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    Clinical Trial Results:
    A phase 1b/2 open-label, dose-escalating study of safety and efficacy of disulfiram, copper and vinorelbine in advanced solid tumors and advanced breast cancer

    Summary
    EudraCT number
    		 2019-001972-12
    Trial protocol
    		 DK  
    Global end of trial date
    19 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2024
    First version publication date
    24 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AA1817
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Oncology, Herlev & Gentofte Hospital
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    PI Rikke Løvendahl Eefsen, Department of Oncology, Herlev & Gentofte Hospital, +45 3868 9381, rikke.helene.loevendahl.eefsen@regionh.dk
    Scientific contact
    PI Rikke Løvendahl Eefsen, Department of Oncology, Herlev & Gentofte Hospital, +45 3868 9381, rikke.helene.loevendahl.eefsen@regionh.dk
    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
    10 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jun 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b: To assess the safety and tolerability of increasing doses of disulfiram in combination with copper and vinorelbine and to determine the dose-limiting toxicities (DLTs) and/or the Recommended Phase 2 Dose (RP2D) to patients with advanced and/or refractory solid malignancies. Phase 2: To determine the efficacy of treatment with disulfiram, copper and vinorelbine in patients with advanced or metastatic HER2-negative breast cancer by assessing the clinical benefit rate (CBR=CR+PR+SD≥18 weeks) per RECIST 1.1.
    Protection of trial subjects
    Patients that signed informed consent and fulfilling eligibility criteria were included. Continued monitoring of standard safety parameters during treatment. Dose escalation i phase 1b part was with 3+3 design and sponsor/investigators review of safety data at each cohort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    5
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was open for recruitment of patients from Jan 2020 to October 2023. All patients are recruited at a single site: Copenhagen University Hospital - Herlev and Gentofte in Denmark. Phase 2 part not opened.

    Pre-assignment
    Screening details
    		 For Phase1b part, eligible patients were ≥ 18 years with advanced solid tumors with PDand/or intolerable adverse effects with established therapy, ECOG PS 0-1, adequate organ and hematologic function. Phase 2 part should have included women wiht Her2 negative breast cancer after max 2 lines of treatment for advanced disease.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose Level 1
    Arm description
    		 Disulfiram (200 mg) orally daily plus Copper 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks. Dose level 1 tested initially with 3 patients and reevaluated with 6 patients after Dose level 2 revealed DLT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Disulfiram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg daily

    Investigational medicinal product name
    Copper
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg daily

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2 day 1 and 8 every 3 weeks

    Arm title
    		 Dose Level 2
    Arm description
    		 Disulfiram 400 mg orally daily plus Cu 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Disulfiram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg daily

    Investigational medicinal product name
    Copper
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg daily

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2 day 1 and 8 every 3 weeks

    Arm title
    		 Dose Level 3
    Arm description
    		 Disulfiram 400 mg orally from day 1 to day 7. Disulfiram 200 mg from day 8 to day 14. Daily copper 2 mg orally from day 1 to day 14 in combination with disulfiram. Vinorelbine 30 mg/m2 IV day 4 and day 11. Dosing schedule will be repeated every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Disulfiram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg orally from day 1 to day 7 and 200 mg from day 8 to day 14. Dosing schedule will be repeated every 3 weeks.

    Investigational medicinal product name
    Copper
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg daily from day 1 to day 14 in combination. Dosing schedule will be repeated every 3 weeks

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine 30 mg/m2 IV day 4 and day 11. Dosing schedule will be repeated every 3 weeks

    Number of subjects in period 1
    		Dose Level 1 Dose Level 2 Dose Level 3
    Started
    9
    4
    3
    Completed
    8
    3
    3
    Not completed
    1
    1
    0
         Adverse event, non-fatal
    -
    1
    -
         Patient wish to stop treatment
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Disulfiram (200 mg) orally daily plus Copper 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks. Dose level 1 tested initially with 3 patients and reevaluated with 6 patients after Dose level 2 revealed DLT.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Disulfiram 400 mg orally daily plus Cu 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks.

