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    Clinical Trial Results:
    An open-label, multi-center, phase II platform study evaluating the efficacy and safety of NIS793 and other new investigational drug combinations with SOC anti-cancer therapy for the 2L treatment of metastatic colorectal cancer (mCRC)

    Summary
    EudraCT number
    		 2021-000553-40
    Trial protocol
    		 CZ   DE   HU   ES   BE   IT   FR  
    Global end of trial date
    20 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Feb 2026
    First version publication date
    05 Feb 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CNIS793E12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04952753
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    20 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the preliminary efficacy and safety of NIS793 and other novel investigational combinations with standard of care (SOC) anti-cancer therapy versus SOC anti-cancer therapy for the second-line treatment of mCRC. This study aimed to explore whether different mechanisms of action could reverse resistance and improve responsiveness to the then-considered SOC anti-cancer therapy in the second-line metastatic colorectal cancer (mCRC) setting.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2021
    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
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Japan: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    202
    EEA total number of subjects
    114
    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)
    149
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study spanned 17 countries with multiple centers: Australia (3), Belgium (3), Canada (4), Switzerland (1), Czech Republic (3), Germany (8), Spain (5), France (3), UK (3), Hong Kong (2), Israel (2), Italy (3), Japan (5), Korea (1), Singapore (1), Taiwan (2), USA (7).

    Pre-assignment
    Screening details
    		 Not Completed = Discontinued from treatment phase

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI)
    Arm description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Irinotecan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6)
    Arm description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Oxaliplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Arm description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Irinotecan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    Other name
    VDT482
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug tislelizumab was administered intravenously (IV)

    Arm title
    		 Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Arm description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Oxaliplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    Other name
    VDT482
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug tislelizumab was administered intravenously (IV)

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI)
    Arm description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Irinotecan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Arm description
    		 Expansion (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    Other name
    VDT482
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug tislelizumab was administered intravenously (IV)

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Irinotecan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Expansion Control Arm: SoC (FOLFIRI)
    Arm description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and FOLFIRI)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Irinotecan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV]

    Arm title
    		 Expansion Arm 1: NIS793 + SoC (mFOLFOX6)
    Arm description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    NIS793
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Investigational drug NIS793 was administered intravenously (IV) at the dose and schedule determined in the safety run-in part

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Oxaliplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously (IV)

    Arm title
    		 Expansion Control Arm: SoC (mFOLFOX6)
    Arm description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    5FU+Leucovorin+Oxaliplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil [administered as a continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV]

    Number of subjects in period 1
    		Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6) Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Expansion Control Arm: SoC (FOLFIRI) Expansion Arm 1: NIS793 + SoC (mFOLFOX6) Expansion Control Arm: SoC (mFOLFOX6)
    Started
    13
    9
    10
    8
    67
    29
    46
    13
    7
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    13
    9
    10
    8
    67
    29
    46
    13
    7
         Adverse event, serious fatal
    -
    -
    -
    -
    1
    -
    1
    -
    -
         Physician decision
    2
    -
    -
    1
    9
    3
    4
    1
    -
         Consent withdrawn by subject
    -
    2
    -
    1
    4
    4
    7
    2
    2
         Adverse event, non-fatal
    1
    1
    1
    1
    4
    1
    -
    -
    -
         Study terminated by sponsor
    -
    -
    -
    -
    3
    6
    7
    -
    -
         Progressive disease
    10
    6
    9
    5
    46
    15
    26
    10
    5
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI)
    Reporting group description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6)
    Reporting group description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Reporting group description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Reporting group description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Expansion Arm 1: NIS793 + SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Control Arm: SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Arm 1: NIS793 + SoC (mFOLFOX6)
    Reporting group description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Expansion Control Arm: SoC (mFOLFOX6)
    Reporting group description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6) Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Expansion Control Arm: SoC (FOLFIRI) Expansion Arm 1: NIS793 + SoC (mFOLFOX6) Expansion Control Arm: SoC (mFOLFOX6) Total
    Number of subjects
    		 13 9 10 8 67 29 46 13 7 202
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 11 6 6 5 46 24 36 11 4 149
        >=65 years
    		 2 3 4 3 21 5 10 2 3 53
    Sex: Female, Male
    Units: Participants
        Female
    		 11 3 2 2 29 11 18 8 2 86
        Male
    		 2 6 8 6 38 18 28 5 5 116
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0 0
        Asian
    		 2 2 1 1 15 5 10 4 0 40
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0 0
        Black or African American
    		 1 0 0 0 1 2 1 0 0 5
        White
    		 10 7 9 7 50 20 34 9 7 153
        More than one race
    		 0 0 0 0 0 1 0 0 0 1
        Unknown or Not Reported
    		 0 0 0 0 1 1 1 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI)
    Reporting group description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6)
    Reporting group description
    		 Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Reporting group description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Reporting group description
    		 Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Expansion Arm 1: NIS793 + SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Control Arm: SoC (FOLFIRI)
    Reporting group description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and FOLFIRI)

