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    Clinical Trial Results:
    SPOTLIGHT 203: Phase 2 single arm clinical study to evaluate the efficacy and safety of intratumoral administration of BO-112 in combination with pembrolizumab in subjects that have progressed on anti-PD-1-based therapy in refractory unresectable malignant melanoma stage III or IV

    Summary
    EudraCT number
    		 2020-003921-51
    Trial protocol
    		 FR  
    Global end of trial date
    03 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2025
    First version publication date
    06 Feb 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BOT112-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04570332
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 KEYNOTE: B77
    Sponsors
    Sponsor organisation name
    Highlight Therapeutics, S.L.
    Sponsor organisation address
    Parque Científico Universidad de Valencia Calle Catedrático Agustín Escardino, 9, Paterna (Valencia), Spain, 46980
    Public contact
    Marisol Quintero Ortiz, Highlight Therapeutics, S.L., +34 682544814, mquintero@highlighttherapeutics.com
    Scientific contact
    Marisol Quintero Ortiz, Highlight Therapeutics, S.L., +34 682544814, mquintero@highlighttherapeutics.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
    17 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the anti-tumor activity of intratumoral (IT) BO-112 in combination with intravenous (IV) pembrolizumab in advanced melanoma patients
    Protection of trial subjects
    The study was conducted in accordance with the protocol and with the following: - Guidelines of the Declaration of Helsinki. - International Council for Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. - Applicable laws and regulations (including the European Union [EU] Clinical Trials Directive and the Code of Federal Regulations).
    Background therapy
    		 -
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    18 Jan 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Spain: 25
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    18
    From 65 to 84 years
    21
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment countries: France and Spain Special populations: patients with advanced and/or metastatic unresectable stage III or stage IV melanoma that has progressed on anti-PD-1-containing treatment, either as monotherapy, or in combination with other checkpoint inhibitors or therapies. Stage III tumor: 4 subjects Stage IV tumor: 38 subjects

    Pre-assignment
    Screening details
    		 From a total of 54 patients screened, 42 were enrolled in the study (17 patients enrolled from 6 sites in France and 25 patients enrolled from 10 sites in Spain) and treated. The majority of screening failures were due to not meeting eligibility criteria relating to prior lines of therapy.

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

    Arms
    Arm title
    		 BO-112 + Pembrolizumab
    Arm description
    		 Multicenter, phase 2, open-label, single-arm, adaptive design study to determine the preliminary anti-tumor activity and confirm the safety of IT BO-112 in combination with IV pembrolizumab. Study treatments were administered until disease progression, unacceptable toxicity, death, withdrawal of consent, study termination or up to 2 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    BO-112
    Investigational medicinal product code
    BO-112
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralesional use, Intratumoral use
    Dosage and administration details
    Dose of BO-112 was based on lesion size as specified below. The minimum number of lesions injected per study visit was 1 and the maximum was 8. The maximum volume to be injected was 3.4 mL per visit, distributed over different injectable tumors. Lesion size Max Dose / Max Volume to be administered ≤ 0.5 cm Up to 0.06 mg / 0.1 mL > 0.5 cm & < 1.5 cm Up to 0.3-0.6 mg / 0.5-1.0 mL ≥ 1.5 cm Up to 1.0 mg / 1.7 mL BO-112 was administered IT once weekly for the first 7 weeks and then once every three weeks.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda, MK-3475
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg by IV infusion every 3 weeks.

