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    Clinical Trial Results:
    Phase I/II study on safety and efficacy of NMS-01940153E in adult patients with unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy.

    Summary
    EudraCT number
    		 2020-001002-26
    Trial protocol
    		 IT  
    Global end of trial date
    06 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2025
    First version publication date
    23 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MPSA-153-001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN00000000
    US NCT number
    		 NCT00000000
    WHO universal trial number (UTN)
    		 U0000-0000-0000
    Other trial identifiers
    		 NA: NA
    Sponsors
    Sponsor organisation name
    Nerviano Medical Sciences S.r.l.
    Sponsor organisation address
    Viale Pasteur, 10 - Nerviano, Milan, Italy,
    Public contact
    Anders Elm Pedersen, Global Clinical Development, Nerviano Medical Sciences S.r.l., 39 0331 58 1111, DL-Clinicaltrials@nervianoms.com
    Scientific contact
    Anders Elm Pedersen, Global Clinical Development, Nerviano Medical Sciences S.r.l., 39 0331 58 1111, DL-Clinicaltrials@nervianoms.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
    06 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Aug 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    • To determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of NMS-01940153E administered as single agent to adult patients with unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy (Phase I). • To assess the anti-tumor efficacy of NMS-01940153E administered as single agent to adult patients with unresectable hepatocellular carcinoma previously treated with systemic therapy (Phase II).
    Protection of trial subjects
    Patients might have continued with therapy unless the occurrence of any of the following: • Disease progression by RECIST 1.1 at any time, unless there is reasonable evidence of clinical benefit to justify continuation on treatment, to be discussed with the Sponsor; • Unacceptable drug-related toxicities incompatible with continuation of treatment with NMS-01940153E according to the judgment of the Investigator, even at a reduced dose; • Any medical event requiring administration of an unauthorised concomitant treatment if it interferes with the study evaluations and/or if it jeopardises patient’s safety (see Section 9.2.7 of the study protocol); • Change in the patient’s medical status (including pregnancy) such that the Investigator believes that patient safety may be compromised or that it would be in the best patient’s interest to stop treatment; • Occurrence of permanent or significant incapacity or disability; • Treatment delay for >1 week from day 28 of any cycle due to treatment related toxicity, unless the investigator believes treatment continuation is in the best patient’s interest. In this case a maximum delay of 2 weeks is allowed; • More than two dose de-escalations required; • Substantial deviation from specified inclusion or exclusion criteria or non-compliance by the patient with protocol requirements; • Patient’s refusal to continue study treatment; • Withdrawal of consent; • Patient lost to follow up; • Death; • Study terminated by the Sponsor. Patients were withdrawn from the study in case of: • Withdrawal of consent; • Patient lost to follow up; • Death; • Study terminated by the Sponsor.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 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: 9
    Country: Number of subjects enrolled
    Italy: 22
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    17
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects with histological, cytological or radiological diagnosis of HCC, according to the American Association for the Study of Liver Diseases/European Association for the Study of the Liver criteria, in subjects that were refractory or not able to tolerate the standard therapy, or for whom the standard therapy is not considered appropriate.

    Pre-assignment period milestones
    Number of subjects started
    		 31
    Number of subjects completed
    		 30

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Enrolled but not treated: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I Participants: 100 mg/m2/week
    Arm description
    		 All participants in Phase I who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NMS-01940153E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NMS-01940153E was administered IV for 3 consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day cycle. The total dose to be administered was calculated based on patient’s body surface area. The duration of infusion was dependent on the total dose to be administered: • 1 hour infusion if ≤255 mg are administered • 1 hour 30 minutes infusion if >255 mg but <375 mg are administered The starting dose for the Phase I portion of the study was 100 mg/m2/week, then according to the observed safety profile, dose increments of 25-35% were to be applied until the maximum tolerated dose was reached. In presence of unacceptable toxicity observed at 100 mg/m2/week, a lower dose level by 25-35% could be tested.

    Arm title
    		 Phase II Participants: 100 mg/m2/week
    Arm description
    		 All participants in Phase II who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NMS-01940153E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Phase II portion of the study, NMS-01940153E was administered at the recommended Phase 2 dose of 100 mg/m2/week defined in the Phase I as starting dose.

