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    Clinical Trial Results:
    Trial SAKK 56/07 Dasatinib first-line treatment in gastrointestinal stromal tumors. A multicenter phase II trial.

    Summary
    EudraCT number
    		 2007-002047-24
    Trial protocol
    		 FR   DE  
    Global end of trial date
    16 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2022
    First version publication date
    28 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK56/07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00568750
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    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
    01 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Efficacy of dasatinib treatment as assessed by fusion PET/CT-scan
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 none
    Evidence for comparator
    		 not applicable. This was a single arm study.
    Actual start date of recruitment
    17 Jan 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    45
    EEA total number of subjects
    27
    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)
    26
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 47 of planned 52 patients at ten sites in France (3 sites, 21 patients), Germany (1 site, 1 patient), Poland (1 site, 7 patients) and Switzerland (8 sites, 18 patients) have been enrolled from January 2008 to November 2011.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Pre-assignment period milestones
    Number of subjects started
    		 47 [1]
    Number of subjects completed
    		 45

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No baseline CT (violation eligibility criteria): 1
    Reason: Number of subjects
    		 PET negative (violation eligibility criteria): 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In total, 47 patients were screened for eligibility. Of these patients, five were deemed ineligible. However, for three of these patients failure of eligibility was noticed as late as after receipt of first study treatment. Thus, these three patients were included in the safety analysis set but rejected from the efficacy analysis set.
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dasatinib treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Sprycel®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    70 mg twice daily

    Number of subjects in period 1
    		Dasatinib treatment
    Started
    45
    Completed
    45
    Period 2
    Period 2 title
    Treatment/FU Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dasatinib treatment
    Arm description
    		 Dasatinib 70 mg BID per os for two years (26 cycles) or until progression or unacceptable toxicity. Elective surgery was allowed after at least six completed cycles in responding and stabilized patients. At time of progression, the patient was transferred to the follow-up phase and was proposed the standard treatment for GIST (i.e. imatinib 400 mg /day per os). Patients were followed up for up to five years after study treatment discontinuation or completing study treatment, respectively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Sprycel®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    70 mg twice daily

    Number of subjects in period 2
    		Dasatinib treatment
    Started
    45
    Completed
    5
    Not completed
    40
         Physician decision
    3
         Death
    2
         Degradation of clinical status
    1
         Disease progression (confirmed by PET)
    14
         Late screening failure (PET negative)
    1
         Unacceptable toxicity
    7
         Surgery
    8
         Late screening failure (No GIST)
    2
         Progressive disease by CT
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dasatinib treatment
    Reporting group description
    		 -

    Reporting group values
    		 Dasatinib treatment Total
    Number of subjects
    		 45 45
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 26 26
        From 65-84 years
    		 19 19
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    Dasatinib treatment
    Reporting group description
    		 -
    Reporting group title
    Dasatinib treatment
    Reporting group description
    		 Dasatinib 70 mg BID per os for two years (26 cycles) or until progression or unacceptable toxicity. Elective surgery was allowed after at least six completed cycles in responding and stabilized patients. At time of progression, the patient was transferred to the follow-up phase and was proposed the standard treatment for GIST (i.e. imatinib 400 mg /day per os). Patients were followed up for up to five years after study treatment discontinuation or completing study treatment, respectively.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Analysis set including all eligible patients receiving at least one dose of the study drug.

    Subject analysis set title
    KIT - Exon 11
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mutational status of KIT = Exon 11.

    Subject analysis set title
    KIT - WT
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mutational status of KIT = Wildtype.

    Subject analysis set title
    KIT - NA / Exon 9
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mutational status of KIT = Exon 9 or N/A.

