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    Clinical Trial Results:
    A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma.

    Summary
    EudraCT number
    		 2009-011020-65
    Trial protocol
    		 DE   FR   AT   FI   DK   ES   GB   NL   BE  
    Global end of trial date
    02 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2016
    First version publication date
    10 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EORTC 21081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01098656
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    Scientific contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    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
    08 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The overall objective is to determine if maintenance treatment with lenalidomide prolongs response after debulking in patients with advanced stage cutaneous T-cell lymphoma (CTCL) who have not been previously treated with intravenous chemotherapy except the chemotherapy received in the preceeding debulking stage. Patients will be randomized to either receive the maintenance therapy or not, and these two study arms will be compared in terms of the difference in progression free survival (PFS). Despite early closure and as the study population is a very rare disease, it was decided by the study coodinator and the team to have the final analysis for the trial adressing: - information related to randomization failures - baseline information - treatment information - descriptive information on primary endpoint: progression-free survival - toxicity
    Protection of trial subjects
    The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice. The protocol must be approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 No background therapy
    Evidence for comparator
    		 No active comparator
    Actual start date of recruitment
    20 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Worldwide total number of subjects
    30
    EEA total number of subjects
    29
    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)
    16
    From 65 to 84 years
    13
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 - Advanced stage mycosis fungoides (stage IIB-IV), or Sézary Syndrome. - Prior debulking therapy with either mono-chemotherapy, Poly-chemotherapy/combination chemo and radiotherapy or radiotherapy alone (e.g. Total Skin Electron Beam body radiation [TSEB]) (according to local institutional guidelines) resulting in complete or partial response

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Number of subjects completed
    		 21

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 progressive disease: 7
    Reason: Number of subjects
    		 other: 2
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenalidomide
    Arm description
    		 Maintenance Lenalidomide: Treatment should be administered until documented disease progression, unacceptable toxicity, or patient refusal. The maximum duration of treatment, calculated in calendar days from the first dose of drug, is 560 days. After that time, the patient will be considered to have completed protocol treatment.
    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
    Lenalidomide capsules should be taken at about the same time each day. The capsules should not be broken or chewed. The capsules should be swallowed whole, preferably with water, either with or without food. If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day. Initial Dose The starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Dosing is continued or modified based upon clinical and laboratory findings as described in the section on "Dose Modification", in the protocol. For patients allocated to the lenalidomide arm, the first treatment dose must be given within 7 days of randomization.

    Arm title
    		 Observation
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Lenalidomide Observation
    Started
    9
    12
    Started allocated treatment
    8
    12
    Completed
    0
    1
    Not completed
    9
    11
         Consent withdrawn by subject
    1
    -
         Treatment not started
    1
    -
         Lost to follow-up
    -
    1
         Adverse event, non-fatal
    1
    -
         Progression
    5
    9
         other
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 30 patients were registered but only 21 patients were randomized. Reasons of non-randomization are given in the pre-assignement period. All results are presented on randomized patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    		 Maintenance Lenalidomide: Treatment should be administered until documented disease progression, unacceptable toxicity, or patient refusal. The maximum duration of treatment, calculated in calendar days from the first dose of drug, is 560 days. After that time, the patient will be considered to have completed protocol treatment.

    Reporting group title
    Observation
    Reporting group description
    		 -

    Reporting group values
    		 Lenalidomide Observation Total
    Number of subjects
    		 9 12 21
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 6 11
        From 65-84 years
    		 3 6 9
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (38 to 87) 64 (53 to 74) -
    Gender categorical
    Gender: Male or Female
    Units: Subjects
        Female
    		 5 8 13
        Male
    		 4 4 8
    Was the patient diagnosed with advanced stage mycosis fungoides (stage IIB-IV),or Sézary syndrome
    Stratification factor for the randomization
    Units: Subjects
        Mycosis fungoides
    		 8 10 18
        Sézary syndrome
    		 1 2 3
    Overall Response to primary debulking therapy
    Stratification factor for the randomization
    Units: Subjects
        CCR
    		 2 3 5
        PR
    		 7 9 16
    Performance Status
    WHO performance status
    Units: Subjects
        0 (Zero)
    		 7 9 16
        1 (One)
    		 2 2 4
        2 (Two)
    		 0 1 1
    Primary debulking
    Primary debulking therapy before entry into the trial according to the recommended debulking regimens specified by protocol
    Units: Subjects
        Gemcitabine
    		 5 10 15
        Liposomal doxorubicin
    		 3 2 5
        Gemcitabine-liposomal doxorubicin switch (or vice
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    		 Maintenance Lenalidomide: Treatment should be administered until documented disease progression, unacceptable toxicity, or patient refusal. The maximum duration of treatment, calculated in calendar days from the first dose of drug, is 560 days. After that time, the patient will be considered to have completed protocol treatment.