    Reporting group title
    Expansion Arm 1: NIS793 + SoC (mFOLFOX6)
    Reporting group description
    		 Expansion (Investigational Arm 1): NIS793 in combination with Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Reporting group title
    Expansion Control Arm: SoC (mFOLFOX6)
    Reporting group description
    		 Expansion (Control Arm): Standard of Care (bevacizumab and modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Expansion Arm 1: NIS793 + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Expansion (Investigational arm 1): NIS793 in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Expansion Arm 2: NIS793 + TISLE + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Expansion (Investigational arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and FOLFIRI)

    Subject analysis set title
    Expansion Control Arm: Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Expansion (control arm): Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 1): NIS793 in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 1): NIS793 in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6)

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 1): NIS793 in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 1): NIS793 in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational arm 2): NIS793 and Tislelizumab in combination with Standard of Care (bevacizumab and either FOLFIRI or modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI/mFOLFOX6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (FOLFIRI and modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI/mFOLFOX6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (FOLFIRI and modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI/mFOLFOX6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational Arm 1): NIS793 in combination with Standard of Care (FOLFIRI and modified FOLFOX6 (mFOLFOX6))

    Subject analysis set title
    Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI/mFOLFOX6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Safety Run-In (Investigational Arm 2): NIS793 and Tislelizumab in combination with Standard of Care (FOLFIRI and modified FOLFOX6 (mFOLFOX6))

    Primary: (Safety run-in part) Number of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment.

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    End point title
    		 (Safety run-in part) Number of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment. [1] [2]
    End point description
    The primary endpoint for the Safety Run-In part was the incidence of dose-limiting toxicities (DLT) during the first 28 days of treatment with investigational drug(s) (NIS793 with or without tislelizumab) and standard of care anti-cancer therapy. Dose tolerability decisions were based on all safety data and a Bayesian Logistic Regression Model (BLRM) using Escalation with Overdose Control (EWOC) criteria. Dose confirmation required at least six evaluable participants, fulfillment of EWOC criteria, and recommendation by Novartis and investigators after reviewing clinical, pharmacokinetic, and laboratory data.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    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: Endpoint applicable to Safety run-in part only
    [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: Endpoint applicable to Safety run-in part only
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Number of subjects analysed
    13
    9
    9
    0 [3]
    Units: Participants
    1
    1
    1
    Notes
    [3] - Study ended before RP2D was set for NIS793 + TISLE + SoC (mFOLFOX6)
    No statistical analyses for this end point

    Primary: (Expansion part) Progression-free survival (PFS) by investigator assessment per RECIST 1.1

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    End point title
    		 (Expansion part) Progression-free survival (PFS) by investigator assessment per RECIST 1.1 [4]
    End point description
    PFS was defined as the time from the date of enrollment (run-in part) or randomization (randomized part) to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause
    End point type
    Primary
    End point timeframe
    From randomization up to disease progression or death, assessed up to approximately 11 months
    Notes
    [4] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care Expansion Control Arm: Standard of Care
    Number of subjects analysed
    80
    29
    53
    Units: Months
        median (confidence interval 95%)
    5.1 (3.6 to 5.7)
    3.7 (2.2 to 5.6)
    7.4 (5.5 to 9.4)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Percentage of participants with Adverse Events (AEs)

