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    Clinical Trial Results:
    A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy of RXC004 in Monotherapy and in Combination with Nivolumab, in Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer who have Progressed following Therapy with Current Standard of Care

    Summary
    EudraCT number
    		 2020-003132-24
    Trial protocol
    		 ES  
    Global end of trial date
    02 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2025
    First version publication date
    11 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RXC004/0002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04907539
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Redx Pharma Limited
    Sponsor organisation address
    Block 33, Mereside, Alderley Park, Alderley Edge, Cheshire, United Kingdom,
    Public contact
    Craig Tilston, Redx Pharma Limited, +44(0) 7787983638, c.tilston@redxpharma.com
    Scientific contact
    Craig Tilston, Redx Pharma Limited, +44(0) 7787983638, c.tilston@redxpharma.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
    02 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the anti-tumour activity of RXC004 monotherapy and RXC004 + Nivolumab.
    Protection of trial subjects
    The study was conducted in accordance with the protocol and Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, applicable ICH Good Clinical Practice (GCP) Guidelines and applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 1
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    25
    EEA total number of subjects
    5
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted from 08 November 2021 to 02 April 2024 at multiple centers in 4 countries (South Korea, Spain, United Kingdom and United States of America).

    Pre-assignment
    Screening details
    		 Patients who met the inclusion criteria, and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the Schedule of Assessment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: RXC004 Monotherapy
    Arm description
    		 Patients received 2 mg of RXC004 once daily orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RXC004
    Investigational medicinal product code
    RXC004
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were administered with 2 mg of RXC004 as a monotherapy once daily.

    Arm title
    		 Arm B: RXC004+Nivolumab
    Arm description
    		 Patients received 1.5 mg of RXC004 once daily orally along with the combination of 480 mg of Nivolumab once every 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RXC004
    Investigational medicinal product code
    RXC004
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were administered with 2 mg of RXC004 as a monotherapy once daily.

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Nivolumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Intravenous drip use
    Dosage and administration details
    Patients were administered with 480 mg of Nivolumab once in 4 weeks in combination with RXC004.

    Number of subjects in period 1
    		Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Started
    17
    8
    Completed
    2
    5
    Not completed
    15
    3
         Consent withdrawn by subject
    1
    -
         Death
    14
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: RXC004 Monotherapy
    Reporting group description
    		 Patients received 2 mg of RXC004 once daily orally.

    Reporting group title
    Arm B: RXC004+Nivolumab
    Reporting group description
    		 Patients received 1.5 mg of RXC004 once daily orally along with the combination of 480 mg of Nivolumab once every 4 weeks.

    Reporting group values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab Total
    Number of subjects
    		 17 8 25
    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)
    		 13 4 17
        From 65-84 years
    		 4 4 8
        85 years and over
    		 0 0 0
        Age categorial
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 53.4 ( 13.87 ) 64.8 ( 7.78 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 13
        Male
    		 9 3 12
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 14 6 20
        Not stated
    		 1 1 2
        Unknown
    		 1 0 1
        Other
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Arm A: RXC004 Monotherapy
    Reporting group description
    		 Patients received 2 mg of RXC004 once daily orally.

    Reporting group title
    Arm B: RXC004+Nivolumab
    Reporting group description
    		 Patients received 1.5 mg of RXC004 once daily orally along with the combination of 480 mg of Nivolumab once every 4 weeks.

    Primary: RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1)

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    End point title
    		 RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) [1] [2]
    End point description
    The anti-tumour activity of RXC004 monotherapy was evaluated. DCR was defined as the percentage of patients with a BOR of either complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks post baseline. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
    End point type
    Primary
    End point timeframe
    Up to 28 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was applicable for Arm A only.
    End point values
    		 Arm A: RXC004 Monotherapy
    Number of subjects analysed
    11
    Units: Percentage of patients
        number (confidence interval 90%)
    18.2 (3.33 to 47.01)
    No statistical analyses for this end point