    Arm title
    		 Phase I Participants: 135 mg/m2/week
    Arm description
    		 All participants in Phase I who received 135 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NMS-01940153E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NMS-01940153E was administered IV for 3 consecutive weeks on days 1, 8, 15 followed by 1 week of rest, in a 28-day cycle. The total dose to be administered was calculated based on patient’s body surface area. The duration of infusion was dependent on the total dose to be administered: • 1 hour infusion if ≤255 mg are administered • 1 hour 30 minutes infusion if >255 mg but <375 mg are administered The starting dose for the Phase I portion of the study was 100 mg/m2/week, then according to the observed safety profile, dose increments of 25-35% were to be applied until the maximum tolerated dose was reached. In presence of unacceptable toxicity observed at 100 mg/m2/week, a lower dose level by 25-35% could be tested.

    Number of subjects in period 1 [1]
    		Phase I Participants: 100 mg/m2/week Phase II Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Started
    6
    18
    6
    Completed
    5
    9
    5
    Not completed
    1
    9
    1
         Study terminated by sponsor
    1
    8
    1
         Lost to follow-up
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant was enrolled but did not receive treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I Participants: 100 mg/m2/week
    Reporting group description
    		 All participants in Phase I who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Reporting group title
    Phase II Participants: 100 mg/m2/week
    Reporting group description
    		 All participants in Phase II who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Reporting group title
    Phase I Participants: 135 mg/m2/week
    Reporting group description
    		 All participants in Phase I who received 135 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Reporting group values
    		 Phase I Participants: 100 mg/m2/week Phase II Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week Total
    Number of subjects
    		 6 18 6 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 10 3 16
        From 65-84 years
    		 3 8 3 14
    Gender categorical
    Units: Subjects
        Female
    		 1 1 0 2
        Male
    		 5 17 6 28
    Race
    Units: Subjects
        White
    		 5 18 6 29
        Black or African American
    		 1 0 0 1
    Eastern cooperative oncology group performance status
    When multiple Eastern cooperative oncology group performance status (ECOG PS) determinations were available, the most recent not missing baseline assessment was considered.
    Units: Subjects
        ECOG PS 0
    		 3 10 3 16
        ECOG PS 1
    		 3 8 3 14

    End points

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    End points reporting groups
    Reporting group title
    Phase I Participants: 100 mg/m2/week
    Reporting group description
    		 All participants in Phase I who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Reporting group title
    Phase II Participants: 100 mg/m2/week
    Reporting group description
    		 All participants in Phase II who received 100 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Reporting group title
    Phase I Participants: 135 mg/m2/week
    Reporting group description
    		 All participants in Phase I who received 135 mg/m2/week intravenous NMS-01940153E. All participants who completed the study were followed up until death.

    Subject analysis set title
    All Treated Participants (Phase I and II; all dose levels)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes all treated participants in the Phase I and Phase II parts of this study, at all dose levels

    Subject analysis set title
    100 mg/m2/weeks (Phase I and II)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes all participants who received 100 mg/m2/weeks in the Phase I and Phase II of this study

    Subject analysis set title
    135 mg/m2/weeks (Phase I only)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes all participants who received 135 mg/m2/weeks in the Phase I of this study

    Subject analysis set title
    100 mg/m2/weeks (Phase I only)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants in Phase I who received 100 mg/m2/week intravenous NMS-01940153E

    Subject analysis set title
    Phase II Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants of the treated set who had measurable disease at baseline assessed according to RECIST 1.1 and at least one tumor evaluation on treatment, unless they died before the first tumor on-treatment assessment, in which case they were considered treatment failure.