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    End point title
    		 (Safety run-in part) Percentage of participants with Adverse Events (AEs) [5]
    End point description
    Percentage of participants who experienced AEs and SAEs, including changes in laboratory parameters, vital signs, body weight, and cardiac assessments
    End point type
    Secondary
    End point timeframe
    Through Safety Run-in completion, an average of 6 months
    Notes
    [5] - 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: Endpoint applicable to Safety run-in part only
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Number of subjects analysed
    13
    9
    10
    8
    Units: Participants
        Adverse Events (AEs)
    13
    9
    10
    8
        Serious Adverse Events (SAEs)
    6
    6
    6
    5
        Fatal SAEs
    0
    0
    0
    0
        AEs leading to discontinuation
    5
    3
    1
    2
        AEs leading to dose adjustment/interruption
    12
    7
    9
    7
        AEs requiring additional therapy
    13
    9
    10
    8
    No statistical analyses for this end point

    Secondary: (Safety Run-In) Percentage of participants with dose interruptions and dose reductions of investigational drug

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    End point title
    		 (Safety Run-In) Percentage of participants with dose interruptions and dose reductions of investigational drug [6]
    End point description
    Tolerability was measured by the percentage of subjects who had dose adjustments (interruptions or reductions) of investigational drug (NIS793, NIS793 + tislelizumab)
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint applicable to Safety run-in part only
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Number of subjects analysed
    13
    9
    10
    8
    Units: Participants
        NIS793: Participants with dose reduction
    1
    0
    0
    0
        NIS793: Participants with dose interruption
    8
    6
    9
    5
        Tislelizumab: Participants with dose reduction
    999
    999
    0
    0
        Tislelizumab: Participants with dose interruption
    999
    999
    5
    2
    No statistical analyses for this end point

    Secondary: (Safety Run-In) Dose intensity of investigational drug

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    End point title
    		 (Safety Run-In) Dose intensity of investigational drug [7]
    End point description
    Tolerability was measured by the dose intensity of the investigational drug (e.g., NIS793, NIS793 + tislelizumab). Dose intensity was computed as the ratio of the actual cumulative dose received to the actual duration of exposure.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint applicable to Safety run-in part only
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI) Safety Run-In Arm 1: NIS793 + SoC (mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Safety Run-In Arm 2: NIS793 + TISLE + SoC (mFOLFOX6)
    Number of subjects analysed
    13
    9
    10
    8
    Units: mg/cycle
    arithmetic mean (standard deviation)
        NIS793
    4171.2 ( 664.81 )
    3792.7 ( 426.97 )
    3550.5 ( 387.83 )
    3703.4 ( 627.94 )
        Tislelizumab
    999 ( 999 )
    999 ( 999 )
    273.1 ( 28.72 )
    277.9 ( 45.58 )
    No statistical analyses for this end point

    Secondary: (Safety run-in part) PFS by investigator assessment per RECIST 1.1

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    End point title
    		 (Safety run-in part) PFS by investigator assessment per RECIST 1.1
    End point description
    PFS was defined as the time from the date of enrollment to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause
    End point type
    Secondary
    End point timeframe
    From enrollment up to disease progression or death, assessed up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Months
        median (confidence interval 95%)
    3.6 (1.9 to 7.3)
    2.1 (1.8 to 4.3)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Disease control rate (DCR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Safety run-in part) Disease control rate (DCR) by investigator assessment per RECIST 1.1
    End point description
    DCR was defined as the proportion of participants with a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD), as per investigator assessment and according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Percentage of Responders
        number (confidence interval 95%)
    63.6 (40.7 to 82.8)
    44.4 (21.5 to 69.2)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Overall response rate (ORR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Safety run-in part) Overall response rate (ORR) by investigator assessment per RECIST 1.1
    End point description
    ORR was defined as the proportion of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Percentage of Responders
        number (confidence interval 95%)
    4.5 (0.1 to 22.8)
    0 (0 to 999)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Duration of response (DOR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Safety run-in part) Duration of response (DOR) by investigator assessment per RECIST 1.1
    End point description
    DOR was defined as the duration of time between the date of the first documented response (CR or PR) and the date of first documented progression or death due to any cause
    End point type
    Secondary
    End point timeframe
    From first documented response up to disease progression or death, assessed up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Months
        median (confidence interval 95%)
    9.4 (0 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Overall Survival (OS)

