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    Clinical Trial Results:
    Phase ll Trial of Fludarabine & Cyclophosphamide followed by Thalidomide for Angioimmunoblastic Lymphoma

    Summary
    EudraCT number
    2005-003931-40
    Trial protocol
    GB  
    Global end of trial date
    08 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Dec 2016
    First version publication date
    09 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BRD/05/95
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00958854
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Public Contact, CR UK & UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific Contact, CR UK & UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the response rate of patients treated with FluCy (Fludarabine and cyclophosphamide) chemptherapy.
    Protection of trial subjects
    FluCy chemotherapy can affect the patients’ sperm or egg cells & might harm an unborn child. If there was a chance that a patient or the partner of a patient could become pregnant, they had to agree to use a reliable form of contraception during the trial and for at least 6 months after the last trial treatment. All women of childbearing potential at risk of becoming pregnant had to undergo a pregnancy test at screening or during baseline investigations. If on day 28 of any cycle of FluCy chemotherapy there was persistent grade 3 to 4 haematological toxicity not related to marrow involvement, treatment could be delayed for up to 2 weeks with a reduction in the doses of Fludarabine and Cyclophosphamide by 25%. Supportive care should have been given as per local practice, but since delayed nausea may occur with this regimen, at least 5 days of antiemetic treatment with a 5-HT3 antagonist was recommended. Patients also received Co-Trimoxazole or Pentamidine prophylaxis for at least six months after the end of FluCy chemotherapy & blood EBV levels were monitored. For the prevention of transfusion related graft-versus-host disease, all cellular blood products administered following treatment with Fludarabine had to be irradiated. FluCy has marked stem cell toxicity and peripheral blood progenitor cells should were harvested early in patients considered candidates for high-dose chemotherapy as second line treatment. For grade 1 or 2 toxicities such as constipation, fatigue, sedation, skin rash, tremor or oedema, adequate supportive care should have been provided. For any persistent grade 2 toxicity (grade 1 if neuropathy), the dose escalation should have been halted. For grade 3 or 4 toxicity (grade 2 if neuropathy) Thalidomide should have been discontinued. It should have been resumed at half the dose after one week if the toxicity had subsided. Any persistent grade 3 toxicity (grade 2 if neuropathy) should have led to the discontinuation of Thalidomide treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Mar 2009
    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
    United Kingdom: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    5
    From 65 to 84 years
    9
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All patients with newly diagnosed AITL presenting to one of the trial sites were screened for eligibility to enter this study. The participating investigators kept a complete anonymised log of all patients screened for eligibility who were not registered in the trial either because they were ineligible or because they decline participation.

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

    Arms
    Arm title
    FluCy & Thalidomide
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    FluCy is was given as a three-day regimen repeated every 28 days. Formal restaging was carried out after four cycles of FluCy. If at that point patients had not experienced at least a partial response FluCy was stopped. At the discretion of the treating physician, responding patients who had not achieved a complete remission after four courses of FluCy could be given a maximum of six courses. FluCy was given by mouth as standard for this study. However, in patients with marked disease-related gastrointestinal symptoms or in those with poor tolerability of oral FluCy, the intravenous route of administration could be used after discussion with the chief investigator. Oral fludarabine was given at 40mg/m2, and intravenous fludarabine was given at 25mg/m2

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    FluCy is was given as a three-day regimen repeated every 28 days. Formal restaging was carried out after four cycles of FluCy. If at that point patients had not experienced at least a partial response FluCy was stopped. At the discretion of the treating physician, responding patients who had not achieved a complete remission after four courses of FluCy could be given a maximum of six courses. FluCy was given by mouth as standard for this study. However, in patients with marked disease-related gastrointestinal symptoms or in those with poor tolerability of oral FluCy, the intravenous route of administration could be used after discussion with the chief investigator. Oral cyclophosphamide and intravenous cylophosphamide were given at 250mg/m2

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were on continuous oral Thalidomide four weeks after the beginning of the last cycle of FluCy. Thalidomide 50 mg hard capsules were be prescribed at the initial dose of 100 mg daily. The daily dose was increased by 100 mg every 4 weeks to the maximum of 300 mg. The Thalidomide treatment was to be continued for at least six months, unless disease progression occurred earlier. In responding patients, the continuation of Thalidomide therapy beyond six months was at the discretion of the treating physician.

