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    Clinical Trial Results:
    A PHASE 2, MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY TO DETERMINE THE EFFICACY AND SAFETY OF SINGLE-AGENT LENALIDOMIDE (REVLIMID®) IN PATIENTS WITH MANTLE CELL NHL WHO HAVE RELAPSED OR PROGRESSED AFTER TREATMENT WITH BORTEZOMIB OR ARE REFRACTORY TO BORTEZOMIB

    Summary
    EudraCT number
    2007-007756-34
    Trial protocol
    BE   DE   ES   AT   HU   FR   IT   GB  
    Global end of trial date
    08 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Nov 2018
    First version publication date
    24 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-5013-MCL-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00737529
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Lei Zhang, MD, Celgene Corporation, 01 908-673-2464, lei_zhang@celgene.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the tumor response and duration of response of lenalidomide monotherapy in patients with mantle cell lymphoma (MCL) who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib.
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice including the archiving of essential documents.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Jan 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Regulatory reason
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 72
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Worldwide total number of subjects
    134
    EEA total number of subjects
    35
    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)
    49
    From 65 to 84 years
    85
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled and treated at 42 centers in 12 countries: US/ Puerto Rico, France, Israel, Belgium, Spain, Turkey, Austria, Hungary, Italy, Colombia, Germany, and Singapore.

    Pre-assignment
    Screening details
    All participants were required to have local histologic confirmation of Mantle Cell Lymphoma (MCL) for entry into the study.

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

    Arms
    Arm title
    Lenalidomide
    Arm description
    Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function

    Number of subjects in period 1
    Lenalidomide
    Started
    134
    Completed
    1
    Not completed
    133
         Protocol deviation
             1
         Disease Progression
             95
         Adverse event, serious fatal
             4
         Adverse event, non-fatal
             24
         Unspecified
             4
         Consent withdrawn by subject
             5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.

    Reporting group values
    Lenalidomide Total
    Number of subjects
    134 134
    Age, Customized
    Units: Subjects
        <65
    49 49
        ≥ 65
    85 85
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    67.2 ± 8.38 -
    Sex: Female, Male
    Units: Subjects
        Female
    26 26
        Male
    108 108
    Race/Ethnicity, Customized
    Units: Subjects
        White or Caucasian
    128 128
        Asian
    3 3
        Black or African American
    1 1
        Other
    2 2
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Eastern Cooperative Oncology Group Performance Status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        0 = (Fully Active)
    43 43
        1 = (Restrictive but ambulatory)
    73 73
        2 = (Ambulatory but unable to work)
    17 17
        3 = (Limited self care)
    1 1
        4 = (Completely Disabled)
    0 0
    Renal function at baseline
    Participants with a Creatinine clearance (as calculated by the Cockcroft-Gault formula, utilizing actual body weight or ideal body weight, whichever was less) of ≥ 60 mL/min received a starting dose of 25 mg once daily. Participants with moderate renal insufficiency (ie, CrCl ≥ 30 mL/min but < 60 mL/min) received a starting dose of 10 mg lenalidomide once daily.
    Units: Subjects
        Normal (CrCl > = 60 mL/min)
    99 99
        Moderate Renal Insufficiency (CrCl ≥ 30 and < 60mL
    28 28
        Severe Renal Insufficiency (CrCl < 30 mL/min)
    1 1
        Missing
    6 6
    Duration of Mantle Cell Lymphoma
    Units: Subjects
        <3 years|
    52 52
        ≥ 3 years|
    82 82
    MCL (Ann Arbor) Stage at Diagnosis
    Ann Arbor staging is the staging system for lymphomas, both in Hodgkin's lymphoma (previously called Hodgkin's disease) and Non-Hodgkin lymphoma (NHL). Stage I = Involvement of 1 Lymph Node (LN) or extralymphatic region; Stage II = ≥ 2 LN sites on the same side of the diaphragm; Stage III = LN regions on both sides of the diaphragm; may include spleen and 1 extralymphatic organ; Stage IV = involvement of ≥ 1 extralymphatic organs with or without associated LN involvement (diffuse or disseminated).
    Units: Subjects
        Stage I
    2 2
        Stage II
    5 5
        Stage III
    19 19
        Stage IV
    105 105
        Missing
    3 3
    MCL International Prognostic Index (MIPI) Score Group at Enrollment
    A prognostic index predictive of the outcome in advanced Mantle Cell Lymphoma
    Units: Subjects
        Low
    39 39
        Intermediate
    51 51
        High
    39 39
        Missing
    5 5
    Prior Bone Marrow Assessment
    Baseline assessment of bone marrow involvement was not required per protocol; however, bone marrow biopsy and aspirate data previously conducted were collected if available.
    Units: Subjects
        Positive
    55 55
        Negative
    52 52
        Indeterminate
    8 8
        Missing
    19 19
    Tumor Burden
    Defined as at least one lesion that was ≥ 5 cm in diameter or ≥ 3 lesions that were ≥ 3 cm in diameter by central radiology review.
    Units: Subjects
        High = having 1 lesion ≥ 5 cm or 3 lesions ≥ 3cm
    78 78
        Low = < 5cm lesions
    54 54
        Missing = unable to characterize
    2 2
    Bulky Disease
    Bulky disease is defined as at least one lesion ≥ 7 cm in diameter
    Units: Subjects
        Yes
    44 44
        No
    88 88
        Missing
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.

