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    Clinical Trial Results:
    PRESERVE 1: A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2019-003826-25
    Trial protocol
    		 GB   SK   PL   HU   IT  
    Global end of trial date
    31 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2024
    First version publication date
    22 May 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    G1T28-207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04607668
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    G1 Therapeutics, Inc.
    Sponsor organisation address
    700 Park Offices Drive, Suite 200, Research Triangle Park, United States, 27709
    Public contact
    Clinical Trial Info, G1 Therapeutics, Inc., +1 919 213 9835, clinicalinfo@g1therapeutics.com
    Scientific contact
    Clinical Trial Info, G1 Therapeutics, Inc., +1 919 213 9835, clinicalinfo@g1therapeutics.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
    31 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effects of trilaciclib on the neutrophil lineage compared with placebo in participants receiving FOLFOXIRI/bevacizumab for proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC).
    Protection of trial subjects
    This study was conducted in full conformance with the ethical principles of the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, and South Africa) or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. A Data Safety Monitoring Committee (DMC) reviewed safety of trilaciclib for all participants enrolled. The DMC monitored accumulating safety and disposition data approximately every 4 months. The committee consisted of individuals with extensive multicenter clinical study experience drawn from the fields of clinical oncology (specifically, CRC) and biostatistics. These individuals were entirely independent of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 25 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    China: 53
    Country: Number of subjects enrolled
    Ukraine: 44
    Country: Number of subjects enrolled
    United States: 125
    Worldwide total number of subjects
    326
    EEA total number of subjects
    91
    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)
    244
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 82 sites enrolled participants in China, Hungary, Italy, Poland, Spain, Ukraine, United Kingdom and United States. The first participant was enrolled on 16 October 2020, and the last participant completed on 31 March 2023.

    Pre-assignment
    Screening details
    		 A total of 458 participants were screened in this study of which 132 were reported as screen failures. Thus, 326 participants were randomized in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trilaciclib + FOLFOXIRI/Bevacizumab
    Arm description
    		 Participants received trilaciclib 240 milligram per meter square (mg/m^2) on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI (fluorouracil [5FU {infusional}], leucovorin, oxaliplatin, and irinotecan)/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received trilaciclib per randomization allocation at study entry. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trilaciclib
    Investigational medicinal product code
    Other name
    G1T28
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trilaciclib 240 mg/m^2 was provided as a single-use, sterile powder to be reconstituted then diluted with 250 milliliter (mL) of dextrose 5% in water or normal saline (NaCl 0.9%).

    Investigational medicinal product name
    FOLFOXIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fluorouracil 2400 to 3200 mg/m^2, Leucovorin 400 mg/m^2 (LEVO leucovorin 200 mg/m^2 was an acceptable alternative), Oxaliplatin 85 mg/m^2 and Irinotecan 165 mg/m^2 was administered as Standard of Care (SOC) therapy.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 5 mg/kilogram (kg) was administered as SOC therapy.

    Arm title
    		 Placebo + FOLFOXIRI/Bevacizumab
    Arm description
    		 Participants received placebo on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received placebo per randomization allocation at study entry. Placebo was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was provided as 250 mL of dextrose 5% in water or normal saline (NaCl 0.9%).

    Investigational medicinal product name
    FOLFOXIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fluorouracil 2400 to 3200 mg/m^2, Leucovorin 400 mg/m^2 (LEVO leucovorin 200 mg/m^2 was an acceptable alternative), Oxaliplatin 85 mg/m^2 and Irinotecan 165 mg/m^2 was administered as SOC therapy.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 5 mg/kilogram (kg) was administered as SOC therapy.

