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    Clinical Trial Results:
    SGI-110 to potentiate platinum response: A phase Ib/randomised IIa open label clinical trial combining SGI-110 with cisplatin and gemcitabine chemotherapy

    Summary
    EudraCT number
    		 2015-004062-29
    Trial protocol
    		 GB  
    Global end of trial date
    01 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2022
    First version publication date
    21 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RHMCAN1142
    Additional study identifiers
    ISRCTN number
    		 ISRCTN16332228
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Southampton NHS Foundation
    Sponsor organisation address
    Tremona Road, Southampton, United Kingdom,
    Public contact
    Denise Dunkley, Southampton Clinical Trials Unit, 44 2381205154, ctu@soton.ac.uk
    Scientific contact
    Denise Dunkley, Southampton Clinical Trials Unit, 44 2381205154, ctu@soton.ac.uk
    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
    01 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To find a safe and effective dose of the trial drug when given in combination with gemcitabine and cisplatin chemotherapy.
    Protection of trial subjects
    Independent Ethics Committee (REC): The protocol, amendments and informed consent forms (ICFs) for this study were reviewed and approved by the REC prior to implementation. No subject was treated until the REC had provided written approval of the study and the ICF to the investigator and the sponsor. Protocol amendments and all revisions to the ICF after initial REC approval were submitted for REC review and approval before implementation in accordance with regulatory requirements. Ethical Conduct of the Study: The study was conducted in accordance with the principles of International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, applicable local regulatory requirements, and the principles enunciated in the Declaration of Helsinki. Subject Information and Consent: The ICF(s) used for each study centre complied with ICH, the principles enunciated in the Declaration of Helsinki, local regulatory requirements, and ICH GCP guidelines and was approved by the sponsor and the REC. The investigator, or a person delegated by the investigator, explained the medical aspects of the study, including the nature and purpose of the study and the treatment, the procedures involved, and the potential benefits and risks. Other tasks in the informed consent process may have been delegated by the investigator. After having been informed that participation was voluntary and that subjects may withdraw from the study at any time, without prejudice, each subject signed the REC-approved ICF prior to undergoing any study specific procedures and enrolment in the study. Concomitant medications and therapies deemed necessary for supportive care and safety of the subject were allowed, including antiemetics and intravenous hydration, per local institutional policy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2016
    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
    United Kingdom: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    0
    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)
    10
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 8 principal investigators at 8 study centres in the UK enrolled 40 eligible patients in this study between May 2016 and September 2019. Phase I = 17 evaluable patients and 3 non-evaluable patients due to rapid disease progression leading to death (were replaced). Phase II = 20 patients with muscle invasive bladder cancer.

    Pre-assignment
    Screening details
    		 Screening criteria: age ≥16y, ECOG 0-1, glomerular filtration rate ≥60 ml/min, adequate haematological/biochemical parameters, life expectancy >3m, written informed consent. Also in Phase I: incurable metastatic solid cancers; and in Phase II: bladder cancer with pure/predominant transitional cell Carcinoma, T2-4a N0 M0, planned GC for 3-4 cycles.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 2 - 20 mg + G-CSF
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Guadecitabine
    Investigational medicinal product code
    SGI-110
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection , Intraabdominal use , Subcutaneous use
    Dosage and administration details
    SGI-110 administration has been established as 20 mg/m2, daily, on days 1-5, by sub-cutaneous injection to all patients and preferably in the abdominal area. • Care must be taken to avoid intradermal injection as this may result in injection site pain. • SGI-110 should be injected slowly (up to one minute) as some injection site discomfort or pain may occasionally be experienced. • If injection site pain is reported upon injection, apply ice packs to the injection site both before and after injection. If injection site events are reported at subsequent injections despite slow injection and the use of ice packs, pretreatment with topical or systemic analgesics can be considered.

