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    Clinical Trial Results:
    Phase Ib-II study of Ramucirumab combined with standard Nab-paclitaxel and Gemcitabine as first-line treatment in patients with advanced pancreatic adenocarcinoma.

    Summary
    EudraCT number
    		 2017-004792-30
    Trial protocol
    		 GR  
    Global end of trial date
    23 Apr 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HE316
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hellenic Cooperative Oncology Group
    Sponsor organisation address
    41 Mesogeion Avenue, Athens, Greece, 115 26
    Public contact
    Clinical Trials, Hellenic Cooperative Oncology Group (HeCOG), 0030 2106912520, hecogoff@otenet.gr
    Scientific contact
    Clinical Trials, Hellenic Cooperative Oncology Group (HeCOG), 0030 2106912520, hecogoff@otenet.gr
    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
    18 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Phase Ib: The safety of the combination of Nab-paclitaxel - Gemcitabine with Ramucirumab in 4-weekly cycles by determining the Recommended Dose (RD) during the first two cycles of therapy (8 weeks). - Phase II: Efficacy by determination of the objective response rate (ORR) by RECIST criteria of the combination of Ramucirumab with Nab-paclitaxel and Gemcitabine administered in 4-weekly cycles.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. A copy of the IEC/IRB approval was received by the sponsor before recruitment of subjects into the study and all subjects provided written informed consent before undergoing any study-related procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jan 2019
    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
    Greece: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    19
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in the study from 29 January 2019 until 18 October 2021 from 11 sites in Greece.

    Pre-assignment
    Screening details
    		 Patients signed the informed consent form and were screened for eligibility before entering the study.

    Period 1
    Period 1 title
    overall trial (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 Ib
    Arm description
    		 The first 12 patients entered the phase Ib study in 2 cohorts of 6 patients each. In the first cohort, six patients started Ramucirumab followed by Nab-paclitaxel and Gemcitabine every 4 weeks for 2 cycles at the specific initial dose level. Modification of the initial dose depended on the frequency of dose limiting toxicities (DLT) and followed specific rules. When the dose was determined in the first cohort, then the second cohort was enrolled to test the safety of this dose. The Phase II Recommended dose (RD) for the phase II part of the study was determined when all 6+6 patients completed a maximum of 2 cycles. In the screening period, 1 patient had a SAE once ICF was signed and was monitored for safety reasons. Patient did not receive any intervention and was set off study protocol. During phase Ib 2 patients were found ineligible they had received at least 1 cycle of therapy and had to be replaced since the Recommended Dose had to be determined in 12 eligible patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose Level 0 Ramucirumab 8mg/kg Dose Level -1 Ramucirumab 8mg/kg

    Arm title
    		 Phase II
    Arm description
    		 In the phase II part of the trial, new patients were recruited and started the study treatment according to the RD determined at the second cohort of the phase Ib part. Phase Ib patients entered the phase II part by continuing the treatment beyond the second cycle at the RD level. The first cohort of the phase Ib part entered the phase II part by continuing the treatment beyond the second cycle at the dose level determined at this cohort. Dose reductions in the phase II study followed the standards according to the drugs’ Summary of Product Characteristics (SPCs). One patient was not included in the analysis due to consent withdrawal prior to receiving any treatment and no SAE was reported.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ramucirumab 10mg/kg was the recomended dose for the Phase II study.

    Number of subjects in period 1
    		Phase Ib Phase II
    Started
    15
    39
    Completed
    11
    9
    Not completed
    4
    30
         Adverse event, serious fatal
    1
    4
         Consent withdrawn by subject
    -
    2
         Physician decision
    -
    1
         Disease progression
    1
    13
         Adverse event, non-fatal
    -
    5
         Death
    -
    2
         Protocol deviation
    2
    -
         Off treatment more than 2 weeks
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase Ib
    Reporting group description
    		 The first 12 patients entered the phase Ib study in 2 cohorts of 6 patients each. In the first cohort, six patients started Ramucirumab followed by Nab-paclitaxel and Gemcitabine every 4 weeks for 2 cycles at the specific initial dose level. Modification of the initial dose depended on the frequency of dose limiting toxicities (DLT) and followed specific rules. When the dose was determined in the first cohort, then the second cohort was enrolled to test the safety of this dose. The Phase II Recommended dose (RD) for the phase II part of the study was determined when all 6+6 patients completed a maximum of 2 cycles. In the screening period, 1 patient had a SAE once ICF was signed and was monitored for safety reasons. Patient did not receive any intervention and was set off study protocol. During phase Ib 2 patients were found ineligible they had received at least 1 cycle of therapy and had to be replaced since the Recommended Dose had to be determined in 12 eligible patients.