    Primary: Percentage of Participants who Achieved an Overall Response According to the Independent Review Committee (IRC)

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    End point title
    Percentage of Participants who Achieved an Overall Response According to the Independent Review Committee (IRC) [1]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants whose best response was Complete Response, Complete Response unconfirmed or Partial Response. Subjects who had discontinued before any response had been observed, or changed to other anti-lymphoma treatments before response had been observed, were considered as non-responders. Tumor Response was assessed by a modification of the International Lymphoma Workshop Response Criteria, IWRC; CR = defined as the disappearance of all clinical and radiographic evidence of disease; CRu = defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow; PR = defined ≥50% decrease in 6 largest nodes or nodal masses. ITT population included all enrolled participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    From Day 1 of study treatment to progession or early treatment discontinuation; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days.
    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: There was no statistical analysis performed.
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: percentage of participants
        number (confidence interval 95%)
    29.9 (22.26 to 38.36)
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Duration of Response (DoR) According to the Independent Review Committee

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    End point title
    Kaplan Meier Estimate of Duration of Response (DoR) According to the Independent Review Committee
    End point description
    Kaplan Meier estimate for the duration of response (DoR) was calculated from the date of the first occurrence of initial response for responders (demonstrating evidence of at least a PR) to the date of first documented disease progression (any new lesion or increase by ≥ 50% of previously involved sites from nadir) or death (without documented progression) for participants who responded; participants who had not progressed (or died) were censored at the last valid assessment. Included participants from the ITT population who achieved a PR or better
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days.
    End point values
    Lenalidomide
    Number of subjects analysed
    40
    Units: months
        median (confidence interval 95%)
    16.64 (10.4219 to 29.8191)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Complete Response (CR) /Complete Response Unconfirmed (CRu) According to the Independent Review Committee

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    End point title
    Percentage of Participants with a Complete Response (CR) /Complete Response Unconfirmed (CRu) According to the Independent Review Committee
    End point description
    The percentage of participants whose best response was CR or CRu. Participants who had discontinued before CR/CRu was observed, or changed to other anti-lymphoma treatments before a CR/CRu response had been observed, were considered as non-responders. CR is defined as the disappearance of all clinical and radiographic evidence of disease; CRu is defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow. The ITT population was defined as all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: percentage of participants
        number (confidence interval 95%)
    9.0 (4.71 to 15.12)
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Duration of Complete Response (DoCR) (CR+CRu) According to the Independent Review Committee

