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    Clinical Trial Results:
    Combination of ibrutinib and bortezomib followed by ibrutinib maintenance to treat patients with relapsed and refractory mantle cell lymphoma; a multicenter Phase I/II trial

    Summary
    EudraCT number
    		 2014-003893-17
    Trial protocol
    		 DE   IT  
    Global end of trial date
    30 Mar 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK36/13
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02356458
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Swiss Group for Clinical Cancer, Head Regulatory Affairs, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Swiss Group for Clinical Cancer, Head Regulatory Affairs, +41 31389 91 91, sakkcc@sakk.ch
    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
    22 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the phase I (dose escalation of ibrutinib) is to establish the recommended phase II dose (RP2D) of ibrutinib in combination with bortezomib in patients with relapsed or refractory Mantle cell Lymphoma (MCL). The primary objective of the phase II is to define the efficacy of ibrutinib in combination with bortezomib in patients with relapsed or refractory Mantle cell Lymphoma.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 none
    Evidence for comparator
    		 none
    Actual start date of recruitment
    31 Aug 2015
    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
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Switzerland: 31
    Worldwide total number of subjects
    55
    EEA total number of subjects
    24
    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)
    13
    From 65 to 84 years
    41
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment phase started on 31-Aug-2015 and and ended on 30-Mar-2021 after the recruitment of 58 patients (including three patients being enrolled in Phase I, receiving the lower study drug dose and thus not passing over to Phase II). Patients were enrolled at three sites in Germany, three sites in Italy and nine sites in Switzerland.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled. One patient was deemed a screening failure and not included into the trial.

    Period 1
    Period 1 title
    Phase I - Dose Finding
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group [1]
    Arm description
    		 Dose level 1 (lower dose of Ibrutinib)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 on day 1, 4, 8, 11

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    420 mg/day

    Arm title
    		 Group [2]
    Arm description
    		 Dose level 2 (higher dose of Ibrutinib)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 on day 1, 4, 8, 11

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    560 mg/day

    Number of subjects in period 1
    		Group [1] Group [2]
    Started
    3
    6
    Completed
    0
    6
    Not completed
    3
    0
         Receipt of lower dose of ibrutinib in Phase I
    3
    -
    Period 2
    Period 2 title
    Phase II - Enrollment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RP2D
    Arm description
    		 Recommended dose for Phase II from Phase I dose finding
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 on day 1, 4, 8, 11

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    560 mg/day

    Number of subjects in period 2
    		RP2D
    Started
    6
    Completed
    55
    Joined
    49
         Phase II Enrollment
    49
    Period 3
    Period 3 title
    Phase II - Baseline
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RP2D
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 on day 1, 4, 8, 11

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    560 mg/day

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: This was a combined Phase I/Phase II study.
    Number of subjects in period 3
    		RP2D
    Started
    55
    Completed
    55
    Period 4
    Period 4 title
    Phase II - Combination Therapy
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RP2D - Combination Therapy
    Arm description
    		 6 cycles of 21 days each
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 on day 1, 4, 8, 11

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    560 mg/day

    Number of subjects in period 4
    		RP2D - Combination Therapy
    Started
    55
    Completed
    42
    Not completed
    13
         Consent withdrawn by subject
    3
         Unacceptable toxicity
    3
         Progressive disease
    6
         Protocol deviation
    1
    Period 5
    Period 5 title
    Phase II - Maintenance therapy
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RP2D - Ibrutinib Monotherapy
    Arm description
    		 Courses of ibrutinib were repeated every 28-days in the absence of disease progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    560 mg/day

    Number of subjects in period 5
    		RP2D - Ibrutinib Monotherapy
    Started
    42
    Completed
    0
    Not completed
    42
         Stem cell transplantation
    1
         Consent withdrawn by subject
    1
         Unacceptable toxicity
    1
         Study termination by sponsor
    19
         Progressive disease
    15
         Protocol deviation
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RP2D
    Reporting group description
    		 -

    Reporting group values
    		 RP2D Total
    Number of subjects
    		 55 55
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 41 41
        85 years and over
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 43 43

    End points

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    End points reporting groups
    Reporting group title
    Group [1]
    Reporting group description
    		 Dose level 1 (lower dose of Ibrutinib)

    Reporting group title
    Group [2]
    Reporting group description
    		 Dose level 2 (higher dose of Ibrutinib)
    Reporting group title
    RP2D
    Reporting group description
    		 Recommended dose for Phase II from Phase I dose finding
    Reporting group title
    RP2D
    Reporting group description
    		 -
    Reporting group title
    RP2D - Combination Therapy
    Reporting group description
    		 6 cycles of 21 days each
    Reporting group title
    RP2D - Ibrutinib Monotherapy
    Reporting group description
    		 Courses of ibrutinib were repeated every 28-days in the absence of disease progression or unacceptable toxicity.

    Subject analysis set title
    FAS (Phase II)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The phase II full analysis set was defined as all patients registered in phase II and patients from phase I treated with the RP2D, excluding patients who (i) failed to satisfy major eligibility criteria or (ii) failed to receive at least one dose of both ibrutinib AND bortezomib. Patients excluded from the phase II full analysis set were replaced.

