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    Clinical Trial Results:
    A Phase I/II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Nintedanib/Vargatef in Combination With Paclitaxel Chemotherapy for Treatment of Patients with BRAF Wildtype Metastatic Melanoma

    Summary
    EudraCT number
    		 2013-004458-34
    Trial protocol
    		 DE  
    Global end of trial date
    17 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Nov 2021
    First version publication date
    17 Nov 2021
    Other versions
    Summary report(s)
    		 CSR_synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    Nipawilma_2013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02308553
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Essen
    Sponsor organisation address
    Hufelandstr. 55, Essen, Germany, 45147
    Public contact
    Department of Dermatology, University of Essen, 0049 2017234345, dirk.schadendorf@uk-essen.de
    Scientific contact
    Department of Dermatology, University of Essen, 0049 2017234345, dirk.schadendorf@uk-essen.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
    30 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study are to characterize the safety and to estimate the efficacy of nintedanib when combined with paclitaxel chemotherapy compared with paclitaxel chemotherapy alone in patients with BRAF wildtype metastatic melanoma not previously treated with taxanes or kinase inhibitors. The primary endpoint of Phase I is the definition of the Maximum Tolerable Dose (MTD) of the nintedanib/paclitaxel combination treatment. The primary endpoint of Phase II is the progression-free survival (PFS) according to RECIST v1.1.
    Protection of trial subjects
    The treatment should be conducted exactly as described in the protocol. Any protocl deviations were reported. The recommendations of Good Clinical Practice (ICH-GCP: International Conference on Harmonisation - Good Clinical Practice), valid since 17.1.1997, were observed. The phase I/phase II study design ensured that the best tolerated doses of the nintedanib/paclitaxel combination therapy as established in phase I part were administerd to patients of phase II. A formal assessment of the phase I results was done by the sponsor in cooperation with 1-2 independent experts. This interim analysis including determination of the Maximal Tolerated Dose was submitted to the higher competent authority and to the ethics committees. After approval, the phase II part started. During phase I/II, dose reductions and treatment interuptions were permitted and specified requirements for continuation had to be observed. Liver enzymes were followed closely during treatment with nintedanib. Since intedanib could have a potential risk of phototoxicity (skin and eyes), patients were advised to avoid sun exposure or artificial UVA/UVB radiation in solaria or tanning booths and to use protective clothing and broad spectrum (UVA/UVB) sunscreens if exposure to sunlight could not be avoided. At the beginning of the study and in regular intervals thereafter, patients received little bottles with enough nintedanib capsules for a treatment period of approximately 8 weeks. Patients had to bring these bottles to every doctor's visit so that the intake of nintedanib during the period could be tracked.
    Background therapy
    		 Sedatives, antibiotics, analgesics, antihistamines, steroids, granulocyte-colony stimulating factor, erythropoetin, or other medications as well as red blood cells, platelets or fresh frozen plasma transfusions could be given to assist in the management of pain, infection, and other complications of the malignancy. Standard premedication according to the current Summary of Product Characteristics for paclitaxel was required prior to administration of paclitaxel to prevent severe hypersensitivity reactions. Such premedication could consist of dexamethasone or methyl prednisone orally administered approximately 12 hours before paclitaxel, diphenhydramine i.v. 30 to 60 minutes prior to paclitaxel and cimetidine or ranitidine i.v. 30 to 60 minutes prior to administration. As anti-emetic 5HT-3 antagonists i.v. or per os (e.g., ondansetron, granisetron) could be given.
    Evidence for comparator
    		 In the double-blinded phase II part of the study, patients were randomized 1:1 to receive either nintedanib or placebo each in combination with paclitaxel (Placebo Comparator). Nintedanib or a placebo (matching the nintedanib capsules) was used in combination with paclitaxel, in order to assess the efficacy of a nintedanib-paclitaxel combination therapy compared to pactlitaxel alone.
    Actual start date of recruitment
    17 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    23
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 After obtaining informed consent, screening evaluations were performed to confirm eligibiliy and to obtain baseline safety data. From 17-Mar-2015 (first patient in) up to 15- Oct-2018 (last patient in), 34 patients were registered by 10 hospitals in Germany; thereof 10 patients were registered into phase I-part from 17-Mar-2015 to 07-Mar-2016.

    Pre-assignment
    Screening details
    		 The selection of patients occurred by the investigators according to the inclusion and exclusion criteria. After having informed the patient orally and in writiing about the study and after obtaining the patient’s informed consent, screening evaluations and procedures had to be performed within 21 days prior to initiating study drug treatment.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Placebo contained 0 mg of nintedanib in capsules matching 100 mg and 150 mg of nintedanib capsules

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I
    Arm description
    		 Finding of maximal tolerated dose of nintedanib in combiantion with paclitaxel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Vargatef
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Intake of 1 x 150 mg twice daily (corresponded to a daily dose of 300 mg) or 2 x 100 mg twice daily (corresponded to a daily dose of 400 mg); on days of paclitaxel infusion, no intake of nintedanib

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Taxomedac
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 90mg/m2 was administered intravenously over a period of one hour on day 1, 8, and 15 during 4-week cycles.

