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    Clinical Trial Results:
    A Phase IIa, Multicenter, Open-Label Study to Assess the Safety and Efficacy of the Combination of BL-8040 and Pembrolizumab in Patients with Metastatic Pancreatic Cancer, the COMBAT study

    Summary
    EudraCT number
    		 2018-004372-36
    Trial protocol
    		 ES  
    Global end of trial date
    06 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2024
    First version publication date
    18 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BL-8040.PAC.201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02826486
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioLineRx Ltd
    Sponsor organisation address
    Modi’in Technology Park, 2 HaMa'ayan Street, Modi'in, Israel, 7177871
    Public contact
    VP Clinical & Medical, BioLineRx Ltd, 972 86429100, clinicaltrials@biolinerx.com
    Scientific contact
    VP Clinical & Medical, BioLineRx Ltd, 972 86429100, clinicaltrials@biolinerx.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
    07 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of BL-8040 in combination with pembrolizumab (Cohort 1) and BL-8040 and pembrolizumab in combination with liposomal irinotecan (Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) (Cohort 2) in subjects with metastatic pancreatic adenocarcinoma.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding Ethical Committee review, Informed Consent and the protection of human subjects participating in research. Only subjects that met all the study inclusion criteria and none of the exclusion criteria were enrolled.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2016
    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
    Israel: 24
    Country: Number of subjects enrolled
    United States: 35
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Spain: 19
    Worldwide total number of subjects
    80
    EEA total number of subjects
    19
    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)
    38
    From 65 to 84 years
    40
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in two cohorts: Cohort 1 (C1) and Cohort 2 (C2) C1: South Korea, United States and Israel; First Patient First Visit (USA): 05 Oct 2016; Last Patient Recruited (USA): 07 Nov 2017 C2: United States, Israel and Spain; First Patient First Visit (Israel): 19 Dec 2018; Last Patient Recruited (USA): 28 Jan 2020

    Pre-assignment
    Screening details
    		 Informed consent, inclusion/exclusion criteria, demographics and medical history, MSI/dMMR status, prior and concomitant medications, AEs, ECG, full PE, vital signs, height, ECOG performance status, labs, HIV, HBV and HCV serology, CA 19-9 and CEA, tumor tissue, blood and serum (for biomarkers), CT/MRI. 37/57 (C1) and 43/55 (C2) enrolled/screened.

    Period 1
    Period 1 title
    Overall trial (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
    		 Cohort 1: BL-8040 + Pembrolizumab
    Arm description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination Therapy: Combination therapy period begins following monotherapy treatment and consists of: - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion) - Beginning on Day 10, BL-8040 three times a week (given as SC injections)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BL-8040
    Investigational medicinal product code
    Other name
    Motixafortide (INN)
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. In Combination Therapy period (begins following monotherapy treatment): Beginning on Day 10, BL-8040 three times a week (given as SC injections)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Combination Therapy period (begins following monotherapy treatment): Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion)

    Arm title
    		 Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Arm description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination therapy: Combination therapy period begins following monotherapy treatment and consists of: - Chemotherapy: IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion). - Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing (given by SC injections).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BL-8040
    Investigational medicinal product code
    Other name
    Motixafortide (INN)
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. In Combination Therapy period (begins following monotherapy treatment): Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing (given as SC injections)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Combination Therapy period (begins following monotherapy treatment): Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion)

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Onivyde + leucovorin + fluorouracil
    Pharmaceutical forms
    Solution for injection/infusion, Powder for concentrate for solution for injection/infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Combination therapy period (begins following monotherapy treatment): IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks.

    Number of subjects in period 1
    		Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Started
    37
    43
    Completed
    37
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: BL-8040 + Pembrolizumab
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination Therapy: Combination therapy period begins following monotherapy treatment and consists of: - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion) - Beginning on Day 10, BL-8040 three times a week (given as SC injections)

    Reporting group title
    Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination therapy: Combination therapy period begins following monotherapy treatment and consists of: - Chemotherapy: IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion). - Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing (given by SC injections).

    Reporting group values
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy Total
    Number of subjects
    		 37 43 80
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ( 8.2 ) 66.3 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 19 38
        Male
    		 18 24 42
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 2 3
        White
    		 33 36 69
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 3 4
    Subject analysis sets

    Subject analysis set title
    ITT Analysis Set - Cohort 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data collected for all subjects who were enrolled into Cohort 1 of the study and treated for at least once with monotherapy of BL-8040 (motixafortide). This analysis set served as the principal analysis set for safety inference and for OS and PFS inferences.

