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    Clinical Trial Results:
    Phase II study of age‐adjusted R‐BAC (Rituximab, Bendamustine, Cytarabine) as induction therapy in older patients with Mantle Cell Lymphoma (MCL)

    Summary
    EudraCT number
    2011-005739-23
    Trial protocol
    IT  
    Global end of trial date
    11 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Aug 2022
    First version publication date
    25 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FIL-RBAC500
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01662050
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Fondazione Italiana Linfomi (FIL) ONLUS
    Sponsor organisation address
    Piazza Turati 5, Alessandria, Italy,
    Public contact
    Segreteria, Fondazione Italiana Linfomi ONLUS, +39 0131/033151, segreteriadirezione@filinf.it
    Scientific contact
    Segreteria, Fondazione Italiana Linfomi ONLUS, +39 0131/033151, segreteriadirezione@filinf.it
    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
    15 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the activity (complete remission rate according to Cheson 2007 criteria) and safety of age‐adjusted Rituximab‐Bendamustine‐Cytarabine (RBAC500) regimen at the end of treatment in older untreated patients with MCL.
    Protection of trial subjects
    1) Occurrence of relevant toxicity for two subsequent or consecutive cycles (the protocol allows for a 25% reduction of drugs dosage when an episode of relevant toxicity occurs for the first time) 2) Grade 3-4 hematological or non‐hematological toxicity on day +28 of a cycle not resolving within two weeks (+28 days+14 days since last cycle) 3) Grade 3-4 hematological or non‐hematological toxicity on day +28 of a cycle after the 25% dose reduction 4) Patient refusal to procede with further cycles due to perceived excessive toxicity 5) Any unpredictable drug related event that suggests against study continuation
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Mar 2012
    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: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    5
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed at 09/11/2017. We adopted the Bryant and Day two-stage design for calculating the sample size. At the end of the first stage, 19 pts, the trial will be stopped if there are <= 8/19 responses and >=7/19 toxicities. Otherwise, further 38 pts will be enrolled.

    Pre-assignment
    Screening details
    Patients with an established histological diagnosis of MCL on lymph-node biopsy, bone marrow biopsy, or extranodal tissue are eligible for entry into the study. All patients must satisfy all the inclusion criteria and none of exclusion criteria.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Single arm
    Arm description
    Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment.
    Arm type
    Single arm study

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose administered: 375 mg/m2 The amount (in mg) of Rituximab to be administered will be determined based on body surface area (BSA) using a standard calculation. Patients presenting with high lymphocyte count in the peripheral blood, defined as total lymphocytes >20000/mmc will receive the dose of Rituximab postponed after chemotherapy, 4 days after the completion of the last dose of Ara-C (+8 from the start of therapy). Patients that still have elevated lymphocyte count at that time point will avoid Rituximab for the first cycle, maintaining the same measures for subsequent cycles.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine will be administered intravenously at a dose of 70 mg/m2 and as a 30-60 minute infusion on Days 2 and 3. Following the first cycle, if no major complication has followed rituximab infusion, bendamustine and ara-C will be administered on day 1 following rituximab, and the complete cycle will last for 3 days, in order to facilitate an outpatient approach.

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Ara-C
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ara-C will be administered intravenously at the dose of 500 mg/m2 as a 2-hour infusion, 2 hours after Bendamustine on Day 2 and 3, and once on Day 4. Following the first cycle, if no major complication has followed rituximab infusion, bendamustine and ara-C will be administered on day 1 following rituximab, and the complete cycle will last for 3 days, in order to facilitate an outpatient approach.

    Number of subjects in period 1
    Single arm
    Started
    57
    Completed
    38
    Not completed
    19
         Adverse Event
    14
         Medical Decision
    4
         Lack of efficacy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed (last follow-up) at 09/11/2017.

    Reporting group values
    Baseline Total
    Number of subjects
    57 57
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    5 5
        From 65-84 years
    52 52
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    71 (67 to 75) -
    Gender categorical
    Units: Subjects
        Female
    14 14
        Male
    43 43
    Ann Arbor stage
    Units: Subjects
        II
    5 5
        III–IV
    52 52
    Bone marrow involvement
    Units: Subjects
        Yes
    36 36
        No
    21 21
    Eastern Cooperative Oncology Group performance status
    Units: Subjects
        ECOG 0-1
    54 54
        ECOG 2
    3 3
    Morphological variants
    Units: Subjects
        Classical
    43 43
        Pleomorphic
    8 8
        Blastoid
    6 6
    Ki67 index
    Units: Subjects
        <30%
    35 35
        ≥30%
    16 16
        NA
    6 6
    MIPI
    Units: Subjects
        Low risk
    9 9
        Intermediate risk
    23 23
        High risk
    25 25
    Ki67 index
    Only 51 patients
    Units: percent
        median (inter-quartile range (Q1-Q3))
    20 (8 to 33) -

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment.

    Subject analysis set title
    Subject analyzed
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed (last follow-up) at 09/11/2017.

