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    Clinical Trial Results:
    A Single-Arm, Open Label Study of Aflibercept as Maintenance Therapy Following Induction with Aflibercept in Combination with XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient

    Summary
    EudraCT number
    2013-000858-22
    Trial protocol
    IT  
    Global end of trial date
    23 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Apr 2016
    First version publication date
    06 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AFLIBC06561
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01955629
    WHO universal trial number (UTN)
    U1111-1143-3015
    Other trial identifiers
    Study name: AMOR
    Sponsors
    Sponsor organisation name
    Sanofi Aventis Groupe (SAG)
    Sponsor organisation address
    54, rue La Boétie, Paris, France, 75008
    Public contact
    Trial Transparency Team, Sanofi Aventis Groupe (SAG), Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Aventis Groupe (SAG), Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Study Part 1: To determine the recommended dose for the aflibercept, oxaliplatin and capecitabine (XELOX) combination to be used in the Part 2 of the study. Study Part 2: To assess the percentage of subjects without progression of the disease at 6 months after the start of maintenance therapy with aflibercept single-agent, following the first-line induction therapy with XELOX and aflibercept combination in subjects with previously untreated metastatic colorectal cancer.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2013
    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
    Italy: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    0
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 2 sites in Italy. A total of 6 subjects were screened between 17 Dec 2013 and 24 Feb 2014, out of which 4 subjects were enrolled and treated.

    Pre-assignment
    Screening details
    Subjects enrolled in Part-1 of study to assess recommended phase 2 dose (RP2D) of combination of aflibercept with oxaliplatin and capecitabine. 3 subjects discontinued due to adverse events (AE) and 1 subject due to disease progression (DP) at dose level 1 of treatment. Part-2 of study (efficacy and safety evaluation) was not performed.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Arm description
    Aflibercept in combination with Oxaliplatin and Capecitabine, up to 6 cycles as induction therapy, followed by aflibercept as maintenance therapy up to DP or unacceptable toxicity or subject's refusal of further treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    AVE0005
    Other name
    Zaltrap
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Aflibercept 6 mg/kg IV infusion (up to 2 hours) on Day 1 every 3 weeks (q3w).

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    SR96669
    Other name
    Eloxatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin 100 mg/m^2 IV infusion for 2 hours on Day 1 q3w.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 850 mg/m^2 twice daily from Day 1 to Day 14 of each cycle of 3 weeks.

    Number of subjects in period 1
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Started
    4
    Completed
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Reporting group description
    Aflibercept in combination with Oxaliplatin and Capecitabine, up to 6 cycles as induction therapy, followed by aflibercept as maintenance therapy up to DP or unacceptable toxicity or subject's refusal of further treatment.

    Reporting group values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine) Total
    Number of subjects
    4 4
    Age categorical
    Units: Subjects
        From 65-84 years
    4 4
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Reporting group description
    Aflibercept in combination with Oxaliplatin and Capecitabine, up to 6 cycles as induction therapy, followed by aflibercept as maintenance therapy up to DP or unacceptable toxicity or subject's refusal of further treatment.

    Primary: Part 1:Number of Subjects With Dose Limiting Toxicities (DLTs)

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    End point title
    Part 1:Number of Subjects With Dose Limiting Toxicities (DLTs) [1]
    End point description
    DLTs were assessed by National Cancer Institute Common Terminology Criteria for AEs version4.03 and were any of the AEs:G4 neutropenia lasting>7 days;febrile neutropenia or neutropenic infection;G4 thrombocytopenia;G3 thrombocytopenia with bleeding requiring transfusion;G4 non-hematological treatment related event;G3 nausea/vomiting/diarrhea lasting>/=4 days despite corrective measures;G3 non-hematological toxicities:anorexia,fatigue,hypertension only if G4 or not medically controlled and G3 peripheral sensory neuropathy not improved to G<2 at retreatment;urinary protein excretion of>3.5 gram per 24hours not recovered to<2.0 gram per 24hours within 2 weeks;symptomatic arterial thromboembolic events including cerebrovascular accidents,myocardial infarction,transient ischemic attacks, new onset/worsening of pre-existing angina.Evaluable DLT population was subset of whole part-1 subjects exposed to at least 1dose of treatment (even incomplete) and with evaluable DLT assessment at cycle1.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Up to 3 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    4
    Units: Subjects
    1
    No statistical analyses for this end point

    Primary: Part 2: Number of Subjects With Progression Free Survival (PFS) at 6 Months After the Start of Maintenance Therapy

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    End point title
    Part 2: Number of Subjects With Progression Free Survival (PFS) at 6 Months After the Start of Maintenance Therapy [2]
    End point description
    It describes the number of subjects alive without progression at 6 months after the start of Aflibercept maintenance therapy. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Primary
    End point timeframe
    6 months after the start of maintenance therapy.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [3]
    Units: Subjects
    Notes
    [3] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 1: Number of Subjects With Tumor Responses (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Progressive Disease [PD])