    Subject analysis set title
    ITT Analysis Set - Cohort 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data collected for all subjects who were enrolled into Cohort 2 of the study and treated for at least once with monotherapy of BL-8040 (motixafortide). This analysis set served as the principal analysis set for safety inference and for OS and PFS inferences.

    Subject analysis set title
    mITT Analysis Set - Cohort 1
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A subset of the ITT set. This set consisted of data from all Cohort 1 subjects who met all of the below criteria: • Treated with motixafortide at least once during the monotherapy treatment period, and, • Underwent at least 1 post-monotherapy CT scan. The mITT analysis set served as the principal analysis set for efficacy inference of all efficacy endpoints except for the OS and PFS analyses.

    Subject analysis set title
    mITT Analysis Set - Cohort 2
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A subset of the ITT set. This set consisted of data from all Cohort 2 subjects who met all of the below criteria: • Treated with motixafortide at least once during the monotherapy treatment period, and, • Started with pembrolizumab and Onivyde®/5-FU/LV treatment thereafter (Cohort 2), and, • Underwent at least 1 post-monotherapy CT scan. The mITT analysis set served as the principal analysis set for efficacy inference of all efficacy endpoints except for the OS and PFS analyses.

    Subject analysis sets values
    		 ITT Analysis Set - Cohort 1 ITT Analysis Set - Cohort 2 mITT Analysis Set - Cohort 1 mITT Analysis Set - Cohort 2
    Number of subjects
    37
    43
    30
    39
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.9 ( 8.2 )
    66.3 ( 9.6 )
    63.4 ( 8.9 )
    66.8 ( 9.7 )
    Gender categorical
    Units: Subjects
        Female
    19
    19
    18
    18
        Male
    18
    24
    12
    21
    Race
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: BL-8040 + Pembrolizumab
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination Therapy: Combination therapy period begins following monotherapy treatment and consists of: - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion) - Beginning on Day 10, BL-8040 three times a week (given as SC injections)

    Reporting group title
    Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination therapy: Combination therapy period begins following monotherapy treatment and consists of: - Chemotherapy: IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion). - Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing (given by SC injections).

    Subject analysis set title
    ITT Analysis Set - Cohort 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data collected for all subjects who were enrolled into Cohort 1 of the study and treated for at least once with monotherapy of BL-8040 (motixafortide). This analysis set served as the principal analysis set for safety inference and for OS and PFS inferences.

    Subject analysis set title
    ITT Analysis Set - Cohort 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data collected for all subjects who were enrolled into Cohort 2 of the study and treated for at least once with monotherapy of BL-8040 (motixafortide). This analysis set served as the principal analysis set for safety inference and for OS and PFS inferences.

    Subject analysis set title
    mITT Analysis Set - Cohort 1
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A subset of the ITT set. This set consisted of data from all Cohort 1 subjects who met all of the below criteria: • Treated with motixafortide at least once during the monotherapy treatment period, and, • Underwent at least 1 post-monotherapy CT scan. The mITT analysis set served as the principal analysis set for efficacy inference of all efficacy endpoints except for the OS and PFS analyses.

    Subject analysis set title
    mITT Analysis Set - Cohort 2
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A subset of the ITT set. This set consisted of data from all Cohort 2 subjects who met all of the below criteria: • Treated with motixafortide at least once during the monotherapy treatment period, and, • Started with pembrolizumab and Onivyde®/5-FU/LV treatment thereafter (Cohort 2), and, • Underwent at least 1 post-monotherapy CT scan. The mITT analysis set served as the principal analysis set for efficacy inference of all efficacy endpoints except for the OS and PFS analyses.