    Number of subjects in period 1
    		BO-112 + Pembrolizumab
    Started
    42
    Completed
    24
    Not completed
    18
         Consent withdrawn by subject
    1
         Death
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 18
        From 65-84 years
    		 21 21
        85 years and over
    		 3 3
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 24 24
    Pathological diagnosis
    Pathological subtype of melanoma
    Units: Subjects
        Cutaneous melanoma
    		 30 30
        Acral melanoma
    		 9 9
        Mucosal melanoma
    		 3 3
    Advanced/metastatic disease
    Units: Subjects
        Yes
    		 14 14
        No
    		 28 28
    Current AJCC8 Tumor Stage
    Units: Subjects
        Stage III
    		 4 4
        Stage IV
    		 38 38
    BRAF Status
    Units: Subjects
        Mutated
    		 7 7
        Not mutated
    		 35 35
    Baseline tumor size
    Units: Subjects
        <30 mm
    		 8 8
        30-50 mm
    		 6 6
        50-100 mm
    		 15 15
        ≥ 100 mm
    		 13 13
    Baseline Lactate Dehydrogenase (LDH) values
    Units: Subjects
        Normal LDH values
    		 26 26
        High LDH values
    		 16 16
    ECOG performance status
    Units: Subjects
        ECOG performance status 0
    		 33 33
        ECOG performance status 1
    		 9 9
    Liver metastases
    Units: Subjects
        Yes
    		 8 8
        No
    		 34 34
    Bone metastases
    Units: Subjects
        Yes
    		 5 5
        No
    		 37 37
    Lung metastases
    Units: Subjects
        Yes
    		 17 17
        No
    		 25 25
    Skin metastases
    Units: Subjects
        Yes
    		 5 5
        No
    		 37 37
    Prior line of treatment (adjuvant only)
    Patients who received only adjuvant treatment prior to the clinical trial
    Units: Subjects
        Nivolumab
    		 4 4
        Pembrolizumab
    		 6 6
        No adjuvant treatment
    		 32 32
    Prior line of treatment (advanced)
    Patients who received advanced treatment prior to the trial
    Units: Subjects
        Nivolumab
    		 10 10
        Pembrolizumab
    		 12 12
        Nivolumab + Ipilimumab
    		 6 6
        Other anti-PD1 combinations
    		 4 4
        No advanced treatment
    		 10 10
    PD-L1 expression
    Patients with negative or positive PD-L1 expression
    Units: Subjects
        Negative
    		 9 9
        Positive
    		 23 23
        Not evaluable
    		 10 10
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 71.60 ( 15.68 ) -
    Time since initial diagnosis
    Units: Months
        arithmetic mean (standard deviation)
    		 39.71 ( 52.63 ) -
    Number of metastatic lesions
    Units: Lesions
        median (inter-quartile range (Q1-Q3))
    		 6.00 (4.00 to 9.00) -
    Number of target metastatic lesions
    Units: Lesions
        median (inter-quartile range (Q1-Q3))
    		 3.00 (2.00 to 4.00) -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as those participants who were enrolled into the study (i.e. received at least one dose of the study drug(s), and was used to analyze the secondary efficacy endpoints, including subgroup analyses. In this trial, the ITT population was the same as the Safety population.

    Subject analysis set title
    Modified intention-to-treat population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified intention-to-treat (mITT) population was defined as all participants who were included, had at least one dose of trial treatment and underwent baseline and at least one post-baseline tumor response assessment by Independent Radiological Central Review (IRCR). The mITT population was used to analyze the primary endpoint.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population was defined as all participants who received at least one dose of study treatment, and was used to analyze the secondary endpoint of safety and tolerability of IT BO-112 + IV pembrolizumab. Safety population was used for all safety related analysis. In this trial, the ITT population was the same as the Safety population.