    Reporting group title
    Observation
    Reporting group description
    		 -

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    Progression free survival will be measured from the date of randomization to either the date that progressive disease was objectively documented or, in the absence of progressive disease, death. If progression has not been observed and the patient is still alive, the patient will be censored at the date of the last examination.
    End point type
    Primary
    End point timeframe
    From randomization till end of study
    End point values
    		 Lenalidomide Observation
    Number of subjects analysed
    9
    12
    Units: months
        median (confidence interval 95%)
    5.3 (1.9 to 22.5)
    2 (0.9 to 7.8)
    Attachments
    		 PFS
    Statistical analysis title
    		 PFS comparison in intent to treat population
    Statistical analysis description
    Hazard ratio was estimated from Cox-Regression
    Comparison groups
    Lenalidomide v Observation
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 1.49
    Notes
    [1] - Given the circumstances of the study which was closed early with only less than 20% of the originally foreseen number of patients accrued, p-value for progression free survival (PFS) comparison should be interpreted carefully was not reported.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected on a CRF to be submitted at pre-specified timepoint: at pre-treatment workup, before each cycle (Lenaledomide arm) or every 8 weeks (observation), and 4 weeks after end of last treatment / observation visit
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (1% of AEs are reported as "other" and are not reported as not available from the list of SOC). AEs are evaluated using CTC v4, SAEs using MedDra. Non-SAEs has not been collected specifically, therefore all AEs (any grade) will be reported in non-SAE section.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Observation
    Reporting group description
    		 Safety population: all patients who started allocated treatment

    Reporting group title
    Lenaledomide
    Reporting group description
    		 Safety population: all patients who started allocated treatment

    Serious adverse events
    		 Observation Lenaledomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: From pharmacovigilance database
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Observation Lenaledomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
    7 / 8 (87.50%)
    Investigations
    Weight gain
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Weight loss
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Cardiac disorders
    Sinus bradycardia
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Other toxicity
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    7
    Paresthesia
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Edema limbs
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    4
    Fatigue
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 8 (50.00%)
         occurrences all number
    3
    19
    Immune system disorders
    Allergic reaction
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Constipation
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Diarrhea
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    13
    Nausea
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Erythema multiforme
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    7
    Periorbital edema
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Pruritus
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 12 (16.67%)
    4 / 8 (50.00%)
         occurrences all number
    3
    6
    Urticaria
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Depression
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory infection
    Additional description: From clinical database. All adverse events (any grade).
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2011
    - To rephrase the debulking regimens criteria and allow sites to follow debulking regimens as per local institutional policies - To extend the registration period (post de-bulking) up to 2 weeks - To add the possibility of biobanking biological material samples for use in future research - To clarify the TR sections - To add pregnancy as withdrawal criteria - Some administrative changes Other documents submitted together with the amendment to the protocol: - the updated version of the IMP’s labels used in this trial to include the address of the sponsor, EORTC. - the updated version of the Investigator’s brochure of Lenalidomide version 14 dated 17 December 2010 .together with the Line Listing (from 16-Jul-2010 to 15-Oct-2010) and the Updated Benefit Risk Assessment and
    11 May 2011
    Due to a shortage of drug, the protocol has been updated so the patients can receive Gemcitabine as an alternative. Although, it may not been available in Belgium. So, as a temporary as a temporary measure until the quality and supply issues of Caelyx are resolved, Belgium may use all drugs of the liposomal doxorubicin class, as per locally applicable policy at participating centres.
    04 Oct 2012
    Rationale for the amendment and its classification: • The company supplying the study drug gave information about an update of the Pregnancy Prevention Program (PPP), leading to changes of the pregnancy • tests frequencies/methods to be implemented in the protocol and PIS/IC. The Program leads also to the implementation of new note to file to be signed by • the Principal Investigator (PI) and reminders that the patient needs to be aware of pregnancy risks before each drug dispensing. As more information will be given in the PIS/IC, the reference to a separate brochure for the partner mentioned in the protocol will be removed. • Addition of monetary support for the trial • Addition of central technical facilities • Addition of subcontractors The timelines of SAE pregnancy reporting are updated from 24h to immediate, as per request of the company. This amendment also includes clarification of the debulking regimens allowed in order to add flexibility in order to match more real clinical practice. Therefore, stratification factors will be modified, as well as the title of the protocol. The amendment also includes: - clarification on the CT-scan and disease assessment frequency - harmonization of the SAE reporting for second primary malignancies - removal of the “Caelyx” trade name in order to permit use of other liposomal doxorubicin agent as Caelyx is encountering a shortage - simplification of the eligibility criteria for registration (unnecessary redundant tests at both registration and randomization are removed) - removal of “2 week” timelines of the registration period - clarification of retention period for study documentation, monitoring of drug compliance at participating sites etc.as per Swissmedic request - Clarification of AE reporting timelines in chapter 6 - correction of late toxicity definition - change of the drug packaging from bottles to b

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Apr 2013
    The EORTC has been informed by the marketing authorization holder/ the company supplying the study drug (Celgene), Lenalidomide/ Revlimid that it withdraws the financial support for the study. As a consequence financial support to any new patients enrolled after the date of withdrawal cannot be secured. A review of feasibility of the studies for all partners needs to be assessed prior to taking further decisions on the continuation of the study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Less than 20% of the originally foreseen number of patients were acccrued, therefore results should be interpreted carefully
    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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