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    Clinical Trial Results:
    A Phase 1b/2 study of derazantinib as monotherapy and combination therapy with paclitaxel, ramucirumab or atezolizumab in patients with HER2-negative gastric adenocarcinoma harboring FGFR genetic aberrations (FIDES-03)

    Summary
    EudraCT number
    		 2019-004505-27
    Trial protocol
    		 GB   DE   FR   BE   IT  
    Global end of trial date
    21 Nov 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    DZB-CS-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04604132
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Basilea Pharmaceutica International Ltd, Allschwil
    Sponsor organisation address
    Hegenheimermattweg 167b, Allschwil, Switzerland, 4123
    Public contact
    Manuel Häckl, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 (0)76 302 53 10, manuel.haeckl@basilea.com
    Scientific contact
    Manuel Häckl, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 (0)76 302 53 10, manuel.haeckl@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
    13 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Substudy 1 The primary objective for Cohorts 1.1 and 1.2 was to evaluate the overall response rate (ORR) of patients with HER2neg FGFR2fus/amp (Cohort 1.1) and FGFR1-3mt (Cohort 1.2) GAC treated with derazantinib monotherapy (300 mg QD). For Cohort 1.3, the primary objective was to evaluate the progression-free survival at 4 months (PFS4) of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib monotherapy (200 mg BID). Substudy 2 The primary objective of Substudy 2 was to determine the recommended Phase 2 dose (RP2D) of derazantinib-paclitaxel-ramucirumab in combination in patients with HER2neg FGFRfus/amp/mt GAC. The study originally planned to include three substudies but was prematurely terminated for administrative reasons before the third substudy (including combination therapy with derazantinib plus atezolizumab) was initiated.
    Protection of trial subjects
    The study was conducted according to the ethical principles that have their origins in the World Medical Association’s Declaration of Helsinki, the International Council for Harmonisation (ICH) E6 Good Clinical Practice, and all applicable national and local laws and regulations for the conduct of clinical research and the protection of personal data. If conflicts between local laws and regulations arose, the more stringent requirements were adopted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Turkey: 4
    Worldwide total number of subjects
    47
    EEA total number of subjects
    17
    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)
    32
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 From 6 October 2020 to 10 June 2022, 919 patients underwent molecular pre-screening. 66 then underwent clinical screening, and 47 were then assigned treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily
    Arm description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib in Substudy 1, Cohort 1.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in Substudy 1. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Investigational medicinal product name
    Derazantinib-paclitaxel-ramucirumab combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Derazantinib was administered orally at a dose of either 200, 300 mg once daily or 200 mg twice daily in combination with paclitaxel and ramucirumab in the Substudy 2. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Arm title
    		 Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily
    Arm description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.
    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 a dose of 300 mg once daily as monotherapy in Substudy 1. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Arm title
    		 Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Arm description
    		 Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1.
    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 a dose of 200 mg twice daily as monotherapy in the Substudy 1. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Arm title
    		 Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab
    Arm description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib-paclitaxel-ramucirumab combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab in the Substudy 2. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Arm title
    		 Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Arm description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of either 300 mg once daily or 200 mg twice daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Derazantinib-paclitaxel-ramucirumab combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Derazantinib was administered orally at a dose of either 300 mg once daily or 200 mg twice daily in combination with paclitaxel and ramucirumab in Substudy 2. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel. All patients were treated until disease progression, patient withdrawal, patient lost to follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the patient from treatment, or until the cohort, substudy, or the study was terminated by the Sponsor, whichever occurred first

    Number of subjects in period 1
    		Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Started
    13
    8
    13
    6
    7
    Completed
    0
    0
    0
    0
    1
    Not completed
    13
    8
    13
    6
    6
         Adverse event, serious fatal
    3
    1
    2
    1
    -
         Adverse event, non-fatal
    2
    -
    -
    1
    2
         Study terminated by sponsor
    -
    -
    -
    -
    1
         Progressive disease: Radiological progression
    8
    7
    10
    4
    3
         Progressive disease: Clinical progression
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.

    Reporting group title
    Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.

    Reporting group title
    Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1.

    Reporting group title
    Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab
    Reporting group description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel

    Reporting group title
    Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Reporting group description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of either 300 mg once daily or 200 mg twice daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.

    Reporting group values
    		 Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab Total
    Number of subjects
    		 13 8 13 6 7 47
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ± 10.77 66.1 ± 9.39 54.8 ± 13.43 55.2 ± 10.53 52.0 ± 11.34 -
    Gender categorical
    Units: Subjects
        Female
    		 5 2 1 1 5 14
        Male
    		 8 6 12 5 2 33
    Race
    Units: Subjects
        Asian
    		 4 1 2 0 2 9
        Black or African American
    		 0 0 1 0 0 1
        White
    		 9 7 9 6 5 36
        Missing
    		 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.