    Primary: RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1

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    End point title
    		 RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1 [3] [4]
    End point description
    The anti-tumour activity as a combination therapy of RXC004 +nivolumab was evaluated. ORR was defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment, as defined in RECIST 1.1. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
    End point type
    Primary
    End point timeframe
    Up to 28 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this end point.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was applicable for Arm B only.
    End point values
    		 Arm B: RXC004+Nivolumab
    Number of subjects analysed
    7
    Units: Percentage of patients
        number (confidence interval 90%)
    14.3 (0.73 to 52.07)
    No statistical analyses for this end point

    Secondary: Best Percentage Change in Tumor Size

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    End point title
    		 Best Percentage Change in Tumor Size
    End point description
    The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The best percentage change in tumor size was determined at a patient level. Percentage change in tumor size was derived at each visit by the percentage change from baseline in the sum of diameters of target lesions. The best percentage change in tumor size was the patients value representing the largest decrease (or smallest increase) from baseline in tumor size. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumor assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may impact outcome were excluded from the population.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    11
    7
    Units: Percentage change in tumor size
        median (full range (min-max))
    9.34 (-11.8 to 59.8)
    0.00 (-40.4 to 39.4)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. PFS was defined as the time from first dose of study treatment until the date of disease progression or death (by any cause in the absence of progression). Full analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004). In the data presentation table, the arbitrary value, 999.999, represented the estimates that were not calculable as there were insufficient number of patients with evaluable events as per methodology specified in Statistical Analysis Plan (SAP).
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    17
    8
    Units: Months
        median (confidence interval 95%)
    2.0 (1.31 to 2.33)
    3.9 (1.58 to 999.999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The DOR was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumor assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population. DOR was not calculated as no patient was analysed for this endpoint due to absence of any patient with a complete response (CR); only 1 patient had a partial response (PR). As pre-specified in the SAP that after the review of the available data, DOR would not be summarized and listed.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - No patient was analysed for this endpoint
    [6] - No patient was analysed for this endpoint
    No statistical analyses for this end point

    Secondary: RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1

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    End point title
    		 RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1 [7]
    End point description
    The preliminary efficacy of RXC004 monotherapy was evaluated. ORR was defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment as defined in RECIST 1.1. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was applicable for Arm A only.
    End point values
    		 Arm A: RXC004 Monotherapy
    Number of subjects analysed
    11
    Units: Percentage of patients
        number (confidence interval 90%)
    0 (0.00 to 23.84)
    No statistical analyses for this end point

    Secondary: RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1

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    End point title
    		 RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1 [8]
    End point description
    The preliminary efficacy of combination therapy of RXC004 + nivolumab was evaluated. DCR was defined as the percentage of patients with a BOR of either CR, PR or SD for at least 16 weeks post baseline. Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was applicable for Arm B only.
    End point values
    		 Arm B: RXC004+Nivolumab
    Number of subjects analysed
    7
    Units: Percentage of patients
        number (confidence interval 90%)
    57.1 (22.53 to 87.12)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. OS is defined as the time from first day of study treatment until death due to any cause. Full analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004). The arbitrary value, 999.999, indicated that due to insufficient follow-up information, the median for Arm B was not reached and therefore estimates were not calculable as per methodology specified in the SAP.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    17
    8
    Units: Months
        median (confidence interval 95%)
    4.8 (1.3 to 6.5)
    999.999 (1.7 to 999.999)
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax)
    End point description
    The pharmacokinetic (PK) (Cmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. The number analyzed "nA" for Arm A and "nB" for Arm B refer to the number of patients included in analysis in specific arms and specific time points. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length) and Cycle 1 Day 15 (28-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    17
    8
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1 (nA=16; nB=8)
    65.2 ( 62.0 )
    56.5 ( 56.4 )
        Cycle 1 Day 15 (nA=11; nB=7)
    80.0 ( 66.8 )
    79.4 ( 42.7 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (Tmax)