    Number of subjects in period 1
    		Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Started
    164
    162
    Completed
    0
    0
    Not completed
    164
    162
         Consent withdrawn by subject
    12
    11
         Study terminated by Sponsor
    92
    114
         Death
    49
    26
         Unspecified
    8
    7
         Lost to follow-up
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trilaciclib + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received trilaciclib 240 milligram per meter square (mg/m^2) on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI (fluorouracil [5FU {infusional}], leucovorin, oxaliplatin, and irinotecan)/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received trilaciclib per randomization allocation at study entry. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Reporting group title
    Placebo + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received placebo on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received placebo per randomization allocation at study entry. Placebo was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Reporting group values
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab Total
    Number of subjects
    		 164 162 326
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 120 124 244
        From 65-84 years
    		 44 38 82
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.2 ( 11.80 ) 55.5 ( 10.60 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 61 119
        Male
    		 106 101 207
    Race
    Units: Subjects
        White
    		 119 112 231
        Black or African American
    		 4 9 13
        Asian
    		 32 33 65
        Other
    		 3 0 3
        Not Reported
    		 3 3 6
        Unknown
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    Trilaciclib + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received trilaciclib 240 milligram per meter square (mg/m^2) on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI (fluorouracil [5FU {infusional}], leucovorin, oxaliplatin, and irinotecan)/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received trilaciclib per randomization allocation at study entry. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Reporting group title
    Placebo + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received placebo on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received placebo per randomization allocation at study entry. Placebo was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Subject analysis set title
    Trilaciclib + FOLFOXIRI/Bevacizumab
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received trilaciclib 240 mg/m^2 on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received trilaciclib per randomization allocation at study entry. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Subject analysis set title
    Placebo + FOLFOXIRI/Bevacizumab
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received placebo on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received placebo per randomization allocation at study entry. Placebo was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Primary: Duration Of Severe Neutropenia (DSN) (Grade 4) in Cycle 1 to Cycle 4

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    End point title
    		 Duration Of Severe Neutropenia (DSN) (Grade 4) in Cycle 1 to Cycle 4
    End point description
    Severe Neutropenia was defined as Absolute neutrophil count(ANC) value<0.5 ×10^9/Liter(L)(Grade 4 neutropenia per National Cancer Institute[NCI] Common Terminology Criteria for Adverse Events[CTCAE] criteria,version 5.0).DSN in Cycle 1-4 defined as number of days of first SN event that occurred in first 4 cycles of Induction.For participants with at least 1 SN event in Induction in Cycle 1,2,3 or 4,DSN was calculated for first occurrence of event following rules:For participants whose SN was resolved,DSN was derived as number of days from date of first SN occurrence to date of SN resolution;for participants who withdraw from study with unresolved neutropenia,DSN was derived as number of days from date of first SN occurrence to date of withdrawal.Modified intent-to-treat(mITT) analysis set:included all participants randomized in countries other than Ukraine and all participants in Ukraine who were randomized prior to 09-Sep-21,and who completed or completed Induction prior to 24-Feb-22
    End point type
    Primary
    End point timeframe
    Cycle 1: Days 1, 2, 4, 6, 8, 10 and 12 and Cycles 2, 3, 4: Days 1 and 8 (each cycle is 14 days)
    End point values
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Number of subjects analysed
    149
    147
    Units: Days
        arithmetic mean (standard deviation)
    0.1 ( 0.84 )
    1.3 ( 3.14 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Trilaciclib + FOLFOXIRI/Bevacizumab v Placebo + FOLFOXIRI/Bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.2
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [1] - Two-sided p-value for treatment effect was generated from a nonparametric ANCOVA controlling for stratification factors of Region and Prior chemotherapy with study baseline ANC value as a covariate.

    Primary: Number Of Participants With Occurrence Of SN During Induction

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    End point title
    		 Number Of Participants With Occurrence Of SN During Induction
    End point description
    Severe neutropenia was defined as an ANC value <0.5 × 10^9/L (Grade 4 neutropenia per NCI CTCAE criteria, version 5.0). Occurrence of SN during Induction for a participant was defined as having as least one ANC value < 0.5 × 10^9/L among all ANC measurements during Induction regardless of scheduled or unscheduled visits. Analysis was performed on the mITT analysis set which included all participants randomized in countries other than Ukraine and all participants in Ukraine who were randomized prior to 09-Sep-21, and who completed or completed Induction prior to 24-Feb-22.
    End point type
    Primary
    End point timeframe
    Cycle 1: Days 1, 2, 4, 6, 8, 10 and 12 and Cycles 2, 3, 4: Days 1 and 8 (each cycle is 14 days)
    End point values
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Number of subjects analysed
    149
    147
    Units: Participants
    2
    29
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Trilaciclib + FOLFOXIRI/Bevacizumab v Placebo + FOLFOXIRI/Bevacizumab
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [2]
    Method
    		 Modified Poisson model
    Parameter type
    		 Adjusted relative risk
    Point estimate
    0.07
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.051
    Notes
    [2] - The aRR, its 96% CI, p-value were generated from modified Poisson model controlling for stratification factors of Region and Prior chemotherapy with baseline ANC value as a covariate. The log-transformed number of cycles was used as offset in model.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time (months) from the date of randomization to the date of death for participants who died in the study regardless of cause, or to the last contact date known to be alive for those who survived as of the date for final database lock (censored cases). 99999 indicates that median and upper limit of confidence interval (CI) was not estimable due to insufficient number of participants with events at study closure. mITT analysis set which included all participants randomized in countries other than Ukraine and all participants in Ukraine who were randomized prior to 09-Sep-21, and who completed or completed Induction prior to 24-Feb-22
    End point type
    Secondary
    End point timeframe
    Up to 26 months
    End point values
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Number of subjects analysed
    149
    147
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 (day of first dose of any study drug) until 30 days after the last dose of study drug, approximately up to 115 weeks
    Adverse event reporting additional description
    Analysis was performed on the Safety analysis set which included all randomized participants who received at least one dose of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Trilaciclib + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received trilaciclib 240 mg/m^2 on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received trilaciclib per randomization allocation at study entry. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Reporting group title
    Placebo + FOLFOXIRI/Bevacizumab
    Reporting group description
    		 Participants received placebo on Days 1 and 2 administered IV prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (induction). Following completion of induction, participants continued in maintenance, where they received placebo per randomization allocation at study entry. Placebo was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during induction. Participants continued to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurred first.

