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    Clinical Trial Results:
    A Phase II, Multicenter, Open-Label Study of YM155 Plus Rituximab in Previously Treated Patients with CD20-Positive B Cell Non-Hodgkin’s Lymphoma Who Are Ineligible for or Have Previously Received an Autologous Stem Cell Transplant

    Summary
    EudraCT number
    2009-010777-20
    Trial protocol
    FR   ES   GB  
    Global end of trial date
    23 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jun 2016
    First version publication date
    24 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    155-CL-031
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01007292
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.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
    05 Mar 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Mar 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine objective response rate (ORR) (complete remission [CR] + partial remission [PR]) per modified International Working Group (IWG) Revised Response Criteria for Malignant Lymphomas.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Mar 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    43
    EEA total number of subjects
    32
    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)
    22
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This multicenter study was conducted at 35 sites; 16 sites in the United States (US), 8 sites in France, 6 sites in Spain, and 5 sites in the United Kingdom (UK).

    Pre-assignment
    Screening details
    A total of 52 participants were screened, 43 enrolled, 41 received treatment. Eligible participants received YM155 5.0 mg/m^2/day and Rituximab 375 mg/m^2. A participant was considered as having completed treatment if the patient met one of the discontinuation criteria.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This section is not applicable since this is an open-label study.

    Arms
    Arm title
    YM155 plus rituximab
    Arm description
    Participants were administered YM155 and rituximab during 14-day cycles. Rituximab (375 mg/m^2) was administered weekly on days 1 and 8 during cycles 1 to 4, repeated every 10 cycles (i.e., cycles 11-14, 21-24, etc.). YM155 (5 mg/m^2 per day intravenously (IV)) was administered by continuous infusion for 168 hours via a central line, port or peripherally-inserted central catheter (PICC) from days 1 to 8 of each cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    YM155
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered YM155 during 14-day cycles. YM155 (5 mg/m^2 per day IV) was administered by continuous infusion for 168 hours via a central line, port or PICC from days 1 to 8 of each cycle. During cycles in which both YM155 and rituximab were administered, the YM155 infusion on day 1 was to be initiated within 1 hour following completion of the rituximab infusion. Each dose of YM155 was based upon body surface area (BSA), calculated using actual weight for participants with body mass index (BMI) < 30 kg/m^2 and adjusted (vs. actual) body weight for participants with BMI ≥ 30 kg/m^2. If a participant gained weight leading to a BMI increase from < 30 to ≥ 30 kg/m^2, then BSA was recalculated based upon the new, adjusted weight to determine if the YM155 dose should be increased. If the YM155 dose actually decreased (compared to original dose) when using the adjusted BSA, then the original dose of YM155 should have been utilized.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan, Mabthera
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered rituximab during 14-day cycles. Rituximab (375 mg/m^2) was administered weekly on days 1 and 8 during cycles 1 to 4, repeated every 10 cycles (i.e., cycles 11-14, 21-24, etc.). On day 8, the rituximab infusion could have been initiated during, but no later than 1 hour following the completion of, the YM155 infusion. If the rituximab infusion was initiated prior to the end of the YM155 infusion, a separate peripheral line in a different anatomical location must have been used.

    Number of subjects in period 1
    YM155 plus rituximab
    Started
    43
    Treated
    41
    Completed
    34
    Not completed
    9
         Ongoing participants
    7
         Enrolled but did not receive study drug
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    YM155 plus rituximab
    Reporting group description
    Participants were administered YM155 and rituximab during 14-day cycles. Rituximab (375 mg/m^2) was administered weekly on days 1 and 8 during cycles 1 to 4, repeated every 10 cycles (i.e., cycles 11-14, 21-24, etc.). YM155 (5 mg/m^2 per day intravenously (IV)) was administered by continuous infusion for 168 hours via a central line, port or peripherally-inserted central catheter (PICC) from days 1 to 8 of each cycle.