    Reporting group title
    Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1.

    Reporting group title
    Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Reporting group description
    		 Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1.

    Reporting group title
    Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab
    Reporting group description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel

    Reporting group title
    Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Reporting group description
    		 Derazantinib-paclitaxel-ramucirumab combination: Derazantinib was administered orally at a dose of either 300 mg once daily or 200 mg twice daily in combination with paclitaxel and ramucirumab. Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab. Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel.

    Subject analysis set title
    Substudy 2 Combined
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Maximum Tolerated Dose (MTD)-determining population comprised all patients enrolled in Substudy 2 who meet the minimum criteria during the first 28-day treatment cycle (Cycle 1): received at least one dose of derazantinib-paclitaxel-ramucirumab in combination and has experienced a DLT or received ≥ 80% of the derazantinib-paclitaxel-ramucirumab dose, respectively, in Cycle 1 and, had been observed for ≥ 28 days following the first dose, and had been evaluated for safety.

    Subject analysis set title
    Substudy 1 Combined
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Derazantinib was administered orally at a dose of either 300 mg once daily or at a dose of 200 mg twice daily as monotherapy in Substudy 1.

    Primary: Objective Response Rate (ORR) in Substudy 1 (in Cohorts 1.1 and 1.2)

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    End point title
    		 Objective Response Rate (ORR) in Substudy 1 (in Cohorts 1.1 and 1.2) [1] [2]
    End point description
    ORR was defined by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR) using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST 1.1). The patients in Cohort 1.1 had FGFR2 fusions or amplification gastric adenocarcinoma (GAC) and FGFR1-3 mutations GAC in Cohort 1.2.
    End point type
    Primary
    End point timeframe
    From first dose and up to 30 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was not powered for formal statistical analysis.
    [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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily
    Number of subjects analysed
    13
    8
    Units: Percentage of participants
        number (confidence interval 90%)
    0.0 (0.0 to 20.6)
    0.0 (0.0 to 31.2)
    No statistical analyses for this end point

    Primary: Progression-free Survival at 4 Months (PFS4) in Substudy 1 in Cohort 1.3

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    End point title
    		 Progression-free Survival at 4 Months (PFS4) in Substudy 1 in Cohort 1.3 [3] [4]
    End point description
    PFS4 was defined by the proportion of patients alive and free of disease progression by BICR per RECIST. 1.1. Patients in this Cohort had HER2negative FGFR fusions, amplfications or mutations GAC
    End point type
    Primary
    End point timeframe
    From first dose and up to 4 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was not powered for formal statistical analysis.
    [4] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Number of subjects analysed
    13
    Units: Percentage of participants
        number (confidence interval 90%)
    7.7 (0.4 to 31.6)
    No statistical analyses for this end point

    Primary: Recommended Phase 2 Dose (RP2D) in Substudy 2 (Derazantinib-paclitaxel-ramucirumab in Combination)

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    End point title
    		 Recommended Phase 2 Dose (RP2D) in Substudy 2 (Derazantinib-paclitaxel-ramucirumab in Combination) [5]
    End point description
    RP2D was determined from safety and tolerability according to the aggregate of dose-limiting toxicity criteria and adverse event (AE) data, and considering further pharmacokinetic and efficacy data of the derazantinib-paclitaxel-ramucirumab combination in patients with FGFR fusions, amplifications or mutations GAC.
    End point type
    Primary
    End point timeframe
    From first dose and up to 18 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 2 Combined
    Number of subjects analysed
    13
    Units: mg
        number (not applicable)
    200
    No statistical analyses for this end point

    Secondary: ORR in Substudy 1 in Cohort 1.3

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    End point title
    		 ORR in Substudy 1 in Cohort 1.3 [6]
    End point description
    ORR was defined by the proportion of patients with CR or PR by BICR according to RECIST Version 1.1
    End point type
    Secondary
    End point timeframe
    From first dose and up to 9 months
    Notes
    [6] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Number of subjects analysed
    13
    Units: Percentage of participants
        number (confidence interval 90%)
    0.0 (0.0 to 20.6)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) in Substudy 1: Cohort 1.1, 1.3 and 1.3 and Combined Cohorts

