dose of domatinostat or Pembrolizumab, whichever was later.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    100 mg once daily 14+7 (DL1)
    Reporting group description
    		 100 mg domatinostat once daily treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 14+7 (DL2a)
    Reporting group description
    		 200 mg domatinostat once daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg twice daily 14+7 (DL3)
    Reporting group description
    		 200 mg domatinostat twice daily, treatment for 14 consecutive days followed by 7 days off treatment, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 2 Day 1 onwards.

    Reporting group title
    200 mg once daily 21 days (DL2b)
    Reporting group description
    		 200 mg domatinostat once daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Reporting group title
    200 mg twice daily 21 days (DL4)
    Reporting group description
    		 200 mg domatinostat twice daily treatment for 21 consecutive days, and 2 mg/kg Pembrolizumab i.v. once every 3 weeks from Cycle 1 Day 1 onwards.

    Serious adverse events
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 6 (66.67%)
    5 / 7 (71.43%)
    5 / 7 (71.43%)
    8 / 10 (80.00%)
         number of deaths (all causes)
    4
    0
    1
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inferior vena caval occlusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular compression
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endodontic procedure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    immune-mediated pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial pressure increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 100 mg once daily 14+7 (DL1) 200 mg once daily 14+7 (DL2a) 200 mg twice daily 14+7 (DL3) 200 mg once daily 21 days (DL2b) 200 mg twice daily 21 days (DL4)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Lymphoedema
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    1
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    1 / 7 (14.29%)
    5 / 10 (50.00%)
         occurrences all number
    3
    1
    8
    1
    8
    Pain
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 6 (66.67%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    5
    3
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    3
    7
    1
    1
    2
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    2
    1
    0
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    2
    0
    1
    Localised oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    4 / 7 (57.14%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    3
    4
    0
    2
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    3
    0
    1
    1
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    0
    1
    0
    2
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    3
    1
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    4 / 10 (40.00%)
         occurrences all number
    1
    3
    0
    3
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    1
    2
    3
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    2
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    1
    0
    0
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    3
    0
    Lipase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    1
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    0
    3
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Glomerular filtration rate decreased0
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    5
    1
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    1
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
         occurrences all number
    2
    1
    0
    1
    3
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    2 / 7 (28.57%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    33
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    0
    0
    2
    Tinnitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    4 / 7 (57.14%)
    6 / 10 (60.00%)
         occurrences all number
    7
    2
    4
    4
    6
    Diarrhoea
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    1 / 7 (14.29%)
    4 / 10 (40.00%)
         occurrences all number
    7
    2
    6
    1
    10
    Nausea
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    2 / 7 (28.57%)
    6 / 10 (60.00%)
         occurrences all number
    5
    0
    3
    2
    10
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    3 / 10 (30.00%)
         occurrences all number
    2
    1
    2
    1
    4
    Colitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    3
    0
    1
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    2
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    1
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 10 (20.00%)
         occurrences all number
    2
    0
    0
    2
    5
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    0
    1
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    1
    1
    Xeroderma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Drug eruption
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Erythema multiforme
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Intertrigo
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Urticaria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Vitiligo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    3
    1
    1
    Hyperthyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
         occurrences all number
    1
    1
    0
    1
    2
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    2
    1
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    0
    1
    Flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    1
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    3
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    4 / 10 (40.00%)
         occurrences all number
    0
    2
    2
    1
    5
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2017
    The changes introduced by this amendment were performed to modify the required contraceptive measures and pregnancy testing, increase the duration of SAE and AE monitoring to a minimum of 18 weeks after last study drug administration, clarify the dose of domatinostat in Cycle 1, and correct minor typos and inconsistencies.
