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    Clinical Trial Results:
    A Phase Ib /II Multicenter, Open Label, Dose Escalation Study of WNT974, LGX818 and Cetuximab in Patients with BRAFV600-mutant Metastatic Colorectal Cancer Harboring Wnt Pathway Mutations.

    Summary
    EudraCT number
    		 2014-002826-11
    Trial protocol
    		 BE   ES   NL   FR  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2018
    First version publication date
    01 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CWNT974X2102C
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Array BioPharma Inc.
    Sponsor organisation address
    3200 Walnut Street, Boulder, Colorado, United States, 80301
    Public contact
    Victor Sandor, MD Chief Medical Officer, Array BioPharma Inc., +34 900353036, info@arraybiopharma.com
    Scientific contact
    Victor Sandor, MD Chief Medical Officer, Array BioPharma Inc., +34 900353036, info@arraybiopharma.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
    25 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to assess the safety and antitumor activity of the triple combination of WNT974, encorafenib and cetuximab in patients with KRAS WT BRAF v600 mutant mCRC with RNF43 mutations or RSPO fusions. Main objective: Phase Ib: To estimate the MTD(s) and/or RP2D(s) of the triple combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant CRC harboring upstream Wnt pathway mutations. Phase II: To estimate the preliminary anti-tumor activity of the RP2D(s) of WNT974 in combination with LGX818 and cetuximab in patients with BRAFV600-mutant CRC harboring upstream Wnt pathway mutations. Note: Further enrollment to the study has been discontinued as of 21 March 2016. Therefore, references to phase II study design and objectives are no longer relevant. Phase 2 of this study was not initiated and this objective was not achieved.
    Protection of trial subjects
    All AEs suspected to be related to study drug were to be followed up weekly, or as clinically indicated, until resolution or stabilization. In addition, after the 30-day safety follow-up, monitoring of the levels of magnesium and additional electrolytes (i.e., calcium, chloride, potassium and sodium) was to be performed according to institutional and published guidelines and as per the locally applicable cetuximab label. Before the first patient was dosed with the triple combination, the Bayesian model was updated with the most recent data from the ongoing dose-escalation studies utilizing the combination drugs to confirm that the proposed starting doses were still appropriate (fulfilled the EWOC criteria).
    Background therapy
    		 Medications that are sensitive substrates of CYP2B6, CYP2C9, CYP3A4 and UGT1A1 or those substrates that have a narrow therapeutic index were permitted to be used with caution.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Israel: 1
    Worldwide total number of subjects
    20
    EEA total number of subjects
    15
    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)
    13
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 16 clinical sites: 7 sites in Europe, 3 sites in the United States, 3 sites in Canada and 1 site each in Australia, Israel and Singapore. When the required mutational status was known, patients were to sign the Main Study ICF and be evaluated against study inclusion and exclusion criteria and safety assessments.

    Pre-assignment
    Screening details
    		 To be considered eligible for this study, patients must have had written documentation of KRAS-WT, BRAFV600 mutation, as well as RNF43 mutation and/or RSPO fusions. Central testing included analysis of a cancer related multigene panel and determination of study eligibility.

    Period 1
    Period 1 title
    Phase 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study was open-label and therefore blinding was not used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 WNT974 5mg + LGX818+ Cetuximab
    Arm description
    		 WNT974 5 mg QD + LGX818 200 mg QD + Cetuximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    WNT974
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    WNT974 capsules were administered orally QD at the assigned dose. WNT974 was supplied as capsules for oral use at dosage strengths of 2.5 mg, 10 mg and 50 mg. WNT974 and encorafenib were always to be dosed together orally QD as a flat-fixed dose and not by body weight or body surface area (BSA).

    Investigational medicinal product name
    Encorafenib
    Investigational medicinal product code
    LGX818
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encorafenib was supplied as capsules for oral use packed in bottles. Encorafenib capsules were formulated in 2 dosage strengths: 50 mg and 100 mg. Encorafenib at the dosage strengths of 10 mg and 25 mg were also supplied if required. WNT974 and encorafenib were always to be dosed together orally QD as a flat-fixed dose and not by body weight or body surface area (BSA).