    Reporting group values
    YM155 plus rituximab Total
    Number of subjects
    43
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63 ± 13.7 -
    Gender categorical
    Units:
        Male
    28 28
        Female
    15 15

    End points

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    End points reporting groups
    Reporting group title
    YM155 plus rituximab
    Reporting group description
    Participants were administered YM155 and rituximab during 14-day cycles. Rituximab (375 mg/m^2) was administered weekly on days 1 and 8 during cycles 1 to 4, repeated every 10 cycles (i.e., cycles 11-14, 21-24, etc.). YM155 (5 mg/m^2 per day intravenously (IV)) was administered by continuous infusion for 168 hours via a central line, port or peripherally-inserted central catheter (PICC) from days 1 to 8 of each cycle.

    Primary: Objective Response Rate (ORR) (Confirmed Complete Remission/Confirmed Partial Remission)

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    End point title
    Objective Response Rate (ORR) (Confirmed Complete Remission/Confirmed Partial Remission) [1]
    End point description
    ORR was based on percentage of participants with confirmed CR/confirmed PR investigator assessed using modified International Working Group (IWG) criteria (2007). Analysis population consisted of Per Protocol Set(PPS) (all participants in the Full Analysis Set(FAS) defined as all participants who received at least 1 dose of YM155), who also met the following: Histologically-confirmed CD20-positive, primary/transformed diffuse large B-cell lymphoma (DLBCL) &/or grade 3 follicular lymphoma(FL). Relapsed/transformed low grade non-Hodgkin’s Lymphoma(NHL) to a DLBCL & documented at least a PR for 3 months prior to progression, following receipt of last dose systemic chemotherapy/autologous stem cell transplant(ASCT). No known central nervous system(CNS) involvement, history of other malignancy or disease free for at least 5 years (with exception of non-invasive cancers), no major protocol deviations/use prohibited concomitant medications. 9999=not available, n=number of participants.
    End point type
    Primary
    End point timeframe
    After the last non-progressing participant received 8 cycles of treatment or discontinued the treatment (by data cut off for primary analysis of 05 March 2013)
    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: Not applicable, descriptive summary statistics provided for the primary endpoint.
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: percentage of participants
    number (confidence interval 90%)
        All participants (n=34)
    50 (34.9 to 65.1)
        Age ≤ 60 (n = 11)
    63.6 (35 to 86.5)
        Age > 60 (n = 23)
    43.5 (25.8 to 62.5)
        Sex Male (n = 22)
    54.5 (35.3 to 72.9)
        Sex Female (n = 12)
    41.7 (18.1 to 68.5)
        Race White (n = 33)
    48.5 (33.3 to 63.9)
        Race Black or African American (n=1)
    100 (5 to 100)
        ECOG performance Grade 0 (n = 20)
    55 (34.7 to 74.1)
        ECOG performance Grade 1 (n = 14)
    42.9 (20.6 to 67.5)
        Diffuse Large B-Cell Lymphoma (n = 33)
    51.5 (36.1 to 66.7)
        Follicular Lymphoma (Grade 3) (n = 1)
    9999 (9999 to 9999)
        Lymphoma Prognostic Index Low (n = 5)
    40 (7.6 to 81.1)
        Lymphoma Prognostic Index Intermediate (n = 21)
    47.6 (28.6 to 67.2)
        Lymphoma Prognostic Index High (n = 8)
    62.5 (28.9 to 88.9)
    No statistical analyses for this end point

    Secondary: Confirmed Complete Remission Rate (CR)

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    End point title
    Confirmed Complete Remission Rate (CR)
    End point description
    CR rate was based on percentage of participants with CR. Investigator’s assessment of tumor response was based on imaging scans that were performed 6-8 weeks after the response was first detected per IWG revised Responses Criteria for malignant lymphoma (2007). Best objective response was derived on time point response reported by the investigator. Analysis population consisted of the PPS.
    End point type
    Secondary
    End point timeframe
    After the last non-progressing participant received 8 cycles of treatment or discontinued the treatment (by data cut off for primary analysis of 05 March 2013)
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: percentage of participants
        number (confidence interval 90%)
    20.6 (10.1 to 35.2)
    No statistical analyses for this end point