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax)
    End point description
    The PK (Tmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. The number analyzed "nA" for Arm A and "nB" for Arm B refer to the number of patients included in analysis in specific arms and specific time points.
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length) and Cycle 1 Day 15 (28-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    17
    8
    Units: Hour (h)
    median (full range (min-max))
        Cycle 0 Day 1 (nA=16; nB=8)
    2.07 (0.983 to 4.18)
    1.95 (0.933 to 2.12)
        Cycle 1 Day 15 (nA=11; nB=7)
    1.35 (0.517 to 6.12)
    1.98 (1.02 to 10.4)
    No statistical analyses for this end point

    Secondary: Minimum Observed Concentration Across the Dosing Interval (Cmin)

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    End point title
    		 Minimum Observed Concentration Across the Dosing Interval (Cmin)
    End point description
    The PK (Cmin) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 1 Day 15 (28-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    11
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 15
    12.8 ( 65.8 )
    17.2 ( 49.4 )
    No statistical analyses for this end point

    Secondary: Terminal Rate Constant (λz)

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    End point title
    		 Terminal Rate Constant (λz)
    End point description
    The PK (λz) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    11
    8
    Units: 1/hour
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1
    0.0769 ( 73.3 )
    0.0540 ( 29.8 )
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t½)

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    End point title
    		 Terminal Half-life (t½)
    End point description
    The PK (t½) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    11
    7
    Units: hour (h)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1
    9.02 ( 73.3 )
    12.2 ( 27.7 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve from Zero to Infinity(AUC0-∞)

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    End point title
    		 Area Under the Plasma Concentration-time Curve from Zero to Infinity(AUC0-∞)
    End point description
    The PK (AUC0-∞) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    10
    6
    Units: hour*nanogram/milliliter (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1
    733 ( 48.9 )
    749 ( 45.0 )
    No statistical analyses for this end point

    Secondary: Total Plasma Clearance After Oral Administration (CL/F)

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    End point title
    		 Total Plasma Clearance After Oral Administration (CL/F)
    End point description
    The PK (CL/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    10
    6
    Units: milliliter per hour (mL/h)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1
    2730 ( 48.9 )
    2000 ( 45.0 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution After Oral Administration (Vz/F)

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    End point title
    		 Apparent Volume of Distribution After Oral Administration (Vz/F)
    End point description
    The PK (Vz/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample. For the geometric coefficient of variation (CV), the unit of measure was percentage (%).
    End point type
    Secondary
    End point timeframe
    On Cycle 0 Day 1 (3–7-day cycle in length)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    10
    6
    Units: milliliter (mL)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1
    32300 ( 89.6 )
    35800 ( 22.0 )
    No statistical analyses for this end point

    Secondary: Number of Patients with Adverse Events (AEs)

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    End point title
    		 Number of Patients with Adverse Events (AEs)
    End point description
    The safety and tolerability of RXC004 monotherapy and RXC004+ nivolumab combination was evaluated. The National Cancer Institute Common Terminology Criteria for Adverse events (CTCAE) Grade refers to the severity of the AE. The CTCAE displays Grades 1-5 with unique clinical descriptions of severity for each AE based on general guideline: Grade 1 Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local/noninvasive intervention indicated; limiting age-appropriate instrumentally. Grade 3 Severe/medically significant but not immediately life threatening; hospitalization/prolongation of hospitalization indicated; disabling; limiting selfcare ADL; Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE. The safety analysis set consisted of all patients who were enrolled and received at least 1 dose of RXC004. Perm=Permanent, Disc=discontinuation, Inter=Interruption, Reduc=reduction.
    End point type
    Secondary
    End point timeframe
    From time of signature of informed consent form throughout the treatment period and until 30 days after the last dose of RXC004 (forRXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months)
    End point values
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Number of subjects analysed
    17
    8
    Units: patients
    number (not applicable)
        Treatment emergent adverse events (TEAE)
    17
    8
        RXC004 Related TEAE
    14
    8
        Nivolumab Related TEAE
    1
    5
        Grade >=3 TEAE
    9
    5
        RXC004 Related Grade>=3 TEAE
    3
    4
        Nivolumab Related Grade>=3 TEAE
    0
    2
        Serious TEAE
    3
    5
        RXC004 Related Serious TEAE
    2
    4
        Nivolumab Related Serious TEAE
    0
    2
        TEAE Leading to Death
    0
    1
        TEAE Leading to Perm Disc or Reduc/Inter of RXC004
    10
    7
        TEAE Leading to Perm Disc RXC004
    2
    3
        TEAE Leading to Reduc of RXC004
    3
    4
        TEAE Leading to Inter of RXC004
    8
    3
        TEAE Leading to Perm Disc or Inter of Nivolumab
    0
    5
        TEAE Leading to Perm Disc Nivolumab
    0
    3
        TEAE Leading to Inter of Nivolumab
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of signature of ICF throughout the treatment period and until 30 days after the last dose of RXC004 (for RXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months).
    Adverse event reporting additional description
    The safety analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Arm A: RXC004 Monotherapy
    Reporting group description
    		 Patients received 2 mg of RXC004 monotherapy once daily orally.

