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    Clinical Trial Results:
    Phase II randomized study with R-DHAP +/- Bortezomib as induction therapy in relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) patients eligible to transplantation. BR-DHAP versus R-DHAP

    Summary
    EudraCT number
    		 2012-000924-16
    Trial protocol
    		 IT  
    Global end of trial date
    20 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2022
    First version publication date
    22 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    FIL_Veral12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01805557
    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
    20 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective is to assess whether the experimental treatment achieves an absolute increase of the CR proportion of at least 20% (from 30% to 50%) with respect to the standard treatment.
    Protection of trial subjects
    Therapy may be interrupted for one of the following reasons: Adverse event(s); Abnormal laboratory value(s); Abnormal test procedure result(s); Protocol deviation; Subject withdrew consent; Lost to follow-up; Administrative problems; Death; Initiation of new cancer therapy; Disease progression. The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (Tokyo, Venice, Hong Kong and Somerset West amendments) or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the ICH Guideline for Good Clinical Practice. The protocol and its annexes are subject to review and approval by the competent Independent Ethics Committee(s) (“IEC”).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 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: 108
    Worldwide total number of subjects
    108
    EEA total number of subjects
    108
    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)
    106
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One hundred and eight (108) patients recruited in Italy from February 4th, 2013, with date of last completed at November 20th, 2020

    Pre-assignment
    Screening details
    		 After providing written informed consent, patients will be evaluated for eligibility during a 28-day screening period. If they continue to meet eligibility criteria, they will be randomized to receive the first dose of BR-DHAP or R-DHAP .

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    After stratification, all patients will be randomized, with a 1:1 ratio, into two arms. The web-based randomization procedure will be completely concealed to researchers. After registering the patient at the study dedicated area, each patient will be assigned a unique ID code. The randomization procedure, based on computer generated random sequence in blocks of variable size and in random order, will be accessible, 24/24h a day, only after the baseline forms have been completely filled out.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ARM A R-DHAP
    Arm description
    		 R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging with PET evaluation
    Arm type
    		 Standard salvage therapy

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Rituximab 375 mg/sqm iv day 0 or 1 • Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/sqm iv day 1 in 6-hours infusion (a 3-hours infusion is allowed)

    Investigational medicinal product name
    Dexametasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg day 1-4

    Investigational medicinal product name
    Pegfilgrastim
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization’s course (II o III cycle R-DHAP)

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg/sqm in 3-hours infusion iv day 2 and day 3

    Arm title
    		 ARM B Bortezomib R-DHAP
    Arm description
    		 Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + Bortezomib + R-DHAP x 2, restaging with PET evaluation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Rituximab 375 mg/sqm iv day 0 or 1 • Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/sqm iv day 1 in 6-hours infusion (a 3-hours infusion is allowed)

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg/sqm in 3-hours infusion iv day 2 and day 3

    Investigational medicinal product name
    Dexametasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg day 1-4

    Investigational medicinal product name
    Pegfilgrastim
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization’s course (II o III cycle R-DHAP)

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Bortezomib SC 1.5 mg/sqm day 1, day 4

    Number of subjects in period 1
    		ARM A R-DHAP ARM B Bortezomib R-DHAP
    Started
    54
    54
    Completed
    25
    29
    Not completed
    29
    25
         Toxicity
    -
    1
         Death
    -
    2
         Other
    -
    2
         Progression
    25
    16
         Clinician decision
    1
    -
         Adverse event
    2
    3
         Early withdrawl
    -
    1
         Stable disease
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ARM A R-DHAP
    Reporting group description
    		 R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging with PET evaluation

    Reporting group title
    ARM B Bortezomib R-DHAP
    Reporting group description
    		 Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + Bortezomib + R-DHAP x 2, restaging with PET evaluation