    Reporting group title
    Phase II
    Reporting group description
    		 In the phase II part of the trial, new patients were recruited and started the study treatment according to the RD determined at the second cohort of the phase Ib part. Phase Ib patients entered the phase II part by continuing the treatment beyond the second cycle at the RD level. The first cohort of the phase Ib part entered the phase II part by continuing the treatment beyond the second cycle at the dose level determined at this cohort. Dose reductions in the phase II study followed the standards according to the drugs’ Summary of Product Characteristics (SPCs). One patient was not included in the analysis due to consent withdrawal prior to receiving any treatment and no SAE was reported.

    Reporting group values
    		 Phase Ib Phase II Total
    Number of subjects
    		 15 39 54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 11 19
        From 65-84 years
    		 7 28 35
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.4 (44.8 to 80) 69.5 (40.4 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 8 18 26
        Male
    		 7 21 28

    End points

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    End points reporting groups
    Reporting group title
    Phase Ib
    Reporting group description
    		 The first 12 patients entered the phase Ib study in 2 cohorts of 6 patients each. In the first cohort, six patients started Ramucirumab followed by Nab-paclitaxel and Gemcitabine every 4 weeks for 2 cycles at the specific initial dose level. Modification of the initial dose depended on the frequency of dose limiting toxicities (DLT) and followed specific rules. When the dose was determined in the first cohort, then the second cohort was enrolled to test the safety of this dose. The Phase II Recommended dose (RD) for the phase II part of the study was determined when all 6+6 patients completed a maximum of 2 cycles. In the screening period, 1 patient had a SAE once ICF was signed and was monitored for safety reasons. Patient did not receive any intervention and was set off study protocol. During phase Ib 2 patients were found ineligible they had received at least 1 cycle of therapy and had to be replaced since the Recommended Dose had to be determined in 12 eligible patients.

    Reporting group title
    Phase II
    Reporting group description
    		 In the phase II part of the trial, new patients were recruited and started the study treatment according to the RD determined at the second cohort of the phase Ib part. Phase Ib patients entered the phase II part by continuing the treatment beyond the second cycle at the RD level. The first cohort of the phase Ib part entered the phase II part by continuing the treatment beyond the second cycle at the dose level determined at this cohort. Dose reductions in the phase II study followed the standards according to the drugs’ Summary of Product Characteristics (SPCs). One patient was not included in the analysis due to consent withdrawal prior to receiving any treatment and no SAE was reported.

    Primary: Safety of the combination of Ramucirumab with Nab-paclitaxel and Gemcitabine

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    End point title
    		 Safety of the combination of Ramucirumab with Nab-paclitaxel and Gemcitabine [1] [2]
    End point description
    One-to-two cohorts of 6 patients each will receive two cycles of the regimen at active dose levels. The final dose will be determined according to a specific algorithm described in the protocol.
    End point type
    Primary
    End point timeframe
    From study initiation until the determination of the Recommended Dose (RD) during the first two cycles of therapy (8 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: The determination of the maximum tolerated dose of Ramucirumab with Nab-paclitaxel and Gemcitabine was the primary endpoint of the Phase Ib part of the study. Gemcitabine doses per dose level are described for patients enrolled in the Phase Ib part of the study.
    [2] - 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: Since this was a single arm Phase Ib/II trial and all patients were treated with Ramucirumab,Nab-paclitaxel and Gemcitabine, no comparisons between different treatment arms were performed. The number of patients evaluable for DLT per dose level is described for patients enrolled in the Phase Ib part of the study.
    End point values
    		 Phase Ib
    Number of subjects analysed
    15 [3]
    Units: Number of patients evaluable for DLT
        Dose Level 0 Gemcitabine 1000 mg/m2
    6
        Dose Level -1 Gemcitabine 800 mg/m2
    6
    Notes
    [3] - One patient did not start treatment and two were found ineligible.
    No statistical analyses for this end point

    Primary: Overall Response rate (ORR)