    Number of subjects in period 1
    FluCy & Thalidomide
    Started
    15
    Completed
    1
    Not completed
    14
         Disease Progression
    6
         Death
    3
         Lack of efficacy
    1
         Allergic reaction to Thalidomide
    1
         Not known
    1
         Adverse event, non-fatal
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Inclusion Criteria • Patients with a new diagnosis of angioimmunoblastic lymphoma and measurable (ie anatomically assessable) disease • WHO/ECOG performance status of 0, 1 or 2 • Age > 18 years • Negative pregnancy test if the patient is of childbearing potential • Prepared to comply with the contraceptive measures stipulated by the Thalidomide Celgene Pregnancy Prevention Programme Signed consent form. Exclusion Criteria • Prior chemotherapy for AITL • Active second malignancy or other concomitant serious medical condition, in particular peripheral neuropathy • Known seropositivity for HBV, HCV or HIV • Breast feeding • Severe impairment of renal or liver function (defined as serum creatinine, bilirubin or alkaline phosphatase > 2.5 times the upper limit of normal).

    Reporting group values
    Overall trial Total
    Number of subjects
    15 15
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    5 5
        From 65-84 years
    9 9
        85 years and over
    1 1
    Gender categorical
    Units: Subjects
        Female
    5 5
        Male
    10 10

    End points

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    End points reporting groups
    Reporting group title
    FluCy & Thalidomide
    Reporting group description
    -