    Subject analysis sets values
    		 Intention-to-treat population Modified intention-to-treat population Safety population
    Number of subjects
    42
    40
    42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    18
    18
    18
        From 65-84 years
    21
    19
    21
        85 years and over
    3
    3
    3
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    18
    18
    18
        Male
    24
    22
    24
    Pathological diagnosis
    Pathological subtype of melanoma
    Units: Subjects
        Cutaneous melanoma
    30
    29
    30
        Acral melanoma
    9
    8
    9
        Mucosal melanoma
    3
    3
    3
    Advanced/metastatic disease
    Units: Subjects
        Yes
    14
    14
    14
        No
    28
    26
    28
    Current AJCC8 Tumor Stage
    Units: Subjects
        Stage III
    4
    4
    4
        Stage IV
    38
    36
    38
    BRAF Status
    Units: Subjects
        Mutated
    7
    7
    7
        Not mutated
    35
    33
    35
    Baseline tumor size
    Units: Subjects
        <30 mm
    8
    8
    8
        30-50 mm
    6
    5
    6
        50-100 mm
    15
    14
    15
        ≥ 100 mm
    13
    13
    13
    Baseline Lactate Dehydrogenase (LDH) values
    Units: Subjects
        Normal LDH values
    26
    25
    26
        High LDH values
    16
    15
    16
    ECOG performance status
    Units: Subjects
        ECOG performance status 0
    33
    32
    33
        ECOG performance status 1
    9
    8
    9
    Liver metastases
    Units: Subjects
        Yes
    8
    7
    8
        No
    34
    33
    34
    Bone metastases
    Units: Subjects
        Yes
    5
    3
    5
        No
    37
    37
    37
    Lung metastases
    Units: Subjects
        Yes
    17
    16
    17
        No
    25
    24
    25
    Skin metastases
    Units: Subjects
        Yes
    5
    5
    5
        No
    37
    35
    37
    Prior line of treatment (adjuvant only)
    Patients who received only adjuvant treatment prior to the clinical trial
    Units: Subjects
        Nivolumab
    4
    3
    4
        Pembrolizumab
    6
    5
    6
        No adjuvant treatment
    32
    32
    32
    Prior line of treatment (advanced)
    Patients who received advanced treatment prior to the trial
    Units: Subjects
        Nivolumab
    10
    10
    10
        Pembrolizumab
    12
    12
    12
        Nivolumab + Ipilimumab
    6
    6
    6
        Other anti-PD1 combinations
    4
    4
    4
        No advanced treatment
    10
    8
    10
    PD-L1 expression
    Patients with negative or positive PD-L1 expression
    Units: Subjects
        Negative
    9
    8
    9
        Positive
    23
    22
    23
        Not evaluable
    10
    10
    10
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    71.60 ( 15.68 )
    71.60 ( 15.68 )
    71.60 ( 15.68 )
    Time since initial diagnosis
    Units: Months
        arithmetic mean (standard deviation)
    39.71 ( 52.63 )
    39.71 ( 52.63 )
    39.71 ( 52.63 )
    Number of metastatic lesions
    Units: Lesions
        median (inter-quartile range (Q1-Q3))
    6.00 (4.00 to 9.00)
    6.00 (4.00 to 9.00)
    6.00 (4.00 to 9.00)
    Number of target metastatic lesions
    Units: Lesions
        median (inter-quartile range (Q1-Q3))
    3.00 (2.00 to 4.00)
    3.00 (2.00 to 4.00)
    3.00 (2.00 to 4.00)

    End points

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    End points reporting groups
    Reporting group title
    BO-112 + Pembrolizumab
    Reporting group description
    		 Multicenter, phase 2, open-label, single-arm, adaptive design study to determine the preliminary anti-tumor activity and confirm the safety of IT BO-112 in combination with IV pembrolizumab. Study treatments were administered until disease progression, unacceptable toxicity, death, withdrawal of consent, study termination or up to 2 years

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) population was defined as those participants who were enrolled into the study (i.e. received at least one dose of the study drug(s), and was used to analyze the secondary efficacy endpoints, including subgroup analyses. In this trial, the ITT population was the same as the Safety population.

    Subject analysis set title
    Modified intention-to-treat population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified intention-to-treat (mITT) population was defined as all participants who were included, had at least one dose of trial treatment and underwent baseline and at least one post-baseline tumor response assessment by Independent Radiological Central Review (IRCR). The mITT population was used to analyze the primary endpoint.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population was defined as all participants who received at least one dose of study treatment, and was used to analyze the secondary endpoint of safety and tolerability of IT BO-112 + IV pembrolizumab. Safety population was used for all safety related analysis. In this trial, the ITT population was the same as the Safety population.

    Primary: Primary Efficacy Endpoint

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    End point title
    		 Primary Efficacy Endpoint [1]
    End point description
    Overall response rate (ORR) using RECIST 1.1, defined as the percentage of patients achieving a complete response (CR) or partial response (PR) as best overall response, by independent radiological central review (IRCR).
    End point type
    Primary
    End point timeframe
    Until all participants with post-baseline imaging had achieved a best overall response during the treatment period.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The scope of this study was to evaluate the efficacy and safety of BO-112 in combination with pembrolizumab. The study was a single arm trial and had no comparison groups. Therefore the study was not amenable to comparative statistical analyses. However, the null hypothesis was H0: ORR=10% (p0) and was tested against H1: ORR>10% at one-sided 5% significance level. 4 (10%) participants achieved CR and 6 (15%) participants achieved PR, yielding an ORR of 25% (95% CI: 12.69%, 41.20%, p=0.0008).
    End point values
    		 BO-112 + Pembrolizumab
    Number of subjects analysed
    40
    Units: Overall Response Rate (ORR)
    number (confidence interval 95%)
        ORR
    25 (12.69 to 41.2)
    No statistical analyses for this end point