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    End point title
    		 (Safety run-in part) Overall Survival (OS)
    End point description
    OS was defined as the time from the date of enrollment to the date of death due to any cause
    End point type
    Secondary
    End point timeframe
    From enrollment up to death, assessed up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Months
        median (confidence interval 95%)
    10.2 (5.8 to 20.8)
    11.0 (6.2 to 15.7)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Time to response (TTR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Safety run-in part) Time to response (TTR) by investigator assessment per RECIST 1.1
    End point description
    TTR was defined as the duration of time between the date of enrollment and the date of the first documented response of either CR or PR
    End point type
    Secondary
    End point timeframe
    From enrollment up to first documented response, assessed up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    22
    18
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Maximum concentration (Cmax) of NIS793 and tislelizumab

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    End point title
    		 (Safety run-in part) Maximum concentration (Cmax) of NIS793 and tislelizumab
    End point description
    Blood samples were collected at indicated time-points for analysis of Cmax of NIS793 and tislelizumab.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 3 Day 1 (1 cycle = 28 days).
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    17
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        NIS793: Cycle 1 Day 1
    556000 ( 161000 )
    663000 ( 999 )
        NIS793: Cycle 3 Day 1
    967000 ( 285000 )
    1130000 ( 999 )
        tislelizumab: Cycle 1 Day 1
    999 ( 999 )
    71800 ( 10300 )
        tislelizumab: Cycle 3 Day 1
    999 ( 999 )
    90300 ( 11100 )
    No statistical analyses for this end point

    Secondary: (Safety run-in part) Trough Concentration (Ctrough) of NIS793 and tislelizumab

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    End point title
    		 (Safety run-in part) Trough Concentration (Ctrough) of NIS793 and tislelizumab
    End point description
    Blood samples were collected at indicated time-points for analysis of Ctrough of NIS793 and tislelizumab
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15, Cycle 3 Day 1, Cycle 3 Day 15, Cycle 6 Day 1 (1 cycle = 28 days)
    End point values
    		 Safety Run-In Arm 1: NIS793 + Standard of Care Safety Run-In Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    19
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        NIS793: Cycle 1 Day 15
    164000 ( 59800 )
    173000 ( 18700 )
        NIS793: Cycle 3 Day 1
    406000 ( 178000 )
    284000 ( 136000 )
        NIS793: Cycle 3 Day 15
    439000 ( 165000 )
    273000 ( 12700 )
        NIS793: Cycle 6 Day 1
    699000 ( 324000 )
    999 ( 999 )
        tislelizumab: Cycle 1 Day 15
    999 ( 999 )
    28600 ( 40300 )
        tislelizumab: Cycle 3 Day 1
    999 ( 999 )
    21500 ( 8710 )
        tislelizumab: Cycle 3 Day 15
    999 ( 999 )
    23600 ( 3700 )
        tislelizumab: Cycle 6 Day 1
    999 ( 999 )
    48800 ( 30300 )
    No statistical analyses for this end point

    Secondary: (Safety run-in part) NIS793 and Tislelizumab Antidrug antibodies (ADA) at baseline

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    End point title
    		 (Safety run-in part) NIS793 and Tislelizumab Antidrug antibodies (ADA) at baseline
    End point description
    Prevalence of NIS793 and Tislelizumab Antidrug antibodies (ADA) at baseline was defined as the proportion of participants who had an ADA positive result at baseline
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI/mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI/mFOLFOX6)
    Number of subjects analysed
    22
    18
    Units: Participants
        NIS793: ADA-positive (i.e. ADA prevalence)
    0
    0
        Tislelizumab: ADA-positive (i.e. ADA prevalence)
    999
    2
    No statistical analyses for this end point

    Secondary: (Safety run-in part) NIS793 and Tislelizumab Antidrug antibodies (ADA) incidence on treatment

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    End point title
    		 (Safety run-in part) NIS793 and Tislelizumab Antidrug antibodies (ADA) incidence on treatment
    End point description
    Incidence of NIS793 and Tislelizumab Antidrug antibodies (ADA) on treatment was defined as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with an ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with a titer that was at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    From the date of first study drug intake up to approximately 7 months
    End point values
    		 Safety Run-In Arm 1: NIS793 + SoC (FOLFIRI/mFOLFOX6) Safety Run-In Arm 2: NIS793 + TISLE + SoC (FOLFIRI/mFOLFOX6)
    Number of subjects analysed
    18
    10
    Units: Participants
        NIS793: Treatment-induced ADA-positive
    0
    0
        NIS793: Treatment-boosted ADA-positive
    0
    0
        Tislelizumab: Treatment-induced ADA-positive
    999
    2
        Tislelizumab: Treatment-boosted ADA-positive
    999
    0
    No statistical analyses for this end point