    Primary: Phase I drug related dose limiting toxicities (DLTs)

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    End point title
    		 Phase I drug related dose limiting toxicities (DLTs) [1]
    End point description
    All 12 Phase I treated patients were evaluable for DLT (Dose-Limiting Toxicity Evaluable Set) and included 6 patients treated at each of the two dose levels explored (i.e., 100 mg/m2/week and 135 mg/m2/week) who received at least 66% of the study drug in the first 28-day cycle of treatment and underwent a DLT assessment within the DLT window. Participants who experienced DLTs are presented.
    End point type
    Primary
    End point timeframe
    Phase I: From screening to end of first 28-day cycle (17 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: Not applicable for this endpoint
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6
    Units: participants
    2
    0
    No statistical analyses for this end point

    Primary: Phase II objective response rate

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    End point title
    		 Phase II objective response rate [2]
    End point description
    The objective response rate (ORR) was calculated as the proportion of evaluable patients who achieved, as best overall response (BOR), confirmed complete response (CR) or partial response (PR) measured by investigator-assessed RECIST 1.1 (Phase II).
    End point type
    Primary
    End point timeframe
    Phase II: From Phase II start to Study Completion (23 months)
    Notes
    [2] - 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: Not applicable for this endpoint
    End point values
    		 Phase II Evaluable Population
    Number of subjects analysed
    14
    Units: participants
        Stable Disease
    3
        Progressive Disease
    11
        Complete Response
    0
        Partial Response
    0
    No statistical analyses for this end point

    Secondary: Treatment-emergent adverse by maximum CTC grade

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    End point title
    		 Treatment-emergent adverse by maximum CTC grade
    End point description
    The number of events are presented by maximum Common Terminology Criteria (CTC) grade (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months). Phase 2 started before Phase 1 completed.
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase II Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Number of subjects analysed
    6
    18
    6
    Units: participants
        Grade 1
    0
    3
    0
        Grade 2
    1
    8
    1
        Grade 3
    3
    7
    3
        Grade 4
    1
    0
    2
    No statistical analyses for this end point

    Secondary: Treatment-emergent adverse events related to NMS-01940153E

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    End point title
    		 Treatment-emergent adverse events related to NMS-01940153E
    End point description
    The number of treatment-emergent adverse events related to NMS-01940153E by maximum CTC grade experienced (graded using NCI CTCAE Version 5.0). Whether the the AE was related or not was assessed by the investigator. If an AE was reported for a participant more than once during treatment, the worst CTC Grade is presented. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months). Phase 2 started before Phase 1 completed.
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase II Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Number of subjects analysed
    6
    18
    6
    Units: events
        Grade 1
    0
    7
    0
        Grade 2
    1
    3
    1
        Grade 3
    2
    2
    2
        Grade 4
    1
    0
    2
    No statistical analyses for this end point

    Secondary: Hematology: Overall treatment-emergent abnormalities by dose level and maximum CTC grade

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    End point title
    		 Hematology: Overall treatment-emergent abnormalities by dose level and maximum CTC grade
    End point description
    Number of treatment emergent abnormalities (at any grade) at all dose levels are presented. CTC = Common Terminology Criteria WBC = white blood cells
    End point type
    Secondary
    End point timeframe
    From screening to 28 days follow-up, an average 6 months
    End point values
    		 All Treated Participants (Phase I and II; all dose levels) 100 mg/m2/weeks (Phase I and II) 135 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    30
    24
    6
    Units: events
        Hemoglobin Decreased
    18
    13
    5
        Neutrophil Count Decreased
    10
    6
    4
        WBC Decreased
    14
    8
    6
        Platelet Count Decreased
    10
    6
    4
    No statistical analyses for this end point

    Secondary: Neutrophils count decrease: Time to first occurrence of >=Grade 3 and time to recovery to Grade 1

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    End point title
    		 Neutrophils count decrease: Time to first occurrence of >=Grade 3 and time to recovery to Grade 1
    End point description
    The mean days to first occurrence of neutrophil count decrease are presented for all dose levels. Grade 0: ≥2,000/mm3 Grade 1: ≥1,500–< 2,000/mm3 Grade 2: ≥1,000– < 1,500/mm3 Grade 3: ≥500– < 1,000/mm3 Grade 4: <500/mm3 >=G3 = Time (days) to Treatment Start to First Occurrence of Neutrophil Count Decrease >=Grade 3 >= G3 to Recovery to G1 = Time (days) to First Occurrence of Neutrophil Count Decrease >= Grade 3 to Recovery to Grade 1
    End point type
    Secondary
    End point timeframe
    From screening to 28 days follow-up, an average 6 months
    End point values
    		 All Treated Participants (Phase I and II; all dose levels) 100 mg/m2/weeks (Phase I and II) 135 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6 [3]
    2
    4 [4]
    Units: days
    arithmetic mean (standard deviation)
        >=G3
    39.67 ( 23.38 )
    63.00 ( 19.80 )
    28.00 ( 15.36 )
        >= G3 to Recovery to G1
    7.20 ( 2.59 )
    7.00 ( 1.41 )
    7.33 ( 3.51 )
    Notes
    [3] - Only 5 participants were included in the >= G3 to Recovery to G1 assessment.
    [4] - Only 3 participants were included in the >= G3 to Recovery to G1 assessment.
    No statistical analyses for this end point