    Other pre-specified: Safety

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    End point title
    		 Safety
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The total duration for each participating subject was up to 2 years of treatment and up to 90 days for a safety follow up after last dose of study drug. The mean cumulative dose was 2223.81 ± 2173.10 mg for pembrolizumab and 18.30 ± 13.01 mg for BO-112.
    End point values
    		 Safety population
    Number of subjects analysed
    42
    Units: Doses and duration
        Number of subjects reporting any TEAEs
    42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAE (Treatment Emergent Adverse Event) was defined as an AE that occurred after the first administration of study treatment until 90 days after last dose in this trial.
    Adverse event reporting additional description
    TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. AEs were coded with the Preferred Term (PT) level, and System Organ Class (SOC) term using the Medical Dictionary for Regulatory Activities (MedDRA dictionary).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 42 (35.71%)
         number of deaths (all causes)
    17
         number of deaths resulting from adverse events
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Epilepsy
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Asthenia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Disease progression
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tracheal compression
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 42 (97.62%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 42 (69.05%)
         occurrences all number
    74
    Chills
         subjects affected / exposed
    12 / 42 (28.57%)
         occurrences all number
    25
    Fatigue
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    5
    Influenza like illness
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    12
    Injection site pain
         subjects affected / exposed
    10 / 42 (23.81%)
         occurrences all number
    12
    Oedema peripheral
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    19 / 42 (45.24%)
         occurrences all number
    90
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 42 (26.19%)
         occurrences all number
    17
    Tremor
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Vision blurred
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    18 / 42 (42.86%)
         occurrences all number
    30
    Dry mouth
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    13 / 42 (30.95%)
         occurrences all number
    32
    Stomatitis
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    12 / 42 (28.57%)
         occurrences all number
    26
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 42 (21.43%)
         occurrences all number
    17
    Rash
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    11
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    12
    Back pain
         subjects affected / exposed
    8 / 42 (19.05%)
         occurrences all number
    13
    Myalgia
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    9
    Pain in extremity
         subjects affected / exposed
    10 / 42 (23.81%)
         occurrences all number
    13
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 42 (23.81%)
         occurrences all number
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2020
    Spain Protocol Substantial Amendment #1: Contraception inclusion criteria updated, Schedule of Assessments (SoA) timing updated.
    23 Mar 2021
    Spain Protocol Substantial Amendment #2 BO-112 administration was updated (not relevant); PK analysis was updated to a subset of participants instead of whole population; serum albumin was removed from incl criteria, Excl. criteria ALT/AST from normal to >2.5 ULN; Excl hepatitis was updated, Excl. HCV was updated, AE reporting was updated to start from first dose rather than from screening initiation, SoA was updated, Serum chemistry was reduced.
    23 Mar 2021
    France Protocol Substantial modification #1 BO-112 administration was updated, PK analysis was updated from all to a subset of participants, Incl # 4 was updated to histologically OR cytolgically confirmed diagnosis, serum albumin was removed, Excl. 4 ALT/AST from normal to > 2.5 ULN, Excl. # 14 interstitial lung disease was added, Excl # 18 hepatitis was updated, Excl. #19 HCV was updated, AE reporting was updated, SoA was updated.
    08 Aug 2021
    Spain Protocol Substantial modification #3 Update on INCL #7 prior anti-PD1 therapy; Excl # 18 was updated with 72 hour wash out for COVID vaccines; handling of participants with skin lesions was only updated to allow for surgical resection in case of pCR.
    18 Aug 2021
    France Protocol Substantial modification #2 Some changes were implemented, mainly to update BO-112 stability data, but also for clarifying how response assessments for participants with only skin lesions and pathological complete response (pCR) were done. Besides, safety wording was updated for BO-112, based on current DSUR and IB. Informed consent form was also updated accordingly.
    18 Jul 2022
    France and Spain Protocol Substantial modification #4 Sponsor personnel was updated, OS shortened to 1 year; the safety profile of BO-112 in section 5.1.2 (Rationale) was updated Some changes have been implemented, mainly to update long term follow up, as secondary endpoint Overall Survival (OS) was only followed up to 1 year (it was 2 years per prior protocol versions). This has been decided once all, primary endpoint and rest of secondary endpoints have been met. Participants who were on treatment, continued on treatment per protocol. This follow up OS assessment update was only applicable to those participants who had discontinued treatment and were still alive at least one year after first study treatment visit. In addition, BO-112 safety and efficacy data were updated to align with the most recent IB and DSUR versions. As minor changes, all references to the updated protocol version and date were updated.

    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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