    Secondary: (Expansion part) Percentage of participants with Adverse Events (AEs)

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    End point title
    		 (Expansion part) Percentage of participants with Adverse Events (AEs) [8]
    End point description
    The percentage of participants who experienced AEs and SAEs, including changes in laboratory parameters, vital signs, body weight, and cardiac assessments
    End point type
    Secondary
    End point timeframe
    Through Expansion completion, an average of 8 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Expansion Control Arm: SoC (FOLFIRI) Expansion Arm 1: NIS793 + SoC (mFOLFOX6) Expansion Control Arm: SoC (mFOLFOX6)
    Number of subjects analysed
    67 [9]
    29
    46
    13
    7
    Units: Participants
        Adverse Events (AEs)
    65
    26
    45
    14
    7
        Serious Adverse Events (SAEs)
    32
    9
    14
    6
    3
        Fatal SAEs
    0
    0
    0
    0
    0
        AEs leading to discontinuation
    19
    5
    9
    5
    3
        AEs leading to dose adjustment/interruption
    47
    17
    34
    9
    5
        AEs requiring additional therapy
    60
    26
    39
    14
    6
    Notes
    [9] - Two participants were mis-randomized to the NIS793+SoC (FOLFIRI) while actually received NIS793+SoC
    No statistical analyses for this end point

    Secondary: (Expansion part) Percentage of participants with dose interruptions and dose reductions of investigational drug

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    End point title
    		 (Expansion part) Percentage of participants with dose interruptions and dose reductions of investigational drug [10]
    End point description
    Tolerability was measured by the percentage of subjects who had dose adjustments (interruptions) of the investigational drug (e.g., NIS793, NIS793 + tislelizumab)
    End point type
    Secondary
    End point timeframe
    Up to approximately 11 months
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Expansion Arm 1: NIS793 + SoC (mFOLFOX6)
    Number of subjects analysed
    67 [11]
    29
    13
    Units: Participants
        NIS793: Participants with dose reduction
    1
    0
    0
        NIS793: Participants with dose interruption
    40
    10
    8
        Tislelizumab: Participants with dose reduction
    0
    0
    0
        Tislelizumab: Participants with dose interruption
    0
    6
    0
    Notes
    [11] - Two participants were mis-randomized to the NIS793+SoC (FOLFIRI) while actually received NIS793+SoC
    No statistical analyses for this end point

    Secondary: (Expansion part) Dose intensity of investigational drug

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    End point title
    		 (Expansion part) Dose intensity of investigational drug [12]
    End point description
    Tolerability was measured by the dose intensity of the investigational drug (e.g., NIS793, NIS793 + Tislelizumab). Dose intensity was computed as the ratio of the actual cumulative dose received to the actual duration of exposure.
    End point type
    Secondary
    End point timeframe
    Up to approximately 11 months
    Notes
    [12] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI) Expansion Arm 1: NIS793 + SoC (mFOLFOX6)
    Number of subjects analysed
    67 [13]
    29
    13
    Units: mg/cycle
    arithmetic mean (standard deviation)
        NIS793
    3865.2 ( 591.35 )
    3982.1 ( 393.43 )
    3786.2 ( 437.93 )
        Tislelizumab
    999 ( 999 )
    290.8 ( 19.39 )
    999 ( 999 )
    Notes
    [13] - Two participants were mis-randomized to the NIS793+SoC (FOLFIRI) while actually received NIS793+SoC
    No statistical analyses for this end point

    Secondary: (Expansion part) Overall response rate (ORR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Expansion part) Overall response rate (ORR) by investigator assessment per RECIST 1.1
    End point description
    ORR was defined as the proportion of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Up to approximately 11 months
    End point values
    		 Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care Expansion Control Arm: Standard of Care
    Number of subjects analysed
    80
    29
    53
    Units: Percentage of Responders
        number (confidence interval 95%)
    8.8 (3.6 to 17.2)
    13.8 (3.9 to 31.7)
    15.1 (6.7 to 27.6)
    No statistical analyses for this end point