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered by IV infusion once weekly (QW) at 400 mg/m2 (initial infusion) and 250 mg/m2 (subsequent infusions). Cetuximab was supplied locally. Cetuximab was to be administered IV QW on Days 1, 8, 15 and 22 (± 3 days) of every cycle at the study site according to institutional standards. Premedication was to be administered as described in compliance with institutional standards 30 minutes prior to cetuximab infusion. A complete treatment cycle was defined as 28 days of uninterrupted continuous treatment with the study drug combinations. Cycle 1 Day 1 was defined as the day that the first dose of WNT974 and encorafenib were administered. Commercially available vials of cetuximab were used in this study according to local regulations in each participating country.

    Arm title
    		 WNT974 7.5 mg+LGX818+Cetuximab
    Arm description
    		 WNT974 7.5 mg QD + LGX818 200 mg QD + Cetuximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    WNT974
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    WNT974 capsules were administered orally QD at the assigned dose. WNT974 was supplied as capsules for oral use at dosage strengths of 2.5 mg, 10 mg and 50 mg.

    Arm title
    		 WNT974 10 mg+LGX818+Cetuximab
    Arm description
    		 WNT974 10 mg QD + LGX818 200 mg QD + Cetuximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    WNT974
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    WNT974 capsules were administered orally QD at the assigned dose. WNT974 was supplied as capsules for oral use at dosage strengths of 2.5 mg, 10 mg and 50 mg.

    Number of subjects in period 1
    		WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab
    Started
    10
    6
    4
    Completed
    0
    0
    0
    Not completed
    10
    6
    4
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    1
         Death
    -
    -
    1
         Progressive desease
    8
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    WNT974 5mg + LGX818+ Cetuximab
    Reporting group description
    		 WNT974 5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 7.5 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 7.5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 10 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 10 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group values
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab Total
    Number of subjects
    		 10 6 4 20
    Age categorical
    Units: Subjects
        Adults < 65
    		 6 3 4 13
        Adults ≥ 65
    		 4 3 0 7
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.5 (50 to 70) 60.5 (51 to 75) 60.5 (60 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 1 11
        Male
    		 4 2 3 9
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) comprises all patients who received at least one full or partial dose of assigned combination of drugs.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set included all patients from the FAS who received at least 1 dose of WNT974, encorafenib or cetuximab and had at least 1 valid postbaseline safety assessment.

    Subject analysis set title
    Dose-Determining Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose-determining set (DDS) consisted of all patients in the Safety Analysis Set who either met the minimum exposure criterion and had sufficient safety evaluations or experienced a DLT during Cycle 1.

    Subject analysis set title
    PK Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK analysis set included all patients with at least 1 available valid PK concentration measurement who received at least 1 dose of study drug.

    Subject analysis sets values
    		 Full Analysis Set Safety Analysis Set Dose-Determining Set PK Analysis Set
    Number of subjects
    20
    20
    18
    20
    Age categorical
    Units: Subjects
        Adults < 65
    13
        Adults ≥ 65
    7
    Age continuous
    Units: years
        median (full range (min-max))
    61.0 (50 to 75)
    Gender categorical
    Units: Subjects
        Female
    11
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    WNT974 5mg + LGX818+ Cetuximab
    Reporting group description
    		 WNT974 5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 7.5 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 7.5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 10 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 10 mg QD + LGX818 200 mg QD + Cetuximab

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS) comprises all patients who received at least one full or partial dose of assigned combination of drugs.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set included all patients from the FAS who received at least 1 dose of WNT974, encorafenib or cetuximab and had at least 1 valid postbaseline safety assessment.

    Subject analysis set title
    Dose-Determining Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose-determining set (DDS) consisted of all patients in the Safety Analysis Set who either met the minimum exposure criterion and had sufficient safety evaluations or experienced a DLT during Cycle 1.

    Subject analysis set title
    PK Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK analysis set included all patients with at least 1 available valid PK concentration measurement who received at least 1 dose of study drug.

