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    Clinical Trial Results:
    A Phase 1B/2 Study to Evaluate Safety and Clinical Activity of Combinations of Avelumab, Binimetinib and Talazoparib in subjects With Locally Advanced or Metastatic Ras-Mutant Solid Tumors

    Summary
    EudraCT number
    		 2018-000124-34
    Trial protocol
    		 BE  
    Global end of trial date
    02 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2022
    First version publication date
    03 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B9991033
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03637491
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc. 
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc. , +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the DLT rate of the doublet and triplet combinations in subjects with mPDAC in order to determine the RP2D for the combinations and to assess the ORR of the doublet and triplet combinations based on investigator assessment per RECIST v1.1 in subjects with mPDAC and other KRASor NRAS-mutant advanced solid tumors.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 31 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    35
    EEA total number of subjects
    3
    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
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Forty six subjects were screened and 36 were enrolled, of whom 1 was not treated. This study was planned to include 2 periods: Phase 1b and Phase 2. Due to the early termination of this study, only the doublet combinations in Phase 1b to find a safe dose were conducted, and neither the triplet combination of Phase 1b nor Phase 2 was initiated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avelumab+Binimetinib 30mg (Phase 1b)
    Arm description
    		 Avelumab was administered at a fixed dose of 800 mg every 2 weeks (Q2W) in combination with binimetinib at 30 mg twice daily (BID) orally on a continuous daily dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    MEK162
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was administered at 30 mg twice daily (BID) orally on a continuous daily dosing schedule.

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    MSB0010718C
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab was administered at a fixed dose of 800 mg every 2 weeks (Q2W).

    Arm title
    		 Avelumab+Binimetinib 45mg (Phase 1b)
    Arm description
    		 Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    MSB0010718C
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab was administered at a fixed dose of 800 mg Q2W.

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    MEK162
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was administered at 45 mg BID orally on a continuous daily dosing schedule.

    Arm title
    		 Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b)
    Arm description
    		 Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talazoparib
    Investigational medicinal product code
    Other name
    PF-06944076
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Talazoparib was administered at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    MEK162
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was administered at 30 mg orally BID (7 days on / 7 days off)

    Arm title
    		 Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Arm description
    		 Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talazoparib
    Investigational medicinal product code
    Other name
    PF-06944076
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Talazoparib was administered at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    MEK162
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Binimetinib was administered at 45 mg orally BID (7 days on / 7 days off)

    Number of subjects in period 1
    		Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Started
    10
    12
    7
    6
    Received treatment
    10
    12
    7
    6
    Completed
    0
    0
    0
    0
    Not completed
    10
    12
    7
    6
         Adverse event, serious fatal
    9
    9
    5
    3
         Consent withdrawn by subject
    1
    -
    1
    2
         Study Terminated By Sponsor
    -
    2
    1
    -
         Lost to follow-up
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab+Binimetinib 30mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg every 2 weeks (Q2W) in combination with binimetinib at 30 mg twice daily (BID) orally on a continuous daily dosing schedule.

    Reporting group title
    Avelumab+Binimetinib 45mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule.

    Reporting group title
    Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Reporting group title
    Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Reporting group values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) Total
    Number of subjects
    		 10 12 7 6 35
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 5 5 2 1 13
        From 65-84 years
    		 5 7 5 5 22
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.30 ± 11.10 65.25 ± 8.56 68.57 ± 9.61 68.00 ± 9.94 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 4 3 6 3 16
        Male
    		 6 9 1 3 19
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 1 0 0 0 1
        White
    		 9 12 6 5 32
        Not Reported
    		 0 0 1 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 0 1
        Not Hispanic or Latino
    		 10 12 5 5 32
        Unknown or Not Reported
    		 0 0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Avelumab+Binimetinib 30mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg every 2 weeks (Q2W) in combination with binimetinib at 30 mg twice daily (BID) orally on a continuous daily dosing schedule.

    Reporting group title
    Avelumab+Binimetinib 45mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule.