    Primary: Primary Endpoint | PET response at 4 weeks

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    End point title
    		 Primary Endpoint | PET response at 4 weeks [1]
    End point description
    Efficacy of dasatinib treatment as assessed by fusion PET/CT-scan. EORTC PET Study Group criteria were assessed by a central review board. [mCR: metabolic complete response, mPR: metabolic partial response, mSD: metabolic stable disease, mPD: metabolic progressive disease). Response defined as mCR+ mPR. Response rate presented with the corresponding 95% Clopper Pearson confidence interval. [mCR: 33%, mPR: 40%, mSD: 14%, mPD: 7%; n/a: 5%]
    End point type
    Primary
    End point timeframe
    4 weeks
    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: This was a single arm study. No comparative statistical analyses were performed. However, with an exact two stage binomial test with N1=17, R1=9 and N= 42 a decision limit R=26 was calculated to decide if treatment was promising.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Response rate (%)
        number (confidence interval 95%)
    74 (58 to 86)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Best response according to RECIST as measured on CT scan/MRI

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    End point title
    		 Secondary Endpoint | Best response according to RECIST as measured on CT scan/MRI
    End point description
    Best response according to RECIST. Best response defined as CR+ PR. Response rate presented with the corresponding 95% Clopper Pearson confidence interval. [CR: 5%, PR: 38%, SD: 31%, PD: 19%; n/a: 7%]
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Best response (%)
        number (confidence interval 95%)
    43 (28 to 59)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Clinical benefit

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    End point title
    		 Secondary Endpoint | Clinical benefit
    End point description
    Clinical benefit was defined as CR, PR, or as SD lasting at least 12 weeks, determined according to RECIST. PET evaluation was not used for clinical benefit analysis as no comparative data exist. Rate presented with the corresponding 95% Clopper Pearson confidence interval. [CR:2 patients, PR: 16 patients, SD: 9 patients]
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Patients with clinical benefit (%)
        number (confidence interval 95%)
    64 (48 to 78)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Best response as measured by fusion PET/CT

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    End point title
    		 Secondary Endpoint | Best response as measured by fusion PET/CT
    End point description
    The best response (mCR+mPR) rate as measur measured by fusion PET/CT scan. The centralized review board had to confirm the mCR. [mCR/mPR: 76%, mSD: 12%, mPD: 7%; n/a: 5%]
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Best response (%)
        number (confidence interval 95%)
    76 (61 to 88)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Response Duration

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    End point title
    		 Secondary Endpoint | Response Duration
    End point description
    Response duration for 32 patients with mPR/mCR.
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    32 [2]
    Units: Response duration (months)
        median (confidence interval 95%)
    13.2 (10.2 to 17.5)
    Notes
    [2] - 32 patients with mPR/mCR
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Time to progression

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    End point title
    		 Secondary Endpoint | Time to progression
    End point description
    Time to progression was calculated from registration until progression or death due to tumor. Kaplan Meier analysis. At the time of the analysis 22 patients had experienced disease progression. A mong the others one patient died due to GIST. There were 23 events for the time to progression analysis.
    End point type
    Secondary
    End point timeframe
    From registration until progression or death due to tumor.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Time to progression (months)
        median (confidence interval 95%)
    14.1 (9.4 to 35.3)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Progression free survival (PFS)

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    End point title
    		 Secondary Endpoint | Progression free survival (PFS)
    End point description
    Time to progression was calculated from registration until progression or death. Kaplan-Meier Analysis. At the time of the analysis 22 patients had experienced disease progression. A mong the others one patient died due to GIST. There were 24 events for the progression free survival analysis.
    End point type
    Secondary
    End point timeframe
    From registration until progression or death.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: PFS (months)
        median (confidence interval 95%)
    14.1 (9.4 to 35.5)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Time to treatment failure

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    End point title
    		 Secondary Endpoint | Time to treatment failure
    End point description
    Time to treatment failure will be calculated from registration until premature trial treatment termination due to any reason. After treatment completion, it is defined as time to progression, time to death if no progression, or change of anti-tumor treatment in absence of progression. Kaplan-Meier Analysis. At the time of the analysis 41 patients had treatment failure: 37 patients stopped before 26 cycles, and four patients completed 26 cycles and had disease progression later on. One patient completed 26 cycles and had no progression so far.
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Time to treatment failure (months)
        median (confidence interval 95%)
    8.5 (5.3 to 11.1)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Overall survival