    Primary: PK Parameters for WNT974

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    End point title
    		 PK Parameters for WNT974 [1]
    End point description
    Incidence of DLTs; exposure to WNT974 and encorafenib as measured by PK parameters. In the Phase 1b dose-escalation part of the study, cohorts of patients were treated with the combination until the MTD and/or RP2D of the triple combination was identified. Duration of exposure for encorafenib and WNT974 QD was defined as Duration of exposure (days) = (study drug end date) – (study drug start date) + 1.
    End point type
    Primary
    End point timeframe
    The study treatment was to be administered during 28-day cycles. The PK parameters were calculated as appropriate using non-compartmental method(s) for WNT974, its active metabolite LHA333 and encorafenib. Steady state was assumed to be reached by Day 15
    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: The PK parameters were calculated as appropriate using non-compartmental method(s) for WNT974. This was summarized for all relevant pharmacokinetic and pharmacodynamics measurements using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for quantitative data and contingency tables. No formal statistical hypothesis was tested.
    End point values
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab
    Number of subjects analysed
    10 [2]
    6 [3]
    4 [4]
    Units: C max (ng/ml)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1
    42.0 ± 22.8
    66.0 ± 30.1
    66.0 ± 27.3
        Cycle 1 Day 15
    51.0 ± 23.2
    93.4 ± 55.7
    42.9 ± 37.1
    Notes
    [2] - 9 subjects in Day 15
    [3] - 5 subjects in Day 15
    [4] - 3 subjects in day 15
    No statistical analyses for this end point

    Primary: PK Parameters for Encorafenib

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    End point title
    		 PK Parameters for Encorafenib [5]
    End point description
    Dose limiting toxicities will be listed by dose level. The maximum tolerated dose (MTD) is defined as the highest dose for a given schedule that causes DLTs in no more than 35% of patients during the first cycle of treatment.
    End point type
    Primary
    End point timeframe
    The study treatment was to be administered during 28-day cycles. The PK parameters were calculated as appropriate using non-compartmental method(s) for WNT974, its active metabolite LHA333 and encorafenib. Steady state was assumed to be reached by Day 15.
    Notes
    [5] - 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: The PK parameters were calculated as appropriate using non-compartmental method(s) for encorafenib. This was summarized for all relevant pharmacokinetic and pharmacodynamics measurements using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for quantitative data and contingency tables. No formal statistical hypothesis was tested.
    End point values
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab
    Number of subjects analysed
    10 [6]
    6 [7]
    4 [8]
    Units: C max (ng/ml)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1
    3510 ± 2110
    3620 ± 1000
    2830 ± 1550
        Cylce 1 Day 15
    3080 ± 1440
    3250 ± 1170
    1440 ± 1340
    Notes
    [6] - 9 subjects / Day 15
    [7] - 5 subjects / Day 15
    [8] - 3 subjects/ Day 15
    No statistical analyses for this end point

    Primary: Incidence of Dose-Limiting Toxicity

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    End point title
    		 Incidence of Dose-Limiting Toxicity [9]
    End point description
    The primary endpoint was the incidence of DLTs in the first cycle of treatment. Estimation of the Maximum tolerated dose (MTD) /Recommended phase 2 dose (RP2D) was based upon the Bayesian logistic regression model (BLRM) of the probability of a DLT in the first cycle of treatment for patients in the Dose Determining Set (DDS). A Dose-Limiting Toxicity (DLT) was defined as an Adverse Event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications that occurred within the first 28 days of treatment with the triple combination of WNT974, encorafenib and cetuximab and met any of the criteria included in protocol.
    End point type
    Primary
    End point timeframe
    The primary endpoint was the incidence of Dose-Limiting Toxicity (DLTs) in the first cycle of treatment (Day 28).
    Notes
    [9] - 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: An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with overdose control (EWOC) principle was used to make dose recommendations and estimate the Maximum Tolerated Dose (MTD(s)/ recommended phase 2 dose (RP2D(s) during the escalation. Only the Phase 1b component of this study was conducted and the CSR only contains study information and results for the Phase 1b part. No formal statistical hypothesis was tested.
    End point values
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab Dose-Determining Set
    Number of subjects analysed
    10
    4
    4
    18
    Units: number of patients
        Lipase increased
    0
    0
    1
    1
        Hypercalcaemia
    0
    1
    0
    1
        Dysgeusia
    0
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Only adverse events occurring during treatment or within 30 days of the last study medication are reported. Deaths occurring 30 days after end of treatment were not included.
    Adverse event reporting additional description
    A patient with multiple adverse events within a primary system organ class is counted only once in the total row. Patients with multiple events in the same category were counted only once in that category. Patients with events in more than 1 category were counted once in each of those categories.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    WNT974 5mg + LGX818+ Cetuximab
    Reporting group description
    		 WNT974 5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 7.5 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 7.5 mg QD + LGX818 200 mg QD + Cetuximab

    Reporting group title
    WNT974 10 mg+LGX818+Cetuximab
    Reporting group description
    		 WNT974 10 mg QD + LGX818 200 mg QD + Cetuximab