    Investigational medicinal product name
    Granulocyte Colony Stimulating Factor
    Investigational medicinal product code
    GCSF
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use, Injection
    Dosage and administration details
    300μg GCSF, daily, on days 15-21, by subcutaneous injection

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Infusion
    Dosage and administration details
    Gemcitabine 1000 mg/m2 on days 8 and 15 of each cycle by IV infusion over 30-60 minutes (and prior to cisplatin on day 8)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m2 on day 8 of each cycle by IV infusion over 2-4 hours

    Arm title
    		 Cohort 3 - 30 mg + G-CSF
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Guadecitabine
    Investigational medicinal product code
    SGI-110
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraabdominal use , Subcutaneous use, Injection
    Dosage and administration details
    SGI-110 administration has been established as 30 mg/m2, daily, on days 1-5, by sub-cutaneous injection to all patients and preferably in the abdominal area. • Care must be taken to avoid intradermal injection as this may result in injection site pain. • SGI-110 should be injected slowly (up to one minute) as some injection site discomfort or pain may occasionally be experienced. • If injection site pain is reported upon injection, apply ice packs to the injection site both before and after injection. If injection site events are reported at subsequent injections despite slow injection and the use of ice packs, pretreatment with topical or systemic analgesics can be considered.

    Investigational medicinal product name
    Granulocyte Colony Stimulating Factor
    Investigational medicinal product code
    GCSF
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use, Injection
    Dosage and administration details
    300μg GCSF, daily, on days 15-21, by subcutaneous injection

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Cisplatin 70 mg/m2 on day 8 of each cycle by IV infusion over 2-4 hours

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Infusion
    Dosage and administration details
    Gemcitabine 1000 mg/m2 on days 8 and 15 of each cycle by IV infusion over 30-60 minutes (and prior to cisplatin on day 8)

    Arm title
    		 Cohort 1 20mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Guadecitabine
    Investigational medicinal product code
    SGI-110
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection , Intraabdominal use , Subcutaneous use
    Dosage and administration details
    SGI-110 administration has been established as 20 mg/m2, daily, on days 1-5, by sub-cutaneous injection to all patients and preferably in the abdominal area. • Care must be taken to avoid intradermal injection as this may result in injection site pain. • SGI-110 should be injected slowly (up to one minute) as some injection site discomfort or pain may occasionally be experienced. • If injection site pain is reported upon injection, apply ice packs to the injection site both before and after injection. If injection site events are reported at subsequent injections despite slow injection and the use of ice packs, pretreatment with topical or systemic analgesics can be considered.

    Number of subjects in period 1
    		Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Started
    9
    6
    4
    Completed
    8
    5
    4
    Not completed
    1
    1
    0
         Death prior to cycle 2
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 2 - 20 mg + G-CSF
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 - 30 mg + G-CSF
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 20mg
    Reporting group description
    		 -

    Reporting group values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg Total
    Number of subjects
    		 9 6 4 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 2 2 9
        From 65-84 years
    		 3 3 2 8
        Not recorded
    		 1 1 0 2
    Age continuous
    Age continuous description
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 56 (52.5 to 65) 68 (47 to 70) 63 (57.5 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 2 6
        Male
    		 5 4 2 11
        Not recorded
    		 1 1 0 2
    ECOG Performance Status
    Eastern Cooperative Oncology Group (ECOG) performance status
    Units: Subjects
        0 - Fully Active
    		 5 2 2 9
        1 - Restricted in Physically Strenuous Activity
    		 3 3 2 8
        Not recorded
    		 1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort 2 - 20 mg + G-CSF
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 - 30 mg + G-CSF
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 20mg
    Reporting group description
    		 -