    Secondary: Blood chemistry: Treatment-emergent abnormalities by dose level

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    End point title
    		 Blood chemistry: Treatment-emergent abnormalities by dose level
    End point description
    Treatment-emergent abnormalities in blood chemistry at any grade are presented by dose level. ALP = Alkaline phosphatase ALT = Alanine aminotransferase AST = Aspartate aminotransferase GGT = Gamma-glutamyl transferase LDH = Lactate dehydrogenase
    End point type
    Secondary
    End point timeframe
    From screening to 28 days follow-up, an average 6 months
    End point values
    		 All Treated Participants (Phase I and II; all dose levels) 100 mg/m2/weeks (Phase I and II) 135 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    24
    6
    30
    Units: events
        Hypoalbuminemia
    8
    4
    12
        Hypoglycemia
    0
    1
    1
        AST Increased
    12
    3
    15
        ALT Increased
    8
    2
    10
        GGT Increased
    9
    1
    10
        Creatinine Increased
    6
    3
    9
        Blood Bilirubin Increased
    7
    1
    8
        ALP Increased
    10
    1
    11
        Blood LDH Increased
    14
    4
    18
        Hypocalcemia
    1
    1
    2
        Hypernatremia
    0
    1
    1
        Hyperkalemia
    7
    0
    7
        Hypomagnesemia
    5
    3
    8
    No statistical analyses for this end point

    Secondary: Blood chemistry and coagulation: Treatment-emergent abnormalities

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    End point title
    		 Blood chemistry and coagulation: Treatment-emergent abnormalities
    End point description
    Treatment Emergent abnormalities by dose Level are presented for blood chemistry and coagulation parameters. INR = international normalized ratio LNL = lower normal limit NL = normal limit ULN = upper limit of normal
    End point type
    Secondary
    End point timeframe
    From screening to 28 days follow-up, an average 6 months
    End point values
    		 All Treated Participants (Phase I and II; all dose levels) 100 mg/m2/weeks (Phase I and II) 135 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    30
    24
    6
    Units: events
        Hyponatremia: Total
    6
    4
    2
        Hyponatremia: Below LNL
    6
    4
    2
        Hypokalemia: Total
    1
    0
    1
        Hypokalemia: Below LNL
    1
    0
    1
        Phosphatemia: Total
    13
    11
    2
        Phosphatemia: Above ULN
    3
    3
    0
        Phosphatemia: Below LNL
    9
    7
    2
        Phosphatemia: Above/Below NL
    1
    1
    0
        Hyperglycemia: Total
    11
    9
    2
        Hyperglycemia: Above ULN
    10
    9
    1
        Hyperglycemia: Above/Below NL
    1
    0
    1
        Blood Urea Nitrogen: Total
    2
    2
    0
        Blood Urea Nitrogen: Above ULN
    2
    2
    0
        Urea: Total
    6
    6
    0
        Urea: Above ULN
    5
    5
    0
        Urea: Below LNL
    1
    1
    0
        Unconjugated Bilirubin: Total
    3
    3
    0
        Unconjugated Bilirubin: Above ULN
    3
    3
    0
        Total Protein: Total
    9
    7
    2
        Total Protein: Above ULN
    2
    2
    0
        Total Protein: Below LNL
    6
    4
    2
        Total Protein: Above/Below NL
    1
    1
    0
        INR: Total
    12
    11
    1
        INR: Above ULN
    9
    8
    1
        INR: Below LNL
    1
    1
    0
        INR: Above/Below NL
    2
    2
    0
    No statistical analyses for this end point