    Serious adverse events
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 159 (29.56%)
    47 / 160 (29.38%)
         number of deaths (all causes)
    8
    3
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic embolus
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 159 (0.63%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 159 (2.52%)
    4 / 160 (2.50%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 159 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 159 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Drain site complication
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial injury
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonic epilepsy
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 159 (0.00%)
    5 / 160 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 159 (0.00%)
    5 / 160 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    4 / 159 (2.52%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 159 (1.26%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 159 (1.89%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 159 (0.63%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 159 (1.26%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 159 (0.63%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trilaciclib + FOLFOXIRI/Bevacizumab Placebo + FOLFOXIRI/Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    155 / 159 (97.48%)
    159 / 160 (99.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    34 / 159 (21.38%)
    35 / 160 (21.88%)
         occurrences all number
    82
    86
    Hypotension
         subjects affected / exposed
    5 / 159 (3.14%)
    8 / 160 (5.00%)
         occurrences all number
    8
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    53 / 159 (33.33%)
    52 / 160 (32.50%)
         occurrences all number
    136
    136
    Asthenia
         subjects affected / exposed
    28 / 159 (17.61%)
    28 / 160 (17.50%)
         occurrences all number
    58
    91
    Pyrexia
         subjects affected / exposed
    17 / 159 (10.69%)
    22 / 160 (13.75%)
         occurrences all number
    27
    30
    Mucosal inflammation
         subjects affected / exposed
    17 / 159 (10.69%)
    18 / 160 (11.25%)
         occurrences all number
    20
    31
    Temperature intolerance
         subjects affected / exposed
    10 / 159 (6.29%)
    5 / 160 (3.13%)
         occurrences all number
    14
    6
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    7 / 159 (4.40%)
    28 / 160 (17.50%)
         occurrences all number
    12
    43
    Cough
         subjects affected / exposed
    13 / 159 (8.18%)
    12 / 160 (7.50%)
         occurrences all number
    16
    17
    Hiccups
         subjects affected / exposed
    14 / 159 (8.81%)
    9 / 160 (5.63%)
         occurrences all number
    17
    12
    Dyspnoea
         subjects affected / exposed
    11 / 159 (6.92%)
    8 / 160 (5.00%)
         occurrences all number
    18
    10
    Nasal congestion
         subjects affected / exposed
    10 / 159 (6.29%)
    6 / 160 (3.75%)
         occurrences all number
    10
    6
    Rhinorrhoea
         subjects affected / exposed
    4 / 159 (2.52%)
    10 / 160 (6.25%)
         occurrences all number
    5
    14
    Oropharyngeal pain
         subjects affected / exposed
    5 / 159 (3.14%)
    8 / 160 (5.00%)
         occurrences all number
    6
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 159 (9.43%)
    15 / 160 (9.38%)
         occurrences all number
    18
    18
    Anxiety
         subjects affected / exposed
    13 / 159 (8.18%)
    12 / 160 (7.50%)
         occurrences all number
    16
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 159 (12.58%)
    24 / 160 (15.00%)
         occurrences all number
    32
    40
    Aspartate aminotransferase increased
         subjects affected / exposed
    20 / 159 (12.58%)
    24 / 160 (15.00%)
         occurrences all number
    42
    41
    Neutrophil count decreased
         subjects affected / exposed
    12 / 159 (7.55%)
    15 / 160 (9.38%)
         occurrences all number
    31
    32
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 159 (8.18%)
    11 / 160 (6.88%)
         occurrences all number
    19
    18
    White blood cell count decreased
         subjects affected / exposed
    8 / 159 (5.03%)
    12 / 160 (7.50%)
         occurrences all number