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    End point title
    Part 1: Number of Subjects With Tumor Responses (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Progressive Disease [PD])
    End point description
    Tumor assessment was performed by Abdomino-Pelvic Computed Tomography Scan or Magnetic Resonance Imaging(MRI) and chest X-ray or chest CT-scan to assess disease status at baseline and every 9 weeks during study treatment up to DP. Target lesions evaluated using Response Evaluation Criteria In Solid Tumors(RECIST) version1.1, wherein CR=disappearance of all target lesions; PR=30% decrease in sum of longest diameter(LD) of target lesions taking as reference baseline sum LD; PD=20% increase in sum of LD of target lesions taking as reference smallest sum in study and SD=small changes not met above criteria. Evaluable Population(EP) for tumor response was subset of ITT population (all subjects who gave informed consent and successfully registered into study) with measurable disease at study entry,received at least 1 cycle of study treatment, with at least 1 post baseline tumor evaluation, except for early DP or death.
    End point type
    Secondary
    End point timeframe
    Baseline and every 9 weeks up to DP (up to 15 months).
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    4
    Units: Subjects
        CR
    0
        PR
    1
        PD
    0
        SD
    3
    No statistical analyses for this end point

    Secondary: Part 2: PFS

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    End point title
    Part 2: PFS
    End point description
    PFS was defined as the time interval from the date of registration into the study to the date of first observation of disease progression or death (due to any cause), whichever was first. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment up to the date of DP or death, whichever occurred first (up to 15 months).
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [4]
    Units: Months
        number (not applicable)
    Notes
    [4] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 2: Overall Survival (OS)

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    End point title
    Part 2: Overall Survival (OS)
    End point description
    OS was defined as the time interval from the date of registration into the study to the date of death due to any cause. In the absence of confirmation of death, survival time was to be censored at the earliest between the last date the subject was known to be alive and the end of study date. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment up to the date of death (up to 15 months).
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [5]
    Units: Months
        number (not applicable)
    Notes
    [5] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 2: Overall Rate of Resectability of Metastatic Lesions

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    End point title
    Part 2: Overall Rate of Resectability of Metastatic Lesions
    End point description
    Overall metastases resection rate was defined as the percentage of subjects reaching an R0 metastases resection, defined as the complete absence of invasive carcinoma on histological examination at the time of definitive surgery (if performed). Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    12 months after the last subject enrolled.
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [6]
    Units: Percentage of Subjects
        number (not applicable)
    Notes
    [6] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjecs With CR or PR

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    End point title
    Part 2: Number of Subjecs With CR or PR
    End point description
    Tumor assessment was performed by Abdomino-Pelvic Computed Tomography Scan or MRI and chest X-ray or chest CT-scan to assess the disease status at baseline and then every 9 weeks during study treatment up to DP. Target lesions were evaluated using RECIST version 1.1, wherein CR = disappearance of all target lesions; PR = 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    Baseline and every 9 weeks up to end of study completion (15 months).
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [7]
    Units: Subjects
    Notes
    [7] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes

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    End point title
    Part 2: Pharmacodynamic Parameters: Modulation of Circulating Analytes
    End point description
    Blood and tumor samples were to be collected to evaluate the pharmacodynamic parameters including the assessment of the modulation of circulating analytes such as cytokines and angiogenic factors. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration.
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [8]
    Units: Not applicable
    Notes
    [8] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Secondary: Part 2: Aflibercept Biomarkers Evaluation

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    End point title
    Part 2: Aflibercept Biomarkers Evaluation
    End point description
    Blood and tumor samples were to be collected to evaluate proteomic biomarkers such as factors and receptors related to angiogenesis process, inflammation, and tumor progression. Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    End point type
    Secondary
    End point timeframe
    Baseline (within 21 days before registration); Day 1/pre-dose of Cycle 1, 2 and 3 of induction phase and maintenance phase; 30 ± 3 days after the last aflibercept administration.
    End point values
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Number of subjects analysed
    0 [9]
    Units: Not applicable
    Notes
    [9] - Due to premature recruitment discontinuation, none of the planned efficacy analysis was performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from signature of the informed consent form up to 30 days after the last administration of treatment regardless of seriousness or relationship to study treatment.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (from the first study treatment administration to 30 days after the last study treatment administration).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Reporting group description
    Aflibercept in combination with Oxaliplatin and Capecitabine, up to 6 cycles as induction therapy, followed by aflibercept as maintenance therapy up to DP or unacceptable toxicity or subject's refusal of further treatment.

    Serious adverse events
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 4 (75.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Aflibercept + XELOX (Oxaliplatin and Capecitabine)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Localised oedema
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Hiccups
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Hydronephrosis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Flank pain
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
         occurrences all number
    2
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    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.
    The study enrollment was prematurely halted due to safety reasons.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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