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    Clinical Trial Results:
    A phase Ib study of metronomic Cyclophosphamide and Methotrexate combined with Zoledronic acid and Sirolimus in patients with solid tumor with bone metastasis and advanced pretreated Osteosarcoma.

    Summary
    EudraCT number
    		 2014-000196-85
    Trial protocol
    		 FR  
    Global end of trial date
    16 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IB_2014-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut Bergonié
    Sponsor organisation address
    229 cours de l'Argonne, Bordeaux, France, 33076
    Public contact
    Regulatory Affairs Management Desk, Institut Bergonié, drci@bordeaux.unicancer.fr
    Scientific contact
    Regulatory Affairs Management Desk, Institut Bergonié, drci@bordeaux.unicancer.fr
    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
    08 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the recommended phase II dose, the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the Dose Limiting Toxicities (DLT) of sirolimus when prescribed in combination with Metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) in patients with solid tumor with bone metastasis and advanced pretreated osteosarcoma.
    Protection of trial subjects
    The study was supervised and monitored by a Steering Committee. This committee ensured the following: - Implementation and regular follow-up of the study - Patient protection, - That the trial is conducted ethically, in accordance with the protocol, - That the trial benefit/risk ratio is evaluated and the scientific results are checked during or at the end of the trial. An independent Data Monitoring Committee (IDMC) was created at the request of the relevant Authority, the sponsor or the Steering Committee. The IDMC plays an advisory role for the Sponsor, who has the final decision regarding the implementation of recommendations put forward by the IDMC. This Committee must comprise at least one qualified oncologist, one pharmacologist and one statistican. The IDMC is responsible for the following: - Analyzing preliminary efficacy and safety data, - Making recommendations on the continuation, early discontinuation (in the case of toxicity or lack of efficacy) or publication of the trial results, - Drafting the minutes after each meeting and monitoring their confidentiality.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    1
    Adults (18-64 years)
    15
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Upon signature of consent, eligible patient were entered in the study centrally at the Institut Bergonié Coordinating Center by the Study Coordinator.

    Pre-assignment
    Screening details
    		 Upon signature of consent, the Coordinator will assign a patient screening number. Upon results of pathological review will be available, the CRA at Institut Bergonie should inform site by e-mail and return results by fax.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 4 mg Sirolimus
    Arm description
    		 -
    Arm type
    		 First dose level

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 50mg b.i.d. - In the morning and evening - One week on / one week off

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 2.5mg b.i.d. - In the morning and evening - On day 1 and day 4, every week

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle length=28 days Administration on day 2 of each cycle

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length= 28 days - 4 mg once a day - In the morning

    Arm title
    		 6mg Sirolimus
    Arm description
    		 -
    Arm type
    		 Second dose level

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 50mg b.i.d. - In the morning and evening - One week on / one week off

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 2.5mg b.i.d. - In the morning and evening - On day 1 and day 4, every week

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle length=28 days Administration on day 2 of each cycle

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length= 28 days - 6 mg once a day - In the morning

    Arm title
    		 Expansion cohort
    Arm description
    		 -
    Arm type
    		 single-arm

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 50mg b.i.d. - In the morning and evening - One week on / one week off

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length=28 days - Twice a day 2.5mg b.i.d. - In the morning and evening - On day 1 and day 4, every week

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle length=28 days Administration on day 2 of each cycle

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cycle Length= 28 days - 4 mg once a day - In the morning

    Number of subjects in period 1
    		4 mg Sirolimus 6mg Sirolimus Expansion cohort
    Started
    6
    3
    14
    Completed
    6
    3
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All study
    Reporting group description
    		 -

    Reporting group values
    		 All study Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 40.8 (26 to 79.5) -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    4 mg Sirolimus
    Reporting group description
    		 -

    Reporting group title
    6mg Sirolimus
    Reporting group description
    		 -

    Reporting group title
    Expansion cohort
    Reporting group description
    		 -

    Primary: Dose limiting toxicity (DLT)

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    End point title
    		 Dose limiting toxicity (DLT) [1] [2]
    End point description
    Adverse event (AE) or laboratory abnormality that fulfills the criteria below: - Is considered to be at least possibly related to the study treatment - Is unrelated to disease, disease progression, inter-current illness, or concomitant medications - Meets one of the criteria below, graded as outlined or according to NCI CTCAEv4.3: o Grade 4 non-haematological toxicity (not laboratory) or lymphopenia o Grade 3 non-haematological toxicity > 3 days (not laboratory) (except for asthenia, 1rst episode of nausea/vomiting without maximal symptomatic/prophylactic treatment) o Grade ≥ 3 non-hematologic laboratory value if medical intervention is required to treat the patient, or the abnormality leads to hospitalization, or the abnormality persists for > 1 week o Grade ≥ 3 hematologic toxicity > 3 days o Confirmed febrile neutropenia - In addition treatment temporary interruption or dose modification leading to dose intensity lower than 70% ere considered as DLT 3+3 design.
    End point type
    Primary
    End point timeframe
    First cycle 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: DLT were assessed in the escalation part according to the traditional 3+3 design. No statistical analysis planned.
    [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: DLT was primary endpoint only for dose escalation part.
    End point values
    		 4 mg Sirolimus 6mg Sirolimus
    Number of subjects analysed
    6
    3
    Units: patients with at least one DLT
    0
    2
    No statistical analyses for this end point