    Arm title
    		 Phase II_Arm A
    Arm description
    		 Nintedanib in combination with paclitaxel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Vargatef
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients had to swallow 2 x 100 mg capsules twice daily (= 400 mg daily); on days of paclitaxel infusion, no intake of nintedanib

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Taxomedac
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90mg/m2 paclitaxel adminitered intravenously on day 1, 8, and 15 during six 4-week cycles

    Arm title
    		 Phase II_Arm B
    Arm description
    		 Placebo in combination with paclitaxel
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients had to swallow 2 x 100 mg capsules twice daily (= 400 mg daily); on days of paclitaxel infusion, no intake of placebo capsules

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Taxomedac
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90mg/m2 paclitaxel administered intravenously on day 1, 8, and 15 during six 4-week cycles

    Number of subjects in period 1
    		Phase I Phase II_Arm A Phase II_Arm B
    Started
    10
    9
    13
    Completed
    10
    9
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Finding of maximal tolerated dose of nintedanib in combiantion with paclitaxel

    Reporting group title
    Phase II_Arm A
    Reporting group description
    		 Nintedanib in combination with paclitaxel

    Reporting group title
    Phase II_Arm B
    Reporting group description
    		 Placebo in combination with paclitaxel

    Reporting group values
    		 Phase I Phase II_Arm A Phase II_Arm B Total
    Number of subjects
    		 10 9 13 32
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of registration (phase I-part) or randomisation (phase II-part) minus year of birth.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 8 6 9 23
        From 65-84 years
    		 2 3 4 9
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.80 ± 13.80 58.89 ± 7.75 58.23 ± 11.62 -
    Gender categorical
    There was no preferrred enrolment of men or women; however, pregnant or breast-feeding women were excluded from participation.
    Units: Subjects
        Female
    		 4 2 5 11
        Male
    		 6 7 8 21
    Subject analysis sets

    Subject analysis set title
    Phase I
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients enrolled in phase I who fulfilled the inclusion and exclusion criteria with at least one administration of study treatment

    Subject analysis set title
    Phase II_Arm A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized into Arm A who fullfilled all eligibility criteria and who received at least one administration of study drugs

    Subject analysis set title
    Phase II_Arm B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to Arm B and who received at least one administration of study drugs

    Subject analysis sets values
    		 Phase I Phase II_Arm A Phase II_Arm B
    Number of subjects
    10
    9
    13
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of registration (phase I-part) or randomisation (phase II-part) minus year of birth.
    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)
    8
    6
    9
        From 65-84 years
    2
    3
    4
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.80 ± 13.80
    58.89 ± 7.75
    58.23 ± 11.62
    Gender categorical
    There was no preferrred enrolment of men or women; however, pregnant or breast-feeding women were excluded from participation.
    Units: Subjects
        Female
    4
    2
    5
        Male
    6
    7
    8

    End points

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    End points reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Finding of maximal tolerated dose of nintedanib in combiantion with paclitaxel

    Reporting group title
    Phase II_Arm A
    Reporting group description
    		 Nintedanib in combination with paclitaxel

    Reporting group title
    Phase II_Arm B
    Reporting group description
    		 Placebo in combination with paclitaxel

    Subject analysis set title
    Phase I
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients enrolled in phase I who fulfilled the inclusion and exclusion criteria with at least one administration of study treatment

    Subject analysis set title
    Phase II_Arm A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized into Arm A who fullfilled all eligibility criteria and who received at least one administration of study drugs

    Subject analysis set title
    Phase II_Arm B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients randomized to Arm B and who received at least one administration of study drugs

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression was determined according to RECIST v1.1 criteria by the respective trial sites. Progression-free survival was calculated by Kaplan-Meier-Analysis. For patients without progress and not known to have died, PFS time was censored at the date of last contact.
    End point type
    Primary
    End point timeframe
    From start of study therapy until progression or death of any cause, whatever occurred first.
    End point values
    		 Phase I Phase II_Arm A Phase II_Arm B
    Number of subjects analysed
    10
    9
    13
    Units: months
        median (confidence interval 95%)
    6.99 (1.61 to 10.46)
    3.47 (1.32 to 5.23)
    1.64 (1.58 to 5.30)
    Statistical analysis title
    		 PFS_Test
    Statistical analysis description
    Kaplan-Meier-estimates
    Comparison groups
    Phase II_Arm A v Phase II_Arm B
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6282
    Method
    		 Logrank
    Confidence interval