    Primary: Objective Response Rate (ORR) Assessed by Imaging According to RECIST 1.1 Criteria

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    End point title
    		 Objective Response Rate (ORR) Assessed by Imaging According to RECIST 1.1 Criteria
    End point description
    Response is determined by assessment of target lesions identified in CT or MRI imaging. The ORR is assessed according to RECIST 1.1, defined as the sum of PRs (Partial Responses) and CRs (Complete Responses) determined according to best response RECIST 1.1 criteria. PR is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. CR is defined as disappearance of all target lesions.
    End point type
    Primary
    End point timeframe
    Change in response between screening, end of monotherapy (Day 5), end of cycle 2 (Day 28) and approximately every 63 days until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.
    End point values
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy ITT Analysis Set - Cohort 1 ITT Analysis Set - Cohort 2 mITT Analysis Set - Cohort 1 mITT Analysis Set - Cohort 2
    Number of subjects analysed
    30
    39
    37
    43
    30
    39
    Units: Subjects
    1
    8
    1
    8
    1
    8
    Statistical analysis title
    		 Statistical Methods
    Statistical analysis description
    This was an open-label, Phase IIa two-cohort study to evaluate the two potential treatments regimens. Neither power assessment nor between-cohort formal hypotheses testing were planned for study outcome measures. The primary efficacy endpoint was the ORR. Principal analysis for inference used the mITT Analysis Set. The ORR and its lower 95% one-sided confidence limit (CL) was displayed for each study cohort. Sensitivity analysis was performed for the Intent-to-Treat (ITT) analysis set.
    Comparison groups
    Cohort 1: BL-8040 + Pembrolizumab v Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 confidence interval
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.3
    Notes
    [1] - This was an open-label, Phase IIa two-cohort study to evaluate the safety, tolerability and preliminary efficacy study of two potential treatments regimens. Neither power assessment nor between-cohort formal hypotheses testing were planned for study.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    The length of time elapsed in months from monotherapy Day 1 to death
    End point type
    Secondary
    End point timeframe
    Through study completion, an average of 2 years for cohort of the study, and follow-up until date of death up to 100 weeks.
    End point values
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy ITT Analysis Set - Cohort 1 ITT Analysis Set - Cohort 2 mITT Analysis Set - Cohort 1 mITT Analysis Set - Cohort 2
    Number of subjects analysed
    37
    43
    37
    43
    30
    39
    Units: Months
        median (confidence interval 95%)
    3.3 (2.8 to 7.5)
    6.6 (4.5 to 8.7)
    3.3 (2.8 to 7.5)
    6.6 (4.5 to 8.7)
    4.5 (3.3 to 8.8)
    6.5 (4.4 to 8.7)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) by Imaging (RECIST 1.1)

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    End point title
    		 Progression-free Survival (PFS) by Imaging (RECIST 1.1)
    End point description
    Progression is determined by assessment of target lesions identified in CT or MRI imaging. Progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
    End point type
    Secondary
    End point timeframe
    Assessed through study completion, an average of 2 years
    End point values
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy ITT Analysis Set - Cohort 1 ITT Analysis Set - Cohort 2 mITT Analysis Set - Cohort 1 mITT Analysis Set - Cohort 2
    Number of subjects analysed
    37
    43
    37
    43
    30
    39
    Units: Months
        median (confidence interval 95%)
    1.5 (1.5 to 1.8)
    3.8 (1.6 to 5.1)
    1.5 (1.5 to 1.8)
    3.8 (1.6 to 5.1)
    1.5 (1.5 to 2.5)
    3.8 (1.5 to 5.6)
    No statistical analyses for this end point

    Secondary: Disease Control (DC)

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    End point title
    		 Disease Control (DC)
    End point description
    Sum of Partial Response (PR), Complete Response (CR) and Stable Disease
    End point type
    Secondary
    End point timeframe
    Through study completion, an average of 2 years
    End point values
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy ITT Analysis Set - Cohort 1 ITT Analysis Set - Cohort 2 mITT Analysis Set - Cohort 1 mITT Analysis Set - Cohort 2
    Number of subjects analysed
    37
    43
    37
    43
    30
    39
    Units: Subjects
    11
    25
    11
    25
    10
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study treatment duration, up to 2 years for each cohort. Cohort 1 and Cohort 2 were conducted sequentially, with Cohort 2 initiated following completion of Cohort 1
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Cohort 1: BL-8040 + Pembrolizumab
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination Therapy: Combination therapy period begins following monotherapy treatment and consists of: - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion) - Beginning on Day 10, BL-8040 three times a week (given as SC injections)

    Reporting group title
    Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Reporting group description
    		 Monotherapy: BL-8040 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment. Combination therapy: Combination therapy period begins following monotherapy treatment and consists of: - Chemotherapy: IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. - Pembrolizumab (Keytruda®) 200 mg once every three weeks (given as a 30 minute IV infusion). - Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing (given by SC injections).

