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    Clinical Trial Results:
    A Phase 1/2 Study of ARQ 087 in Adult Subjects with Advanced Solid Tumors with FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma with FGFR2 Gene Fusion

    Summary
    EudraCT number
    		 2015-001443-36
    Trial protocol
    		 IT  
    Global end of trial date
    28 Aug 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jun 2023
    First version publication date
    08 Sep 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Update the contact details

    Trial information

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    Trial identification
    Sponsor protocol code
    ARQ 087-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01752920
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Basilea Pharmaceutica International Ltd.
    Sponsor organisation address
    Grenzacherstrasse 487, Basel, Switzerland, 4005
    Public contact
    Chief Medical Officer, Basilea Pharmaceutica International Ltd., +41 79 701 0551, marc.engelhardt@basilea.com
    Scientific contact
    Chief Medical Officer, Basilea Pharmaceutica International Ltd., +41 79 701 0551, marc.engelhardt@basilea.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
    03 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this first-in-humans study was to assess the safety and tolerability of ARQ 087 in patients with advanced solid tumors (Part 1; Dose Escalation/Food-effect Cohorts) or with advanced solid tumors with FGFR genetic aberrations, including iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal finding).
    Protection of trial subjects
    No additional pain or distress was caused by the use of the investigational product.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Dec 2012
    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
    United States: 101
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    119
    EEA total number of subjects
    18
    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)
    66
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 12 study centers, 8 in the US and 4 in Italy. 119 patients were recruited between December 2012 and January 2017.

    Pre-assignment
    Screening details
    		 A fresh core needle biopsy or fine needle aspiration could be collected during the screening period if archival tumor tissue biopsy samples were not available.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low Dose Group
    Arm description
    		 Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Derazantinib was administered orally at dose levels from 25 mg every other day (QOD) - 200 mg daily (QD) on a 28-day schedule.

    Arm title
    		 Middle Dose Group
    Arm description
    		 Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Derazantinib was administered orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule.

    Arm title
    		 High Dose Group
    Arm description
    		 Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Derazantinib was administered orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule.

    Arm title
    		 Expanded Cohort Group
    Arm description
    		 Patients who received derazantinib orally at the recommended Phase 2 dose (RP2D) of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Derazantinib was administered orally at the recommended phase 2 dose of 300 mg QD on a 28-day schedule.

    Number of subjects in period 1
    		Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Started
    29
    13
    19
    58
    Completed
    0
    0
    0
    0
    Not completed
    29
    13
    19
    58
         Physician decision
    1
    -
    -
    2
         Consent withdrawn by subject
    -
    1
    -
    1
         Radiographic disease progression
    20
    7
    12
    29
         Adverse event, non-fatal
    1
    -
    5
    10
         Other
    1
    1
    1
    2
         Clinical disease progression
    6
    4
    1
    13
         Study terminated by sponsor
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    Middle Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    High Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    Expanded Cohort Group
    Reporting group description
    		 Patients who received derazantinib orally at the recommended Phase 2 dose (RP2D) of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group values
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group Total
    Number of subjects
    		 29 13 19 58 119
    Age categorical
    Units: Subjects
        Age < 65
    		 19 4 8 35 66
        Age >=65
    		 10 9 11 23 53
    Gender categorical
    Units: Subjects
        Female
    		 17 9 11 32 69
        Male
    		 12 4 8 26 50
    Race
    Units: Subjects
        Black or African American
    		 3 1 2 3 9
        White
    		 24 11 16 54 105
        Other
    		 2 1 1 1 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 1 3 2 9
        Not Hispanic or Latino
    		 26 12 16 56 110

    End points

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    End points reporting groups
    Reporting group title
    Low Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    Middle Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    High Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Reporting group title
    Expanded Cohort Group
    Reporting group description
    		 Patients who received derazantinib orally at the recommended Phase 2 dose (RP2D) of 300 mg QD on a 28-day schedule until documented progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria.