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    End point title
    Kaplan Meier Estimate of Duration of Complete Response (DoCR) (CR+CRu) According to the Independent Review Committee
    End point description
    Kaplan Meier estimates for the duration of CR/CRu was calculated from the date of the first occurrence of CR/CRu to the date of documented disease progression or death (without documented progression) for participants who obtained a CR/CRu; participants who had not progressed (or died) were censored at the last valid assessment. Includes participants from the ITT population who achieved a CRu or better. 99999 indicates upper limit not estimable at the time of final data cut off.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to progression or early discontinuation; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months
    End point values
    Lenalidomide
    Number of subjects analysed
    12
    Units: months
        median (confidence interval 95%)
    24.43 (5.063 to 99999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Progression-Free Survival (PFS) According to the Independent Review Committee

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    End point title
    Kaplan-Meier Estimate of Progression-Free Survival (PFS) According to the Independent Review Committee
    End point description
    Kaplan Meier estimates of PFS was defined as the start of study drug therapy to the first observation of disease progression or death due to any cause, whichever comes first. If a participant had not progressed or died, PFS was censored at the time of last adequate assessment when the participant was known not to have progressed. For participants who received other anti-lymphoma therapy with no evidence of progression, PFS was censored at time of last adequate tumor assessment with no evidence of progression prior to the start of new anti-lymphoma treatment. ITT population defined as all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to first documented date of disease progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: months
        median (confidence interval 95%)
    4.01 (3.6822 to 7.2329)
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Time to Progression (TTP) According to the Independent Review Committee

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    End point title
    Kaplan Meier Estimate of Time to Progression (TTP) According to the Independent Review Committee
    End point description
    Kaplan Meier estimate of time to progression was calculated as time from the start of the study drug therapy to the first observation of disease progression. Participants who died without progression were censored at the date of death; otherwise, the censoring rules presented above for PFS applied to the analysis of TTP. Progressive Disease(PD): Appearance of new lesion or increase by ≥50% from previously involved sites from nadir. ITT population was defined as all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to first documented time of progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: months
        median (confidence interval 95%)
    5.46 (3.7479 to 9.4685)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Time to Treatment Failure (TTF) According to the Independent Review Committee

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    End point title
    Kaplan-Meier Estimate of Time to Treatment Failure (TTF) According to the Independent Review Committee
    End point description
    Time to treatment failure (TTF) was calculated from the start of study drug therapy to early discontinuation from treatment due to any cause, including disease progression, toxicity, or death and was based on site-reported data. ITT population was defined as all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to first documented time of treatment failure; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: months
        median (confidence interval 95%)
    3.75 (2.3342 to 4.6356)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    Time to Response (TTR)
    End point description
    Time to Response was defined as the time from first dose of study drug to the date of the first response (having at least a PR) and was calculated only for responding participants. Included participants from the ITT population who achieved a PR or better
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to time of first documented PR or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days
    End point values
    Lenalidomide
    Number of subjects analysed
    40
    Units: months
        median (full range (min-max))
    3.5 (1.7 to 15.9)
    No statistical analyses for this end point

    Secondary: Time to Complete Response (CR+CRu) According to the Independent Review Committee