    Secondary: (Expansion part) Disease control rate (DCR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Expansion part) Disease control rate (DCR) by investigator assessment per RECIST 1.1
    End point description
    DCR was defined as the proportion of participants with a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD), as per investigator assessment and according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Up to approximately 11 months
    End point values
    		 Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care Expansion Control Arm: Standard of Care
    Number of subjects analysed
    80
    29
    53
    Units: Percentage of Responders
        number (confidence interval 95%)
    66.3 (54.8 to 76.4)
    65.5 (45.7 to 82.1)
    79.2 (65.9 to 89.2)
    No statistical analyses for this end point

    Secondary: (Expansion part) Duration of response (DOR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Expansion part) Duration of response (DOR) by investigator assessment per RECIST 1.1
    End point description
    DOR was defined as the duration of time between the date of the first documented response (CR or PR) and the date of first documented progression or death due to any cause
    End point type
    Secondary
    End point timeframe
    From first documented response up to disease progression or death, assessed up to approximately 11 months
    End point values
    		 Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care Expansion Control Arm: Standard of Care
    Number of subjects analysed
    80
    29
    53
    Units: Months
        median (confidence interval 95%)
    9.5 (4.0 to 999)
    999 (999 to 999)
    11.1 (3.8 to 999)
    No statistical analyses for this end point

    Secondary: (Expansion part) Time to response (TTR) by investigator assessment per RECIST 1.1

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    End point title
    		 (Expansion part) Time to response (TTR) by investigator assessment per RECIST 1.1 [14]
    End point description
    TTR was defined as the duration of time between the date of enrollment and the date of first documented response of either CR or PR
    End point type
    Secondary
    End point timeframe
    From enrollment up to first documented response, assessed up to approximately 11 months
    Notes
    [14] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Control Arm: SoC (FOLFIRI) Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [15] - Median and 95% CI not estimable due to too few participants with events
    [16] - Median and 95% CI not estimable due to too few participants with events
    [17] - Median and 95% CI not estimable due to too few participants with events
    No statistical analyses for this end point

    Secondary: (Expansion part) Overall Survival (OS)

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    End point title
    		 (Expansion part) Overall Survival (OS)
    End point description
    OS was defined as the time from the date of enrollment to the date of death due to any cause
    End point type
    Secondary
    End point timeframe
    From randomization up to death, assessed up to approximately 11 months
    End point values
    		 Expansion Arm 1: NIS793 + Standard of Care Expansion Arm 2: NIS793 + TISLE + Standard of Care Expansion Control Arm: Standard of Care
    Number of subjects analysed
    80
    29
    53
    Units: Months
        median (confidence interval 95%)
    12.8 (8.0 to 14.2)
    10.9 (6.1 to 999)
    999 (11.6 to 999)
    No statistical analyses for this end point

    Secondary: (Expansion part) Maximum concentration (Cmax) of NIS793 and tislelizumab

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    End point title
    		 (Expansion part) Maximum concentration (Cmax) of NIS793 and tislelizumab [18]
    End point description
    Blood samples were collected at indicated time-points for analysis of Cmax of NIS793 and tislelizumab
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 3 Day 1 (NIS793 only) (1 cycle = 28 days)
    Notes
    [18] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Number of subjects analysed
    58
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        NIS793: Cycle 1 Day 1
    598000 ( 178000 )
    694000 ( 478000 )
        NIS793: Cycle 3 Day 1
    904000 ( 301000 )
    871000 ( 315000 )
        tislelizumab: Cycle 1 Day 1
    999 ( 999 )
    93400 ( 999 )
    No statistical analyses for this end point

    Secondary: (Expansion part) Trough Concentration (Ctrough) of NIS793 and tislelizumab