    Reporting group title
    Arm B: RXC004+Nivolumab
    Reporting group description
    		 Patients received 1.5 mg of RXC004 once daily along with the combination of 480 mg of Nivolumab every 4 weeks orally.

    Serious adverse events
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 17 (17.65%)
    5 / 8 (62.50%)
         number of deaths (all causes)
    14
    3
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         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
    Death
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: RXC004 Monotherapy Arm B: RXC004+Nivolumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    Chills
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 8 (50.00%)
         occurrences all number
    2
    5
    Influenza like illness
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 8 (37.50%)
         occurrences all number
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Mental status changes
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Amylase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 8 (37.50%)
         occurrences all number
    2
    5
    Blood creatinine increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Carcinoembryonic antigen increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Gastric pH decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Protein urine present
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Urine calcium decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 8 (50.00%)
         occurrences all number
    3
    4
    Injury, poisoning and procedural complications
    Stoma prolapse
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    9 / 17 (52.94%)
    6 / 8 (75.00%)
         occurrences all number
    11
    7
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Lethargy
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    Loss of consciousness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Neurotoxicity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Seizure
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 8 (12.50%)
         occurrences all number
    5
    2
    Lymphopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 8 (25.00%)
         occurrences all number
    3
    2
    Diarrhoea
         subjects affected / exposed
    4 / 17 (23.53%)
    5 / 8 (62.50%)
         occurrences all number
    6
    7
    Dyspepsia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    9 / 17 (52.94%)
    4 / 8 (50.00%)
         occurrences all number
    15
    8
    Vomiting
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 8 (37.50%)
         occurrences all number
    10
    3
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Jaundice
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 8 (50.00%)
         occurrences all number
    2
    4
    Dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    Nail discolouration
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    2
    Nail disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nail ridging
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Onychoclasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    4
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Coccydynia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Muscular weakness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Osteomyelitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 17 (47.06%)
    5 / 8 (62.50%)
         occurrences all number
    10
    6
    Hyperammonaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    4
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    4
    Hypomagnesaemia
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 8 (25.00%)
         occurrences all number
    3
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    Malnutrition
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2021
    Version 4.0: Dose of RXC004 in Arm A updated to 2 mg QD, due to data from Phase 1 study and Safety Review Committee recommendations. RXC004 background, risk/benefit, dose rationale and dose modification sections also updated with most recent data from Phase 1 dose escalation study. Inclusion criteria for entry into the combination treatment phase in Arm A added, to clarify when crossover to combination treatment can occur. Acceptable methods of contraception in the lifestyle consideration updated to be consistent with the Clinical Trial Facilitation Group (CTFG) recommendations for highly effective methods of contraception in Sub section Contraception of Section Lifestyle Consideration. A new section-Appendix: Management of colitis events was added presenting the Management plan for RXC004 related diarrhoea/colitis events added after safety