    Primary: Dose Limiting Toxicity

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    End point title
    		 Dose Limiting Toxicity [1]
    End point description
    Any of the following events occurring between the first dose administration of SGI-110 and day 1 of the second cycle of treatment will constitute a DLT if, in the opinion of the investigator, the event is defined as definitely or probably related to the combination of SGI-110, cisplatin and gemcitabine: • Greater than 14 days of delay in commencing a second cycle of treatment due to drug toxicity • Grade 4 neutropenia ≥ 7 days duration • Grade 3 – 4 neutropenia associated with a temperature ≥ 38.5°C • Grade 3 – 4 neutropenia associated with bacteriologically proven sepsis • Any grade 4 thrombocytopenia ≥ 7 days duration • Grade 3 thrombocytopenia associated with non-traumatic bleeding • Any other clinically significant grade 3 or above toxicity except nausea or vomiting A DLT excludes isolated laboratory changes of any grade (except as specified above) without clinical sequelae or clinical significance.
    End point type
    Primary
    End point timeframe
    Phase I - Trial 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: Phase 1 trial, no statistical analyses
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Subjects
        ≥ 14 days of delay commencing 2nd cycle
    0
    1
    0
        Grade 4 Neutropenia ≥ 7 days
    0
    1
    1
        Grade 3 or Grade 4 Febrile Neutropenia (≥38.5oC)
    2
    1
    1
        Grade 3 or Grade 4 Neutropenic Sepsis
    0
    0
    0
        Grade 4 Thrombocytopenia ≥ 7 days
    0
    2
    0
        G3 Thrombocytopenia with non-traumatic bleeding
    0
    0
    0
        Other Clinically Significant G3 or above toxicity
    0
    2
    1
    No statistical analyses for this end point

    Secondary: Number of complete cycles of Guadecitabine

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    End point title
    		 Number of complete cycles of Guadecitabine
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Subjects
        1 cycle
    1
    2
    0
        2 cycles
    1
    2
    0
        3 cycles
    2
    0
    1
        4 cycles
    1
    0
    0
        5 cycles
    2
    0
    2
        6 cycles
    1
    1
    1
    No statistical analyses for this end point

    Secondary: Gemcitabine - Number of cycles received

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    End point title
    		 Gemcitabine - Number of cycles received
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Cycles
        median (full range (min-max))
    3.5 (1.0 to 6.0)
    2.0 (1.0 to 6.0)
    5 (3 to 6)
    No statistical analyses for this end point

    Secondary: Cisplatin - Number of Cycles Received

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    End point title
    		 Cisplatin - Number of Cycles Received
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Cycles
        median (full range (min-max))
    3.5 (1.0 to 6.0)
    2.0 (1.0 to 6.0)
    5 (3 to 6)
    No statistical analyses for this end point

    Secondary: G-CSF Administration as Per Protocol

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    End point title
    		 G-CSF Administration as Per Protocol [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment Period
    Notes
    [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: Phase 1 trial, no statistical analyses
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF
    Number of subjects analysed
    8
    5
    Units: Subjects
        Yes
    7
    4
        No
    1
    1
    No statistical analyses for this end point

    Secondary: Number of deaths on trial

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    End point title
    		 Number of deaths on trial
    End point description
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Change in Line 1 Percentage Methylation from Cycle 1 Day 1

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    End point title
    		 Mean Change in Line 1 Percentage Methylation from Cycle 1 Day 1
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        arithmetic mean (standard error)
    0 ± 0
    0 ± 0
    0 ± 0
    Attachments
    		 Untitled (Filename: Line-1 plot1.pdf)
    No statistical analyses for this end point

    Secondary: Hgb-F Fold Change from Cycle 1 Day 1

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    End point title
    		 Hgb-F Fold Change from Cycle 1 Day 1
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        number (not applicable)
    0
    0
    0
    Attachments
    		 Untitled (Filename: Hbf panel plot1.pdf)
    No statistical analyses for this end point

    Secondary: Mean Change in LTR12C

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    End point title
    		 Mean Change in LTR12C
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        arithmetic mean (standard error)
    0 ± 0
    0 ± 0
    0 ± 0
    Attachments
    		 Untitled (Filename: LTR12C plot1.pdf)
    No statistical analyses for this end point

