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    Clinical Trial Results:
    Phase IIa open-label clinical study of intratumoural administration of BO-112 in combination with pembrolizumab in subjects with liver metastasis from colorectal cancer or gastric/gastro-oesophageal junction cancer

    Summary
    EudraCT number
    		 2019-004624-38
    Trial protocol
    		 BE   ES   IT   DE  
    Global end of trial date
    02 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2023
    First version publication date
    16 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BOT112-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Highlight Therapeutics, S.L.
    Sponsor organisation address
    Parc Científic de la Universitat de València, c/ Catedrático Agustín Escardino, 9, 46980 Paterna (Valencia), Spain,
    Public contact
    Clinical operations, Pivotal S.L., +34 917081250, maria.moreno@pivotalcr.com
    Scientific contact
    Clinical operations, Pivotal S.L., +34 917081250, maria.moreno@pivotalcr.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
    14 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Investigation of the anti-tumour efficacy and safety of repeated IT administrations of BO-112 in metastatic liver lesions in combination with IV pembrolizumab
    Protection of trial subjects
    To limit the number of patients exposed to a potentially non-effective treatment, a Simon’s 2-stage design was applied with a Data Monitoring Committee (DMC) review of available safety and efficacy data of the Stage 1 patients for each cohort separately.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    11
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient gave informed consent on 08 July 2020 and last patient gave informed consent on 21 December 2020. Type of location was medical hospital.

    Pre-assignment
    Screening details
    		 Patients were approved by the sponsor´s Medical Director before entering the treatment phase. Approval was given after reviewing of the eligibility package, checking the inclusion/exclusion criteria and, if needed, after discussion with the PIs. 25 patients were enrolled in the study and 18 patients were included in the treatment phase.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BO-112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Injection
    Dosage and administration details
    1 mg of 0.6 mg/mL administered in 1.7 mL volume as an IT injection on Day 1 or 2 and Day 8 of Cycle 1, then Day 1 or 2 of each subsequent cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Injection
    Dosage and administration details
    200mg IV administered on Day 1 of each 3-week cycle

    Arm title
    		 Cohort B
    Arm description
    		 Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BO-112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Injection
    Dosage and administration details
    1 mg of 0.6 mg/mL administered in 1.7 mL volume as an IT injection on Day 1 or 2 and Day 8 of Cycle 1, then Day 1 or 2 of each subsequent cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Injection
    Dosage and administration details
    200mg IV administered on Day 1 of each 3-week cycle

    Number of subjects in period 1
    		Cohort A Cohort B
    Started
    11
    7
    Completed
    0
    0
    Not completed
    11
    7
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    2
         Protocol specified withdrawal criteria met
    -
    1
         Progressive disease
    9
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease.

    Reporting group values
    		 Cohort A Cohort B Total
    Number of subjects
    		 11 7 18
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 4 11
        From 65-84 years
    		 4 3 7
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 55.6 (37 to 74) 56.1 (37 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 7 6 13

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease.

    Primary: Determination of the objective response rate (ORR) based on best overall response (all time points) using RECIST 1.1

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    End point title
    		 Determination of the objective response rate (ORR) based on best overall response (all time points) using RECIST 1.1 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Overall study duration dependent on the duration of achieved clinical benefit; expected to be in the range of 24-36 months. Individual subject study duration depended on maintenance of clinical benefit and tolerability; expected to range from 2-12 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not appropriate for this end point, so was therefore not performed.
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    7
    Units: Objective response rate (ORR)
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs from ICF signing to end of study (follow up) visit recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study.

    Reporting group title
    Cohort B
    Reporting group description
    		 Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease.

    Serious adverse events
    		 Cohort A Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 11 (45.45%)
    2 / 7 (28.57%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort A Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    7 / 7 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 11 (27.27%)
    2 / 7 (28.57%)
         occurrences all number
    6
    2
    Chills
         subjects affected / exposed
    5 / 11 (45.45%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    Fatigue
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 7 (14.29%)
         occurrences all number
    2
    2
    Injection site pain
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    5
    Pyrexia
         subjects affected / exposed
    8 / 11 (72.73%)
    4 / 7 (57.14%)
         occurrences all number
    20
    8
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 7 (14.29%)
         occurrences all number
    4
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 7 (28.57%)
         occurrences all number
    2
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Eye disorders
    Eczema eyelids
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 7 (14.29%)
         occurrences all number
    5
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 7 (28.57%)
         occurrences all number
    2
    2
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 7 (14.29%)
         occurrences all number
    12
    1
    Vomiting
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 7 (28.57%)
         occurrences all number
    7
    3
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Hepatomegaly
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Groin pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Asymptomatic COVID-19
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Hypercalcemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hyperglycemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2020
    - The epidemiological situation at the time forced the introduction of COVID-19 infection as a specific risk. Based on that, the protocol and the ICF were amended to include some recommendations for the investigators and specific information in this regard for the patients. - Administratively, the names of the sponsor and CRO were changed, and personnel changes were documented. - Addition of site as releaser of BO-112 and site as releaser of pembrolizumab, and updated pembrolizumab IB.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jan 2021
    Cohort B (GC/GEJ cancer patients with liver metastasis) was put on hold due to low recruitment in 2021; 7 patients were analyzed.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    It was planned to enrol 25 patients in Germany but no patients were subsequently enrolled.
    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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