    Reporting group title
    Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Reporting group title
    Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Primary: Number of Subjects with Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b

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    End point title
    		 Number of Subjects with Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b [1]
    End point description
    Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as Hematologic: febrile neutropenia; neutropenic infection; Grade >=3 thrombytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; Non-hematologic: Grade≥3 creatinine phosphokinase (CPK) with creatinine >= 1.5 x baseline; Grade 3 troponin increase with cardiac toxicity; potential Hy’s Law cases; Eye disorders: retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for >21 consecutive days; other Grade 4; Cardiac disorders; Respiratory disorders: bronchospasm Grade 3; Skin and subcutaneous tissue disorders; Non-adherence to treatment schedule; Dose reductions. Analysis population included subjects in Phase 1b who received at least one dose of the combination treatment, and either experienced DLT or completed the DLT observation period for the first cycle of treatment without DLT.
    End point type
    Primary
    End point timeframe
    From date of first study treatment to day 28 of study treatment (Up to 28 days)
    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: Statistical analysis was not planned for this endpoint
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    11
    6
    5
    Units: Subjects
    3
    5
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events During the On-Treatment Period

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    End point title
    		 Number of Subjects With Adverse Events During the On-Treatment Period
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death, inpatient hospitalization, life-threatening experience, disability, congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 1 day) assessed for a maximum duration of up to 31 months
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: Subjects
        TEAEs
    10
    12
    7
    6
        grade ≥ 3 TEAEs
    10
    9
    4
    5
        treatment-related TEAEs
    10
    12
    7
    6
        grade ≥ 3 treatment-related TEAEs
    8
    4
    0
    3
        serious TEAEs
    6
    9
    3
    3
        serious treatment-related TEAEs
    2
    1
    0
    2
        TEAEs leading to discontinuation of Avelumab
    1
    2
    0
    0
        TEAEs leading to discontinuation of Binimetinib
    3
    4
    1
    2
        TEAEs leading to discontinuation of Talazoparib
    0
    0
    1
    2
        TEAEs leading to discontinuation of any drug
    3
    4
    1
    2
        TEAEs leading to discontinuation of all drugs
    1
    1
    1
    0
        treatment-related TEAE discontinued by Avelumab
    1
    1
    0
    0
        treatment-related TEAE discontinued by Binimetinib
    3
    3
    0
    1
        treatment-related TEAE discontinued by Talazoparib
    0
    0
    0
    1
        treatment-related TEAE discontinued by any drug
    3
    3
    0
    1
        treatment-related TEAE discontinued by all drugs
    1
    0
    0
    0
        TEAEs leading to death
    0
    3
    2
    1
        treatment-related TEAEs leading to death
    0
    0
    0
    0
        infusion-related reactions (IRRs)
    3
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    Laboratory abnormalities were graded by NCI CTCAE version 4.03. Anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased were evaluated. This outcome measure calculated the number of subjects with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4. The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: Subjects
        ANEMIA
    9
    9
    7
    5
        HEMOGLOBIN INCREASED
    0
    0
    1
    0
        LYMPHOCYTE COUNT DECREASED
    6
    7
    5
    6
        LYMPHOCYTE COUNT INCREASED
    1
    1
    0
    0
        NEUTROPHIL COUNT DECREASED
    0
    1
    1
    2
        PLATELET COUNT DECREASED
    3
    3
    4
    3
        WHITE BLOOD CELL DECREASED
    2
    2
    0
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    Laboratory abnormalities were graded by NCI CTCAE version 4.03. Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (CPK) increased, creatinine increased, gamma-glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased and serum amylase increased were evaluated. This outcome measure calculated the number of subjects with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4. The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: Subjects
        ALANINE AMINOTRANSFERASE INCREASED
    5
    5
    3
    2
        ALKALINE PHOSPHATASE INCREASED
    9
    7
    6
    5
        ASPARTATE AMINOTRANSFERASE INCREASED
    8
    8
    6
    3
        BLOOD BILIRUBIN INCREASED
    4
    0
    0
    1
        CPK INCREASED
    6
    7
    3
    1
        CREATININE INCREASED
    8
    11
    6
    4
        GGT INCREASED
    8
    4
    6
    2
        HYPERCALCEMIA
    2
    1
    1
    0
        HYPERGLYCEMIA
    5
    6
    4
    5
        HYPERKALEMIA
    1
    3
    1
    0
        HYPERMAGNESEMIA
    0
    0
    0
    0
        HYPERNATREMIA
    0
    0
    0
    1
        HYPOALBUMINEMIA
    7
    11
    5
    3
        HYPOCALCEMIA
    0
    1
    0
    0
        HYPOGLYCEMIA
    2
    2
    0
    1
        HYPOKALEMIA
    4
    1
    3
    3
        HYPOMAGNESEMIA
    3
    2
    2
    1
        HYPONATREMIA
    5
    4
    2
    0
        HYPOPHOSPHATEMIA
    3
    1
    1
    0
        LIPASE INCREASED
    1
    3
    0
    1
        SERUM AMYLASE INCREASED
    2
    5
    0
    0
    No statistical analyses for this end point