    Secondary: Confirmed Partial Remission Rate (PR)

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    End point title
    Confirmed Partial Remission Rate (PR)
    End point description
    Confirmed PR was based on percentage of participants with PR. Investigator’s assessment of tumor response was based on imaging scans that were performed 6-8 weeks after the response was first detected per IWG revised Responses Criteria for malignant lymphoma (2007). Best objective response was derived on time point response reported by the investigator. Analysis population consisted of the PPS.
    End point type
    Secondary
    End point timeframe
    After the last non-progressing participant received 8 cycles of treatment or discontinued the treatment (by data cut off for primary analysis of 05 March 2013)
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: percentage of participants
        number (confidence interval 90%)
    29.4 (16.9 to 44.8)
    No statistical analyses for this end point

    Secondary: Time To Response (TTR)

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    End point title
    Time To Response (TTR)
    End point description
    Time to response was based on the investigator’s assessment of tumor response in participants with confirmed CR or confirmed PR and calculated using Kaplan-Meier estimates and defined as the time from the first dose of study drug until the first documentation of response (CR or PR). Analysis population consisted of the PPS. N is the number of responders/participants/patients with confirmed CR or confirmed PR.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to data cut off for primary analysis of 05 March 2013
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    17
    Units: days
        median (confidence interval 95%)
    56 (52 to 57)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    Duration of response was defined as the time from the first documentation of response (CR or PR) until objective tumor/disease progression. N is the number of responders/participants/patients with confirmed CR or confirmed PR. Analysis population consisted of the PPS. The median duration of response could not be estimated (calculated using Kaplan-Meier estimates) because the value of the smallest observed survival function was > 0.5. At the time of the analysis, the upper limit of the confidence could not be estimated. 9999=not available
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to data cut off for primary analysis of 05 March 2013
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    17
    Units: days
        median (confidence interval 95%)
    9999 (176 to 9999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    Clinical Benefit Rate (CBR)
    End point description
    Clinical benefit rate (CR + PR + stable disease) defined as percentage of participants with confirmed CR, confirmed PR and stable disease was based on the investigator’s assessment of tumor response in all participants. Analysis population consisted of the PPS. Stable disease (SD) defined per IWG criteria (2007) as the following: A subject is considered to have SD when he or she fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease. Typically fluoro-deoxy-glucose (FDG)-avid lymphomas: the Positron Emission Tomography (PET) should be positive at prior sites of disease with no new areas of involvement on the post-treatment Computed Tomography (CT) or PET. Variably FDG-avid lymphomas/FDG-avidity unknown: for subjects without a pretreatment PET scan or if the pretreatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment CT scan.
    End point type
    Secondary
    End point timeframe
    After the last non-progressing participant received 8 cycles of treatment or discontinued the treatment (by data cut off for primary analysis of 05 March 2013)
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: percentage of participants
        number (confidence interval 90%)
    82.4 (68.1 to 92)
    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
    PFS was defined as the time from the first dose of study drug until objective tumor progression or death and was based on the investigator’s assessment of tumor response in all participants and calculated using Kaplan-Meier estimates. Analysis population consisted of the PPS. Disease progression includes progression based radiological outcome and clinical signs and symptoms per IWG criteria. At the time of the analysis, the upper limit of the confidence could not be estimated. 9999=not available
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to data cut off for primary analysis of 05 March 2013
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: days
        median (confidence interval 95%)
    537 (154 to 9999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    OS was defined as the time from the first dose of study drug until death. Analysis population consisted of the PPS. Participants without death date were censored. The median OS could not be estimated (calculated using Kaplan-Meier estimates) because the value of the smallest observed survival function was > 0.5. Median survivor time could not be estimated due to the value of the smallest observed survival function > 0.5. Median survivor time could not be estimated due to the value of the smallest observed survival function > 0.5. At the time of the analysis, the upper limit of the confidence could not be estimated. 9999=not available
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to data cut off for primary analysis of 05 March 2013
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    34
    Units: days
        median (confidence interval 95%)
    9999 (483 to 9999)
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events (AEs)