    Primary: Phase II | Primary endpoint (OR during combination therapy) - 1/2

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    End point title
    		 Phase II | Primary endpoint (OR during combination therapy) - 1/2 [1]
    End point description
    ORR defined as the proportion of patients whose best overall response, is either complete response (CR), complete response unconfirmed (CRu) or partial response (PR) according to the International Working group criteria for NHL. The primary endpoint of phase II is OR observed during the combination therapy. Tumor assessments until 21 days after the end of the last treatment cycle started with both trial drugs, were considered. [CR: 16.4%; CRu: 5.5%; PR: 60.0%; SD: 9.1%; PD: 7.3%; not assessed: 1.8%]
    End point type
    Primary
    End point timeframe
    Start of trial treatment up to 14 days (tolerance +7 days) after end of last cycle.
    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: This was a single arm study.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: OR (%) incl. 90% CI (Clopper- Pearson)
        number (confidence interval 90%)
    81.8 (71.1 to 89.8)
    No statistical analyses for this end point

    Primary: Phase II | Primary endpoint (OR during combination therapy) - 2/2

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    End point title
    		 Phase II | Primary endpoint (OR during combination therapy) - 2/2 [2]
    End point description
    ORR defined as the proportion of patients whose best overall response, is either complete response (CR), complete response unconfirmed (CRu) or partial response (PR) according to the International Working group criteria for NHL. The primary endpoint of phase II is OR observed during the combination therapy. Tumor assessments until 21 days after the end of the last treatment cycle started with both trial drugs, were considered. [CR: 16.4%; CRu: 5.5%; PR: 60.0%; SD: 9.1%; PD: 7.3%; not assessed: 1.8%]
    End point type
    Primary
    End point timeframe
    Start of trial treatment up to 14 days (tolerance +7 days) after end of last cycle.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a single arm study.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: OR (%) incl. 95% CI (Clopper- Pearson)
        number (confidence interval 95%)
    81.8 (69.1 to 90.9)
    No statistical analyses for this end point

    Secondary: Phase II | Secondary endpoint (OR during trial treatment) - 1/2

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    End point title
    		 Phase II | Secondary endpoint (OR during trial treatment) - 1/2
    End point description
    OR, as defined for the primary endpoint, but based on the best response observed during trial treatment (including both combination and maintenance therapy). [CR: 34.5%; CRu: 7.3%; PR: 45.5%; SD: 5.5%; PD: 7.3%]
    End point type
    Secondary
    End point timeframe
    Start of trial treatment up to 14 days (tolerance +7 days) after end of last cycle.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: OR (%) incl. 90% CI (Clopper- Pearson)
        number (confidence interval 90%)
    87.3 (77.4 to 93.9)
    No statistical analyses for this end point

    Secondary: Phase II | Secondary endpoint (OR during trial treatment) - 2/2

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    End point title
    		 Phase II | Secondary endpoint (OR during trial treatment) - 2/2
    End point description
    OR, as defined for the primary endpoint, but based on the best response observed during trial treatment (including both combination and maintenance therapy). [CR: 34.5%; CRu: 7.3%; PR: 45.5%; SD: 5.5%; PD: 7.3%]
    End point type
    Secondary
    End point timeframe
    Start of trial treatment up to 14 days (tolerance +7 days) after end of last cycle.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: OR (%) incl. 95% CI (Clopper- Pearson)
        number (confidence interval 95%)
    87.3 (75.5 to 94.7)
    No statistical analyses for this end point

    Secondary: Phase II | Secondary endpoint (PFS)

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    End point title
    		 Phase II | Secondary endpoint (PFS)
    End point description
    Progression free survival (PFS) was calculated from registration until progression of disease or death as a result of any cause. Patients not experiencing an event, including patients receiving a subsequent anti-MCL therapy without documented progressive disease (or relapse after CR), were censored at the last time they were known to be without progression (i.e. last date of tumor assessment without progression) and before the start of a new anti-MCL therapy, if any. NOTE: UPPER LIMIT FOR PFS NOT REACHED. DUMMY DATA "999" FOR UPPER LIMIT ENTERED DUE TO DATABASE RESTRICTIONS.
    End point type
    Secondary
    End point timeframe
    From start until end of study.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: PFS (months)
        median (confidence interval 95%)
    18.6 (12.5 to 999)
    No statistical analyses for this end point

    Secondary: Phase II | Secondary endpoint (TTF)

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    End point title
    		 Phase II | Secondary endpoint (TTF)
    End point description
    Time to treatment failure (TTF) was calculated from registration until treatment failure (due to unacceptable toxicity, progression, patient refusal, death, start of subsequent anti-MCL therapy or any other event that determines the termination of the trial treatment was considered as treatment failure). Patients not experiencing an event were censored at the last time they were known to be under trial treatment.
    End point type
    Secondary
    End point timeframe
    From start until end of study.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    55
    Units: TTFS (months)
        median (confidence interval 95%)
    10.1 (7.0 to 14.4)
    No statistical analyses for this end point