    Secondary: Electrocardiogram abnormalities

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    End point title
    		 Electrocardiogram abnormalities
    End point description
    The number of participants who experienced electrocardiogram abnormalities are presented.
    End point type
    Secondary
    End point timeframe
    From screening to 28 days follow-up, an average 6 months
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase II Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Number of subjects analysed
    6
    18
    6
    Units: participants
        ECG Abnormalities
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Tmax and Tlast of NMS-01940153E

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    End point title
    		 Tmax and Tlast of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Tmax = Time to maximum observed plasma concentration Tlast = Time of last detectable concentration
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [5]
    Units: hours
    arithmetic mean (standard deviation)
        Tmax: Day 1
    1.19 ( 0.513 )
    0.933 ( 0.0327 )
        Tmax: Day 15
    1.87 ( 1.90 )
    1.10 ( 0.216 )
        Tlast: Day 1
    154 ( 39.2 )
    169 ( 3.01 )
        Tlast: Day 15
    169 ( 0.418 )
    144 ( 48.5 )
    Notes
    [5] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: Cmax and Clast of NMS-01940153E

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    End point title
    		 Cmax and Clast of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Cmax = Maximum observed plasma concentration Clast = Last detectable concentration
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [6]
    Units: μM
    arithmetic mean (standard deviation)
        Cmax: Day 1
    1.91 ( 0.640 )
    0.754 ( 0.174 )
        Cmax: Day 15
    1.59 ( 1.31 )
    1.35 ( 1.10 )
        Clast: Day 1
    0.0840 ( 0.0335 )
    0.0590 ( 0.0191 )
        Clast: Day 15
    0.133 ( 0.0779 )
    0.113 ( 0.0454 )
    Notes
    [6] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: AUClast, AUCweekly, and AUCinf of NMS-01940153E

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    End point title
    		 AUClast, AUCweekly, and AUCinf of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Infusions occurred on Days 1, 8, and 15. AUClast = Area under the interpolated observed plasma time-concentration curve from infusion start to the last observed plasma concentration AUCweekly = Area under the interpolated observed plasma time-concentration curve from infusion start to 168 hours AUCinf = Area under the interpolated observed plasma time-concentration curve from infusion start extrapolated to infinity based on the last observed plasma concentration
    End point type
    Secondary
    End point timeframe
    From Day 1 to 21 (168 hours after the Day 15 infusion)
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [7]
    Units: h·μM
    arithmetic mean (standard deviation)
        AUClast: Day 1
    24.8 ( 8.55 )
    20.8 ( 4.31 )
        AUClast: Day 15
    39.1 ( 14.9 )
    30.0 ( 9.16 )
        AUCweekly: Day 1
    25.7 ( 7.11 )
    20.8 ( 4.35 )
        AUCweekly: Day 15
    39.0 ( 14.8 )
    32.4 ( 6.49 )
        AUCinf: Day 1
    37.1 ( 14.9 )
    28.7 ( 6.88 )
        AUCinf: Day 15
    62.9 ( 34.1 )
    48.1 ( 19.6 )
    Notes
    [7] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: t½,z of NMS-01940153E

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    End point title
    		 t½,z of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) PK profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. t½,z = Half-life of the terminal phase of observed plasma concentration
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [8]
    Units: days
    arithmetic mean (standard deviation)
        t½,z Day 1
    4.17 ( 1.40 )
    3.74 ( 0.800 )
        t½,z Day 15
    4.79 ( 1.15 )
    4.38 ( 2.64 )
    Notes
    [8] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: CL and CLss of NMS-01940153E

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    End point title
    		 CL and CLss of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) PK profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. CL = Clearance based on last observed concentration and extrapolation to infinity CLss = Clearance calculated for a dosing period of 168 h either after a single dose or in steady-state
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [9]
    Units: L/h
    arithmetic mean (standard deviation)
        CL: Day 1
    10.2 ( 4.01 )
    10.1 ( 3.16 )
        CL: Day 15
    6.19 ( 2.08 )
    6.12 ( 2.24 )
        CLss: Day 1
    13.8 ( 3.73 )
    13.8 ( 4.14 )
        CLss: Day 15
    9.31 ( 2.52 )
    8.53 ( 2.50 )
    Notes
    [9] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: Vss and Vss,SS of NMS-01940153E