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    End point title
    		 Overall Response rate (ORR) [4] [5]
    End point description
    ORR is defined as the proportion of patients with confirmed Complete Response (CR) or confirmed Partial Response (PR) as best overall response to treatment, based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 guidelines .
    End point type
    Primary
    End point timeframe
    CT or MRI scan performed to assess disease status at baseline and every 8 weeks from the start of study treatment for the first 8months of study treatment, then every 12 weeks, or until disease progression.
    Notes
    [4] - 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: Since this was a single arm Phase Ib/II trial and all patients were treated with Ramucirumab, Nab-paclitaxel and Gemcitabine no comparisons between different treatment arms were performed. The percentage of patients surviving 6 months since study entry has been provided for the patients included in the Phase II part of the study.
    [5] - 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: Since this was a single arm Phase Ib/II trial and all patients were treated with Ramucirumab, Nab-paclitaxel and Gemcitabine no comparisons between different treatment arms were performed. The 6-month Overall Response rate was the primary endpoint of the Phase II part of the study. The percentage of Phase II patients surviving 6 months since study entry is described.
    End point values
    		 Phase II
    Number of subjects analysed
    38 [6]
    Units: months
        median (confidence interval 95%)
    9.9 (5.4 to 15)
    Attachments
    		 Kaplan - Meier for DOR
    Notes
    [6] - 1 patient withdrew consent prior to receiving any treatment and no SAE was reported.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival is defined as the time interval from registration to the date of death due to any cause or last contact.
    End point values
    		 Phase Ib Phase II
    Number of subjects analysed
    15 [7]
    38 [8]
    Units: months
        median (confidence interval 95%)
    14 (7.3 to 18)
    14 (7.3 to 18)
    Attachments
    		 Kaplan - Meier for Overall Survival
    Notes
    [7] - OS endpoint was collectively estimated for both Phase Ib and Phase II.
    [8] - 1 patient withdrew consent prior to receiving any treatment and no SAE was reported.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    PFS is defined as the time interval from registration to the first date of documented tumor progression, death from any cause or last contact.
    End point values
    		 Phase Ib Phase II
    Number of subjects analysed
    15 [9]
    38 [10]
    Units: months
        median (confidence interval 95%)
    4 (4 to 10)
    4 (4 to 10)
    Attachments
    		 Kaplan - Meier for PFS
    Notes
    [9] - PFS endpoint was collectively estimated for both Phase Ib and Phase II.
    [10] - 1 patient withdrew consent prior to receiving any treatment and no SAE was reported.
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    Safety was recorded for the nab-paclitaxel – gemcitabine – ramucirumab treatment part as well during the maintenance therapy.
    End point type
    Secondary
    End point timeframe
    Adverse event data, vital signs and laboratory data of all patients were recorded and assessed upon signature of the inform consent until 30 days after the last administration of study treatment.
    End point values
    		 Phase Ib Phase II
    Number of subjects analysed
    15
    38 [11]
    Units: Number of patients analysed
        Any Adverse Event
    15
    37
        Fatal Adverse Events
    1
    5
        Serious Adverse Events
    10
    10
    Notes
    [11] - 1 patient withdrew consent prior to receiving any treatment and no SAE was reported.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Upon signature of the the informed consent form up to 30 days after the last administration of any investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Phase Ib
    Reporting group description
    		 The first 12 patients entered the phase Ib study in 2 cohorts of 6 patients each. In the first cohort, six patients started Ramucirumab followed by Nab-paclitaxel and Gemcitabine every 4 weeks for 2 cycles at the specific initial dose level. Modification of the initial dose depended on the frequency of dose limiting toxicities (DLT) and followed specific rules. When the dose was determined in the first cohort, then the second cohort was enrolled to test the safety of this dose. For the second cohort, the same dose modification rules according to the occurrence of DLT was followed. The Phase II Recommended dose (RD) for the phase II part of the study was determined when all 6+6 patients completed a maximum of 2 cycles.

    Reporting group title
    Phase II
    Reporting group description
    		 In the phase II part of the trial, new patients were recruited and started the study treatment according to the RD determined at the second cohort of the phase Ib part. Phase Ib patients entered the phase II part by continuing the treatment beyond the second cycle at the RD level. The first cohort of the phase Ib part entered the phase II part by continuing the treatment beyond the second cycle at the dose level determined at this cohort. Dose reductions in the phase II study followed the standards according to the drugs’ Summary of Product Characteristics (SPCs).