    20
    36
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 159 (5.66%)
    9 / 160 (5.63%)
         occurrences all number
    16
    22
    Platelet count decreased
         subjects affected / exposed
    9 / 159 (5.66%)
    7 / 160 (4.38%)
         occurrences all number
    22
    11
    Weight decreased
         subjects affected / exposed
    20 / 159 (12.58%)
    29 / 160 (18.13%)
         occurrences all number
    27
    42
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    37 / 159 (23.27%)
    34 / 160 (21.25%)
         occurrences all number
    67
    53
    Neuropathy peripheral
         subjects affected / exposed
    36 / 159 (22.64%)
    26 / 160 (16.25%)
         occurrences all number
    81
    89
    Headache
         subjects affected / exposed
    32 / 159 (20.13%)
    26 / 160 (16.25%)
         occurrences all number
    52
    55
    Paraesthesia
         subjects affected / exposed
    20 / 159 (12.58%)
    15 / 160 (9.38%)
         occurrences all number
    29
    22
    Dizziness
         subjects affected / exposed
    13 / 159 (8.18%)
    19 / 160 (11.88%)
         occurrences all number
    17
    24
    Neurotoxicity
         subjects affected / exposed
    10 / 159 (6.29%)
    13 / 160 (8.13%)
         occurrences all number
    21
    36
    Dysgeusia
         subjects affected / exposed
    12 / 159 (7.55%)
    10 / 160 (6.25%)
         occurrences all number
    17
    11
    Tremor
         subjects affected / exposed
    8 / 159 (5.03%)
    1 / 160 (0.63%)
         occurrences all number
    9
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    61 / 159 (38.36%)
    92 / 160 (57.50%)
         occurrences all number
    212
    293
    Anaemia
         subjects affected / exposed
    57 / 159 (35.85%)
    61 / 160 (38.13%)
         occurrences all number
    164
    222
    Thrombocytopenia
         subjects affected / exposed
    34 / 159 (21.38%)
    36 / 160 (22.50%)
         occurrences all number
    106
    85
    Leukopenia
         subjects affected / exposed
    27 / 159 (16.98%)
    35 / 160 (21.88%)
         occurrences all number
    109
    129
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    83 / 159 (52.20%)
    118 / 160 (73.75%)
         occurrences all number
    212
    306
    Nausea
         subjects affected / exposed
    85 / 159 (53.46%)
    101 / 160 (63.13%)
         occurrences all number
    260
    253
    Vomiting
         subjects affected / exposed
    54 / 159 (33.96%)
    64 / 160 (40.00%)
         occurrences all number
    118
    139
    Abdominal pain
         subjects affected / exposed
    34 / 159 (21.38%)
    36 / 160 (22.50%)
         occurrences all number
    45
    61
    Constipation
         subjects affected / exposed
    38 / 159 (23.90%)
    29 / 160 (18.13%)
         occurrences all number
    53
    45
    Stomatitis
         subjects affected / exposed
    25 / 159 (15.72%)
    42 / 160 (26.25%)
         occurrences all number
    36
    69
    Dyspepsia
         subjects affected / exposed
    11 / 159 (6.92%)
    10 / 160 (6.25%)
         occurrences all number
    14
    10
    Abdominal pain upper
         subjects affected / exposed
    9 / 159 (5.66%)
    8 / 160 (5.00%)
         occurrences all number
    10
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 159 (6.29%)
    6 / 160 (3.75%)
         occurrences all number
    18
    8
    Haemorrhoids
         subjects affected / exposed
    5 / 159 (3.14%)
    11 / 160 (6.88%)
         occurrences all number
    5
    14
    Rectal haemorrhage
         subjects affected / exposed
    7 / 159 (4.40%)
    9 / 160 (5.63%)
         occurrences all number
    7
    10
    Abdominal distension
         subjects affected / exposed
    9 / 159 (5.66%)
    6 / 160 (3.75%)
         occurrences all number
    10
    8
    Oral dysaesthesia
         subjects affected / exposed
    5 / 159 (3.14%)
    8 / 160 (5.00%)
         occurrences all number
    10
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    23 / 159 (14.47%)
    25 / 160 (15.63%)
         occurrences all number
    25
    29
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    4 / 159 (2.52%)
    8 / 160 (5.00%)
         occurrences all number
    11
    23
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 159 (11.95%)
    25 / 160 (15.63%)
         occurrences all number
