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    Clinical Trial Results:
    Open-label, Multicentre, Phase Ib/II Study of MEN1611, a PI3K Inhibitor, and Cetuximab in Patients With PIK3CA Mutated Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU and Anti-EGFR Containing Regimens

    Summary
    EudraCT number
    		 2019-003727-38
    Trial protocol
    		 FR   ES   NL   IT  
    Global end of trial date
    27 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2025
    First version publication date
    15 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEN1611-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04495621
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Menarini Ricerche S.p.A
    Sponsor organisation address
    Via Tito Speri 10, Pomezia/Rome, Italy, 00071
    Public contact
    Clinical Sciences, Menarini Ricerche S.p.A., 39 05556809990,
    Scientific contact
    Clinical Sciences, Menarini Ricerche S.p.A., 39 05556809990,
    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
    22 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Step 1: To determine the recommended phase 2 dose (RP2D) of MEN1611 when administered orally in combination with cetuximab to participants with phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene (PIK3CA) mutated colorectal cancer failing irinotecan, oxaliplatin, 5-fluorouracil (5-FU) and anti-epidermal growth factor receptor (EGFR) containing regimens. Step 2: To assess the anti-tumour activity of MEN1611 in combination with cetuximab in participants with PIK3CA mutated metastatic colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens.
    Protection of trial subjects
    All clinical trial information shall be recorded, processed, handled, and stored in such a way that it can be accurately reported, interpreted and verified; at the same time, the confidentiality of records and of the personal data of the participants shall remain protected in accordance with the Laws and Regulation on personal data protection from time to time applicable such as the EU General Data Protection Regulation 679/2016 and the EU Regulation on clinical trials on medicinal products for human use 536/2014 or the US Health Insurance Portability and Accountability Act regulations (HIPAA), the US Common Rule (45 CFR 46.116). The study protocol defines the appropriate technical and organisational measures that shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss as well as to assure the fulfilment of participants' privacy rights.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 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
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    29
    EEA total number of subjects
    29
    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)
    20
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 748 participants were pre-screened, of which 700 were considered as pre-screen failures. Out of 48 participants who were screened for study eligibility, 19 were considered screen failures.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b (Dose Confirmation)
    Arm description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEN1611
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MEN1611 administered twice daily for a continuous 28-day cycle.

    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 administered weekly via intravenous infusion for every 28-day cycle.

    Arm title
    		 Phase 2 (Cohort Expansion)
    Arm description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEN1611
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MEN1611 administered twice daily for a continuous 28-day cycle.

    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 administered weekly via intravenous infusion for every 28-day cycle.

    Number of subjects in period 1
    		Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Started
    7
    22
    Received At Least 1 Dose of Study Drug
    7
    22
    Completed
    0
    0
    Not completed
    7
    22
         Consent withdrawn by subject
    -
    3
         Death
    7
    11
         Investigator Decision
    -
    7
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b (Dose Confirmation)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Reporting group title
    Phase 2 (Cohort Expansion)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Reporting group values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion) Total
    Number of subjects
    		 7 22 29
    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)
    		 6 14 20
        From 65-84 years
    		 1 8 9
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.9 ( 12.16 ) 58.9 ( 12.38 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 11 12
        Male
    		 6 11 17
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 7 15 22
        Not Reported
    		 0 7 7

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b (Dose Confirmation)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Reporting group title
    Phase 2 (Cohort Expansion)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received at least 1 dose of MEN1611.

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least 2 complete treatment cycles and had at least 1 disease assessment.

    Subject analysis set title
    Pharmacokinetics (PK) Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received MEN1611 and for whom a PK sample was obtained and analysed.

    Subject analysis set title
    Dose-limiting Toxicity (DLT) Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received at least 80% of MEN1611 and 75% of cetuximab during Cycle 1 with a Safety Follow-up of 28 days after the first administration of the study treatment. Any participant who experienced DLT was also considered evaluable, regardless of the dose received.