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    End point title
    Time to Complete Response (CR+CRu) According to the Independent Review Committee
    End point description
    Time to Complete Response (CR+CRu) was defined as the time from the first dose of study drug to the date of the first occurrence of at least CRu and was calculated only for participants with CR or CRu. Included participants from the ITT population who achieved a CRu or better.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to first documented CR/CRu or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days
    End point values
    Lenalidomide
    Number of subjects analysed
    12
    Units: months
        median (full range (min-max))
    3.9 (1.9 to 13.0)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Kaplan Meier estimate of overall survival was calculated from the time the first dose of study drug to death from any cause. Participants who had not died were censored at the last date the participant was known to be alive. Intent to Treat population defined as all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug to first documented date of progressive disease or death; up to the final data cut-off date of 30 March 2017; median duration of follow-up for surviving participants was 62.94 months
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: months
        median (confidence interval 95%)
    19.50 (13.6767 to 25.5781)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    AEs were assessed using National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3: according to the following scale: Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe and Undesirable AE, Grade 4 = Life-threatening or Disabling AE, and Grade 5 = Death; Serious AEs (SAEs) = resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above after the first dose of study drug and within 28 days after the last dose. A TEAE = any AE occurring or worsening on or after the first dose of IP and within 28 days after the last dose of IP. Included those in the safety population who received at least one dose of lenalidomide.
    End point type
    Secondary
    End point timeframe
    From the first dose of lenalidomide through 28 days after the last dose during the follow-up phase; median (minimum, maximum) duration of treatment was 94.0 (1.0, 1950 days)
    End point values
    Lenalidomide
    Number of subjects analysed
    134
    Units: participants
        Any TEAE
    132
        Any TEAE Related to Investigational Product (IP)
    118
        Any TEAE Grade 3-5 AE
    106
        Any TEAE Grade 3 AE
    101
        Any TEAE Grade 4 AE
    57
        Any TEAE Grade 5 AE
    18
        Any Grade 3-5 AE Related to IP
    90
        Any Grade 3 AE Related to IP
    88
        Any Grade 4 AE Related to IP
    41
        Any Grade 5 AE Related to IP
    2
        Any TEAE Serious Adverse Event (SAE)
    70
        Any SAE Related to IP
    30
        Any TEAE Leading to Discontinuation (D/C) of IP
    28
        Any Treatment Related AE Leading to D/C of IP
    16
        Any AE Leading to Dose Reduction
    55
        Any AE Leading to IP Interruption
    81
        Any Treatment Related AE Leading to Dose Reduction
    52
        Treatment Related AE Leading to IP Interruption
    66
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of lenalidomide through 28 days after the last dose of lenalidomide; maximum duration of study drug was 1940 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.