    Serious adverse events
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 37 (72.97%)
    27 / 43 (62.79%)
         number of deaths (all causes)
    5
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Genital pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 43 (13.95%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute kidney injury
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abscess limb
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: BL-8040 + Pembrolizumab Cohort 2: BL-8040 + Pembrolizumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 37 (100.00%)
    42 / 43 (97.67%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    14 / 37 (37.84%)
    7 / 43 (16.28%)
         occurrences all number
    27
    29
    Hypertension
         subjects affected / exposed
    7 / 37 (18.92%)
    2 / 43 (4.65%)
         occurrences all number
    30
    47
    Hypotension
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 43 (4.65%)
         occurrences all number
    10
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 37 (13.51%)
    16 / 43 (37.21%)
         occurrences all number
    7
    24
    Chills
         subjects affected / exposed
    6 / 37 (16.22%)
    3 / 43 (6.98%)
         occurrences all number
    12
    4
    Fatigue
         subjects affected / exposed
    21 / 37 (56.76%)
    21 / 43 (48.84%)
         occurrences all number
    33
    58
    Injection site bruising
         subjects affected / exposed
    5 / 37 (13.51%)
    0 / 43 (0.00%)
         occurrences all number
    8
    0
    Injection site discomfort
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 43 (4.65%)
         occurrences all number
    4
    6
    Injection site erythema
         subjects affected / exposed
    11 / 37 (29.73%)
    5 / 43 (11.63%)
         occurrences all number
    36
    7
    Injection site haemorrhage
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Injection site induration
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 43 (9.30%)
         occurrences all number
    3
    5
    Injection site nodule
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Injection site pain
         subjects affected / exposed
    22 / 37 (59.46%)
    28 / 43 (65.12%)
         occurrences all number
    45
    63
    Injection site pruritus
         subjects affected / exposed
    13 / 37 (35.14%)
    5 / 43 (11.63%)
         occurrences all number
    15
    8
    Injection site rash
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 43 (0.00%)
         occurrences all number
    5
    0
    Injection site reaction
         subjects affected / exposed
    8 / 37 (21.62%)
    6 / 43 (13.95%)
         occurrences all number
    11
    8
    Injection site swelling
         subjects affected / exposed
    5 / 37 (13.51%)
    1 / 43 (2.33%)
         occurrences all number
    7
    1
    Injection site warmth
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Oedema peripheral
         subjects affected / exposed
    7 / 37 (18.92%)
    7 / 43 (16.28%)
         occurrences all number
    9
    10
    Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 43 (6.98%)
         occurrences all number
    3
    3
    Pyrexia
         subjects affected / exposed
    8 / 37 (21.62%)
    10 / 43 (23.26%)
         occurrences all number
    21
    16
    Influenza like illness
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    0
    4
    Mucosal inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 43 (13.95%)
         occurrences all number
    0
    10
    Oedema
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 43 (13.95%)
         occurrences all number
    0
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 43 (6.98%)
         occurrences all number
    5
    3
    Dyspnoea
         subjects affected / exposed
    11 / 37 (29.73%)
    5 / 43 (11.63%)
         occurrences all number
    15
    14
    Pleural effusion
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    2
    1
    Pulmonary embolism
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 43 (4.65%)
         occurrences all number
    4
    2
    Depression
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 43 (4.65%)
         occurrences all number
    4
    2
    Insomnia
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 43 (9.30%)
         occurrences all number
    1
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 43 (13.95%)
         occurrences all number
    3
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 37 (10.81%)
    6 / 43 (13.95%)
         occurrences all number
    4
    10
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 37 (18.92%)
    5 / 43 (11.63%)
         occurrences all number
    12
    6
    Blood bilirubin increased
         subjects affected / exposed
    7 / 37 (18.92%)
    5 / 43 (11.63%)
         occurrences all number
    11
    5
    Blood creatinine increased
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 43 (6.98%)
         occurrences all number
    5
    7
    Blood glucose increased
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 43 (0.00%)
         occurrences all number
    7
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 43 (11.63%)
         occurrences all number
    3
    6
    Platelet count decreased
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 43 (4.65%)
         occurrences all number
    4
    2
    Weight decreased
         subjects affected / exposed
    5 / 37 (13.51%)
    9 / 43 (20.93%)
         occurrences all number