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    End point title
    		 Secondary Endpoint | Overall survival
    End point description
    Overall survival will be calculated from registration until death or last follow-up, up to 5 years. Kaplan-Meier Analysis. Seventeen patients had died at the time of the analysis. Two deaths occurred during treatment. Fifteen deaths occurred in the follow up phase. The median follow up time based on the reverse Kaplan Meier method was 6.2 years the range in surviving patients 3.4 to 7.6 years. NOTE: UPPER LIMIT OF 95% CI NOT REACHED. DUMMY DATA ("999") ENTERED DUE TO DATABASE RESTRICTIONS.
    End point type
    Secondary
    End point timeframe
    From registration until death or last follow-up, up to 5 years.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    42
    Units: Overall Survival (months)
        median (confidence interval 95%)
    6.5 (5.6 to 999)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Best response of 2nd-line treatment with another TK-inhibitor

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    End point title
    		 Secondary Endpoint | Best response of 2nd-line treatment with another TK-inhibitor
    End point description
    37 patients had started a 2nd-line treatment but 15 of them had elective surgery or started 2nd-line treatment before progression under 1st-line treatment. Thus for the analysis of 2nd-line treatment 22 patients were remaining. Best response according to RECIST.
    End point type
    Secondary
    End point timeframe
    From second-line treatment with another TK-inhibitor until end of study.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    22 [3]
    Units: Number of patients
        CR
    2
        PR
    9
        SD
    8
        PD
    3
    Notes
    [3] - See description for endpoint.
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Time to progression (TTP) of 2nd-line treatment with another TK-inhibitor

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    End point title
    		 Secondary Endpoint | Time to progression (TTP) of 2nd-line treatment with another TK-inhibitor
    End point description
    Time to progression (TTP) of 2nd-line treatment with another TK-inhibitor. 37 patients had started a 2nd-line treatment but 15 of them had elective surgery or started 2nd-line treatment before progression under 1st-line treatment. 17 of the 22 patients had a progression under 2nd-line treatment. Note: This TTP analysis is descriptive only and for the moment non informative as some of these patient had been disease free after surgery.
    End point type
    Secondary
    End point timeframe
    From start of 2nd-line treatment until progression or death.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    22 [4]
    Units: TTP (months)
        median (confidence interval 95%)
    13.6 (5.7 to 21.7)
    Notes
    [4] - See endpoint desciption.
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | PET response by mutational status of KIT

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    End point title
    		 Secondary Endpoint | PET response by mutational status of KIT
    End point description
    PET response at 4 weeks by mutational status of KIT. The mutational status of the most common KIT mutations (exons 9, 11, 13 and 17 of KIT) was assessed using standard PCR techniques and/or DHPLC. Mutational status of PDGFR was not available.
    End point type
    Secondary
    End point timeframe
    At 4 weeks
    End point values
    		 KIT - Exon 11 KIT - WT KIT - NA / Exon 9
    Number of subjects analysed
    20
    7
    15
    Units: Number of patients
        mCR
    6
    3
    5
        mPR
    10
    1
    6
        mSD
    2
    2
    2
        mPD
    0
    1
    2
        N/A
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Time to progression (KIT Exon 11)

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    End point title
    		 Secondary Endpoint | Time to progression (KIT Exon 11)
    End point description
    Time to progression (TTP) was calculated from registration until progression or death due to tumor. Kaplan Meier analysis of TTP for subgroup of patients with KIT = Exon 11.
    End point type
    Secondary
    End point timeframe
    From registration until progression or death due to tumor.
    End point values
    		 KIT - Exon 11
    Number of subjects analysed
    20
    Units: Time to progression (months)
        median (confidence interval 95%)
    17.3 (11.1 to 26.7)
    No statistical analyses for this end point

    Secondary: Secondary Endpoint | Time to progression (KIT WT)

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    End point title
    		 Secondary Endpoint | Time to progression (KIT WT)
    End point description
    Time to progression (TTP) was calculated from registration until progression or death due to tumor. Kaplan Meier analysis of TTP for subgroup of patients with KIT = WT.
    End point type
    Secondary
    End point timeframe
    From registration until progression or death due to tumor.
    End point values
    		 KIT - WT
    Number of subjects analysed
    7
    Units: Time to progression (months)
        median (confidence interval 95%)
    11.1 (2.4 to 56.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From registration up to 30 days after last dose of trial treatment.
    Adverse event reporting additional description
    SAEs were recorded from registration up to 30 days after last dose of trial treatment. After this period the following events were recorded: (i) fatalities and severe events possibly, probably or definitely related to late effects of therapy, (ii) disabling events, (iii) second primary cancer, (iv) congenital anomaly
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 The Safety Analysis Set (n=45) includes 42 patients of the FAS and three additional patients initiating study treatment but who were deemed screening failures later on.