    47
    49
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    20 / 159 (12.58%)
    9 / 160 (5.63%)
         occurrences all number
    31
    12
    Arthralgia
         subjects affected / exposed
    9 / 159 (5.66%)
    13 / 160 (8.13%)
         occurrences all number
    11
    23
    Back pain
         subjects affected / exposed
    9 / 159 (5.66%)
    11 / 160 (6.88%)
         occurrences all number
    12
    19
    Pain in extremity
         subjects affected / exposed
    8 / 159 (5.03%)
    6 / 160 (3.75%)
         occurrences all number
    9
    9
    Infections and infestations
    COVID-19
         subjects affected / exposed
    18 / 159 (11.32%)
    22 / 160 (13.75%)
         occurrences all number
    18
    24
    Urinary tract infection
         subjects affected / exposed
    11 / 159 (6.92%)
    10 / 160 (6.25%)
         occurrences all number
    20
    11
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 159 (4.40%)
    12 / 160 (7.50%)
         occurrences all number
    8
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 159 (22.64%)
    39 / 160 (24.38%)
         occurrences all number
    44
    71
    Hypokalaemia
         subjects affected / exposed
    21 / 159 (13.21%)
    21 / 160 (13.13%)
         occurrences all number
    44
    33
    Dehydration
         subjects affected / exposed
    12 / 159 (7.55%)
    11 / 160 (6.88%)
         occurrences all number
    12
    18
    Hyperglycaemia
         subjects affected / exposed
    11 / 159 (6.92%)
    8 / 160 (5.00%)
         occurrences all number
    15
    14
    Hypophosphataemia
         subjects affected / exposed
    6 / 159 (3.77%)
    12 / 160 (7.50%)
         occurrences all number
    9
    21
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 159 (3.77%)
    11 / 160 (6.88%)
         occurrences all number
    13
    18
    Hypomagnesaemia
         subjects affected / exposed
    9 / 159 (5.66%)
    3 / 160 (1.88%)
         occurrences all number
    12
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2021
    China was added to the study and to the list of countries for stratification. Regions include Unites States, Eastern Europe, Western Europe, and China. An exclusion criterion (#15) was added to exclude those with chronic inflammatory bowel disease and/or intestinal obstruction. It was noted that participants should not be treated until the obstruction has resolved. An exclusion criterion (#19) was added to specify that participants requiring ongoing or anticipated treatment with potent CYP450 3A4 inhibitors or inducers should not be included. An exclusion criterion (#20) was added to prohibit the inclusion of participants with ongoing or anticipated treatment with sorivudine or brivudine. Exclusion criterion # 28 was added to specify any contraindications to the administration of FOLFOXIRI and bevacizumab at the discretion of the investigator. Language was added to clarify that the strata information entered in Interactive web response system (IWRS) at the time of randomization would be used for all stratified statistical analyses.
    07 Jul 2021
    Text was added to the criteria for starting Cycle 2 in Section 9.4 to clarify the guidance for initiating subsequent treatment cycles. In addition, the dose modification guidelines for Grade 2 peripheral sensory neuropathy were updated in Table 9 to accommodate differences in clinical practice.
    30 Aug 2022
    The sample size was adjusted from 296 to 326 to mitigate the impact of the Russian-Ukraine war on data integrity and to ensure that the objectives of PRESERVE-1 would not be comprised. An additional 30 participants were randomized from outside Ukraine. To account for data integrity issues resulting from the war in Ukraine, a modified intent-to-treat (mITT) population would be utilized as the primary analysis population for all efficacy evaluations. The criteria for the mITT were included in the protocol. The primary myelosuppression endpoint was updated to duration of severe neutropenia (DSN) from Cycles 1 to 4. Measuring DSN during the timeframe of occurrence of the majority of severe neutropenia events, ie, Cycles 1 through 4 allowed an assessment of the risk of febrile neutropenia during the time of greatest clinical risk to participants.

    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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