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    End point title
    Number of participants with adverse events (AEs)
    End point description
    Analysis population consisted of the Safety Analysis Set (SAF) population. The SAF was defined as all patients who received at least 1 dose of study regimen (rituximab or YM155). An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a study drug or study regimen and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug or study regimen, whether or not related to the study drug or study regimen. Treatment-emergent adverse event (TEAE) was defined as an AE starting after first administration of the study drug up to the End of Treatment Visit (ETV).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to data cut off for primary analysis of 05 March 2013
    End point values
    YM155 plus rituximab
    Number of subjects analysed
    41
    Units: Participants
        Any TEAE
    38
        Drug-related TEAEs
    29
        Deaths
    4
        Serious TEAEs
    26
        Drug-related Serious TEAEs
    12
        TEAEs Leading to Discontinuation
    10
        Drug-related TEAEs Leading to Discontinuation
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to data cut off for primary analysis of 05 March 2013.
    Adverse event reporting additional description
    Treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) starting after first administration of the study drug up to the End of Treatment Visit (ETV).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    YM155 plus rituximab
    Reporting group description
    Participants were administered YM155 and rituximab during 14-day cycles. Rituximab (375 mg/m^2) was administered weekly on days 1 and 8 during cycles 1 to 4, repeated every 10 cycles (i.e., cycles 11-14, 21-24, etc.). YM155 (5 mg/m^2 per day iv) was administered by continuous infusion for 168 hours via a central line, port or peripherally-inserted central catheter (PICC) from days 1 to 8 of each cycle.