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    End point title
    		 (Expansion part) Trough Concentration (Ctrough) of NIS793 and tislelizumab [19]
    End point description
    Blood samples were collected at indicated time-points for analysis of Ctrough of NIS793 and tislelizumab
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 (NIS793 only), Cycle 2 Day (tislelizumab only), Cycle 3 Day 1, Cycle 3 Day 15 (NIS793 only), Cycle 4 Day (tislelizumab only), Cycle 6 Day 1 (NIS793 only) (1 cycle = 28 days)
    Notes
    [19] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Number of subjects analysed
    63
    18
    Units: ng/mL
    arithmetic mean (standard deviation)
        NIS793: Cycle 1 Day 15
    189000 ( 56200 )
    181000 ( 50000 )
        NIS793: Cycle 3 Day 1
    371000 ( 1116000 )
    391000 ( 100000 )
        NIS793: Cycle 3 Day 15
    394000 ( 121000 )
    342000 ( 186000 )
        NIS793: Cycle 6 Day 1
    365000 ( 180000 )
    999 ( 999 )
        tislelizumab: Cycle 2 Day 1
    999 ( 999 )
    25400 ( 19600 )
        tislelizumab: Cycle 3 Day 1
    999 ( 999 )
    29400 ( 12700 )
        tislelizumab: Cycle 4 Day 1
    999 ( 999 )
    39400 ( 17100 )
    No statistical analyses for this end point

    Secondary: (Expansion part) NIS793 and Tislelizumab Antidrug antibodies (ADA) incidence on treatment

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    End point title
    		 (Expansion part) NIS793 and Tislelizumab Antidrug antibodies (ADA) incidence on treatment [20]
    End point description
    Incidence of NIS793 and Tislelizumab Antidrug antibodies (ADA) on treatment was defined as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with an ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with a titer that was at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    From the date of first study drug intake up to approximately 11 months
    Notes
    [20] - 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: Endpoint applicable to Expansion part only
    End point values
    		 Expansion Arm 1: NIS793 + SoC (FOLFIRI) Expansion Arm 2: NIS793 + TISLE + SoC (FOLFIRI)
    Number of subjects analysed
    67
    20
    Units: Participants
        NIS793: Treatment-induced ADA-positive
    0
    0
        NIS793: Treatment-boosted ADA-positive
    0
    0
        Tislelizumab: Treatment-induced ADA-positive
    999
    0
        Tislelizumab: Treatment-boosted ADA-positive
    999
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from first dose of study medication to 30 days after the last dose of Standard of Care, assessed up to approximately 38 months. Safety Run-in lasted about 162.5 days (5.4 months), and Expansion lasted about 221.3 days (7.4 months).
    Adverse event reporting additional description
    For both the Safety run-in and Expansion phases, the Safety population comprised all participants who received at least one dose of any study drug, including incomplete infusions, with data pooled by treatment arm. In the Expansion phase, two participants were mis-randomized to NIS793 + SoC (FOLFIRI) but actually received NIS793 + SoC (mFOLFOX6).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    NIS793+SoC(S)
    Reporting group description
    		 NIS793+SoC(S)

    Reporting group title
    NIS793+TISLE+SoC(E)
    Reporting group description
    		 NIS793+TISLE+SoC(E)

    Reporting group title
    SoC(E)
    Reporting group description
    		 SoC(E)

    Reporting group title
    NIS793+TISLE+SoC(S)
    Reporting group description
    		 NIS793+TISLE+SoC(S)

    Reporting group title
    NIS793+SoC(E)
    Reporting group description
    		 NIS793+SoC(E)

