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    Clinical Trial Results:
    A Phase III, Randomized, Multi-Centre, Double-Blind, Placebo Controlled Clinical Trial of F-627 in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

    Summary
    EudraCT number
    		 2016-001930-93
    Trial protocol
    		 HU  
    Global end of trial date
    18 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2024
    First version publication date
    16 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GC-627-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02872103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Evive Biotechnology (Shanghai) Ltd
    Sponsor organisation address
    Building 2-B, 797 Puxing HWY, Shanghai, China, 201114
    Public contact
    GCR, Evive Biotechnology (Shanghai) Ltd, prr@evivebiotech.com
    Scientific contact
    GCR, Evive Biotechnology (Shanghai) Ltd, prr@evivebiotech.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
    05 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy: The objective of the study was to evaluate the efficacy and safety of F-627 given as a single 20 mg fixed dose pre-filled syringe (PFS) in the subject’s first chemotherapy cycle in comparison to Placebo Safety: To assess safety in subjects treated with the 20 mg fixed dose of F-627 using the adverse event (AE)/serious adverse event (SAE) reporting, and other standard laboratory findings including hematology and blood chemistry, urinalysis, and symptoms including, but not limited to, bone and back pain.
    Protection of trial subjects
    This study was conducted in accordance with ICH GCP regulations. The IEC/IRB approved the protocol and ICF. Only 1/3 of the subjects enrolled were randomized to the placebo arm and received treatment only in chemotherapy cycle 1. Short-acting G-CSF drugs were not permitted during the normal course of the study. However, a short-acting G-CSF may have been used if rescue therapy was needed due to the development of febrile neutropenia (FN) or prolonged severe neutropenia (>6 days).
    Background therapy
    		 Chemotherapy: 75 mg/m2 docetaxel and 60 mg/m2 doxorubicin
    Evidence for comparator
    		 No comparator used in this trial.
    Actual start date of recruitment
    17 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Ukraine: 68
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    122
    EEA total number of subjects
    5
    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)
    112
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted between 17 August 2016 and 28 November 2017 at 16 study centers in the United States, Ukraine, Russia, and Hungary.

    Pre-assignment
    Screening details
    		 A total of 135 subjects were screened and 122 (90.4%) subjects were randomized to the study, including 83 subjects randomized to F-627 and 39 subjects randomized to Placebo as their treatment in chemotherapy cycle 1. Overall, 118 subjects completed the study and 4 subjects discontinued prematurely.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 F-627
    Arm description
    		 F-627, 20 mg fixed dose pre-filled syringe, dosed on Day 2 of each of 4 chemotherapy cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    efbenmalenograstim alfa
    Investigational medicinal product code
    L03AA18
    Other name
    Ryzneuta, F-627
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use, Solution for injection
    Dosage and administration details
    F-627, 20 mg fixed dose pre-filled syringe, dosed by subcutaneous injection on Day 2 of each of 4 chemotherapy cycles.

    Arm title
    		 Placebo
    Arm description
    		 Placebo, pre-filled syringe administered on Day 2 of the first chemotherapy cycle; and F-627, 20 mg fixed dose pre-filled syringe administered on Day 2 of each of the following 3 chemotherapy cycles.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Placebo, pre-filled syringe administered by subcutaneous injection on Day 2 of the first chemotherapy cycle. F-627, 20 mg fixed dose pre-filled syringe administered on Day 2 of each of the following 3 chemotherapy cycles.

    Number of subjects in period 1
    		F-627 Placebo
    Started
    83
    39
    Completed
    81
    37
    Not completed
    2
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    1
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    F-627
    Reporting group description
    		 F-627, 20 mg fixed dose pre-filled syringe, dosed on Day 2 of each of 4 chemotherapy cycles

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, pre-filled syringe administered on Day 2 of the first chemotherapy cycle; and F-627, 20 mg fixed dose pre-filled syringe administered on Day 2 of each of the following 3 chemotherapy cycles.

    Reporting group values
    		 F-627 Placebo Total
    Number of subjects
    		 83 39 122
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 76 36 112
        From 65-84 years
    		 7 3 10
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.8 ± 9.25 51.5 ± 9.00 -
    Gender categorical
    Units: Subjects
        Female
    		 83 39 122
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-Treat Analysis Set (ITT) included all randomized subjects

    Subject analysis sets values
    		 ITT
    Number of subjects
    122
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    112
        From 65-84 years
    10
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.0 ± 9.14
    Gender categorical
    Units: Subjects
        Female
    122
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    F-627
    Reporting group description
    		 F-627, 20 mg fixed dose pre-filled syringe, dosed on Day 2 of each of 4 chemotherapy cycles

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, pre-filled syringe administered on Day 2 of the first chemotherapy cycle; and F-627, 20 mg fixed dose pre-filled syringe administered on Day 2 of each of the following 3 chemotherapy cycles.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-Treat Analysis Set (ITT) included all randomized subjects