    Primary: Phase 1b: RP2D of MEN1611 in Combination with Cetuximab

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    End point title
    		 Phase 1b: RP2D of MEN1611 in Combination with Cetuximab [1] [2]
    End point description
    RP2D was defined as the highest dose level in milligrams (mg) at which no more than 1 participant during the dose confirmation phase (Phase 1b) experienced a dose-limiting toxicity (DLT) during the DLT assessment window (28 days), or the maximum dose judged to be tolerable by the data safety committee.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 28 of Cycle 1 (28 days/cycle)
    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 analyses were carried out for this primary end point, as prespecified in the statistical analysis plan.
    [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: Data was collected only for the 'Phase 1b (Dose Confirmation)' arm for this end point.
    End point values
    		 Phase 1b (Dose Confirmation)
    Number of subjects analysed
    7 [3]
    Units: mg
    48
    Notes
    [3] - Safety Population
    No statistical analyses for this end point

    Primary: Best Overall Response Rate (ORR) of MEN1611 in Combination with Cetuximab

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    End point title
    		 Best Overall Response Rate (ORR) of MEN1611 in Combination with Cetuximab [4]
    End point description
    The best ORR was defined as percentage of participants who had a best overall response to therapy of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) and was defined according to Response Evaluation Criteria in Solid Tumors version 1.1 assessment locally performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
    End point type
    Primary
    End point timeframe
    Up to 37 months
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics (percentage of participants) are reported for this primary end point, as prespecified in the statistical analysis plan.
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    5 [5]
    14 [6]
    Units: Percentage of Participants
    number (not applicable)
        Complete Response
    0.0
    7.1
        Partial Response
    40.0
    7.1
        Stable Disease
    40.0
    57.1
        Progressive Disease
    20.0
    28.6
    Notes
    [5] - Efficacy Population
    [6] - Efficacy Population
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants with DLTs for MEN1611

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    End point title
    		 Phase 1b: Number of Participants with DLTs for MEN1611 [7] [8]
    End point description
    A DLT was defined as any of the following adverse drug reactions (ADRs) related to the combination regimens or to MEN1611 alone and unrelated to the participants’ underlying disease or concomitant medication occurring during Cycle 1 over the DLT assessment window of 28 days: any Grade 3 (lasting >7 days) or Grade 4 increase in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase; any Grade ≥3 cardiac disorder or new segmental wall-motion abnormalities; any Grade ≥3 non-haematologic toxicity with the following exceptions: nausea, vomiting, diarrhoea, skin rash, hyperglycaemia. An ADR was defined as any adverse event suspected by the investigator and/or the sponsor to be related to MEN1611, cetuximab, or both given in combination.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 28 of Cycle 1 (28 days/cycle)
    Notes
    [7] - 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 analyses were carried out for this primary end point, as prespecified in the statistical analysis plan.
    [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: Data was collected only for the 'Phase 1b (Dose Confirmation)' arm for this end point.
    End point values
    		 Phase 1b (Dose Confirmation)
    Number of subjects analysed
    6 [9]
    Units: Participants
    0
    Notes
    [9] - DLT Population
    No statistical analyses for this end point

    Secondary: Plasma Concentration of MEN1611 in Combination with Cetuximab

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    End point title
    		 Plasma Concentration of MEN1611 in Combination with Cetuximab
    End point description
    Blood samples were taken for the analyses of MEN1611 in plasma at designated time points. Results are reported as nanograms/millilitre (ng/mL). '9999' = value non-estimable (insufficient number of participants with events).
    End point type
    Secondary
    End point timeframe
    Day 22 (1.5 hours postdose) of Cycle 1 (28 days/cycle)
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    7 [10]
    1 [11]
    Units: ng/mL
        arithmetic mean (standard deviation)
    173.37 ( 125.513 )
    241.2 ( 9999 )
    Notes
    [10] - PK Population
    [11] - PK Population
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) of MEN1611 in Combination with Cetuximab