    Serious adverse events
    Lenalidomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 134 (52.24%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    2
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    2 / 2
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    MANTLE CELL LYMPHOMA
         subjects affected / exposed
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    5 / 5
    MENINGIOMA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    METASTATIC SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    1 / 18
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    ASTHENIA
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    2 / 2
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PYREXIA
         subjects affected / exposed
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    4 / 8
         deaths causally related to treatment / all
    1 / 1
    SUDDEN DEATH
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    FALL
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    CREATININE RENAL CLEARANCE DECREASED
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    1 / 1
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    OBSTRUCTIVE AIRWAYS DISORDER
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    LEUKOCYTOSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences causally related to treatment / all
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    LYMPH NODE PAIN
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LYMPHOCYTOSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MIGRAINE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    TRANSIENT GLOBAL AMNESIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ASCITES
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    FAECES DISCOLOURED
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INTRA-ABDOMINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INTESTINAL ISCHAEMIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    BLADDER NECK OBSTRUCTION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN TOXICITY
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    NECK PAIN
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    GOUT
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    CELLULITIS
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    ENTEROCOCCAL SEPSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LOBAR PNEUMONIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences causally related to treatment / all
    5 / 10
         deaths causally related to treatment / all
    2 / 2
    PNEUMONIA KLEBSIELLA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    PSEUDOMONAL SEPSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SEPSIS
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    1 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    STREPTOCOCCAL BACTERAEMIA
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lenalidomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 134 (93.28%)
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences all number
    9
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences all number
    9
    WEIGHT DECREASED
         subjects affected / exposed
    20 / 134 (14.93%)
         occurrences all number
    26
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR FLARE
         subjects affected / exposed
    13 / 134 (9.70%)
         occurrences all number
    16
    Respiratory, thoracic and mediastinal disorders
    DYSPHONIA
         subjects affected / exposed
    9 / 134 (6.72%)
         occurrences all number
    11
    COUGH
         subjects affected / exposed
    41 / 134 (30.60%)
         occurrences all number
    57
    DYSPNOEA
         subjects affected / exposed
    24 / 134 (17.91%)
         occurrences all number
    35
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    14 / 134 (10.45%)
         occurrences all number
    15
    PLEURAL EFFUSION
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    42 / 134 (31.34%)
         occurrences all number
    84
    LEUKOPENIA
         subjects affected / exposed
    22 / 134 (16.42%)
         occurrences all number
    60
    LYMPHOPENIA
         subjects affected / exposed
    10 / 134 (7.46%)
         occurrences all number
    20
    NEUTROPENIA
         subjects affected / exposed
    68 / 134 (50.75%)
         occurrences all number
    396
    THROMBOCYTOPENIA
         subjects affected / exposed
    51 / 134 (38.06%)
         occurrences all number
    140
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences all number
    9
    DYSGEUSIA
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    9
    HEADACHE
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    9
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    9 / 134 (6.72%)
         occurrences all number
    13
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    18 / 134 (13.43%)
         occurrences all number
    22
    CHILLS
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    10
    OEDEMA PERIPHERAL
         subjects affected / exposed
    22 / 134 (16.42%)
         occurrences all number
    28
    FATIGUE
         subjects affected / exposed
    47 / 134 (35.07%)
         occurrences all number
    85
    PYREXIA
         subjects affected / exposed
    30 / 134 (22.39%)
         occurrences all number
    54
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    11 / 134 (8.21%)
         occurrences all number
    11
    INSOMNIA
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    10
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    10 / 134 (7.46%)
         occurrences all number
    18
    CONSTIPATION
         subjects affected / exposed
    21 / 134 (15.67%)
         occurrences all number
    25
    DIARRHOEA
         subjects affected / exposed
    45 / 134 (33.58%)
         occurrences all number
    107
    VOMITING
         subjects affected / exposed
    16 / 134 (11.94%)
         occurrences all number
    23
    NAUSEA
         subjects affected / exposed
    41 / 134 (30.60%)
         occurrences all number
    50
    Skin and subcutaneous tissue disorders
    DRY SKIN
         subjects affected / exposed
    10 / 134 (7.46%)
         occurrences all number
    10
    NIGHT SWEATS
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    8
    PRURITUS
         subjects affected / exposed
    23 / 134 (17.16%)
         occurrences all number
    33
    RASH
         subjects affected / exposed
    30 / 134 (22.39%)
         occurrences all number
    55
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    12 / 134 (8.96%)
         occurrences all number
    13
    BACK PAIN
         subjects affected / exposed
    19 / 134 (14.18%)
         occurrences all number
    19
    MUSCLE SPASMS
         subjects affected / exposed
    17 / 134 (12.69%)
         occurrences all number
    35
    PAIN IN EXTREMITY
         subjects affected / exposed
    9 / 134 (6.72%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    21 / 134 (15.67%)
         occurrences all number
    30
    DEHYDRATION
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    10
    HYPOCALCAEMIA
         subjects affected / exposed
    7 / 134 (5.22%)
         occurrences all number
    8
    HYPOKALAEMIA
         subjects affected / exposed
    19 / 134 (14.18%)
         occurrences all number
    25
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    12
    PNEUMONIA
         subjects affected / exposed
    8 / 134 (5.97%)
         occurrences all number
    10
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    9 / 134 (6.72%)
         occurrences all number
    13
    SINUSITIS
         subjects affected / exposed
    9 / 134 (6.72%)
         occurrences all number
    15
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    20 / 134 (14.93%)
         occurrences all number
    34