    Reporting group values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP Total
    Number of subjects
    		 54 54 108
    Age categorical
    Units: Subjects
        <50
    		 15 18 33
        50-59
    		 17 17 34
        60+
    		 22 18 40
        Not recorded
    		 0 1 1
    Gender categorical
    Units: Subjects
        Female
    		 24 19 43
        Male
    		 30 34 64
        Not recorded
    		 0 1 1
    Disease status
    Units: Subjects
        Refractory/Progressed
    		 27 27 54
        Relapsed
    		 27 26 53
        Not recorded
    		 0 1 1
    First line chemotherapy
    Units: Subjects
        R-CHOP
    		 42 48 90
        R-mega CHOP
    		 1 1 2
        Other
    		 11 4 15
        Not recorded
    		 0 1 1
    Systemic Symptoms
    Units: Subjects
        Systemic Symptoms A
    		 36 37 73
        Systemic Symptoms B
    		 18 13 31
        Missing
    		 0 3 3
        Not recorded
    		 0 1 1
    Ann Arbor classification
    Units: Subjects
        Stage I
    		 3 1 4
        Stage II
    		 10 9 19
        Stage III
    		 17 13 30
        Stage IV
    		 23 30 53
        Missing
    		 1 0 1
        Not recorded
    		 0 1 1
    Patients with extranodal sites
    Units: Subjects
        No
    		 23 19 42
        Yes
    		 31 33 64
        Missing
    		 0 1 1
        Not recorded
    		 0 1 1
    IPI
    Units: Subjects
        Score 1
    		 12 15 27
        Score 2
    		 17 18 35
        Score 3
    		 14 12 26
        Score 4
    		 7 2 9
        Score 5
    		 1 1 2
        Missing
    		 3 5 8
        Not recorded
    		 0 1 1
    Age-Adjusted IPI
    Units: Subjects
        Score 1
    		 18 23 41
        Score 2
    		 23 20 43
        Score 3
    		 10 4 14
        Missing
    		 3 6 9
        Not recorded
    		 0 1 1
    Performance Status (ECOG)
    Units: Subjects
        ECOG 0
    		 30 37 67
        ECOG 1
    		 14 11 25
        ECOG 2
    		 9 5 14
        Missing
    		 1 0 1
        Not recorded
    		 0 1 1
    Supra-diaphragmatic nodal sites
    Units: Subjects
        Yes
    		 41 34 75
        No
    		 13 19 32
        Not recorded
    		 0 1 1
    Sub-diaphragmatic nodal sites
    Units: Subjects
        Yes
    		 35 36 71
        No
    		 19 17 36
        Not recorded
    		 0 1 1
    Extranodal sites
    Units: Subjects
        Yes
    		 27 33 60
        No
    		 27 20 47
        Not recorded
    		 0 1 1
    Bone marrow involvement
    Units: Subjects
        Positive
    		 4 4 8
        Negative
    		 42 43 85
        Not evaluable
    		 8 6 14
        Not recorded
    		 0 1 1
    Leukemia
    Units: Subjects
        No
    		 0 3 3
        Yes
    		 53 50 103
        Missing
    		 1 0 1
        Not recorded
    		 0 1 1
    Mediastinic syndrome
    Units: Subjects
        No
    		 50 52 102
        Yes
    		 3 1 4
        Missing
    		 1 0 1
        Not recorded
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    ARM A R-DHAP
    Reporting group description
    		 R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging with PET evaluation

    Reporting group title
    ARM B Bortezomib R-DHAP
    Reporting group description
    		 Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + Bortezomib + R-DHAP x 2, restaging with PET evaluation

    Primary: Complete Response (CR) Rate

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    End point title
    		 Complete Response (CR) Rate
    End point description
    End point type
    Primary
    End point timeframe
    Evaluated by PET scan after four cycles of R-DHAP ± Bortezomib before transplantation according to Cheson criteria. At the end of the induction phase (6 months)
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: CR proportion
        number (not applicable)
    27.78
    26.42
    Statistical analysis title
    		 Complete Response (CR) Rate
    Comparison groups
    ARM A R-DHAP v ARM B Bortezomib R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.563 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - Primary objective is to assess whether the experimental treatment achieves an absolute increase of the CR proportion of at least 20% (from 30% to 50%) with respect to the standard treatment.
    [2] - The proportion of CR have been compared between the two arms with a chi-square test, without continuity correction, using a test critical value of 1.282 (corresponding to a one-sided p-value of 0.10) to reject the null hypothesis.

    Secondary: Overall Response Rate (ORR) prior to consolidation

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    End point title
    		 Overall Response Rate (ORR) prior to consolidation
    End point description
    Overall response rate (ORR): a patient is defined as a responder if he has a complete or partial response, evaluated by PET/TC, after four cycles of R-DHAP ± Bortezomib
    End point type
    Secondary
    End point timeframe
    Evaluated by PET/TC, after four cycles of R-DHAP ± Bortezomib, at the end of the induction phase (6 months).
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: ORR
        number (not applicable)
    35.19
    35.85
    Statistical analysis title
    		 Overall Response Rate (ORR)
    Comparison groups
    ARM B Bortezomib R-DHAP v ARM A R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4714 [3]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - One sided P-value

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Progression free survival (PFS): measured from the date of randomization to the date of disease progression, relapse or death from any cause. Responding patients and patients who are lost to follow up will be censored at their last assessment date. For PFS minimum follow up time required for all patients is 2 years.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: Kaplan Meier estimates
        number (confidence interval 95%)
    29.41 (17.94 to 41.83)
    40.99 (27.67 to 53.84)
    Statistical analysis title
    		 Progression Free Survival (PFS)
    Statistical analysis description
    The time-to-event functions have been estimated by the Kaplan-Meier product-limit method and the difference between arms have been tested with the log-rank test, stratified by disease status.
    Comparison groups
    ARM A R-DHAP v ARM B Bortezomib R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0594 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Log-rank test, stratified by disease status.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS: measured from the date of randomization to the date of death from any cause. Patients alive at the time of the final analysis have been censored at the date of the last contact. OS minimum follow up time required for all patients is 2 years.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: Kaplan Meier estimates
        number (confidence interval 95%)
    43.02 (28.98 to 56.3)
    52.08 (37.8 to 64.56)
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    The time-to-event functions have been estimated by the Kaplan-Meier product-limit method and the difference between arms have been tested with the log-rank test, stratified by disease status.
    Comparison groups
    ARM B Bortezomib R-DHAP v ARM A R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.242 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - Log-rank test, stratified by disease status.