    Primary: Incidence of adverse events

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    End point title
    		 Incidence of adverse events [1]
    End point description
    Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    Adverse events were collected and reported from the time of receiving first dose of derazantinib to the end of study assessment and follow-up period
    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: Descriptive statistics are considered appropriate for this Phase 1/2 clinical study endpoint
    End point values
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Number of subjects analysed
    29
    13
    19
    58
    Units: Number of subjects
        TEAE Grade 1
    3
    1
    1
    11
        TEAE Grade 2
    14
    5
    3
    14
        TEAE Grade 3
    9
    6
    13
    24
        TEAE Grade 4
    0
    1
    0
    4
        TEAE Grade 5
    2
    0
    2
    5
        no TEAE
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Objective tumor response (ORR) per RECIST 1.1

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    End point title
    		 Objective tumor response (ORR) per RECIST 1.1
    End point description
    The number of patients with an objective tumor response, which included those with either a complete response (CR) or a partial response (PR). The objective response rate (ORR) was defined as the proportion of patients with a CR or PR.
    End point type
    Secondary
    End point timeframe
    At the End of Treatment visit (7 [+3] days after the last dose of derazantinib)
    End point values
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Number of subjects analysed
    29
    13
    19
    58
    Units: Number of subjects
    0
    0
    1
    5
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) per RECIST 1.1

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    End point title
    		 Disease control rate (DCR) per RECIST 1.1
    End point description
    The number of patients with tumor disease control, which included those with either a complete or partial tumor response, or a stable disease (SD). The disease control rate (DCR) was defined as the proportion of patients with CR, PR or SD.
    End point type
    Secondary
    End point timeframe
    At the End of Treatment visit (7 [+3] days after the last dose of derazantinib)
    End point values
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Number of subjects analysed
    29
    13
    19
    58
    Units: Number of subjects
    8
    4
    7
    32
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS was calculated as the time from the date of first dose until radiographic disease progression or death from any cause.
    End point type
    Secondary
    End point timeframe
    At the End of Treatment visit (7 [+3] days after the last dose of derazantinib)
    End point values
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Number of subjects analysed
    29
    13
    19
    58
    Units: weeks
        median (confidence interval 95%)
    8.3 (6.3 to 9.3)
    15.3 (6.7 to 22.1)
    8.1 (6.7 to 23.9)
    17.4 (7.9 to 24.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study medication up to 30 days after the last administration.
    Adverse event reporting additional description
    Treatment-emergent adverse events and serious adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Low Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 25 mg QOD - 200 mg QD on a 28-day schedule until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria was documented.

    Reporting group title
    Middle Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 250 mg QD - 325 mg QD on a 28-day schedule until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria was documented.

    Reporting group title
    High Dose Group
    Reporting group description
    		 Patients who received derazantinib orally at dose levels from 400 mg QD - 425 mg QD on a 28-day schedule until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria was documented.

    Reporting group title
    Expanded Cohort Group
    Reporting group description
    		 Patients who received derazantinib orally at the recommended phase 2 dose (RP2D) of 300 mg QD on a 28-day schedule until progression of disease (clinical or radiological), unacceptable toxicity, or another of the discontinuation criteria was documented.