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    End point title
    		 Disease Control Rate (DCR) in Substudy 1: Cohort 1.1, 1.3 and 1.3 and Combined Cohorts [7]
    End point description
    Defined as the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From first dose and up to 18 months
    Notes
    [7] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily Substudy 1 Combined
    Number of subjects analysed
    13
    8
    13
    34
    Units: Percentage of participants
        number (confidence interval 90%)
    30.8 (11.3 to 57.3)
    25.0 (4.6 to 60.0)
    15.4 (2.8 to 41.0)
    23.5 (12.3 to 38.5)
    No statistical analyses for this end point

    Secondary: PFS in Substudy 1 in Cohort 1.3

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    End point title
    		 PFS in Substudy 1 in Cohort 1.3 [8]
    End point description
    PFS was calculated from patient enrollment to progressive disease (PD) date by BICR per RECIST version 1.1
    End point type
    Secondary
    End point timeframe
    From first dose and up to 9 months
    Notes
    [8] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Number of subjects analysed
    13
    Units: Months
        number (confidence interval 90%)
    1.7 (1.0 to 1.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in Substudy 1 in Cohort 1.3

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    End point title
    		 Overall Survival (OS) in Substudy 1 in Cohort 1.3 [9]
    End point description
    OS was measured from patient enrollment to time of death.
    End point type
    Secondary
    End point timeframe
    From first dose and up to 9 months
    Notes
    [9] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily
    Number of subjects analysed
    13
    Units: Months
        median (confidence interval 95%)
    3.3 (2.2 to 3.7)
    No statistical analyses for this end point

    Secondary: ORR in Substudy 2

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    End point title
    		 ORR in Substudy 2 [10]
    End point description
    ORR was defined by the proportion of patients with CR or PR by BICR per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From first dose and up to 15 months
    Notes
    [10] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Number of subjects analysed
    5
    7
    Units: Percentage of participants
        number (confidence interval 90%)
    40.0 (7.6 to 81.1)
    57.1 (22.5 to 87.1)
    No statistical analyses for this end point

    Secondary: DCR in Substudy 2

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    End point title
    		 DCR in Substudy 2 [11]
    End point description
    Defined as the proportion of patients with confirmed CR, PR or SD by BICR per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From first dose and up to 15 months
    Notes
    [11] - 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: This study was not powered for formal statistical analysis.
    End point values
    		 Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab Substudy 2 Combined
    Number of subjects analysed
    5
    7
    12
    Units: Percentage of participants
        number (confidence interval 90%)
    80.0 (34.3 to 99.0)
    71.4 (34.1 to 94.7)
    75.0 (47.3 to 92.8)
    No statistical analyses for this end point

    Secondary: Number of Patients With at Least Grade 3 Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Patients With at Least Grade 3 Treatment-emergent Adverse Events (TEAEs)
    End point description
    Number of patients experiencing TEAE of Grade 3 and above according to Common Terminology Criteria for Adverse Events (CTCAE)
    End point type
    Secondary
    End point timeframe
    Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the first dose of study treatment and until safety follow-up visit (inclusive).
    End point values
    		 Substudy 1: Cohort 1.1 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.2 Derazantinib 300 mg Once Daily Substudy 1: Cohort 1.3 Derazantinib 200 mg Twice Daily Subst.2: Derazantinib 200 mg +Paclitaxel+ Ramucirumab Subst. 2: Derazantinib 300 / 400 mg +Paclitaxel+ Ramucirumab
    Number of subjects analysed
    13
    8
    13
    6
    7
    Units: Counts of participants
    number (not applicable)
        Unrelated TEAEs of Grade 3 or above
    9
    3
    5
    1
    1
        Related TEAEs of Grade 3 or above
    0
    3
    6
    4
    6
        No TEAEs of Grade 3 or above
    4
    2
    2
    1
    0
    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
    25.0
    Reporting groups
    Reporting group title
    SS1 - C1.1 - DZB 300mg
    Reporting group description
    		 SS1 - C1.1 - DZB 300 mg

    Reporting group title
    SS1 - C1.2 - DZB 300mg
    Reporting group description
    		 SS1 - C1.2 - DZB 300 mg

    Reporting group title
    SS1 - C1.3 - DZB 200mg BID
    Reporting group description
    		 SS1 - C1.3 - DZB 200 mg BID

    Reporting group title
    SS2 - DZB 200mg + RAM 8mg/kg + PAC 80mg/m2
    Reporting group description
    		 SS2 - DZB 200mg + RAM 8mg/kg + PAC 80mg/m2

    Reporting group title
    SS2 - DZB 300mg + RAM 8mg/kg + PAC 80mg/m2
    Reporting group description
    		 SS2 - DZB 300mg + RAM 8mg/kg + PAC 80mg/m2