    Secondary: Predose Concentration During Multiple Dosing (Ctrough) for Avelumab

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    End point title
    		 Predose Concentration During Multiple Dosing (Ctrough) for Avelumab [2]
    End point description
    Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The lower limit of quantification (LLQ) was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. Number of subjects that started the Arm: subjects who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number of Subjects Analyzed: subjects who had avelumab concentrations above the LLQ at specific time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12.
    Notes
    [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: Analysis was planned only for the arms specified.
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b)
    Number of subjects analysed
    10
    12
    Units: microgram per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        CYCLE1_DAY15
    22.38 ± 59
    28.82 ± 57
        CYCLE2_DAY1
    29.26 ± 39
    38.28 ± 52
        CYCLE2_DAY15
    40.86 ± 42
    37.26 ± 59
        CYCLE3_DAY1
    31.30 ± 999999
    34.69 ± 75
        CYCLE5_DAY1
    28.00 ± 999999
    36.51 ± 38
        CYCLE9_DAY1
    999999 ± 999999
    46.49 ± 999999
        CYCLE12_DAY1
    999999 ± 999999
    38.77 ± 999999
    No statistical analyses for this end point

    Secondary: Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib

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    End point title
    		 Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib
    End point description
    Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. Number of subjects that started the Arm: subjects who had at least 1 concentration measurement for binimetinib. Number of Subjects Analyzed: subjects who had binimetinib concentration values above the LLQ at specific time point.
    End point type
    Secondary
    End point timeframe
    Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2 and Day 1 of Cycle 3 for Binimetinib+Talazoparib groups
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        CYCLE1_DAY8
    999999 ± 999999
    999999 ± 999999
    82.90 ± 999999
    128.6 ± 49
        CYCLE1_DAY15
    87.85 ± 48
    88.67 ± 16
    22.80 ± 999999
    999999 ± 999999
        CYCLE2_DAY1
    55.71 ± 56
    107.5 ± 999999
    999999 ± 999999
    999999 ± 999999
        CYCLE2_DAY15
    93.45 ± 90
    88.33 ± 999999
    999999 ± 999999
    999999 ± 999999
        CYCLE3_DAY1
    56.60 ± 999999
    74.90 ± 999999
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib

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    End point title
    		 Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib [3]
    End point description
    Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 25 pg/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. Number of subjects that started the Arm: subjects who had at least 1 concentration measurement for talazoparib. Therefore, only 2 treatment groups including talazoparib were analyzed. Number of Subjects Analyzed: subjects who had talazoparib concentrations above the LLQ at specific time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3
    Notes
    [3] - 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: Analysis was planned only for the arms specified.
    End point values
    		 Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    7
    6
    Units: picograms per millilitre (pg/mL)
    geometric mean (geometric coefficient of variation)
        CYCLE1_DAY8
    4856 ± 999999
    2926 ± 49
        CYCLE1_DAY15
    5960 ± 999999
    2683 ± 65
        CYCLE2_DAY1
    8620 ± 999999
    2753 ± 999999
        CYCLE3_DAY1
    999999 ± 999999
    1520 ± 999999
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) for Avelumab

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) for Avelumab [4]
    End point description
    Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. Number of subjects that started the Arm: subjects who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number of Subjects Analyzed: subjects who had avelumab concentrations above the LLQ at specific time point.
    End point type
    Secondary
    End point timeframe
    Post dose on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned only for the arms specified.
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b)
    Number of subjects analysed
    10
    12
    Units: microgram per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        CYCLE1_DAY1
    205.3 ± 22
    248.6 ± 14
        CYCLE1_DAY15
    214.2 ± 20
    237.4 ± 45
        CYCLE2_DAY1
    213.0 ± 20
    241.5 ± 26
        CYCLE2_DAY15
    211.5 ± 17
    243.0 ± 19
        CYCLE3_DAY1
    176.0 ± 999999
    233.7 ± 28
        CYCLE5_DAY1
    188.0 ± 999999
    241.9 ± 21
        CYCLE9_DAY1
    999999 ± 999999
    257.0 ± 999999
        CYCLE12_DAY1
    999999 ± 999999
    255.8 ± 999999
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) for Binimetinib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) for Binimetinib
    End point description
    Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. When Cmax for binimetinib was planned to be evaluated, data collecting for Avelumab+Binimetinib cohort had already been done. Therefore, data of Cmax for binimetinib in Avelumab+Binimetinib groups hadn't been collected. Number of subjects that started the Arm: subjects who had at least 1 concentration measurement for binimetinib. Number of Subjects Analyzed: subjects who had binimetinib concentrations above the LLQ at specific time point.
    End point type
    Secondary
    End point timeframe
    Post dose on Day 1 and Day 8 of Cycle 1
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    0 [5]
    0 [6]
    7
    6
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        CYCLE1_DAY1
    ±
    ±
    370.24 ± 64
    331.74 ± 63
        CYCLE1_DAY8
    ±
    ±
    183.53 ± 180
    446.81 ± 59
    Notes
    [5] - Data of Cmax for binimetinib in Avelumab+Binimetinib groups hadn't been collected
    [6] - Data of Cmax for binimetinib in Avelumab+Binimetinib groups hadn't been collected
    No statistical analyses for this end point