    Secondary: Toxicity

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    End point title
    		 Toxicity
    End point description
    Toxicity: severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events are defined according to “Common Terminology Criteria for Adverse Events” (CTCAE), version 4.0, during therapy
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: Toxicity incidence
    number (not applicable)
        Any hematological toxicity of grade >=3
    88.89
    90.57
        Any extra-hematological toxicity of grade >=3
    25.93
    32.08
    Statistical analysis title
    		 Any hematological toxicity of grade >=3
    Comparison groups
    ARM A R-DHAP v ARM B Bortezomib R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.775 [6]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - Pearson chi2 test, within 4 cycles
    Statistical analysis title
    		 Any extra-hematological toxicity of grade >=3
    Comparison groups
    ARM A R-DHAP v ARM B Bortezomib R-DHAP
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.483 [7]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [7] - Pearson chi2 test, within 4 cycles

    Secondary: Mobilizing potential

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    End point title
    		 Mobilizing potential
    End point description
    Mobilizing potential: amount of CD34 + stem cell collected /Kg
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    34 [8]
    35 [9]
    Units: CD34 + stem cell collected /Kg
        median (inter-quartile range (Q1-Q3))
    6.43 (4.40 to 9.11)
    6.78 (5.00 to 9.68)
    Notes
    [8] - Missing 4
    [9] - Missing 4
    Statistical analysis title
    		 Mobilizing potential
    Comparison groups
    ARM A R-DHAP v ARM B Bortezomib R-DHAP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.526
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Number of Patients completing ASCT

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    End point title
    		 Number of Patients completing ASCT
    End point description
    Proportion of randomized patients successfully completing ASCT
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Number of subjects analysed
    54
    53
    Units: percent
    number (not applicable)
        Autologus
    37.04
    35.85
        Allogenic
    7.41
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Adverse event reporting additional description
    Severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events All toxic reactions will be annotated and their grade will be assessed according to the Common Toxicity Criteria (CTC) Version
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    ARM A R-DHAP
    Reporting group description
    		 R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging with PET evaluation

    Reporting group title
    ARM B Bortezomib R-DHAP
    Reporting group description
    		 Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + Bortezomib + R-DHAP x 2, restaging with PET evaluation

    Serious adverse events
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 54 (18.52%)
    18 / 53 (33.96%)
         number of deaths (all causes)
    31
    29
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Progression disease
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary adenocarcinoma
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension and hypertension
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncopal episode
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emesis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal mucositis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyloric prothesis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney failure
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute renal failure
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute rhabdomyolysis
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    CMV reactivation
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella infection
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Creatinine increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ARM A R-DHAP ARM B Bortezomib R-DHAP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 54 (88.89%)
    48 / 53 (90.57%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    2
    Thrombosis/Embolism
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 53 (1.89%)
         occurrences all number
    1
    2
    Nervous system disorders
    Motor neuropathy
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    Sensory neuropathy
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    4
    Blood and lymphatic system disorders
    GB
         subjects affected / exposed
    17 / 54 (31.48%)
    25 / 53 (47.17%)
         occurrences all number
    32
    55
    Granulocytes
         subjects affected / exposed
    38 / 54 (70.37%)
    34 / 53 (64.15%)
         occurrences all number
    87
    81
    Hemoglobin
         subjects affected / exposed
    14 / 54 (25.93%)
    15 / 53 (28.30%)
         occurrences all number
    21
    23
    Platelets
         subjects affected / exposed
    45 / 54 (83.33%)
    48 / 53 (90.57%)
         occurrences all number
    107
    121
    General disorders and administration site conditions
    Mucositis
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    2
    Fever in documented homeless neutropenia and/or isolation
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Other
         subjects affected / exposed
    8 / 54 (14.81%)
    6 / 53 (11.32%)
         occurrences all number
    11
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Kidney failure
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Viral infectione
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2014
    The main changes concerned the title of the study, because the primary objective is the evaluation of the complete response after 4 cycles of RDHAP vs BRDHAP induction. In fact, the protocol accepts a subsequent consolidation (off-protocol) with autologous or allogeneic transplantation and the previous title also included the evaluation of consolidation. In addition, some errors in the previous version have been corrected and the treatment of patients who have undergone first-line GA-CHOP is allowed. The information sheets and informed consents have been adapted to the contents of the amendment. In addition, the changes requested by the Ethics Committees of the satellite centers during the local evaluation phase have been incorporated into the information sheets. The new IB (ver. 17) of the drug under study has also been sent.
    20 Oct 2016
    The amendment relates to the risks and adverse effects section of the disclosure following the issuance of Investigator Brochure 18. The enrolment period has also been extended and the insurance policy has been adjusted accordingly. The reference for centralized histological reviews has also been updated. The information sheets and informed consents have been adapted to the contents of the amendment
    11 Nov 2019
    Due to the retirement of Dr. Umberto Vitolo, the Principal Investigator of the coordinating center of Turin (A.O.U. Città della Salute e della Scienza di Torino - S.C. Hematology) has been changed. The new PI designated is Dr. Barbara Botto.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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