    Secondary: Mean Change in SAT2 percentage methylation

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    End point title
    		 Mean Change in SAT2 percentage methylation
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        arithmetic mean (standard error)
    0 ± 0
    0 ± 0
    0 ± 0
    Attachments
    		 Untitled (Filename: SAT2 plot1.pdf)
    No statistical analyses for this end point

    Secondary: Mean Change in D4Z4 percentage methylation

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    End point title
    		 Mean Change in D4Z4 percentage methylation
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        arithmetic mean (standard error)
    0 ± 0
    0 ± 0
    0 ± 0
    Attachments
    		 Untitled (Filename: D4Z4 plot1.pdf)
    No statistical analyses for this end point

    Secondary: Mean Change in NBL2 percentage methylation

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    End point title
    		 Mean Change in NBL2 percentage methylation
    End point description
    AT EACH TIME-POINT (plot is attached; no mean over all time periods is available).
    End point type
    Secondary
    End point timeframe
    Trial Period
    End point values
    		 Cohort 2 - 20 mg + G-CSF Cohort 3 - 30 mg + G-CSF Cohort 1 20mg
    Number of subjects analysed
    8
    5
    4
    Units: Percentage
        arithmetic mean (standard error)
    0 ± 0
    0 ± 0
    0 ± 0
    Attachments
    		 Untitled (Filename: NBL2 plot1.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The reporting requirement applies for all adverse events occurring up to 4 weeks after the last administration of study drugs. SAEs, SARs and SUSARs should be reported within 24 hours of the site becoming aware of the event.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Phase I - 20mg + G-CSF
    Reporting group description
    		 -

    Reporting group title
    Phase I - 20mg
    Reporting group description
    		 -

    Reporting group title
    Phase I - 30mg + G-CSF
    Reporting group description
    		 -