    Serious adverse events
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    4 / 6 (66.67%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    8
    4
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 WNT974 5mg + LGX818+ Cetuximab WNT974 7.5 mg+LGX818+Cetuximab WNT974 10 mg+LGX818+Cetuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Skin papilloma
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Haemangioma of skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Keratoacanthoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Haematoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 10 (60.00%)
    2 / 6 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    6
    2
    3
    Pyrexia
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    5
    2
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 6 (0.00%)
    4 / 4 (100.00%)
         occurrences all number
    3
    0
    4
    Chills
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Pain
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Catheter site ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Xerosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Penile pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    Epistaxis
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Dysphonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    2
    Insomnia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    Claustrophobia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Encopresis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    3 / 4 (75.00%)
         occurrences all number
    0
    1
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Lipase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Amylase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Foot fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    2
    2
    3
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Dysaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nerve root compression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Sciatica
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Spinal claudication
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Bradyphrenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 6 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    5
    2
    3
    Lymph node pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Dysacusis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Ear discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    5 / 10 (50.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 10 (50.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    5
    2
    2
    Nausea
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 6 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    4
    4
    1
    Vomiting
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    4
    2
    2
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    2
    Diarrhoea
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    1
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Ascites
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Colonic fistula
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Faecaloma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Lip dry
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary duct inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Sensitivity of teeth
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Papule
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nail dystrophy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nail ridging
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    2
    Nocturia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 6 (66.67%)
    4 / 4 (100.00%)
         occurrences all number
    5
    4
    4
    Back pain
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    3
    3
    2
    Myalgia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    3
    2
    2
    Osteoporosis
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    1
    Pain in extremity
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    1
    2
    Osteopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Fibromyalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypercreatinaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Joint stiffness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pathological fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Labyrinthitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nail infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rash pustular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Scrotal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Urethritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    5 / 10 (50.00%)
    5 / 6 (83.33%)
    4 / 4 (100.00%)
         occurrences all number
    5
    5
    4
    Hypophosphataemia
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    4
    2
    2
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    3
    2
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    3
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    3 / 4 (75.00%)
         occurrences all number
    3
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    3 / 4 (75.00%)
         occurrences all number
    1
    1
    3
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypercreatininaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypovitaminosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2014
    Protocol Amendment 01: The reason for this current amendment was to comply with health authority request for better defining some DLT criteria grade 4 (hypertension, diarrhea, infections and fever and laboratory abnormalities) and clarifying the sequence of drug administration. In addition, minor changes for consistency and clarification were implemented. The sequence of drug administration (QD regimen) was revised to clarify that WNT974 and encorafenib were to be taken in the fasted state, at least 1 hour after or 2 hours before a meal as recommended by the health authority. The criteria for defining some DLT criteria Grade 4 (hypertension, diarrhea, infections and fever and laboratory abnormalities) were revised.
    13 Jul 2015
    Protocol Amendment 02: The purpose of this amendment was to document a change in study sponsorship from Novartis to Array BioPharma. Study design and procedures were not affected.
    19 Apr 2016
    Protocol Amendment 03: • Added notification of the decision to discontinue further enrollment in Phase 1b and to not initiate the Phase 2 portion of the study due to evidence of bone toxicity and lack of improved efficacy of the triple combination, WNT974 + encorafenib + cetuximab over the dual combination, encorafenib + cetuximab. • Additional monitoring and treatment of bone-related toxicities were incorporated into the protocol following observations of bone toxicity. • Added notification of the decision that survival follow-up would continue until/unless the Sponsor decided to discontinue such assessments. • Added information to clarify that in exceptional cases, if WNT974 was discontinued due to toxicity and if the patient might benefit from continuing encorafenib and cetuximab, the patient may have remained on study following discussion with the Sponsor’s Medical Monitor. Also added that due to the lack of demonstrated activity with single-agent encorafenib or cetuximab, patients who could not tolerate the dual combination were discontinued from the study. • Added dose modification information for bone toxicity. • Added DEXA scans (at screening, at Cycle 3 Day 1, every 16 weeks and as clinically indicated) to the “Visit Evaluation Schedule” to assess bone toxicity.
    30 May 2017
    Administrative letter: The frequency of tumor assessments in an ongoing patient was reduced to minimize the burden on patients and reduce radiation exposure.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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