    Serious adverse events
    		 SS1 - C1.1 - DZB 300mg SS1 - C1.2 - DZB 300mg SS1 - C1.3 - DZB 200mg BID SS2 - DZB 200mg + RAM 8mg/kg + PAC 80mg/m2 SS2 - DZB 300mg + RAM 8mg/kg + PAC 80mg/m2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 13 (53.85%)
    4 / 8 (50.00%)
    10 / 13 (76.92%)
    4 / 6 (66.67%)
    3 / 7 (42.86%)
         number of deaths (all causes)
    10
    6
    10
    4
    0
         number of deaths resulting from adverse events
    4
    2
    8
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to meninges
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 8 (25.00%)
    6 / 13 (46.15%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 6
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 6
    0 / 3
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SS1 - C1.1 - DZB 300mg SS1 - C1.2 - DZB 300mg SS1 - C1.3 - DZB 200mg BID SS2 - DZB 200mg + RAM 8mg/kg + PAC 80mg/m2 SS2 - DZB 300mg + RAM 8mg/kg + PAC 80mg/m2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    8 / 8 (100.00%)
    13 / 13 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Colon cancer
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 8 (50.00%)
    2 / 13 (15.38%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
         occurrences all number
    1
    4
    2
    1
    4
    Chills
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 8 (37.50%)
    5 / 13 (38.46%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    3
    5
    2
    1
    Feeling hot
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    2
    1
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Penile haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 8 (25.00%)
    1 / 13 (7.69%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
         occurrences all number
    0
    3
    1
    2
    6
    Dyspnoea exertional
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 8 (25.00%)
    6 / 13 (46.15%)
    2 / 6 (33.33%)
    5 / 7 (71.43%)
         occurrences all number
    2
    2
    6
    2
    7
    Amylase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    1
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 8 (25.00%)
    7 / 13 (53.85%)
    3 / 6 (50.00%)
    4 / 7 (57.14%)
         occurrences all number
    2
    2
    9
    4
    7
    Blood albumin decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    5 / 13 (38.46%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    5
    1
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    2 / 13 (15.38%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    2
    0
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    5
    14
    Lipase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    0
    0
    2
    Platelet count increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Protein total decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    2 / 13 (15.38%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    0
    2
    Neuralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    3
    2
    Neurotoxicity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    13
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    0
    2
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 13 (23.08%)
    4 / 8 (50.00%)
    4 / 13 (30.77%)
    3 / 6 (50.00%)
    3 / 7 (42.86%)
         occurrences all number
    3
    4
    4
    5
    5
    Lymphopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Leukopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    2
    1
    Neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    4 / 6 (66.67%)
    5 / 7 (71.43%)
         occurrences all number
    0
    0
    0
    5
    15
    Thrombocytopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    1
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    1
    1
    2
    Iridocyclitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Punctate keratitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Keratitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    Visual impairment
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    2
    1
    Abdominal distension
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    2 / 13 (15.38%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    2
    1
    1
    Breath odour
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    5 / 13 (38.46%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    6
    2
    5
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    4 / 13 (30.77%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    4 / 13 (30.77%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    4
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    0
    1
    Erosive oesophagitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gingival swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Melaena
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    5 / 13 (38.46%)
    4 / 8 (50.00%)
    6 / 13 (46.15%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    5
    4
    6
    1
    2
    Odynophagia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    0
    1
    4
    Rectal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    0
    2
    Vomiting
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 8 (37.50%)
    4 / 13 (30.77%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    3
    4
    0
    3
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    0
    3
    Dermatitis acneiform
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Nail disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    1
    2
    Nail dystrophy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Onycholysis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin toxicity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin mass
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Muscle haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    3 / 13 (23.08%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    COVID-19
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 8 (25.00%)
    4 / 13 (30.77%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    5
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 8 (12.50%)
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    1
    1
    0
    4
    Hyperphosphatasaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2019