    Secondary: Number of Subjects With anti-drug antibody (ADA) Categories

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    End point title
    		 Number of Subjects With anti-drug antibody (ADA) Categories [7]
    End point description
    Blood samples were collected for avelumab immunogenicity testing. Samples positive for ADA were analyzed for titer. Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA was defined as subjects with ADA-negative at baseline and had at least one positive post-baseline ADA result; or if subject did not have a baseline sample, the subject had at least one positive post-baseline ADA result. Subjects in the safety analysis set had at least one ADA/nAb sample collected for avelumab, so only two groups (Avelumab+Binimetinib 30mg [Phase 1b] and Avelumab+Binimetinib 45mg [Phase 1b]) were analyzed.
    End point type
    Secondary
    End point timeframe
    From the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned only for the arms specified.
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b)
    Number of subjects analysed
    10
    12
    Units: Subjects
        ADA never-positive
    8
    11
        ADA ever-positive
    2
    1
    No statistical analyses for this end point

    Secondary: Neutralizing Antibodies (nAb) Against Avelumab

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    End point title
    		 Neutralizing Antibodies (nAb) Against Avelumab [8]
    End point description
    The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response and persistent nAb response. Subjects in the safety analysis set had at least one ADA/nAb sample collected for avelumab; however, due to the low observed immunogenicity rate, nAb analysis was not conducted.
    End point type
    Secondary
    End point timeframe
    From the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned only for the arms specified.
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Subjects
    Notes
    [9] - nAb analysis was not conducted.
    [10] - nAb analysis was not conducted.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)
    End point description
    OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' (date of first study treatment) until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as a 20% increase in the sum of diameters of target lesions or unequivocal progression of non-target lesions or the appearance of any new malignant lesion. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Clopper-Pearson method was used. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: Percentage of subjects
        number (confidence interval 95%)
    0 (0.0 to 30.8)
    8.3 (0.2 to 38.5)
    0 (0.0 to 41.0)
    0 (0.0 to 45.9)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b

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    End point title
    		 Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b
    End point description
    PFS is defined as the time from the 'start date' (date of first study treatment) to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD was defined as a 20% increase in the sum of diameters of target lesions or unequivocal progression of non-target lesions or the appearance of any new malignant lesion. CIs were calculated using Brookmeyer and Crowley method. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: months
        median (confidence interval 95%)
    1.7 (1.6 to 2.9)
    3.3 (1.6 to 7.1)
    1.6 (1.0 to 2.3)
    1.8 (1.1 to 4.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in Phase 1b

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    End point title
    		 Overall Survival (OS) in Phase 1b
    End point description
    OS is defined as the time from the 'start date' (date of first study treatment) to the date of death due to any cause. CIs were calculated using Brookmeyer and Crowley method. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months).
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    10
    12
    7
    6
    Units: months
        median (confidence interval 95%)
    5.9 (2.9 to 8.6)
    8.0 (3.0 to 20.1)
    2.9 (1.0 to 999999)
    10.7 (1.1 to 10.7)
    No statistical analyses for this end point

    Secondary: Time-to-Tumor Response (TTR) in Phase 1b

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    End point title
    		 Time-to-Tumor Response (TTR) in Phase 1b
    End point description
    TTR is defined, for subjects with an OR, as the time from the date of first study treatment to the first documentation of objective response (CR or PR) which was subsequently confirmed. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the ‘start date’ until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Subjects who received at least 1 dose of study treatment and achieved objective response were analyzed: only 1 subject in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 subject).
    End point type
    Secondary
    End point timeframe
    From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [11] - There is no subject achieved OR.
    [12] - Only one subject achieved OR.
    [13] - There is no subject achieved OR.
    [14] - There is no subject achieved OR.
    No statistical analyses for this end point

    Secondary: Duration of Response (DR) in Phase 1b

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    End point title
    		 Duration of Response (DR) in Phase 1b
    End point description
    DR is defined, for subjects with OR, as the time from the first documentation of objective response (CR or PR) to the date of first documentation of PD or death due to any cause. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the ‘start date’ until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment and achieved objective response: only 1 subject in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 subject).
    End point type
    Secondary
    End point timeframe
    From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).
    End point values
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [15] - There is no subject achieved OR.
    [16] - Only one subject achieved OR.
    [17] - There is no subject achieved OR.
    [18] - There is no subject achieved OR.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 1 day) assessed for a maximum duration of up to 31 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Avelumab+Binimetinib 30mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule.