    11
    20
    White blood cell count increased
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Fall
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Infusion related reaction
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 43 (0.00%)
         occurrences all number
    6
    0
    Skin injury
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Sinus tachycardia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Tachycardia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 43 (4.65%)
         occurrences all number
    2
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 37 (10.81%)
    9 / 43 (20.93%)
         occurrences all number
    4
    11
    Dysgeusia
         subjects affected / exposed
    3 / 37 (8.11%)
    8 / 43 (18.60%)
         occurrences all number
    3
    11
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 43 (11.63%)
         occurrences all number
    4
    8
    Neuropathy peripheral
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 43 (9.30%)
         occurrences all number
    1
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 37 (18.92%)
    14 / 43 (32.56%)
         occurrences all number
    9
    42
    Leukocytosis
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 43 (4.65%)
         occurrences all number
    2
    2
    Thrombocytopenia
         subjects affected / exposed
    4 / 37 (10.81%)
    5 / 43 (11.63%)
         occurrences all number
    8
    10
    Neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    7
    Eye disorders
    Visual impairment
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Vitreous floaters
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Vision blurred
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Abdominal distension
         subjects affected / exposed
    5 / 37 (13.51%)
    3 / 43 (6.98%)
         occurrences all number
    5
    3
    Abdominal pain
         subjects affected / exposed
    14 / 37 (37.84%)
    14 / 43 (32.56%)
         occurrences all number
    21
    22
    Ascites
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 43 (4.65%)
         occurrences all number
    12
    2
    Constipation
         subjects affected / exposed
    10 / 37 (27.03%)
    8 / 43 (18.60%)
         occurrences all number
    17
    13
    Diarrhoea
         subjects affected / exposed
    10 / 37 (27.03%)
    22 / 43 (51.16%)
         occurrences all number
    15
    70
    Dyspepsia
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 43 (9.30%)
         occurrences all number
    2
    5
    Flatulence
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 43 (9.30%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    13 / 37 (35.14%)
    29 / 43 (67.44%)
         occurrences all number
    21
    71
    Rectal haemorrhage
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Stomatitis
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 43 (6.98%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    13 / 37 (35.14%)
    23 / 43 (53.49%)
         occurrences all number
    29
    72
    Abdominal pain upper
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 43 (9.30%)
         occurrences all number
    1
    4
    Dry mouth
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 43 (6.98%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    5 / 37 (13.51%)
    8 / 43 (18.60%)
         occurrences all number
    19
    11
    Night sweats
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 43 (6.98%)
         occurrences all number
    5
    3
    Pruritus
         subjects affected / exposed
    19 / 37 (51.35%)
    15 / 43 (34.88%)
         occurrences all number
    68
    44
    Rash
         subjects affected / exposed
    12 / 37 (32.43%)
    12 / 43 (27.91%)
         occurrences all number
    19
    25
    Rash erythematous
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 43 (4.65%)
         occurrences all number
    15
    9
    Urticaria
         subjects affected / exposed
    9 / 37 (24.32%)
    2 / 43 (4.65%)
         occurrences all number
    29
    11
    Pruritus generalized
         subjects affected / exposed
    0 / 37 (0.00%)
    14 / 43 (32.56%)
         occurrences all number
    0
    20
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 37 (0.00%)
    14 / 43 (32.56%)
         occurrences all number
    0
    20
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 43 (4.65%)
         occurrences all number
    2
    2
    Hypothyroidism
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 37 (16.22%)
    5 / 43 (11.63%)
         occurrences all number
    13
    7
    Back pain
         subjects affected / exposed
    11 / 37 (29.73%)
    6 / 43 (13.95%)
         occurrences all number
    14
    10
    Muscular weakness
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 43 (4.65%)
         occurrences all number
    2
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Myalgia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    2
    1
    Pain in extremity
         subjects affected / exposed
    6 / 37 (16.22%)
    2 / 43 (4.65%)
         occurrences all number
    9
    5
    Bone pain
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Skin infection
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 43 (2.33%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 43 (6.98%)
         occurrences all number
    3
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 37 (45.95%)
    18 / 43 (41.86%)
         occurrences all number
    22
    30
    Dehydration