    Serious adverse events
    		 Phase I - 20mg + G-CSF Phase I - 20mg Phase I - 30mg + G-CSF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    3 / 4 (75.00%)
    4 / 5 (80.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Peripheral ischaemia
    Additional description: Peripheral ischaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
    Additional description: Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureteric obstruction
    Additional description: Ureteric obstruction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
    Additional description: Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase I - 20mg + G-CSF Phase I - 20mg Phase I - 30mg + G-CSF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Embolism
    Additional description: Embolism
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    0
    Phlebitis
    Additional description: Phlebitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Face oedema
    Additional description: Face oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Injection site pain
    Additional description: Injection site pain
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
         occurrences all number
    21
    17
    3
    Malaise
    Additional description: Malaise
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Injection site discomfort
    Additional description: Injection site discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Mucosal inflammation
    Additional description: Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Injection site bruising
    Additional description: Injection site bruising
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Injection site erythema
    Additional description: Injection site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Chills
    Additional description: Chills
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    8 / 8 (100.00%)
    3 / 4 (75.00%)
    5 / 5 (100.00%)
         occurrences all number
    15
    9
    8
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site reaction
    Additional description: Injection site reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    15
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    4
    0
    0
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    4
    1
    1
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Investigations
    White blood cell count decreased
    Additional description: White blood cell count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    1
    20
    Gamma-glutamyltransferase increased
    Additional description: Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood alkaline phosphatase increased
    Additional description: Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Blood urea increased
    Additional description: Blood urea increased
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Monocyte count decreased
    Additional description: Monocyte count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    2
    Platelet count increased
    Additional description: Platelet count increased
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    4
    1
    0
    Red blood cell count decreased
    Additional description: Red blood cell count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
    Additional description: Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Stoma site haemorrhage
    Additional description: Stoma site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral motor neuropathy
    Additional description: Peripheral motor neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    Headache
    Additional description: Headache
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    2
    1
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    4
    0
    Extrapyramidal disorder
    Additional description: Extrapyramidal disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Lethargy
    Additional description: Lethargy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    6 / 8 (75.00%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    9
    8
    19
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    7 / 8 (87.50%)
    4 / 4 (100.00%)
    4 / 5 (80.00%)
         occurrences all number
    25
    16
    31
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    5 / 8 (62.50%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
         occurrences all number
    15
    5
    12
    Lymphopenia
    Additional description: Lymphopenia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    4
    0
    0
    Pancytopenia
    Additional description: Pancytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Deafness
    Additional description: Deafness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    3
    7
    Vestibular disorder
    Additional description: Vestibular disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoacusis
    Additional description: Hypoacusis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal disorders
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    6
    1
    1
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    3
    2
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Melaena
    Additional description: Melaena
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    6 / 8 (75.00%)
    4 / 4 (100.00%)
    3 / 5 (60.00%)
         occurrences all number
    12
    13
    4
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    2
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    4 / 8 (50.00%)
    4 / 4 (100.00%)
    1 / 5 (20.00%)
         occurrences all number
    4
    5
    3
    Mouth ulceration
    Additional description: Mouth ulceration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
    Additional description: Oral pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Skin induration
    Additional description: Skin induration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Dermatitis acneiform
    Additional description: Dermatitis acneiform
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Acne
    Additional description: Acne
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Purpura
    Additional description: Purpura
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritis
    Additional description: Pruritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 4 (75.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    4
    1
    Erythema
    Additional description: Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Urticaria
    Additional description: Urticaria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    0
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    3
    Rash macular
    Additional description: Rash macular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Urinary tract pain
    Additional description: Urinary tract pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Urine odour abnormal
    Additional description: Urine odour abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Groin pain
    Additional description: Groin pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    3
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
    Additional description: Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    0
    1
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    1
    Infections and infestations
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    5
    0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Furuncle
    Additional description: Furuncle
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
    Additional description: Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Lip infection
    Additional description: Lip infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Corona Virus Infection
    Additional description: Corona Virus Infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    3
    1
    Hypomagnesaemia
    Additional description: Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    6
    Hyponatraemia
    Additional description: Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Hypocalcaemia
    Additional description: Hypocalcaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    0
    1
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Hypocalcemia
    Additional description: Hypocalcemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2016
    MHRA requested changes to the protocol, PIS/ICF updates and addition of a 4th site (Rob Jones).
    08 Dec 2016
    Updated IB v07 18 Aug 2016, updated protocol RIS, PIS/ICF side effects and exposure numbers updated in line with new IB.
    25 May 2018
    -Provide clarification to ensure that, as was the original intention, all patients in the control arm (GC alone) should not have a delay in treatment (Gemcitabine and Cisplatin) administration following randomisation, is clear. -Alter the neutrophil and platelet count criteria for proceeding to subsequent cycles to ensure patients are not unduly delayed. It has been noted in the dose escalation phase that patients were experiencing dose delays enforced by the protocol that would not have usually clinically been implemented and that those patients with reduced neutrophil and platelets counts were returning to within limits within 2 weeks. The TMG have agreed that unnecessary dose delays should be avoided in the neoadjuvant setting that the dose expansion phase will be conducted in. -Request additional sites to be added for dose expansion phase. - Include updates to IMPD previously sent only to the MHRA
    07 Feb 2019
    Updated IB v08 18 Aug 2016, updated protocol RIS, PIS/ICF side effects and exposure numbers updated in line with new IB.
    02 Jul 2019
    Amendment changes: • Pre-treatment assessments permitted within 3 days prior to Day 1, 8 and 15. • Gemcitabine SmPC updated. • Cisplatin SmPC updated. • RSI table in protocol updated. • PIS – new common side effect of Cisplatin added. • ICF – updated to reflect change in version of PIS. • Changes to predicted timelines – recruitment completion, patient follow-up and final report. Dr Crabb (SPIRE Chief Investigator) has stated ‘The changes within this amendment take into account the greater level of safety data now available for this combination of drugs and brings the protocol into line with standard levels of monitoring and toxicity assessment for this form of treatment.’

    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/33472913
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