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2009
    1. Clarified that the determination of tumor response and DOR was based on the 1999 IWRC. 2. Clarified that the evaluation of response using FDG-PET scans was based on the 2007 IWRC and that this was an exploratory evaluation. 3. Clarified that all exploratory objectives were optional for both sites and subjects. 4. Clarified that the requirement for collection of bone marrow biopsy/aspirate in cases of radiologic CR were to be obtained within 28 days from the scan confirming the CR. 5. Added language to further outline the medical management of TLS, including grading and treatment based on local standard of care with vigorous IV hydration and rasburicase. 6. Added guidance on the detection of TEEs. 7. Clarified Exclusion Criterion 6 that subjects who were candidates for high-dose chemotherapy/autologous or allogeneic transplant at the time of enrollment were not eligible unless other conditions were clearly documented (see Section 9.3.1). 8. Removed Exclusion Criterion 14, subjects with ≥ Grade 2 neuropathy. 9. Added dose modifications for subjects who developed Grade 3 peripheral neuropathy and for subjects who developed abnormal liver enzymes on study. 10. Clarified that the preferred method for assessment of tumor burden was conventional (or spiral) CT with contrast and that CT scans without contrast could be used but were not preferred. 11. Clarified that both target and non-target lesions were to be considered when assessing response and date of progression. 12. Clarified that radiographic assessments of tumor lesions were to be obtained every 56 days (± 7 days) from Cycle 1, Day 1. 13. Added language that subjects who discontinued from treatment who had not progressed were to be followed every 56 days (± 7 days) and that scans were required every 90 days (± 14 days) until PD or subsequent anti-lymphoma treatment.
    12 Mar 2010
    1. Based on a recommendation from a European Union competent authority, the section on VTEs was updated to clarify that the investigators should choose the most appropriate antithrombotic prophylaxis for each subject, taking into account the individual thrombotic risk (eg, history of venous thrombosis), bleeding risk, and the quality of compliance with antithrombotic treatment. 2. Shortened the steroid washout period from 4 weeks to 1 week and permitted treatment of exacerbated conditions with peak doses of steroids > 10 mg for a limited time. 3. Clarified Exclusion Criterion 3 for elevated serum total bilirubin and elevated AST or ALT. Subjects with serum total bilirubin > 1.5 x ULN were excluded, except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma. Subjects with ALT or AST > 3.0 x ULN were excluded, except those with documented liver involvement by lymphoma. 4. Dose modifications for subjects with abnormal liver function were clarified and aligned with the exclusion criterion regarding exceptions. 5. Added dose modifications for TFR and TLS. 6. Added an allowance for more than one dose reduction per cycle after consultation with the clinical research physician. 7. Changed the timing of study termination to occur after 70% of the subjects had died or a maximum of 4 years from enrollment of the last subject, whichever occurred first.
    11 Apr 2011
    1. Added the requirement that SPMs be treated as SAEs and reported from the time of informed consent up to and including study termination. 2. Clarified that tumor/lymph node biopsy specimens were to be sent to the central pathology laboratory for confirmation of MCL preferably before enrollment, but no later than 8 weeks after enrollment. 3. Added an allowance for bone marrow aspirates/biopsies to be used in rare situations when archival tumor tissue specimens were not available and re-biopsy was not possible or put the subject at risk. 4. Added an allowance for baseline radiographic scans to be conducted > 28 days prior to Cycle 1, Day 1 with prior clinical research physician approval to limit subject exposure to radiation. 5. Removed the requirement for collecting time of, and best response to, first anti-lymphoma treatment used after discontinuation from this study. 6. For sites in Germany, the following change was also included in Amendment 3.0 DE: Per the Health Authority, removed the requirement that the investigator obtain clinical research physician approval for a second dose reduction within a cycle.
    05 Aug 2011
    1. Based on a Health Authority request, added back in the requirement for collecting time of and best response to first anti-lymphoma treatment used after discontinuation from this study.
    12 Oct 2011
    1. Expanded Exclusion Criterion 10 to require subjects to be free of any other malignancies except for MCL for at least 5 years (from at least 3 years) prior to study entry. This resulted from multivariate analyses conducted by the sponsor that demonstrated that subjects with a history of prior invasive malignancies are at risk for developing another malignancy during lenalidomide-containing therapy. 2. Increased the follow-up time for subjects for the reporting of cases of SPM from 4 to 5 years after enrollment of the last subject.
    16 Jul 2012
    1. The timing of the treatment phase CT or MRI diagnostic imaging was modified to occur every 56 (± 7days) for the first 2 years and then every 4 months (± 2 weeks) until disease progression or start of a new anti-lymphoma therapy.
    12 Sep 2013
    1. Based on a postmarketing commitment issued by the FDA, the follow-up of all subjects, for both safety and efficacy, was to continue for 4 years from date the last subject enrolled, or until the time of 100% of subjects died, were lost to follow-up, or had withdrawn consent, whichever came first. 2. The follow-up time for subjects for the reporting of cases of SPM was updated to require 4 years of follow-up from date the last subject enrolled in order to concur with the 4-year follow-up of safety and efficacy.
    16 May 2014
    1. The SPM follow-up was extended from 4 to 5 years after last subject enrolled, until the time 100% of patients died, are lost to follow-up or have withdrawn consent, whichever comes first. (The efficacy follow-up was to remained unchanged at 4 years.)

    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
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