    Primary: Complete response rate (CR)

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    End point title
    Complete response rate (CR)
    End point description
    Primary efficacy end point of the study is the proportion of CR defined according to Cheson criteria (2007) at the end of treatment (6 or 4 cycles)
    End point type
    Primary
    End point timeframe
    At the end of treatment (6 or 4 cycles)
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    57
    57
    Units: subject
        CR
    52
    52
    Statistical analysis title
    Complete Response (CR) Rate
    Comparison groups
    Single arm v Subject analyzed
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    CR proportion
    Point estimate
    91
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    85
         upper limit
    -

    Primary: Patients with at least a relevant one episode of relevant toxicities

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    End point title
    Patients with at least a relevant one episode of relevant toxicities
    End point description
    Relevant toxicity was defined as grade 4 cytopenia lasting for more than 6 days, grade 3–4 non haematological toxicity, or febrile neutropenia lasting for more than 3 consecutive days.
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    57
    57
    Units: Subject
        Patients with relevant toxicities
    23
    23
    Statistical analysis title
    Patients with relevant toxicities
    Comparison groups
    Single arm v Subject analyzed
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Proportion
    Point estimate
    40
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    53

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS is measured from the time of enrollment until disease progression, relapse or death from any cause.
    End point type
    Secondary
    End point timeframe
    30 months. The reported value corresponds to PFS% at 2-years.
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    57
    57
    Units: Probability
        number (confidence interval 95%)
    81 (68 to 89)
    81 (68 to 89)
    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 is measured from enrollment until death from any cause.
    End point type
    Secondary
    End point timeframe
    30 months. The reported value corresponds to OS% at 2-years.
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    57
    57
    Units: Probability
        number (confidence interval 95%)
    86 (74 to 93)
    86 (74 to 93)
    No statistical analyses for this end point

    Secondary: Duration of responses (DOR)

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    End point title
    Duration of responses (DOR)
    End point description
    DOR is measured from the first assessment that documents response (CR or PR) to the date of disease relapse or progression.
    End point type
    Secondary
    End point timeframe
    30 months. The reported value corresponds to DOR% at 2-years.
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    57
    57
    Units: Probability
        number (confidence interval 95%)
    90 (85 to 94)
    90 (85 to 94)
    No statistical analyses for this end point

    Secondary: Rate of molecular response

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    End point title
    Rate of molecular response
    End point description
    Molecular response is the proportion of patients with molecular rearrangements at baseline that become negative during treatment, measured by qualitative and quantitative PCR.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Single arm Subject analyzed
    Number of subjects analysed
    45 [1]
    45 [2]
    Units: Patients
        Bone Marrow
    24
    24
        Peripheral Blood
    35
    35
    Notes
    [1] - Of 57 patients, 45 (79%) had a molecular marker
    [2] - Of 57 patients, 45 (79%) had a molecular marker
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 months
    Adverse event reporting additional description
    All subjects will be monitored for adverse events throughout the study and for 30 days after the end of treatment. During the follow-up, patients will be monitored for adverse events every 3 months.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Single arm
    Reporting group description
    Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment.

    Serious adverse events
    Single arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 57 (36.84%)
         number of deaths (all causes)
    12
         number of deaths resulting from adverse events
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia G4, Thrombocytopenias G3
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Severe Leukopenia and Thrombocytopenias
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Cough and fever
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis and fever
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Fever and cutaneous rash
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia and Temperature max 38° C
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia and Temperature max 38.2° C
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever, CMV reactivation and pancytopenia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis with fever and cought
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena, with findings of severe anemia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Left cheek lesion and Melaena
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia and fever
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever, Dehydration, Hypoalbuminaemia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction and pseudomonas aeruginosa sepsis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pancytopenia and Epistaxis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Severe bone pain
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    CMV Reactivation
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Single arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 57 (96.49%)
    Vascular disorders
    Other hemorrhage
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    5
    Cardiac disorders
    Supraventricular arrhythmia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    2
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    2
    Hypotension
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Nervous system disorders
    Motor neuropathy
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    2
    Sensory neuropathy
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Platelets
         subjects affected / exposed
    51 / 57 (89.47%)
         occurrences all number
    217
    Leucocytes
         subjects affected / exposed
    52 / 57 (91.23%)
         occurrences all number
    209
    Haemoglobin
         subjects affected / exposed
    49 / 57 (85.96%)
         occurrences all number
    190
    Granulocytes
         subjects affected / exposed
    53 / 57 (92.98%)
         occurrences all number
    205
    Febrile neutropenia
         subjects affected / exposed
    15 / 57 (26.32%)
         occurrences all number
    20
    General disorders and administration site conditions
    Other toxicities
         subjects affected / exposed
    33 / 57 (57.89%)
         occurrences all number
    111
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Mucositis
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    4
    Hepatobiliary disorders
    Liver dysfunction
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    11
    Infections and infestations
    Viral infection
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Bacterial infection
         subjects affected / exposed
    10 / 57 (17.54%)
         occurrences all number
    12
    Fungal infection
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    4
    Hyperbilirubinemia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Hyperuricemia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    5

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27927586
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