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    End point title
    		 Vss and Vss,SS of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Vss = Volume of distribution at steady state based last observed concentration extrapolated to infinity and Clearance calculated for a dosing period of 168 h either after a single dose or in steady-state Vss,SS = Volume of distribution at steady state based last observed concentration extrapolated to infinity and clearance based on last observed concentration and extrapolation to infinity
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [10]
    Units: L
    arithmetic mean (standard deviation)
        Vss: Day 1
    1210 ( 199 )
    1230 ( 395 )
        Vss: Day 15
    919 ( 245 )
    787 ( 304 )
        Vss,SS: Day 1
    1630 ( 285 )
    1700 ( 620 )
        Vss,SS: Day 15
    1380 ( 354 )
    1180 ( 649 )
    Notes
    [10] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: RA AUCweekly and RA Cmax of NMS-01940153E

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    End point title
    		 RA AUCweekly and RA Cmax of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. Infusions occurred on Days 1, 8, and 15. RA AUCweekly = Accumulation ratio Day 1 to 15 calculated using area under the interpolated observed plasma time-concentration curve from infusion start to 168 hours RA Cmax = Accumulation ratio Day 1 to 15 calculated using maximum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    From Day 1 to 21 (168 hours after the Day 15 infusion)
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [11]
    Units: ratio
    arithmetic mean (standard deviation)
        RA AUCweekly: Day 15
    1.51 ( 0.293 )
    1.66 ( 0.188 )
        RA Cmax: Day 15
    0.858 ( 0.547 )
    1.78 ( 1.36 )
    Notes
    [11] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: FE of NMS-01940153E

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    End point title
    		 FE of NMS-01940153E
    End point description
    Plasma pharmacokinetic (PK) profiles of NMS-01940153E were characterized on Day 1 and 15 of the first Cycle after infusion. FE = Molar fraction of excreted compound relative to the administered molar dose calculated using urine concentration and volume data
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15
    End point values
    		 135 mg/m2/weeks (Phase I only) 100 mg/m2/weeks (Phase I only)
    Number of subjects analysed
    6
    6 [12]
    Units: percentage
    arithmetic mean (standard deviation)
        FE Day 1
    0.357 ( 0.260 )
    0.458 ( 0.374 )
        FE Day 15
    0.826 ( 0.713 )
    0.563 ( 0.424 )
    Notes
    [12] - Only 4 evaluable participants on Day 15
    No statistical analyses for this end point

    Secondary: Phase I objective tumor response (partial and complete response)

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    End point title
    		 Phase I objective tumor response (partial and complete response) [13]
    End point description
    Phase I any dose level, objective response and best overall tumor response are presented, as measured by investigator assessed RECIST 1.1 (Phase I). The objective response rate was calculated as the proportion of evaluable patients who achieved best overall response (BOR), confirmed complete response (CR) or partial response (PR).
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Number of subjects analysed
    6
    6
    Units: participants
        Objective Response (Partial Response)
    1
    1
        Objective Response (Complete Response)
    0
    0
        Stable Disease
    1
    2
        Progressive Disease
    4
    2
    No statistical analyses for this end point

    Secondary: Phase II objective response rate as measured by investigator-assessed mRECIST

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    End point title
    		 Phase II objective response rate as measured by investigator-assessed mRECIST [14]
    End point description
    Objective response rate as measured by investigator-assessed mRECIST in Phase II.
    End point type
    Secondary
    End point timeframe
    Phase II: From Phase II start to Study Completion (23 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase II Participants: 100 mg/m2/week
    Number of subjects analysed
    14
    Units: participants
        Stable Disease
    3
        Progressive Disease
    11
        Objective Response (Partial Response)
    0
        Objective Response (Complete Response)
    0
    No statistical analyses for this end point

    Secondary: Progression free survival, as measured by investigator-assessed RECIST 1.1, in Phases I and II