    Serious adverse events
    		 Phase Ib Phase II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 14 (64.29%)
    10 / 38 (26.32%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    Investigations
    Creatinine increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular disorders - Other, specify - Mesenterium thrombosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death NOS
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pancreatic fistula
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, specify - Febrile Cholangitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, specify - Liver absesses
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, specify - Cholangitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, specify - Billiary Obstruction
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations - Other, specify - Infection Pseudomonas
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, specify - Covid19
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, specify - Bacteremia -
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, specify - Perianal abscess
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders - Other, specify - Hyperbilirubinemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Phase Ib Phase II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    37 / 38 (97.37%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 14 (35.71%)
    17 / 38 (44.74%)
         occurrences all number
    9
    41
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 14 (21.43%)
    13 / 38 (34.21%)
         occurrences all number
    5
    26
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 14 (14.29%)
    17 / 38 (44.74%)
         occurrences all number
    5
    39
    Blood bilirubin increased
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Creatinine increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    GGT increased
         subjects affected / exposed
    2 / 14 (14.29%)
    13 / 38 (34.21%)
         occurrences all number
    3
    16
    Weight loss
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    White blood cell decreased
         subjects affected / exposed
    2 / 14 (14.29%)
    15 / 38 (39.47%)
         occurrences all number
    5
    42
    Platelet count decreased
         subjects affected / exposed
    4 / 14 (28.57%)
    22 / 38 (57.89%)
         occurrences all number
    9
    93
    Neutrophil count decreased
         subjects affected / exposed
    5 / 14 (35.71%)
    19 / 38 (50.00%)
         occurrences all number
    9
    53
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    INR increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Investigations - Other, specify - LDH increased
         subjects affected / exposed
    0 / 14 (0.00%)
    5 / 38 (13.16%)
         occurrences all number
    0
    15
    Investigations - Other, specify - Platelet count increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 38 (15.79%)
         occurrences all number
    1
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders - Other, specify - Sensory neurotoxicity
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Nervous system disorders - Other, specify -Neuropathic pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Nervous system disorders - Other, specify -Numbness
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    5 / 14 (35.71%)
    22 / 38 (57.89%)
         occurrences all number
    8
    37
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    0 / 14 (0.00%)
    5 / 38 (13.16%)
         occurrences all number
    0
    5
    Fatigue
         subjects affected / exposed
    5 / 14 (35.71%)
    13 / 38 (34.21%)
         occurrences all number
    5
    17
    Fever
         subjects affected / exposed
    5 / 14 (35.71%)
    5 / 38 (13.16%)
         occurrences all number
    11
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    3
    Diarrhea
         subjects affected / exposed
    1 / 14 (7.14%)
    10 / 38 (26.32%)
         occurrences all number
    1
    21
    Ileus
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 38 (13.16%)
         occurrences all number
    2
    8
    Gastrointestinal disorders - Other, specify - Dental extraction
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    2
    Gastrointestinal disorders - Other, specify - Dental abscess
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Gastrointestinal disorders - Other, specify - Hemorrhagic diarrhea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 14 (0.00%)
    8 / 38 (21.05%)
         occurrences all number
    0
    14
    Pneumothorax
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 38 (13.16%)
         occurrences all number
    1
    5
    Rash acneiform
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Proteinuria
         subjects affected / exposed
    0 / 14 (0.00%)
    6 / 38 (15.79%)
         occurrences all number
    0
    10
    Renal and urinary disorders - Other, specify - Microalbuminuria
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Joint effusion
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, specify - Covid19
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Infections and infestations - Other, specify - Furuncle
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 14 (0.00%)
    5 / 38 (13.16%)
         occurrences all number
    0
    7
    Hypercalcaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Hyperglycemia
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 38 (13.16%)
         occurrences all number
    7
    10
    Hyperkalemia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Hypernatremia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    5
    Hyperuricemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Hypoalbuminemia
         subjects affected / exposed
    2 / 14 (14.29%)
    14 / 38 (36.84%)
         occurrences all number
    2
    23
    Hypocalcemia
         subjects affected / exposed
    2 / 14 (14.29%)
    10 / 38 (26.32%)
         occurrences all number
    2
    11
    Hypoglycemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    5
    Hyponatremia
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    4
    Hypophosphatemia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2020
    - Change of Coordinating Principal Investigator - Addition of Statistician and Safety Coordinator - Update of communication information

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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