    Primary: Duration of Severe Neutropenia (DSN) in Cycle 1

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    End point title
    		 Duration of Severe Neutropenia (DSN) in Cycle 1
    End point description
    DSN was calculated as the number of consecutive days from the first day when a patient’s ANC was <0.5 × 10^9/L until the patient reached an ANC ≥ 0.5 × 10^9/L.
    End point type
    Primary
    End point timeframe
    Chemotherapy Cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    74
    27
    Units: days
        arithmetic mean (standard deviation)
    1.3 ± 1.2
    3.9 ± 1.4
    Statistical analysis title
    		 Cycle 1
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Duration of Moderate Neutropenia in Cycle 1

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    End point title
    		 Duration of Moderate Neutropenia in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    74
    28
    Units: day
        arithmetic mean (standard deviation)
    2.1 ± 1.51
    5.1 ± 1.90
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Duration of Mild Neutropenia in Cycle 1

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    End point title
    		 Duration of Mild Neutropenia in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    74
    28
    Units: day
        arithmetic mean (standard deviation)
    2.6 ± 1.47
    6.8 ± 2.54
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Incidence Rate of Febrile Neutropenia in Cycle 1

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    End point title
    		 Incidence Rate of Febrile Neutropenia in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    39
    Units: event
    4
    10
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Incidence Rate of Severe Neutropenia in Cycle 1

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    End point title
    		 Incidence Rate of Severe Neutropenia in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    39
    Units: event
    58
    37
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to ANC Recovery Post Nadir in Cycle 1

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    End point title
    		 Time to ANC Recovery Post Nadir in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    38
    Units: day
        arithmetic mean (standard deviation)
    2.1 ± 1.09
    4.1 ± 2.06
    No statistical analyses for this end point

    Secondary: Incidence Rate of Infection in Cycle 1

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    End point title
    		 Incidence Rate of Infection in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    39
    Units: event
    2
    3
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3258
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Incidence Rate of Use of Antibiotic Medications in Cycle 1

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    End point title
    		 Incidence Rate of Use of Antibiotic Medications in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    39
    Units: event
    9
    13
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Incidence Rate of Use of Pain Medications in Cycle 1

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    End point title
    		 Incidence Rate of Use of Pain Medications in Cycle 1
    End point description
    End point type
    Secondary
    End point timeframe
    Chemotherapy cycle 1
    End point values
    		 F-627 Placebo
    Number of subjects analysed
    83
    39
    Units: event
    8
    9
    Statistical analysis title
    		 FAS
    Comparison groups
    F-627 v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0545
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were collected from the time of randomization until 28 days after the completion of the trial (a total of 16 weeks) or 28 days after the premature withdrawal of a subject from the trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    F-627
    Reporting group description
    		 Patients received F-627 all cycles

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 F-627 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 83 (4.82%)
    11 / 39 (28.21%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 83 (3.61%)
    11 / 39 (28.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    pneumonia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 F-627 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 83 (98.80%)
    39 / 39 (100.00%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 83 (8.43%)
    3 / 39 (7.69%)
         occurrences all number
    9
    5
    Headache
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 39 (5.13%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    82 / 83 (98.80%)
    39 / 39 (100.00%)
         occurrences all number
    881
    396
    Leukopenia
         subjects affected / exposed
    42 / 83 (50.60%)
    15 / 39 (38.46%)
         occurrences all number
    109
    44
    Anaemia
         subjects affected / exposed
    31 / 83 (37.35%)
    7 / 39 (17.95%)
         occurrences all number
    45
    17
    Thrombocytopenia
         subjects affected / exposed
    17 / 83 (20.48%)
    3 / 39 (7.69%)
         occurrences all number
    36
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 83 (26.51%)
    11 / 39 (28.21%)
         occurrences all number
    41
    19
    Asthenia
         subjects affected / exposed
    17 / 83 (20.48%)
    8 / 39 (20.51%)
         occurrences all number
    39
    18
    Pyrexia
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 39 (5.13%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    51 / 83 (61.45%)
    23 / 39 (58.97%)
         occurrences all number
    125
    53
    Vomiting
         subjects affected / exposed
    15 / 83 (18.07%)
    8 / 39 (20.51%)
         occurrences all number
    21
    17
    Stomatitis
         subjects affected / exposed
    11 / 83 (13.25%)
    5 / 39 (12.82%)
         occurrences all number
    15
    7
    Constipation
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Gastritis
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 39 (5.13%)
         occurrences all number
    2
    3
    Cough
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    61 / 83 (73.49%)
    26 / 39 (66.67%)
         occurrences all number
    65
    26
    Erythema
         subjects affected / exposed
    9 / 83 (10.84%)
    5 / 39 (12.82%)
         occurrences all number
    20
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 83 (16.87%)
    3 / 39 (7.69%)
         occurrences all number
    34
    7
    Bone pain
         subjects affected / exposed
    7 / 83 (8.43%)
    6 / 39 (15.38%)
         occurrences all number
    13
    6
    Pain in extremity
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 39 (7.69%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 83 (10.84%)
    3 / 39 (7.69%)
         occurrences all number
    12
    4
    Hypomagnesaemia
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 39 (5.13%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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