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    End point title
    		 Progression free survival, as measured by investigator-assessed RECIST 1.1, in Phases I and II [15]
    End point description
    Progression Free Survival as measured by investigator assessed RECIST 1.1, for all treated participants in Phase I and Phase II.
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months). Phase 2 started before Phase 1 completed.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week Phase II Evaluable Population
    Number of subjects analysed
    6
    6
    14
    Units: months
        median (confidence interval 95%)
    1.9 (1.7 to 6.5)
    7.8 (1.8 to 25.1)
    1.9 (1.8 to 4.1)
    No statistical analyses for this end point

    Secondary: Overall survival in Phases I and II

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    End point title
    		 Overall survival in Phases I and II [16]
    End point description
    Overall Survival for all treated participants in Phases I and II. The estimates are based on the Kaplan-Meier (KM) method. 9999 = not applicable
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months). Phase 2 started before Phase 1 completed.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week Phase II Evaluable Population
    Number of subjects analysed
    6
    6
    14
    Units: months
        median (confidence interval 95%)
    9.7 (5.2 to 9999)
    15.7 (4.7 to 9999)
    7.3 (3.9 to 9999)
    No statistical analyses for this end point

    Secondary: Phase I: Duration of response (DoR) as measured by investigator-assessed RECIST 1.1

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    End point title
    		 Phase I: Duration of response (DoR) as measured by investigator-assessed RECIST 1.1 [17]
    End point description
    Duration of response (DoR) as measured by investigator-assessed Response evaluation criteria in solid tumours (RECIST) 1.1. Duration of Response (months): was time in months from response start date to either date of disease progression/death due to progression of disease. It was calculated only for participants with complete response or partial response as best overall response. 8.888 = not calculated
    End point type
    Secondary
    End point timeframe
    Phase I: From the Study Start Date to Phase I Completion (32 months)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase I Participants: 100 mg/m2/week Phase I Participants: 135 mg/m2/week
    Number of subjects analysed
    1
    1
    Units: months
        number (not applicable)
    2.6
    9.3
    No statistical analyses for this end point

    Secondary: Phase II: Duration of response (DoR) as measured by investigator-assessed RECIST 1.1. and investigator-assessed mRECIST

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    End point title
    		 Phase II: Duration of response (DoR) as measured by investigator-assessed RECIST 1.1. and investigator-assessed mRECIST [18]
    End point description
    Duration of response (DoR) as measured by investigator-assessed Response evaluation criteria in solid tumours (RECIST) 1.1. and investigator-assessed modified RECIST (mRECIST) . No participants had a RECIST or mRECIST complete or partial response observed. Duration of Response (months): was time in months from response start date to either date of disease progression/death due to progression of disease. It was calculated only for participants with complete response or partial response as best overall response.
    End point type
    Secondary
    End point timeframe
    Phase II: From Phase II start to Study Completion (23 months)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable for this endpoint
    End point values
    		 Phase II Participants: 100 mg/m2/week
    Number of subjects analysed
    0 [19]
    Units: participants
        RECIST Response Observed
        mRECIST Response Observed
    Notes
    [19] - Phase II participants who experienced partial response
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Phase I: From the Study Start Date to Phase I Completion (32 months) - Phase II: From Phase II start to Study Completion (23 months). Phase 2 started before Phase 1 completed.
    Adverse event reporting additional description
    For non-serious AEs, the number of participants who experienced at least 1 occurrence of a treatment-emergent non-serious AEs, by MedDRA System Organ Class and Preferred Term are presented. The one participant who was enrolled but not treated was not assessed for adverse events and therefore this cohort has not been included.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Phase I: 100 mg/m2/weeks
    Reporting group description
    		 Includes all participants who received 100 mg/m2/weeks in the Phase I of this study

    Reporting group title
    Phase I: 135 mg/m2/weeks
    Reporting group description
    		 Includes all participants who received 135 mg/m2/weeks in the Phase I of this study

    Reporting group title
    Phase II: 100 mg/m2/weeks
    Reporting group description
    		 Includes all participants who received 100 mg/m2/weeks in the Phase II of this study