    Serious adverse events
    		 Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 45 (60.00%)
         number of deaths (all causes)
    17
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Gastrointestinal anastomotic leak
    Additional description: Duodenal leak grade 1 post duodenectomy
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal anastomosis complication
    Additional description: Pleural effusion grade 3, anastomosis insufficiency, Staphylococcus infection grade 3
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Including one event: Abdominal pain NOS G3, nausea G2, vomiting G2
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
    Additional description: Including one event: Anorexia grade 1, nausea grade 2, diarrhea grade 2, repeated dark stools
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
    Additional description: Acute intratumoral hemorrhage (liver metastases), acute gastrointestinal bleeding
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Ileus
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
    Additional description: Including one event (1): Functional intestinal obstruction grade 3 with vomiting caused by stromal tumor mass (without tumor progression); and one event (2): Intestinal obstruction grade 4 due to gastrointestinal stromal tumor with stable disease
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
    Additional description: Hemorrhage grade2 of lower gastrointestinal (NOS), hemorrhage grade 1 GU (bladder), INR grade 2, PTT grade 1 due to diverticulosis, probably acquired auto-antibodies against factor II and possible vitamine K deficit
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
    Additional description: Paralytic ileus and small intestine occlusion
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
    Additional description: Decompensated digestive problems related to gastrointestinal stromal tumor, vomiting and diarrhea grade 3
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
    Additional description: Benign prostatic hyperplasia requiring surgical excision
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
    Additional description: Ovarian cyst requiring laparotomic excision
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Abdominal pain grade 3 due to cholecystitis grade 3 requiring cholecystectomy
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
    Additional description: Including one event (1): Dyspnea grade 1 in context of pleural effusion grade 3; and one event (2): Dyspnea grade 2 due to pleural effusion
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Pulmonary edema
    Additional description: Dyspnea grade 4 due to pulmonary capillary leak grade 3
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
    Additional description: Including one event (1): Pulmonary embolism grade 4, headache grade 3, dyspnea grade 2, heart failure grade 2; and one event (2): Irreversible cardiac arrest due to massive pulmonary embolism
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
    Additional description: Degenerative arthrosis grade 3 (hip) requiring total hip replacement
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
    Additional description: Diarrhea grade 3, fever grade 2 due to suspected gastroenteritis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
    Additional description: Pulmonary infection, pulmonary edema
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Nausea, vomiting, diarrhea, dehydration grade 3, fever grade 1
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
    Additional description: Hypocalcemia grade 2, diarrhea grade 1
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 45 (100.00%)
    Investigations
    Haemoglobin
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Aspartate aminotransferase
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    5
    Nervous system disorders
    Taste disorder
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Dizziness
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    8
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    21 / 45 (46.67%)
         occurrences all number
    32
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    35 / 45 (77.78%)
         occurrences all number
    59
    Pyrexia
         subjects affected / exposed
    10 / 45 (22.22%)
         occurrences all number
    10
    Chills
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    Localised oedema
    Additional description: Edema: head and neck
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    10
    Oedema peripheral
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Influenza like illness
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 45 (15.56%)
         occurrences all number
    12
    Diarrhoea
         subjects affected / exposed
    29 / 45 (64.44%)
         occurrences all number
    60
    Nausea
         subjects affected / exposed
    19 / 45 (42.22%)
         occurrences all number
    31
    Vomiting
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    16
    Abdominal pain
         subjects affected / exposed
    19 / 45 (42.22%)
         occurrences all number
    25
    Respiratory, thoracic and mediastinal disorders
    Laryngeal pain
    Additional description: Throat/pharynx/larynx pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    16
    Dyspnoea
         subjects affected / exposed
    22 / 45 (48.89%)
         occurrences all number
    37
    Pleural effusion
         subjects affected / exposed
    21 / 45 (46.67%)
         occurrences all number
    44
    Dysphonia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    6
    Alopecia
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Dry skin
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    8
    Pruritus
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    15 / 45 (33.33%)
         occurrences all number
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Arthralgia
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 45 (31.11%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This study was terminated by the sponsor due to low accrual after about 90% of patients had been enrolled.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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