    Serious adverse events
    		 NIS793+SoC(S) NIS793+TISLE+SoC(E) SoC(E) NIS793+TISLE+SoC(S) NIS793+SoC(E)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    0 / 18 (0.00%)
    0 / 79 (0.00%)
         number of deaths (all causes)
    22
    26
    52
    18
    79
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NIS793+SoC(S) NIS793+TISLE+SoC(E) SoC(E) NIS793+TISLE+SoC(S) NIS793+SoC(E)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 22 (77.27%)
    13 / 26 (50.00%)
    32 / 52 (61.54%)
    13 / 18 (72.22%)
    37 / 79 (46.84%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    6 / 52 (11.54%)
    3 / 18 (16.67%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    8
    3
    0
    Fatigue
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
    4 / 52 (7.69%)
    0 / 18 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    1
    2
    4
    0
    3
    Mucosal inflammation
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
    1 / 52 (1.92%)
    0 / 18 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    1
    1
    1
    0
    5
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 26 (7.69%)
    2 / 52 (3.85%)
    1 / 18 (5.56%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    2
    1
    2
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    2 / 18 (11.11%)
    1 / 79 (1.27%)
         occurrences all number
    1
    0
    0
    2
    2
    Pleural effusion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Investigations
    Blood thrombin abnormal
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
    6 / 52 (11.54%)
    1 / 18 (5.56%)
    10 / 79 (12.66%)
         occurrences all number
    2
    1
    10
    1
    14
    Injury, poisoning and procedural complications
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    1 / 52 (1.92%)
    1 / 18 (5.56%)
    2 / 79 (2.53%)
         occurrences all number
    0
    0
    1
    1
    2
    Infusion related reaction
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 26 (0.00%)
    2 / 52 (3.85%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    5
    0
    2
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 26 (15.38%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    9 / 79 (11.39%)
         occurrences all number
    2
    5
    0
    2
    13
    Neutropenia
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 26 (11.54%)
    14 / 52 (26.92%)
    3 / 18 (16.67%)
    10 / 79 (12.66%)
         occurrences all number
    8
    10
    20
    4
    18
    Eye disorders
    Keratitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Proctalgia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
    4 / 52 (7.69%)
    0 / 18 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    1
    0
    5
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
    6 / 52 (11.54%)
    2 / 18 (11.11%)
    3 / 79 (3.80%)
         occurrences all number
    3
    2
    8
    3
    3
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    1 / 79 (1.27%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
    1 / 52 (1.92%)
    2 / 18 (11.11%)
    0 / 79 (0.00%)
         occurrences all number
    1
    1
    1
    2
    0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 26 (7.69%)
    1 / 52 (1.92%)
    1 / 18 (5.56%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    1
    1
    1
    Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
    1 / 52 (1.92%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Rectal abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
    3 / 52 (5.77%)
    1 / 18 (5.56%)
    3 / 79 (3.80%)
         occurrences all number
    0
    1
    3
    1
    3
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 26 (0.00%)
    0 / 52 (0.00%)
    1 / 18 (5.56%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Nov 2021
    Amendment 1: The key purpose of this amendment was to add additional treatment arm(s) with new investigational drug(s) in combination with SoC anti-cancer therapy for the second-line treatment of mCRC.
    20 Sep 2022
    Amendment 2: The main purpose of this amendment was to clarify independent determination of RP2D for each of the tested regimens, as RP2D for each investigational arm were different for the combination with FOLFIRI and mFOLFOX6, depending on the tolerability of each regimen.
    30 May 2023
    Amendment 3 (withdrawn on 01-Sep-2023): The key purpose of this amendment was to update the relevant protocol sections to reflect the latest changes made in the Investigator’s Brochure Edition 8. Amendment 3 was released on 30-May-2023. On 31 Jul 2023 a communication instructing all participants to discontinue treatment with NIS793 and hold tislelizumab was issued. On 01-Sep-2023, an investigator notification was issued requesting withdrawal of amendment 3 and the corresponding Informed Consent Form (ICFs) in cases where the documents were already submitted to HAs and/or ECs/IRBs, because the newly introduced changes were no longer applicable. Amendment 3 was not implemented in any countries/sites. All countries/sites continued to operate under amendment 2. However, approvals were granted by the Health Authority of Germany and an EC of a single site in Hong Kong and Australia and could not be withdrawn. Accordingly, in these sites, amendment 3 was replaced by amendment 4.
    11 Mar 2024
    Amendment 4: As of 20-Feb-2024, 205 participants had been enrolled in the study and 20 were still receiving SoC therapy. Specifically, 39 participants enrolled in the SRI Part (22 in Arm 1, 16 in Arm 2, 1 discontinued at C1D1) and 166 participants enrolled in the Expansion Part (81 in Arm 1, 31 in Arm 2, 53 in Control arm, 1 discontinued at C1D1). No participants were receiving NIS793 nor tislelizumab in the study. Following the daNIS-2 study (CNIS793B12301) DMC’s recommendation to stop administration of NIS793 to participants with PDAC, Novartis also decided to halt daNIS-3 study screening and enrollment of new participants, a communication for this was released on 12-Jul-2023. On 31-Jul-2023 the daNIS-3 DMC recommended to stop NIS793 and tislelizumab treatment due to an unfavorable benefit-risk profile observed in the investigational treatment arms in participants with mCRC. Based on the available data, NIS793 showed a deleterious PFS signal and a trend in reduced OS compared to SoC in participants with mCRC. The participant could continue to receive SoC therapy, as per Investigator's assessment.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please go to https://www.novctrd.com/#/ for complete trial results
    For support, Contact us.
    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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