    Serious adverse events
    		 Phase I: 100 mg/m2/weeks Phase I: 135 mg/m2/weeks Phase II: 100 mg/m2/weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    5 / 18 (27.78%)
         number of deaths (all causes)
    5
    5
    9
         number of deaths resulting from adverse events
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related bacteraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase I: 100 mg/m2/weeks Phase I: 135 mg/m2/weeks Phase II: 100 mg/m2/weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    18 / 18 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 18 (16.67%)
         occurrences all number
    0
    1
    8
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    8 / 18 (44.44%)
         occurrences all number
    2
    1
    10
    Infusion site reaction
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 18 (16.67%)
         occurrences all number
    1
    2
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    1
    1
    2
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Infusion site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Infusion site pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Infusion site phlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    1
    1
    2
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    1
    0
    3
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 18 (16.67%)
         occurrences all number
    0
    1
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    0
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Coronavirus test positive
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Adverse event following immunisation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    3
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 18 (11.11%)
         occurrences all number
    7
    6
    4
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    2
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    7
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    5
    Ascites
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    2
    Dysphagia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Haemoperitoneum
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Melaena
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Peptic ulcer
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Tooth loss
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    Eczema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Actinic keratosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    2
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    3 / 18 (16.67%)
         occurrences all number
    2
    2
    5
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    4
    2
    Arthralgia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    4
    0
    2
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Joint effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    4
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    Acarodermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Burn infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Oral fungal infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2021
    The main reason for this amendment to study protocol was to address the Spanish competent authority (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) request to include an independent Data Safety Monitoring Board (DSMB) as a body to make recommendations on study progress and provide periodic study safety oversight. Moreover, a typo error in the inclusion criterion number 5 has been corrected (Child-Pugh score ≤ 6).
    18 Feb 2022
    The primary purpose of this update was to refine the treatment administration and dose modifications (dose increase, reduction, interruption) and define the sampling times for the population PK analysis in the Phase II portion of the study, based on data collected during the Phase I portion, and update the schedule of events. The protocol amendment also includes updates on background information, compound shelf-life and concomitant medications and minor changes on eligibility criteria. Besides, some typos and inaccuracies were corrected and to clarity and readability were enhanced.
    30 Jun 2022
    The primary purpose of this protocol amendment was to update the study endpoints for Phase II part of the study, in line with single arm studies, expectations and study design and futility analysis were aligned accordingly; to update inclusion criterion 4 to be in line with the Standard of Care proposed by both National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines; to request collection of cfDNA samples to correlate with clinical outcome; to introduce additional assessments of tumor responses with mRECIST criteria, as by European Association for the Study of the Liver (EASL), ESMO and American Association for the Study of Liver Diseases (AASLD) guidelines, with the possibility to perform a retrospective centralized analysis on tumors’ assessment performed both with RECIST1.1 and mRECIST criteria. The protocol amendment also introduces and modifies exploratory analysis to match with the new assessments introduced, and requests retention of digital data of all radiological scans performed to evaluate tumoral burden. Amendment #3 clarifies possibility of enrollment for patients with controlled chronic HIV infection and modifies requirement for assessing presence of esophageal varices as by guidelines. Besides, few inconsistencies were corrected and other minor specifications and changes were added. Administrative changes were also applied.
    09 Jan 2023
    The main reason for this amendment to study protocol was to address the US competent authority (FDA) comments. Few DLT definitions were updated, the justification of the RP2D was added, intra-patient dose escalation was removed, dose modification rules were updated, stopping criteria for unacceptable toxicity were added, ECG monitoring added in cycle 1 and contraception period following the discontinuation of the study drug was extended for female patients.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Jul 2024
    In the Phase II part of the study, among the patients evaluable for efficacy, no objective response (PR or CR) was observed at the first futility analysis. Therefore, this study was terminated for clinical futility, according to the protocol rules. In the protocol it was considered that if less than one response (i.e., patients who achieved CR or PR) as best overall response, was observed among the first 10 evaluable patients, the study should be terminated. In the Phase II part of the study, three of the patients evaluable for efficacy experienced SD, with one patient experiencing SD lasting for more than six months. In addition, three patients that were excluded from the evaluable population, also experienced SD as best overall response and two of these were lasting for more than six months. Also, two patients (one evaluable and one non-evaluable for efficacy) continued treatment on nominal use, outside the study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In the Phase II part of the study, among the patients evaluable for efficacy, no objective response (PR or CR) was observed at the first futility analysis. Therefore, this study was terminated for clinical futility, according to the protocol rules.
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    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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