    Secondary: Phase II | Secondary endpoint (DOR)

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    End point title
    		 Phase II | Secondary endpoint (DOR)
    End point description
    Duration of objective response (DOR) was calculated from first observation of CR, CRu or PR until documentation of progression, or relapse thereafter. Only patients with CR, CRu or PR were included in this analysis. Patients without any documentation of progression, or relapse thereafter were censored at the last time they were known to be without progression (i.e. last date of tumor assessment without progression) and before the start of a new anti-MCL therapy, if any. Only patients with CR, CRu or a PR were included in this analysis. NOTE: UPPER LIMIT FOR PFS NOT REACHED. DUMMY DATA "999" FOR UPPER LIMIT ENTERED DUE TO DATABASE RESTRICTIONS.
    End point type
    Secondary
    End point timeframe
    From start until end of study.
    End point values
    		 FAS (Phase II)
    Number of subjects analysed
    48 [3]
    Units: DOR (months)
        median (confidence interval 95%)
    22.7 (12.3 to 999)
    Notes
    [3] - Number of patients with response = 48.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between registration and up to 30 days after end of trial treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 The phase II safety analysis set was defined as all patients who received any dose of trial treatment in phase II and patients from phase I treated with the RP2D.

    Serious adverse events
    		 Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 55 (70.91%)
         number of deaths (all causes)
    17
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Aortic aneurysm repair
    Additional description: Endovascular aneurysm repair and splenic artery embolization
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast tumour excision
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Epididymitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Endocarditis
    Additional description: Bacteremia with gonarthritis and endocarditis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cranial nerve infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences causally related to treatment / all
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    Prostate infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
    Additional description: Sepsis grade 5 due to agranulocytosis in context of lymphoma progression
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 55 (1.82%)
         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
    		 Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 55 (100.00%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    17
    Platelet count decreased
         subjects affected / exposed
    22 / 55 (40.00%)
         occurrences all number
    38
    Vascular disorders
    Haematoma
         subjects affected / exposed
    11 / 55 (20.00%)
         occurrences all number
    17
    Hot flush
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Hypertension
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    8
    Dysgeusia
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    6
    Paraesthesia
         subjects affected / exposed
    9 / 55 (16.36%)
         occurrences all number
    10
    Peripheral motor neuropathy
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 55 (25.45%)
         occurrences all number
    19
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    22 / 55 (40.00%)
         occurrences all number
    42
    Pyrexia
         subjects affected / exposed
    16 / 55 (29.09%)
         occurrences all number
    27
    Influenza like illness
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    8
    Injection site reaction
         subjects affected / exposed
    12 / 55 (21.82%)
         occurrences all number
    18
    Localised oedema
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 55 (20.00%)
         occurrences all number
    14
    Diarrhoea
         subjects affected / exposed
    26 / 55 (47.27%)
         occurrences all number
    47
    Gastritis
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Stomatitis
         subjects affected / exposed
    10 / 55 (18.18%)
         occurrences all number
    20
    Nausea
         subjects affected / exposed
    12 / 55 (21.82%)
         occurrences all number
    16
    Vomiting
         subjects affected / exposed
    9 / 55 (16.36%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    17
    Dyspnoea
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    8
    Epistaxis
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    23
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    10
    Hyperhidrosis
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Rash maculo-papular
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    10
    Myalgia
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    4
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    10
    Bronchitis
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    8
    Lung infection
         subjects affected / exposed
    8 / 55 (14.55%)
         occurrences all number
    13
    Skin infection
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    8
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    11
    Urinary tract infection
         subjects affected / exposed
    4 / 55 (7.27%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 55 (12.73%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2015
    Substantial protocol amendment in order to remove the PET measurements for bone marrow assessment. Due to new discussions with experts for PET imaging it was clarified that the bone marrow involvement for patients with MCL can only be analyzed via PET/CT for a certain subgroup of patients (focal FDG uptake in the bone marrow) and not for the whole patient population of the trial. The PET measurements for bone marrow assessment were therefore deleted in the amended protocol.
    23 Dec 2016
    Substantial protocol amendment in order to update the risk section of the protocol due to the update of the investigator brochure of ibrutinib. In addition, the inclusion criterion 6.1.3 was changed from maximum 2 previous treatment lines to any treatment line. The duration of combination treatment was also updated allowing patients who received at least 4 cycles of ibrutinib and bortezomib (instead of 6 cycles) to proceed with maintenance therapy.
    22 Jun 2018
    Substantial protocol amendment in order to update the adverse event reporting, the implementation of the adapted serious adverse event reporting form and the adaptation of the uncommon side effects section in the protocol due to the release of the new investigator brochure of ibrutinib.
    11 Mar 2019
    Due to low accrual, a substantial amendment has been issued in order to allow an interim efficacy analysis once the first 31 patients of phase II have completed the combination therapy. The continuation of the trial should have depended on the outcome of this analysis.

    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.
    Primary and final analysis was performed after all patients in the Phase II FAS completed combination therapy. Originally, final analysis was planned after trial termination (LPLV). However, the trial was terminated after primary analysis.
    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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