    • Updated guidance on derazantinib dose reduction for management of toxicity in patients treated with derazantinib plus paclitaxel-ramucirumab in substudy 2. • Amended entry criteria to add a new Exclusion criterion 6 to exclude from the study patients with systolic blood pressure ≥ 150 mm Hg or diastolic ≥ 90 mm Hg. • Amended entry criteria to exclude from the planned (but not initiated) Substudy 3 patients who receive a live vaccine within 30 days prior to randomization. • Amended criteria for determination of RP2D and dose escalation in Substudy 2 to ensure that patients who received < 80% of the scheduled derazantinib, paclitaxel, or ramucirumab dose because of non-DLT toxicity were taken into consideration. • Amended study treatment description to ensure that in cohorts where paclitaxel is to be administered, co-administration of or premedication with drugs known to inhibit or induce either CYP2C8 or CYP3A4 was avoided. • Updated preparation procedures for atezolizumab (which was to have been used in the planned but not initiated Substudy 3). • Updated warnings, precautions and potential risks for derazantinib. • Biomarker and Patient Reported Outcome Manuals have been deleted from the protocol. • Proposed health economic assessment was deleted from the protocol.
    13 Mar 2020
    • The study title was amended. • Substudy 1 was amended to remove comparator treatment (paclitaxel-ramucirumab) and randomization, and to assign patients to cohorts based on type of FGFR GA. • Substudy 2 was amended to include only patients with FGFR GAs, and the number of patients to be enrolled in the expansion part of the study under the rules of the 3 + 3 design, and the decision making process for R2PD determination were clarified. • Secondary objectives that related to the pooling of randomized patient data from Substudy 1 and the planned (but not initiated) Substudy 3 were removed from Substudy 1 due to removal of randomization and comparator group from this substudy. • New non-clinical data were added to the study rationale. • Clarification of the composition and operation of the Independent Data Monitoring Committee. • Other changes affecting only Substudy 3, which was not initiated.
    03 Jul 2020
    • Transaminase elevations were removed from the list of potential risks for derazantinib, and upgraded to an identified risk. Phototoxicity was removed from the list of potential risks for derazantinib. The list of important potential risks for derazantinib was updated to include hyponatremia, and redefine ‘creatinine increase’ as ‘blood creatinine increased / renal disorders’. • The list of adverse events of special interest was modified • Dose modification rules for ramucirumab in the event of proteinuria being observed were updated. • Patient eligibility criteria were revised for patients who would receive ramucirumab to more clearly reflect the Cyramza USPI and the Cyramza EPAR with respect to thrombotic and bleeding events. The eligibility criterion for Substudies in which atezolizumab was planned to be used were also modified to allow enrollment of patients with a chronic hepatitis B or hepatitis C infection, provided that these infections were not concurrent. • Revised definitions of potentially activating FGFRfus/amp/mt gene variants were implemented. • Screening procedures were amended so that sites at which local FGFR testing was performed as routine institutional practice were excepted from the requirement for a positive central FGFRfus/amp/mt test result prior to potentially study related assessments. • Anti-drug antibody analysis for ramucirumab was deleted from the exploratory endpoints. • Spot urine protein-creatinine ratio was added as an alternative test for the purposes of determining eligibility for the study in regard to urinary protein levels. • Administration of derazantinib with a light meal was permitted in the event of nausea or vomiting which is assessed as moderate. • Changes were made to the eligibility requirements for members of the Independent Data Monitoring Committee. • Translational Clinical Study groups and associated molecular analyses (in the planned but not initiated Substudy 3) were removed from the protocol.
    21 Mar 2021
    • Cohort 1.3 was introduced as a new cohort in patients with metastatic or recurrent locally advanced HER2neg FGFRfus/amp/mt GAC and radiologically confirmed disease progression after one or two standard treatment regimens. • Substudy 2 was amended to enroll approximately 32 patients with HER2neg FGFRfus/amp/mt GAC with radiologically confirmed disease progression after first-line standard treatment. •The design was modified to include a Phase-2-type Expansion Part, planned to enroll approximately 14 additional patients to ensure that approximately 20 efficacy-evaluable patients were dosed at the MTD, to support declaration of the RP2D and investigate the benefit-risk ratio of derazantinib-paclitaxel-ramucirumab. • The exclusion criterion referring to corneal or retinal disorder was revised to clarify that the disorder had to be clinically significant and likely to increase the risk of eye toxicity. • Exclusion criteria were amended to clarify the eligibility of patients with active/chronic hepatitis B and active hepatitis C. • A new exclusion criterion was added for patients with a serious or non healing wound, ulcer, or bone fracture. • A 90-day Safety Follow-up visit for all patients was added. • Positive FGFR1–3 GA test results obtained from local NGS testing of archival tissue isolated DNA, and/or RNA, and other liquid biopsy derived DNA for prospective patient enrolment were permitted in addition to central NGS testing. • Criteria for derazantinib dose reduction were amended. • The IDMC membership qualifications were amended. • Two additional changes related to atezolizumab-specific adverse events were also made (atezolizumab would have been used in the planned but not initiated Substudy 3).

    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.
    The following secondary endpoints in Substudy 2 could not be shown due to the restrictions of the EudraCT system;OS, DOR and PFS . The figures are on CT.gov: https://clinicaltrials.gov/study/NCT04604132
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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