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    End point title
    		 Disease Control Rate (DCR) of MEN1611 in Combination with Cetuximab
    End point description
    DCR was defined as percentage of participants whose disease shrank or remained stable over a certain time period and was calculated based on the sum of the CR, PR, and SD rates according to local assessment.
    End point type
    Secondary
    End point timeframe
    Up to 37 months
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    5 [12]
    14 [13]
    Units: percentage of participants
        number (confidence interval 95%)
    80 (28.4 to 99.5)
    71.4 (41.9 to 91.6)
    Notes
    [12] - Efficacy Population
    [13] - Efficacy Population
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) of MEN1611 in Combination with Cetuximab

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    End point title
    		 Duration of Response (DOR) of MEN1611 in Combination with Cetuximab
    End point description
    DOR was defined as the time from confirmation of a PR, CR or SD as locally assessed, until the disease had been shown to progress following treatment. Participants with a previous response who did not show a relapse or died without recording a relapse were censored at their last available relapse-free tumour assessment date. Participants with only one tumour assessment after baseline showing a PD were not included in the calculation. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point. '9999'=values were non-estimable (insufficient number of participants with events).
    End point type
    Secondary
    End point timeframe
    Up to 37 months
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    4 [14]
    10 [15]
    Units: days
        median (confidence interval 95%)
    85 (47 to 9999)
    169 (120 to 9999)
    Notes
    [14] - Efficacy Population
    [15] - Efficacy Population
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) of MEN1611 in Combination with Cetuximab

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    End point title
    		 Progression-free Survival (PFS) of MEN1611 in Combination with Cetuximab
    End point description
    PFS was defined as the number of days between the first study treatment administration to the date of first documented disease progression as per local assessment, relapse or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last tumour assessment date. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point. '9999'=values were non-estimable (insufficient number of participants with events).
    End point type
    Secondary
    End point timeframe
    Up to 37 months
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    5 [16]
    14 [17]
    Units: days
        median (confidence interval 95%)
    121 (75 to 9999)
    162 (57 to 218)
    Notes
    [16] - Efficacy Population
    [17] - Efficacy Population
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) of MEN1611 in Combination with Cetuximab

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    End point title
    		 Overall Survival (OS) of MEN1611 in Combination with Cetuximab
    End point description
    OS was defined as the number of days between the first study treatment administration and death from any cause. Participants still alive that had withdrawn from the study were censored using the latest among end of study and follow-up dates. Drop-out participants were considered censored and the last available date in which the participant was known to be alive was considered. Here, ‘Number of subjects analysed’ signifies those participants who were evaluable for this end point. '9999'=values were non-estimable (insufficient number of participants with events).
    End point type
    Secondary
    End point timeframe
    Up to 37 months
    End point values
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Number of subjects analysed
    5 [18]
    14 [19]
    Units: days
        median (confidence interval 95%)
    471 (171 to 9999)
    308 (177 to 9999)
    Notes
    [18] - Efficacy Population
    [19] - Efficacy Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to the end of study (37 months)
    Adverse event reporting additional description
    All reported safety data based upon the Safety Population: all participants who received at least 1 dose of MEN1611.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Phase 1b (Dose Confirmation)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Reporting group title
    Phase 2 (Cohort Expansion)
    Reporting group description
    		 Participants received MEN1611 twice daily and cetuximab weekly, every 28-day cycle.