    Serious adverse events
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 29 (31.03%)
    2 / 13 (15.38%)
    6 / 19 (31.58%)
    16 / 58 (27.59%)
         number of deaths (all causes)
    2
    0
    2
    9
         number of deaths resulting from adverse events
    2
    0
    2
    5
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord injury cervical
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Pyrexia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Low Dose Group Middle Dose Group High Dose Group Expanded Cohort Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 29 (96.55%)
    13 / 13 (100.00%)
    19 / 19 (100.00%)
    58 / 58 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    3
    0
    0
    2
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    4 / 19 (21.05%)
    5 / 58 (8.62%)
         occurrences all number
    0
    0
    4
    5
    Hypotension
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    2
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    13 / 58 (22.41%)
         occurrences all number
    0
    0
    0
    26
    Chest pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    1
    0
    0
    4
    Discomfort
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    18 / 29 (62.07%)
    8 / 13 (61.54%)
    11 / 19 (57.89%)
    26 / 58 (44.83%)
         occurrences all number
    24
    14
    18
    40
    Feeling abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Feeling hot
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    2
    Malaise
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    2
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    0
    3
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    4 / 58 (6.90%)
         occurrences all number
    1
    1
    1
    5
    Pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    2
    Performance status decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    6 / 58 (10.34%)
         occurrences all number
    4
    0
    1
    9
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    7 / 58 (12.07%)
         occurrences all number
    4
    0
    2
    7
    Dysphonia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    6 / 29 (20.69%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    5 / 58 (8.62%)
         occurrences all number
    6
    0
    1
    5
    Epistaxis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    8 / 58 (13.79%)
         occurrences all number
    0
    2
    0
    9
    Hypoxia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    0
    0
    4
    Nasal dryness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Nasal mucosal disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    3 / 58 (5.17%)
         occurrences all number
    0
    1
    1
    3
    Productive cough
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    1
    Pulmonary congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 13 (23.08%)
    2 / 19 (10.53%)
    2 / 58 (3.45%)
         occurrences all number
    5
    3
    3
    2
    Depression
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    3 / 58 (5.17%)
         occurrences all number
    4
    0
    1
    3
    Hallucination
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    2 / 19 (10.53%)
    4 / 58 (6.90%)
         occurrences all number
    2
    1
    2
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 13 (23.08%)
    4 / 19 (21.05%)
    17 / 58 (29.31%)
         occurrences all number
    2
    3
    6
    31
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 29 (24.14%)
    7 / 13 (53.85%)
    10 / 19 (52.63%)
    17 / 58 (29.31%)
         occurrences all number
    10
    10
    14
    30
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    8 / 29 (27.59%)
    2 / 13 (15.38%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    8
    2
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 13 (7.69%)
    4 / 19 (21.05%)
    4 / 58 (6.90%)
         occurrences all number
    4
    1
    4
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 13 (15.38%)
    3 / 19 (15.79%)
    0 / 58 (0.00%)
         occurrences all number
    6
    2
    3
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    3 / 19 (15.79%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Electrocardiogram QT interval abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Visual acuity tests abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    1
    1
    1
    2
    Excoriation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    3 / 19 (15.79%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    4
    1
    Head injury
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scratch
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Congenital, familial and genetic disorders
    Ichthyosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Cardiomegaly
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    1
    Burning sensation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Clumsiness
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    5 / 19 (26.32%)
    9 / 58 (15.52%)
         occurrences all number
    2
    1
    11
    15
    Dizziness postural
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 13 (15.38%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Dysgeusia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 13 (23.08%)
    3 / 19 (15.79%)
    11 / 58 (18.97%)
         occurrences all number
    3
    3
    3
    14
    Head discomfort
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    3 / 19 (15.79%)
    12 / 58 (20.69%)
         occurrences all number
    1
    1
    5
    14
    Hypoaesthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    0
    0
    7
    Paraesthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    1
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    0
    0
    0
    5
    Tremor
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    1
    0
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 29 (24.14%)
    3 / 13 (23.08%)
    0 / 19 (0.00%)
    10 / 58 (17.24%)
         occurrences all number
    12
    4
    0
    18
    Leukopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    2
    0
    1
    2
    Lymphopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    3 / 19 (15.79%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hearing impaired
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    1
    0
    0
    9
    Dry eye
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 13 (15.38%)
    0 / 19 (0.00%)
    7 / 58 (12.07%)
         occurrences all number
    2
    2
    0
    8
    Lacrimation increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    7 / 58 (12.07%)
         occurrences all number
    0
    0
    1
    14
    Visual acuity reduced
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    0
    1
    0
    5
    Visual impairment
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    6 / 58 (10.34%)
         occurrences all number
    4
    1
    1
    6
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 13 (15.38%)
    1 / 19 (5.26%)
    5 / 58 (8.62%)
         occurrences all number
    2
    2