review of data from the Phase 1 study. Several items have been added to the protocol as a result of the COVID-19 vaccination risk assessment. Several changes were made in Schedule of Assessment (SOA). Section Dysgeusia, SOA for Arms A and B, Objectives and Endpoints and Appendix Dysgeusia treatment guidelines were updated. Details of a Safety Monitoring Committee for Redx Phase 2 RCX004 studies added to protocol to aid patient safety monitoring. Additional language added to sample size determination to ensure that the decision for stopping development is not based purely on patients with RNF43 mutation or RSPO fusions alone. In the section Background, the subsection Nivolumab was updated in Nivolumab toxicity management guidelines. Section Inclusion criteria and Section efficacy assessment were updated: Language about collection of scans preformed before consent moved from Inclusion criteria #4 and added into section Tumor assessment so that availability of theses scans does not affect patient eligibility for the study.
    14 Sep 2021
    Version 5.0: The following updates were made to the eligibility criteria: a) Exclusion criteria updated to exclude patients with QTcF >470 ms; b) Creatinine clearance (CLcr) inclusion criteria and monitoring added to enable future population PK analysis of effect of CLcr on PK of RXC004. Guidelines for management of colitis events updated after Information Brochure (IB) was updated. Dose modification tables prohibited medications and safety labs also updated accordingly. Discontinuation of RXC004 and nivolumab (for patients on the combination) for grade 3 colitis events added as per MHRA request. RXC004 background, risk assessment, and dose justification were updated. Adverse Events of Potential Interest (AEPI) identified for monitoring: bone toxicities and colitis events were updated in Section AEPI. In section Contraception, contraception requirements updated to include the definition of sexual abstinence, as per MHRA request. Clarification for treating patients after RECIST 1.1 progression added in Section Discontinuation of Study Treatment. RXC004 fasting requirements from section Meals and Dietary Restrictions added to SOA footnotes and RXC004 handling instructions for clarity. The section, Prohibited medications, was updated. Restrictions on the use of concomitant CYP3A4 inhibitors and inducers updated to include 2 weeks prior to first dose of study treatment, as well as throughout the study treatment. The Dose modification section, Appendix J, maximum 14 days RXC004 interruption without Sponsor approval’s language removed. Language also amended to allow Microsatellite instability status of patients to be confirmed at the central laboratory. Ability of patients to enrol in concomitant COVID-19 vaccination studies removed as per MHRA request. Dysgeusia dose modifications from Table 10 and added to Table 9 Retention of ECG traces added to programme initiative to enable future QT investigations if required. Arm A primary endpoint updated.
    13 Jan 2022
    Version 6.0: Section Inclusion criteria creatinine clearance amended to ≥60mL/min instead of > 60mL/min following FDA advice. RXC004 related colitis management guideline was revised to clarify the maximum time a patient with Grade 1 colitis can continue RXC004 at a lower dose before switching to Grade 2 management and to clarify the maximum time that RXC004 treatment can be held before permanent discontinuation, following FDA advice in Appendix J. In Table Dose Modification and Stopping Criteria of Appendix I, dose modification table was revised if a patient has >5kg weight loss associated with dysgeusia and dysgeusia treatment guidelines modified to clarify management options. Tables for Dose Modification and Stopping Criteria and Table for Guidance for dose reductions for RXC004-related adverse events were updated where dose modification table was revised to include permanent discontinuation of RXC004 in the event of a RXC004 related Grade 4 event. Several changes were made in SOA. Echocardiography monitoring plan was revised.
    19 Aug 2022
    Version 7.0: In section Justification for Doses of RXC004 and Nivolumab and its subsections Investigational Products, Dose Modification, The RXC004 dose to be used in combination therapy (1.5 mg QD) has been defined and justified by updated and new text, to support combination therapy. Supporting information has been added on the dose regimen and dose reductions. Details of allocation of patients to Arm A or Arm B by randomisation once Arm B has started enrolment have been added in Sections SOA, Overall Design and Randomisation.

    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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