    Serious adverse events
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    11 / 22 (50.00%)
         number of deaths (all causes)
    7
    11
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b (Dose Confirmation) Phase 2 (Cohort Expansion)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    22 / 22 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    9 / 22 (40.91%)
         occurrences all number
    0
    17
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    3
    Condition aggravated
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    7 / 22 (31.82%)
         occurrences all number
    0
    8
    Oedema peripheral
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 22 (4.55%)
         occurrences all number
    2
    4
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 22 (27.27%)
         occurrences all number
    3
    11
    Vaccination site pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Scrotal swelling
         subjects affected / exposed [1]
    1 / 6 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    3
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Amylase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Blood albumin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Blood potassium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    5
    Blood pressure increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Lipase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Protein total decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Weight decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 22 (22.73%)
         occurrences all number
    2
    5
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Dysgeusia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    1
    5
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    10
    Neuropathy peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Neurotoxicity
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 7 (57.14%)
    6 / 22 (27.27%)
         occurrences all number
    5
    9
    Lymphopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    1
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    5 / 7 (71.43%)
    16 / 22 (72.73%)
         occurrences all number
    7
    40
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    7 / 22 (31.82%)
         occurrences all number
    1
    12
    Stomatitis
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 22 (22.73%)
         occurrences all number
    0
    8
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Decubitus ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 22 (22.73%)
         occurrences all number
    0
    7
    Dry skin
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 22 (13.64%)
         occurrences all number
    1
    7
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Nail disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    3
    Palmar erythema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 22 (22.73%)
         occurrences all number
    0
    9
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 22 (13.64%)
         occurrences all number
    1
    3
    Rash
         subjects affected / exposed
    7 / 7 (100.00%)
    11 / 22 (50.00%)
         occurrences all number
    9
    23
    Skin fissures
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Skin toxicity
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    5
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 22 (18.18%)
         occurrences all number
    0
    6
    COVID-19
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Escherichia infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Localised infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    3 / 7 (42.86%)
    5 / 22 (22.73%)
         occurrences all number
    3
    5
    Staphylococcal infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    7 / 22 (31.82%)
         occurrences all number
    0
    7
    Hyperglycaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    13 / 22 (59.09%)
         occurrences all number
    6
    30
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 22 (4.55%)
         occurrences all number
    3
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 22 (9.09%)
         occurrences all number
    2
    3
    Hypomagnesaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    8 / 22 (36.36%)
         occurrences all number
    3
    11
    Hypophosphataemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event affected only male participants.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2020
    - Identification of the DLT population clarified by specifying it will include also any participant experiencing one DLT regardless of the MEN1611 and cetuximab doses received. - Inclusion criterion modified to include participants with disease progression or recurrence following any prior anti-EGFR treatment, and not only cetuximab, since all anti-EGFR therapies (cetuximab and panitumumab) are considered equal for efficacy and mechanism of resistance. - Exclusion criteria modified to clarify that those participants with a PIK3CA wild type status assessment performed before the last anti-EGFR treatment can be actually pre-screened, since - although not frequently - the mutation can be acquired upon treatment. - Inclusion criterion amended to include participants with adequate renal function defined as creatinine clearance = 50 millilitres/minute (calculated by Cockcroft-Gault formula) following the Food and Drug Administration (FDA) recommendation in the “Study may proceed” letter. - 12-lead electrocardiogram (ECG) assessments added to Cycle 1 Day 1 and Day 22, pre-dose and between 2 and 4 hours post the first daily MEN1611 dose administration, as requested by FDA in the “Study may proceed” letter. - The evaluation of the anti-tumour activity of MEN1611 combined with cetuximab by using retrospective central radiological assessment added as exploratory objective. The central radiological assessment will improve radiological data quality, validity, and homogeneity in readability and interpretation. - A Blinded Independent Review Committee added as required by the implementation of the retrospective radiological central assessment that will be performed by independent reviewers.
    01 Feb 2021
    - Inclusion criteria modified to extend the inclusion also of participants who have had progression or recurrence following fluoropyrimidine containing regimen (5-FU and capecitabine). - 12-lead ECG assessments and PK sampling time points changed to provide time matched PK/ECG data for a subsequent PK/QT analysis. - Based on the current pre-screening rate as of January 2021, around 1000 participants would have to be pre-screened to complete participant accrual for the study. - The “Management of Misuse and Overdose Cases” section added with the purpose of giving clearer guidance to Investigators on how to report misuse and overdose cases, as per applicable guidelines.
    15 May 2023
    - The “End of Study” definition modified to reflect the enrolment termination, and the decision made that all participants who are under treatment will receive the study drugs and undergo all study procedures until a reason for withdrawal from the study treatment as per currently approved protocol is met. - The Risk Benefit Assessment section updated in order to include data from B-PRECISE-01 with the latest cutoff date of 30-Jan-2023.

    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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