    Reporting group title
    Dose Level 3
    Reporting group description
    		 Disulfiram 400 mg orally from day 1 to day 7. Disulfiram 200 mg from day 8 to day 14. Daily copper 2 mg orally from day 1 to day 14 in combination with disulfiram. Vinorelbine 30 mg/m2 IV day 4 and day 11. Dosing schedule will be repeated every 3 weeks

    Reporting group values
    		 Dose Level 1 Dose Level 2 Dose Level 3 Total
    Number of subjects
    		 9 4 3 16
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 2 0 5
        From 65-84 years
    		 6 2 3 11
    Age continuous
    Units: years
        median (full range (min-max))
    		 68 (54 to 74) 66.5 (58 to 77) 73 (69 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 5 0 1 6
        Male
    		 4 4 2 10
    ECOG Performance status
    Units: Subjects
        PS 0
    		 6 3 1 10
        PS 1
    		 3 1 2 6
    Cancer
    Units: Subjects
        Pancreatic cancer
    		 4 0 0 4
        Uveal melanoma
    		 2 0 2 4
        Cholangiocarcinoma
    		 1 0 0 1
        Prostate cancer
    		 1 3 0 4
        Colon cancer
    		 1 0 1 2
        Rectal cancer
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Disulfiram (200 mg) orally daily plus Copper 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks. Dose level 1 tested initially with 3 patients and reevaluated with 6 patients after Dose level 2 revealed DLT.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Disulfiram 400 mg orally daily plus Cu 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks.

    Reporting group title
    Dose Level 3
    Reporting group description
    		 Disulfiram 400 mg orally from day 1 to day 7. Disulfiram 200 mg from day 8 to day 14. Daily copper 2 mg orally from day 1 to day 14 in combination with disulfiram. Vinorelbine 30 mg/m2 IV day 4 and day 11. Dosing schedule will be repeated every 3 weeks

    Primary: Dose limiting toxicities

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    End point title
    		 Dose limiting toxicities [1]
    End point description
    End point type
    Primary
    End point timeframe
    From start to end of treatment
    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: Descriptive endpoint - statistical analyses N/A
    End point values
    		 Dose Level 1 Dose Level 2 Dose Level 3
    Number of subjects analysed
    9
    4
    3
    Units: subjects
        Fatigue grade 3
    1
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from start of study treatment until 28 days after last treatment
    Adverse event reporting additional description
    For non-serious AE section, only AEs with causal relationship to treatment (AR) are listed (numbers includes subjects/occurences reported as SARs as well).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Dose Level 1
    Reporting group description
    		 Disulfiram (200 mg) orally daily plus Copper 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1 and 8 every 3 weeks. Dose level 1 tested initially with 3 patients and reevaluated with 6 patients after Dose level 2 revealed DLT.

    Reporting group title
    Dose Level 2
    Reporting group description
    		 Disulfiram 400 mg orally daily plus Cu 2 mg p.o. daily in combination with vinorelbine 30 mg/m2 day 1and 8 every 3 weeks.

    Reporting group title
    Dose Level 3
    Reporting group description
    		 Disulfiram 400 mg orally from day 1 to day 7. Disulfiram 200 mg from day 8 to day 14. Daily copper 2 mg orally from day 1 to day 14 in combination with disulfiram. Vinorelbine 30 mg/m2 IV day 4 and day 11. Dosing schedule will be repeated every 3 weeks

    Serious adverse events
    		 Dose Level 1 Dose Level 2 Dose Level 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    9
    4
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose Level 1 Dose Level 2 Dose Level 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    3
    White blood cell count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    5
    Platelet count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Paresthesia
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    0
    3
    Balance disorder
    Additional description: includes verbatims impaired balance/balance difficulties, tendency to fall
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    3
    Memory impairment
    Additional description: Impaired short-term memory
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Concentration impairment
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 9 (44.44%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    0
    2
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 9 (66.67%)
    3 / 4 (75.00%)
    3 / 3 (100.00%)
         occurrences all number
    9
    5
    3
    Heavy Legs
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 9 (66.67%)
    3 / 4 (75.00%)
    2 / 3 (66.67%)
         occurrences all number
    10
    9
    2
    Nausea
         subjects affected / exposed
    4 / 9 (44.44%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    10
    3
    3
    Vomiting
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    0
    Mucositis oral
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Sore throat
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    nail changes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Fungal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2022
    Based on observations of a high incidence of fatigue and constipation among the patients in the initial dose escalation part, an amendment for optimization of the therapy was done. Dose level 3, a treatment schedule with staggered dosing of disulfiram/copper and vinorelbine as well as a drug holiday in the third week of each 3-week cycle was introduced.

    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.
    After phase 1b, trial was terminated with recommended dose found. As per risk/benefit assessment it was not feasible to continue treatment combination for metastatic breast cancer patients in a phase 2 trial. Efficacy of treatment was not assessed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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