    Serious adverse events
    YM155 plus rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 41 (63.41%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superior vena caval occlusion
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter thrombosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Hyperthermia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Infusion site necrosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Central line infection
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lemierre syndrome
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mediastinitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    YM155 plus rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 41 (82.93%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    8
    Chills
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    13 / 41 (31.71%)
         occurrences all number
    20
    Pyrexia
         subjects affected / exposed
    13 / 41 (31.71%)
         occurrences all number
    34
    Oedema peripheral
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    8
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 41 (24.39%)
         occurrences all number
    14
    Neutropenia
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    72
    Thrombocytopenia
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 41 (29.27%)
         occurrences all number
    16
    Dyspnoea
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    8 / 41 (19.51%)
         occurrences all number
    12
    Paraesthesia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    10 / 41 (24.39%)
         occurrences all number
    16
    Nausea
         subjects affected / exposed
    10 / 41 (24.39%)
         occurrences all number
    14
    Stomatitis
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    19
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Back pain
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    8
    Muscle spasms
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Hypokalaemia
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Hypomagnesaemia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Hypophosphataemia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    5
    Oral candidiasis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 41 (14.63%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2009
    Remove the collection of tumor biopsy slides and bone marrow slides as inclusion criteria. Remove the requirement to collect tumor biopsy slides for biomarker analysis. Update the Events Always Considered to be Serious List. Remove the statement on the protocol cover page regarding legal representation of sponsor as stipulated under Directive 2001/20/EC of the European Parliament and of the Council.
    21 Jan 2010
    Clarify that registration was to occur as close as possible to day 1 of cycle 1. Update the National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) version. Update the Overall Response Rate to ORR. Update the primary variable definition. Update the safety variable in the synopsis to match the safety variable in the main protocol. Update the CR and PR variable definition. Add safety analysis after the 10th patient completed 1 cycle of YM155 plus rituximab treatment. Update inclusion criteria. Remove the acceptability of a legally authorized representative consenting on a patient’s behalf. Update the inclusion/exclusion criteria. Add cycle 1 day 2 visit and a physical exam in the cycle 1 day 4 visit. Update the test drug storage condition. Highlight that generic rituximab could not be administered to study patients. Update the drug destruction and drug return requirement. Update the medical history and baseline condition definition. Update language regarding consistency in radiological review of scans and that diagnostic quality computed tomography (CT) scans were required. Update the lab assessment to include hepatitis tests. Update language to clarify that other staining methods such as, but not limited to, immunohistochemistry (IHC) could be conducted. Clarification on AE assessment and documentation. Update blood collection volumes. Update procedure in case of pregnancy. Update the statistical analysis. Appendices updated.
    04 May 2010
    Revise inclusion and exclusion criteria. Update the protocol introduction to include information that was then available in the Investigator’s Brochure and clinical database for YM155. Allow for investigator discretion in lowering of the YM155 dose. Clarify the retreatment criterion regarding toxicities. Clarify AE descriptions for rituximab. Provide guidance for destroying or returning study drug. Provide guidance for administering growth factors. Revise the frequency of post-treatment imaging. Clarify the type of imaging used when contrast CT was contraindicated. Clarify how YM155 dose interruptions were to be handled Clarify procedures for administering rituximab and YM155. Clarify where medical history and baseline conditions were recorded on the case report form (CRF). Allow for dosing of rituximab and YM155 at the same time on day 8. Clarify statistical methodology.
    12 Jul 2010
    Clarify inclusion criterion regarding prior chemotherapy, prior malignancies and definition of relapse. Clarify biomarker testing. Clarify serious adverse event (SAE) reporting period.
    07 Jul 2011
    Delete all reference to Canada. Clarify accepted scans prior to informed consent. Update study timelines. Clarify inclusion criteria 5, 9, and 10. Add a window to the screening period CT and FDG-PET scans. Update statistical methods. Clarify what scans needed to be obtained after a PR/CR. Clarify YM155 dosing per patient’s weight. Delete vital signs and electrocardiogram (ECG) on cycle 1, days 2 and 6. Add a window to the follow-up CT and magnetic resonance imaging (MRI) scans. Clarify the SAE capturing of agranulocytosis (myelosuppression). Add Drug-Induced Liver Injury (DILI) information. Clarify the minimum of days in each cycle. Add a window to allow scans obtained (±) 3 days at the 12-week follow-up visit.
    23 Feb 2012
    Incorporate updated safety language. Update the planned study period. Decrease the sample size. The sample size was reduced from 60 to 40 patients based on the efficacy and safety data from interim analyses, which suggested that findings from 40 patients in this proof-of-concept study would be sufficient to plan subsequent studies. Delete specific assessments due to lack of safety alert signals. Decrease the estimated total amount of blood drawn based on fewer planned laboratory assessments. Update the imaging and statistical portion of the protocol to change the assessment of the primary endpoint to the Investigator
    30 Oct 2012
    Update the projected last patient out date. Clarify the criteria used for ORR. Remove the timeframe for inclusion criteria 1 (aged 18 years or older), as it was not applicable. Clarify patient assessment regarding life expectancy was based on investigator’s judgment. Clarify adequate method of birth control. Clarify exclusion criteria 8. Clarify prohibited medications or therapies while on study. Update the 1) number of patients in the PPS and the number of observed ORR at final analysis, 2) number of non-progressing patients in the PPS, and 3) power and the observed ORR at final analysis, all to correspond with the updated PPS definition. Clarify when diagnostic CT and FDG-PET scans were performed. Clarify when patients were contacted during the survival follow-up period. Delete Appendix 10 (Events Always Considered to be Serious), as the listing was not mandated by regulations. Clarify timing of study termination if the study had to be closed for any reason. Clarify the version of CTCAE being used for the study. Include further instructions to Investigators for reporting protocol deviations to the Sponsor. Clarify best objective response in the event of a CR to a PR.
    12 Sep 2013
    Clarify the obligations for reporting SAEs. Ensure that the principal investigator’s protocol acknowledgement adhered to country-specific regulations, as applicable. Update the current study period. Clarify the end of trial in the protocol. Update the number or timing of assessment to either clarify the data collection endpoint or to reflect standard of care. Include a systematic process for identifying and summarizing protocol deviations.

    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 primary analysis is considered final and no end of study report will be completed. The 7 ongoing participants at the time of the data cutoff are now completed.
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