    Primary: 6-month non-progression

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    End point title
    		 6-month non-progression [3] [4]
    End point description
    6-month non-progression rate, defined as the rate of complete (CR) or partial response (PR) or stable disease (SD) at 6 months using RECIST v1.1. As per RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions. The expansion cohort is designed to enable to detect antitumor activity observed with sirolimus combined with CP, MT and ZA. - Sample size is calculated based on the first stage of a 2-stage Gehan design assuming a 20% efficacy rate, 5% false positive rate and 10% precision (Gehan 1961). - 14 eligible and assessable subjects are required. - If at least one objective response or stable disease (> 24 weeks) is observed in the 14 patients recruited in the expansion cohort, the study drug association will be considered worthy of further testing in this indication.
    End point type
    Primary
    End point timeframe
    Tumor assessment at 6 months using RECIST v1.1.
    Notes
    [3] - 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: Primary endpoint in the expansion cohort was based on the first stage of a 2-stage Gehan design assuming a 20% efficacy rate, 5% false positive rate and 10% precision (Gehan 1961). No statistical analysis planned.
    [4] - 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: 6-month non progression was primary endpoint only for expansion cohort.
    End point values
    		 Expansion cohort
    Number of subjects analysed
    14
    Units: patients with CR or PR or SD
    2
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    OS is defined as the time from first infusion to death (of any cause)
    End point values
    		 4 mg Sirolimus 6mg Sirolimus Expansion cohort
    Number of subjects analysed
    6
    3
    14
    Units: Months
        median (confidence interval 95%)
    12 (5.2 to 9999999)
    6.6 (5.2 to 8.7)
    12.8 (2.8 to 21.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety profile was continuously followed during treatment up to 30 days after the last treatment administration or until the start of a new antitumor therapy, whichever occurs first. All AEs will be classified according to the NCI-CTCAE, version 4.0.
    Adverse event reporting additional description
    Adverse event (AE) are reported for all patients who received at least one administration of treatment. All AE and SAE (related and unrelated to treatment) are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.3
    Reporting groups
    Reporting group title
    Dose escalation part – Sirolimus dose 4 mg
    Reporting group description
    		 -

    Reporting group title
    Dose escalation part – Sirolimus dose 6 mg
    Reporting group description
    		 -

    Reporting group title
    Expansion cohort
    Reporting group description
    		 -

    Serious adverse events
    		 Dose escalation part – Sirolimus dose 4 mg Dose escalation part – Sirolimus dose 6 mg Expansion cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 3 (66.67%)
    9 / 14 (64.29%)
         number of deaths (all causes)
    5
    3
    12
         number of deaths resulting from adverse events
    0
    0
    2
    Investigations
    Gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphopenia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 23
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 24
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Septic shock
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
    Additional description: Occurrences causally related to treatment number included relation to the treatment according to investigator and/or sponsor.
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         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 escalation part – Sirolimus dose 4 mg Dose escalation part – Sirolimus dose 6 mg Expansion cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    14 / 14 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    subcutaneous nodule
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    tumor pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 3 (100.00%)
    6 / 14 (42.86%)
         occurrences all number
    3
    3
    6
    Fever
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    4 / 14 (28.57%)
         occurrences all number
    1
    0
    4
    Flu like symptoms
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    WORSENING OF GENERAL STATUS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    INFLAMMATORY SYNDROM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    HOT FLUSHES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    POLYDYPSIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Vaginal ulceration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    3
    0
    3
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    0
    3
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    hoarseness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Sinus disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    5 / 14 (35.71%)
         occurrences all number
    2
    1
    5
    Alkalosis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    3 / 14 (21.43%)
         occurrences all number
    1
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 3 (66.67%)
    4 / 14 (28.57%)
         occurrences all number
    3
    2
    4
    Blood bilirubin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Creatine urine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    cholesterol high
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
         occurrences all number
    1
    1
    2
    LDH increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    CRP increase
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Lymphocyte count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    6 / 14 (42.86%)
         occurrences all number
    2
    1
    6
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 3 (100.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    3
    2
    Platelet count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 3 (100.00%)
    7 / 14 (50.00%)
         occurrences all number
    2
    3
    8
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    dysesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    1
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    paresthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    4 / 14 (28.57%)
         occurrences all number
    1
    2
    6
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Cheilitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    5 / 14 (35.71%)
         occurrences all number
    2
    0
    5
    Dry mouth
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Mucositis management
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 3 (66.67%)
    6 / 14 (42.86%)
         occurrences all number
    5
    2
    8
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    5 / 14 (35.71%)
         occurrences all number
    2
    1
    5
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    1
    0
    4
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    nail loss
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    ESCHAR OF THE SACRUM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin hypopigmentation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    skin ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nocturia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    urinary disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Polyuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    2
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    bronchial infection
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    1
    gum infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nail infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    1 / 14 (7.14%)
         occurrences all number
    2
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    hypocalcemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
         occurrences all number
    0
    1
    2
    hypoglycemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    2
    Iron deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? 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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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