    Primary: Maximal tolerated dose

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    End point title
    		 Maximal tolerated dose [1] [2]
    End point description
    Dose finding will proceed in a classical 3+3, open-label, single arm design (phase I).
    End point type
    Primary
    End point timeframe
    First treatment cycle of 28 days plus one week washout
    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: No statistical analysis was performed for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was performed for this endpoint.
    End point values
    		 Phase I Phase I
    Number of subjects analysed
    10
    10
    Units: mg twice daily
        number (not applicable)
    200
    200
    No statistical analyses for this end point

    Secondary: Progression-free survival rates

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    End point title
    		 Progression-free survival rates
    End point description
    Progression-free survival (PFS) rates defined as number of patients alive and without progression at 6, 12, 18 and 24 months after start of therapy was derived by Kaplan-Meier methods for patients of Arm A and Arm B of phase II. PFS rates were analysed for Arm A and Arm B of phase II.
    End point type
    Secondary
    End point timeframe
    6, 12, 18 and 24 months after start of study therapy.
    End point values
    		 Phase II_Arm A Phase II_Arm B
    Number of subjects analysed
    9
    13
    Units: Number of patients alive and without PD
        6 months
    1
    3
        12 months
    1
    2
        18 months
    1
    2
        24 months
    1
    2
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS) was measured from start of therapy until death occurred due to any cause. OS was estmated by Kaplan-meier-method. OS for patients not known to have died were censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    From start of study therapy until death occurred due to any cause.
    End point values
    		 Phase I Phase II_Arm A Phase II_Arm B
    Number of subjects analysed
    10
    9
    13
    Units: months
        median (confidence interval 95%)
    19.64 (7.30 to 999.99)
    20.63 (4.31 to 999.99)
    19.31 (3.59 to 999.99)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring from signing the informed consent onwards until 30 days after last administration of nintedanib/placebo
    Adverse event reporting additional description
    Recurrence of disease or death due to underlying metastatic melanoma or findings that are clearly consistent with the expected progression of the underlying cancer should not be reported as an adverse event or a serious adverse event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Safety analysis phase I
    Reporting group description
    		 Patients who were registered into phase I and who received at least one administration of study medication

    Reporting group title
    Safety analysis phase II_Arm A
    Reporting group description
    		 All patients who were randomised into Arm A and who received at least one administration of study treatment.

    Reporting group title
    Safety analysis phase II_Arm B
    Reporting group description
    		 Patients who were randomised into Arm B (placebo control) and who received at least one administration of study therapy.

    Serious adverse events
    		 Safety analysis phase I Safety analysis phase II_Arm A Safety analysis phase II_Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    9 / 13 (69.23%)
         number of deaths (all causes)
    6
    3
    6
         number of deaths resulting from adverse events
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to meninges
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestinal stenosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis phase I Safety analysis phase II_Arm A Safety analysis phase II_Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    9 / 9 (100.00%)
    13 / 13 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ganglioneuroma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Tumour pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    0
    Haematoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphoedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    1
    Complication associated with device
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    8 / 10 (80.00%)
    6 / 9 (66.67%)
    1 / 13 (7.69%)
         occurrences all number
    14
    7
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Localised oedema
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 9 (33.33%)
    2 / 13 (15.38%)
         occurrences all number
    5
    6
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    CD4 lymphocytes decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    3
    4
    2
    Granulocyte count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Monocyte count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    10
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Protein total decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Troponin T increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 9 (22.22%)
    2 / 13 (15.38%)
         occurrences all number
    13
    2
    5
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Wound complication
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrial tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Conduction disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    2
    2
    1
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoglossal nerve disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Monoparesis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 9 (22.22%)
    1 / 13 (7.69%)
         occurrences all number
    4
    2
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    3
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Vagus nerve disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    2 / 13 (15.38%)
         occurrences all number
    3
    2
    2
    Bone marrow failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    Anal eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Anal ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Angular cheilitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    0
    1
    Diarrhoea
         subjects affected / exposed
    8 / 10 (80.00%)
    6 / 9 (66.67%)
    3 / 13 (23.08%)
         occurrences all number
    10
    13
    3
    Dry mouth
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Eructation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Glossitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    4 / 10 (40.00%)
    6 / 9 (66.67%)
    1 / 13 (7.69%)
         occurrences all number
    6
    9
    1
    Pancreatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Tongue coated
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    3
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 10 (100.00%)
    5 / 9 (55.56%)
    3 / 13 (23.08%)
         occurrences all number
    11
    6
    3
    Dermatitis acneiform
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Erythema multiforme
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Hair colour changes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    4
    Intertrigo
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Nail discolouration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Papule
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Rosacea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    2
    Bone pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Body tinea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    Mucosal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Rash pustular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    2
    Iron deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2016
    Maximal tolerated dose determined in phase I was included in treatment description for phase II patients and timelines due to delay in recruitment during phase I part were adapted.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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