    06 Jun 2018
    The changes introduced by this amendment were performed to modify the in- and exclusion criteria (i.e. clarify allowed prior anti-PD-1 antibody or combination therapies; consent of FCBP to comply with contraceptive requirement), remove the requirement of an anti-PD-1 monotherapy (provided that a 4-week wash-out period for anti-CTLA-4 antibody was performed upon receipt of prior combination therapy), add guidance on expected immune-mediated adverse reactions for pembrolizumab, allow simultaneous recruitment into the next dose level after clearance of the first 3 patients in a dose level, administer domatinostat in fasted state (to minimize variability in PK analyses), introduce a new dosing schedule in case of non-tolerability (3-day on/ 4-day off regime), add precautions for concomitant administration of domatinostat and strong inhibitors or inducers of CYP3A4 (based on in vitro findings) and of domatinostat and proton-pump-inhibitors (based on pH-dependency of domatinostat resorption), and to correct minor typos and inconsistencies as well as readability.
    09 Aug 2018
    National Amendment for USA only, provided in response to advice from the FDA. The changes introduced by this amendment were performed to define or explain more precisely the prior exposure to anti-PD-1 therapy, the recovery from non-hematological toxicities related to domatinostat (resolved to Grade 1 before re-start of study treatment), and the use of pembrolizumab at US study sites (commercial product to be sourced in US); furthermore, to add a clarification that toxicity associated with immunotherapy will be considered for determination of the MTD, specify the irRECIST criteria, add information on FDA approvals of PD-1 inhibitors, align the protocol toxicity guidelines with the SmPC of Keytruda, to revise the calculation of AE duration, and remove inconsistencies between synopsis and main text of the protocol.
    07 May 2019
    The changes introduced by this amendment were performed to introduce a continuous dosing schedule for domatinostat (including an optional participation in taking sequential tumor biopsies), allow more than one expansion cohort (to be specified in a separate Amendment, if applicable), remove the optional DL “-1” (not required since the first dose level was tolerated), allow intra-patient dose escalation after the first tumor assessment following Cycle 4 into the next higher dose level (provided this dose level has been declared as tolerable by the SRC), remove asymptomatic increases of amylase and/or lipase from the list of DLTs (provided AEs resolved by ≥ 1 grade within 7 days of treatment interruption), and align the protocol toxicity guidelines with the SmPC of Keytruda. In addition, minor issues were clarified and inconsistencies between synopsis and main text of the protocol were removed.
    18 Jun 2019
    The changes introduced by this amendment were performed to inform about the availability of the additional vial strength of 100 mg concentrate of pembrolizumab (in addition to 50 mg concentrate of pembrolizumab) and to correct minor inconsistencies and typos of the protocol.
    13 Jan 2020
    The changes introduced by this amendment were performed to change the dose in DL 4 (from 300 mg TDD into 400 mg TDD in a continuous dose schedule), introduce the collection of blood samples for a 24 h PK profile in DL 4 after administration of a single dose of 400 mg domatinostat, remove the restriction to formulation II in cohorts with continuous dosing schedule (i.e. formulation I also might have been applied), re-introduce a mandatory biopsy at screening and in Cycle 1, align the criteria for start of a new treatment cycle in continuous dosing with the criteria for start of treatment after an interruption, remove too detailed information on statistics, extend the time window for weight to determine the pembrolizumab dose (up to 3 days prior to first treatment), restrict the reporting of immediately reportable events (IRE) to the DLT period, add precautions regarding use of substrates of the CYP enzymes 2C8 or 2C9 and the transporters BCRP and OATP1B1, and correct typos of the protocol.
    10 Mar 2020
    The changes introduced by this amendment were performed to modify the protocol toxicity guidelines for handling of rash and allergic/hypersensitivity reactions (including optional skin biopsies in case of skin reactions).
    09 Sep 2020
    The changes introduced by this amendment were performed to modify the duration of treatment (discontinuation of treatment with pembrolizumab at the earliest one year after the first documentation of at least irSD), remove the option for domatinostat monotherapy in individual patients after the end of study (no regulatory-compliant procedure available), clarify the requirement of biopsies for the different dose levels, the intra-individual dose escalation (switch between schedules not allowed), melanoma staging for inclusion and body weight to be used for determination of pembrolizumab dose, remove inconsistencies in definitions of “best overall response” and “disease control rate”, total sample size estimate and PK sampling (regarding 10 h and 12 h PK samples), and align the protocol toxicity guidelines of pembrolizumab with the updated recommendations in the SmPC.
    22 Oct 2021
    The changes introduced by this amendment were performed to limit the follow-up for survival to 52 weeks after the first dose of trial medication. Patients who remained on treatment for more than 52 weeks (up to the maximum of 102 weeks), were to be followed up for survival up to 20 weeks after the last study drug administration.

    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.
    Due to the limited number of patients treated in this trial, no conclusion can be drawn regarding a potential effect of domatinostat on the frequency of immune-related events. Survival data was incomplete with 17 of the 40 patients being censored.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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