    Reporting group title
    Avelumab+Binimetinib 45mg (Phase 1b)
    Reporting group description
    		 Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule.

    Reporting group title
    Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Reporting group title
    Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Reporting group description
    		 Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule.

    Serious adverse events
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 10 (60.00%)
    9 / 12 (75.00%)
    3 / 7 (42.86%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    9
    9
    5
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Avelumab+Binimetinib 30mg (Phase 1b) Avelumab+Binimetinib 45mg (Phase 1b) Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    12 / 12 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diastolic hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 12 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    6
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 12 (33.33%)
    4 / 7 (57.14%)
    1 / 6 (16.67%)
         occurrences all number
    3
    5
    7
    6
    Mucosal inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 12 (33.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    6
    1
    1
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    2
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    4
    0
    1
    Ammonia increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    10
    3
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 12 (33.33%)
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    9
    16
    4
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    4
    4
    Troponin T increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye contusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    2
    Infusion related reaction
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Skin wound
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    2
    2
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tension headache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    0
    5
    3
    2
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Glaucoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Macular oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Periorbital oedema
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Retinopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Subretinal fluid
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    6
    3
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Ascites
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    1
    2
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 12 (33.33%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    3
    6
    4
    4
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip blister
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 12 (33.33%)
    3 / 7 (42.86%)
    4 / 6 (66.67%)
         occurrences all number
    2
    4
    4
    5
    Obstruction gastric
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Retching
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 12 (33.33%)
    4 / 7 (57.14%)
    2 / 6 (33.33%)
         occurrences all number
    3
    6
    6
    3
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 12 (25.00%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    8
    3
    2
    8
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema multiforme
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Rash
         subjects affected / exposed
    5 / 10 (50.00%)
    7 / 12 (58.33%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    5
    11
    2
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Coccydynia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Nail infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    Wound infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    1
    2
    Dehydration
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 12 (16.67%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    5
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2019
    1. Due to dose-limiting toxicities seen with the doublet of avelumab and continuous daily binimetib dosing, the study design has been updated. 2. Phase 2 design has been modified to remove the randomized NSCLC cohort due to enrollment concerns. This tumor agnostic cohort was also increased in size from 20 to 30 subjects to accommodate this change. 3. The study title, schedule of activities, protocol background section, study objectives and endpoints, inclusion and exclusion criteria, assessments (Section 7) and references have been updated. 4. The maximum administered dose definition has been updated to reflect the intermittent schedule of binimetinib and the modified doublet combination of binimetinib and talazoparib. 5. Section 5.5 has been updated to clarify the treatment administration procedures to be followed due to the updated study design. 6. The dose-limiting toxicity definitions have been updated to align with visit scheduling and the current guidance for binimetinib protocols. 7. The dose modification guidance has been updated to improve consistency and align with the guidance in the prescribing information and current protocol guidance for binimetinib, talazoparib and avelumab. 8. Section 5.8.3 has been updated to clarify requirements for use of steroids in the management of treatment-related adverse events. 9. Sections 5.8.6 and 5.8.7 have been updated based on current guidance for prohibited medications. 10. Section 6.4 has been updated to clarify that all subjects are expected to enter survival follow-up, even if they discontinue short-term follow-up prior to completing the 90 day follow-up period. 11. Section 8.3 has been updated to remove Grade 0 from the ‘Clinical Description of Severity’ table. 12. The statistical sections of the protocol (Section 9) was updated to reflect the changes in study design, including the addition of Appendix 6.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Mar 2020
    COVID-19 pandemic was occurring globally. When the pandemic occurred, the study recruitment was temporarily paused from 24 March 2020 to 03 May 2020. The objectives of the study were not affected by the pandemic and the impact was minimal.
    04 May 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    A decision on early termination of this study was made on 14 Dec 2020. Due to this, only the doublet combinations in Phase 1b to find a safe dose were conducted. Due to the low observed immunogenicity rate, nAb analysis was not conducted.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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