         subjects affected / exposed
    6 / 37 (16.22%)
    6 / 43 (13.95%)
         occurrences all number
    8
    11
    Hyperglycaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 43 (6.98%)
         occurrences all number
    4
    6
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 37 (16.22%)
    4 / 43 (9.30%)
         occurrences all number
    6
    12
    Hypokalaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    9 / 43 (20.93%)
         occurrences all number
    2
    22
    Hyponatraemia
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 43 (13.95%)
         occurrences all number
    3
    9
    Hypomagnesaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 43 (6.98%)
         occurrences all number
    1
    4
    Hypophosphataemia
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    0
    6
    Hypothyroidism
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 43 (13.95%)
         occurrences all number
    0
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2016
    AMENDMENT 1 (Protocol version 2) - submitted in US only (on 12 Aug 2016): - A revision to the definition of a DLT to include Grade 4 (life-threatening) vomiting or diarrhea, Grade 4 electrolyte abnormalities, or Grade 4 systemic reaction systems as well as all other clinically significant, adverse events that were common terminology for adverse events (CTCAE) Grade 3 or higher with the exception of injection site reactions unless they resulted in missing one full cycle of motixafortide treatment. - Inclusion Criterion #5 was revised to clarify what constitutes “one or more prior treatments” in the eligibility criteria. - Exclusion Criteria #7 and #10 were revised to clarify that systemic steroids for baseline adrenal insufficiency were permitted. - Exclusion Criterion #15 was revised to exclude subjects with unstable angina, new onset angina within the last 3 months, myocardial infarction within the last six months, and current congestive heart failure New York Heart Association Class III or higher. - A 14-day time window was added to the termination or early discontinuation study visit
    23 Jul 2018
    AMENDMENT 2 (Protocol version 3) - submitted in US only (on 23 July 2018): - The study population was divided into two cohorts: Cohort 1 (pembrolizumab + motixafortide) and Cohort 2 (pembrolizumab + motixafortide + chemotherapy). - The rationale for the addition of chemotherapy in Cohort 2, as well as the rationale for chemotherapy dose and regimen selection, was added. - The protocol was revised to include the additional cohort (Cohort 2). - A second safety interim analysis was added, after 6 subjects from Cohort 2 have completed the first cycle of combination therapy. - Inclusion criteria regarding previous treatments and biopsies were updated to reflect the differences between the two cohorts. - Identity of chemotherapy, its administration, manufacturing, storage, dispensing and returns were added. - information regarding concomitant medication with respect to the chosen chemotherapy was added. • Sample size considerations were revised to include the statistical justification for the selection of the sample size and the null hypothesis response rate, as well as the sample size for Cohort 2. • Inclusion Criteria #5 was revised to clarify what constitutes “one or more prior treatments” in the eligibility criteria. • DLT was clarified to include Grade 4 (life-threatening) vomiting or diarrhea, Grade 4 electrolyte abnormalities, or Grade 4 systemic reactions as well as all other clinically significant AEs that were CTCAE) Grade 3 or higher with the exception of injection site reactions unless they resulted in missing one full cycle of motixafortide treatment. • The optionality was removed from the DNA and RNA assessment. • Clarification was provided that tumor tissue collection from metastasis for tumor and correlative studies assessments and blood for DNA and RNA for correlative studies (only if biopsy was taken at this time point) were for Cohort 1 only - For Cohort 2 only, subjects with bowel obstruction were excluded from entering the trial
    21 Aug 2018
    AMENDMENT 3 (Protocol version 3.1) - dated 21-Aug-2018 - not submitted: - The screening period sampling for immunophenotyping, CXCR4 and PD-1 expression, etc was deleted. Sampling for these tests was to take place on Day 1, prior to the first motixafortide dose.
    13 Mar 2019
    AMENDMENT 4 (Protocol version 4.0) - submitted in US only (on 14 Mar 2016): - Changes in timing of motixafortide dosing were made to remove the requirement for motixafortide administration to be at least 24 hours after chemotherapy. - Dosing of chemotherapy to allow dosing according to local standard was added. - Collection of microsatellite instability / deficient mismatch repair status if available at screening or testing of these using the biopsy sample if not previously tested was included. - The safety follow-up period was extended to 90 days. - Additional guidance regarding dose modifications relating to overlapping toxicities of the study drugs was provided.
    28 Jun 2019
    AMENDMENT 5 (Protocol version 4.1) - approved by AEMPS (RA Spain) on 28 Jun 2019: - Premedication with dexamethasone for the prevention of emesis related to Onivyde® treatment was permitted. - Additional timing for electrocardiogram (ECG) assessment during monotherapy period Predose Day 1 was included.

    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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