    2
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 13 (23.08%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    1
    5
    0
    2
    Ascites
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    4 / 58 (6.90%)
         occurrences all number
    1
    0
    1
    5
    Cheilitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    1
    0
    1
    1
    Constipation
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 13 (30.77%)
    7 / 19 (36.84%)
    16 / 58 (27.59%)
         occurrences all number
    5
    5
    9
    20
    Diarrhoea
         subjects affected / exposed
    6 / 29 (20.69%)
    5 / 13 (38.46%)
    9 / 19 (47.37%)
    17 / 58 (29.31%)
         occurrences all number
    11
    5
    10
    37
    Dry mouth
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 13 (7.69%)
    6 / 19 (31.58%)
    19 / 58 (32.76%)
         occurrences all number
    3
    1
    8
    23
    Dyspepsia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 13 (0.00%)
    3 / 19 (15.79%)
    6 / 58 (10.34%)
         occurrences all number
    3
    0
    3
    7
    Flatulence
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    1
    0
    0
    3
    Frequent bowel movements
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 13 (15.38%)
    3 / 19 (15.79%)
    1 / 58 (1.72%)
         occurrences all number
    0
    2
    4
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Intestinal obstruction
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lip disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lip pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    14 / 29 (48.28%)
    8 / 13 (61.54%)
    13 / 19 (68.42%)
    27 / 58 (46.55%)
         occurrences all number
    18
    14
    15
    46
    Odynophagia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral dysaesthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    4 / 58 (6.90%)
         occurrences all number
    1
    0
    1
    6
    Tongue disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    10 / 29 (34.48%)
    2 / 13 (15.38%)
    7 / 19 (36.84%)
    23 / 58 (39.66%)
         occurrences all number
    11
    5
    7
    48
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    11 / 58 (18.97%)
         occurrences all number
    2
    1
    1
    11
    Decubitus ulcer
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    2
    0
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 13 (15.38%)
    5 / 19 (26.32%)
    5 / 58 (8.62%)
         occurrences all number
    2
    2
    6
    5
    Erythema
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    2
    1
    0
    2
    Nail discolouration
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Onychomadesis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Pruritus
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    3 / 58 (5.17%)
         occurrences all number
    2
    0
    1
    3
    Rash
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    1
    0
    4
    Rash erythematous
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    0
    1
    Scab
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scar
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin fissures
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin mass
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    2 / 19 (10.53%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    0
    2
    Hydronephrosis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Micturition frequency decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    5
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 13 (7.69%)
    2 / 19 (10.53%)
    4 / 58 (6.90%)
         occurrences all number
    2
    1
    3
    4
    Muscle twitching
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    1
    2
    Pain in extremity
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    0
    3
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    1
    1
    Cystitis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    1
    1
    1
    3
    Ear infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    2 / 58 (3.45%)
         occurrences all number
    2
    0
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    2 / 58 (3.45%)
         occurrences all number
    1
    0
    2
    3
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    12 / 29 (41.38%)
    3 / 13 (23.08%)
    6 / 19 (31.58%)
    13 / 58 (22.41%)
         occurrences all number
    14
    6
    8
    15
    Dehydration
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    4 / 19 (21.05%)
    3 / 58 (5.17%)
         occurrences all number
    2
    0
    5
    4
    Hypercalcaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    3 / 19 (15.79%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    1
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    1
    0
    0
    6
    Hyperphosphataemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    1
    2
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 13 (23.08%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    10
    4
    1
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 13 (23.08%)
    2 / 19 (10.53%)
    1 / 58 (1.72%)
         occurrences all number
    3
    4
    3
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    1
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 13 (0.00%)
    3 / 19 (15.79%)
    5 / 58 (8.62%)
         occurrences all number
    2
    0
    4
    6
    Hypophosphataemia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 58 (0.00%)
         occurrences all number
    0
    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
    29 Oct 2012
    The original protocol was amended based on comments and/or requests from the FDA made during IND review.
    21 Jun 2013
    1. Based on the preliminary pharmacokinetic results obtained in patients enrolled in Cohorts 1-3, new derazantinib dose escalation guidelines were introduced. 2. The study design was changed so that patients would participate in a single treatment period of continuous dosing instead of participating in two treatment periods.
    12 Jun 2014
    1. A food-effect cohort was added 2. Inclusion / exclusion criteria were amended to permit patients to be enrolled in the Expanded Cohort 3. A specification was added with regard to collection of biopsies
    04 Nov 2014
    1. The recommended phase 2 dose was defined as 300 mg QD (fasted) 2. The eligibility requirements for the Expanded Cohort were clarified based on tumor type and/or tumor genomic profile
    10 Apr 2015
    1. The expanded tumor sub-cohorts were specified to include only patients with advanced solid tumors with FGFR genetic aberrations, including intrahepatic cholangiocarcinoma with FGFR2 gene fusion 2. The study title was changed to reflect the updated definition of tumor type and genomic profile 3. Changes were made to some inclusion and exclusion criteria 4. A clarification was added to dose delays / reduction for Grade 3-4 toxicity

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28972963
    http://www.ncbi.nlm.nih.gov/pubmed/30420614
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