    Primary: Response rate after FluCy chemotherapy

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    End point title
    Response rate after FluCy chemotherapy [1]
    End point description
    End point type
    Primary
    End point timeframe
    Response is assessed following Fludarabine and Cyclophosphamide Chemotherapy
    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: As advised on 23/Jun/16 by Chersoni Raffaella from the EMA service desk: we can post the result without entering the details of the statistical analysis because currently the system cannot accommodate one arm study.
    End point values
    FluCy & Thalidomide
    Number of subjects analysed
    15 [2]
    Units: number of patients with complete respons
        Complete Response (CR)
    5
        Unconfirmed CR
    1
        Partial Response (PR)
    3
        Stable Disease (SD)
    0
        Progressive Disease (PD)
    4
        Not assessable
    2
    Notes
    [2] - Two patients only received one cycle of FluCy and response was not assessable in these patients
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All adverse events that occurred between informed consent and end of trial had to be recorded in the patient notes and the trial CRFs.
    Adverse event reporting additional description
    Grade 3 or 4 haematological toxicity occurred in eight (53%) patients, grade 3 or 4 non-haematological toxicity was experienced in nine (60%) patients
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Fludarabine & cyclophosphamide followed by Thalidomide
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: AE line listings were not reported in the final publication for this study and are therefore not provided on the results database. Grade 3 or 4 haematological toxicity occurred in eight (53%) patients, grade 3 or 4 non-haematological toxicity was experienced in nine (60%) patients.
    Serious adverse events
    Fludarabine & cyclophosphamide followed by Thalidomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 15 (66.67%)
         number of deaths (all causes)
    14
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm, wheezing
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Guillain Barre Syndrome
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Rigors/Chills
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage - upper GI NOS
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
    Additional description: Urine colour change
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection - Upper respiratory
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection with grade 4 neutrophils
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection - Urinary tract infection NOS
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection - normal neutrophils
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection (pneumonia) - lung
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection - Diarrhoea norovirus + campylobactirtive
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection - Lower respiratory tract
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection - normal ANC
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fludarabine & cyclophosphamide followed by Thalidomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2006
    All reference to Thalidomide supplied by Pharmion has been removed from the protocol. The Thalidomide will now be supplied by Durbin PLC who are acting as agents for the importing company Essential Nutrition Ltd. Durbin do not operate a Risk Management Programme for Thalidomide use, so it has been stipulated in the protocol, that in order for sites to particpate in the study, they must provide evidence that their site and NHS Trust have a Risk management Programme and pregnancy testing schedule in place prior to recruiting patients. Failure to provide such evidence will result in the site being suspended from participating in the study any further. The associated trial documentation such as the PIS and GP letter state that the patient must be willing or shall be monitored through the Risk Management mechanisms in place at their treatment site. The Lymphoma Trials Office has also moved location and this information has now been amended on the protocol.
    01 Dec 2007
    The Thalidomide for the trial will no longer be supplied through Durbin PLC, instead participating sites will be responsible for supplying all of the IMPs for the trial from their own pharmacy stocks. These drugs are Fludarabine, Cyclophosphamide and Thalidomide. This information has been detailed in the protocol under section 21. Clearer information regarding the diagnostic and research samples to be taken has been provided under section 12. The pharmacovigilance section has also be expanded substantially to ensure that all reporting guidelines required by the Regulatory Authorities are met and that there is a robust Risk management and pregnancy testing schedule in place at each site due to the involvement of thalidomide in this trial. The PIS, Consent form and GP letter have been amended accordingly to reflect the various changes made to the protocol.
    20 Jan 2009
    submission of copies of the sample labels to be used in this trial as requested in the CTA notice of acceptance dated 12th April 2006
    05 Feb 2009
    Changes have been made to the protocol, Patient information, consent form and GP letter. The change reflects the current availability and licensing of thalidomide in the UK by the supplier, Pharmion. All sites from now on will be supplied this drug by Pharmion. Name of contact in the general information section was changed, more information was given on the responsibility for the conduct of the study. Information in the safety assessment and pharmacovigilance section and expected adverse events was also changed.
    15 Jun 2009
    To notify that the Leeds Teaching Hospitals NHS Trust clinical trials website will contain information about this trial. This will be limited to the trial title, inclusion and exclusion criteria and primary endpoints.
    21 Jun 2010
    An audit of information about contraception given in Patient Information Sheets (PIS) compared with that given in SmPCs was carried out at our trials centre, and we found that the information in the PIS for this trial was incorrect (ie we told them to use contraception but not for as long as they ought to according to the SmPCs). The PIS was amended with revised guidance regarding contraception
    12 Apr 2011
    A list of amendments made to the main protocol, are as follows: The following changes were made to the CT application form: Section A: • Update to the sponsor’s protocol code number • Inclusion of the US NCT number Section B: • Update of the sponsor’s contact details • Addition of the contact point designated by the sponsor CANCER RESEARCH UK & UCL CANCER TRIALS CENTRE Cancer Research UK & UCL Cancer Trials Centre University College London Haematology Trials Director: Professor J A Ledermann 90 Tottenham Court Road London W1T 4TJ Tel: +44 (0)20 7679 9538 Fax: +44 (0)20 7679 9861 e-mail: aitl@ctc.ucl.ac.uk website: www.ctc.ucl.ac.uk General CTC Enquiries Tel: +44 (0)20 7679 9898 Fax:+44 (0)20 7679 9899 UCL Cancer Ins titute Section C: • Update to the request for Authorisation to Competent Authority Section D: • Update to IMPs information Section E: • Additional Information to the trial information – MedDRA • Change in the definition of ‘End of Trial’ • Addition of the recruitment start date Section G: • Addition of a central technical facility Section H: • Change of National Competent Authority details
    16 May 2011
    We are proposing the following changes to the labelling for the IMPs that were submitted as a substantial amendment for this Clinical Trial on 20 January 2009, which was subsequently issued with a notice of acceptance on 06 February 2009: Dispensing labels for Fludarabine, Cyclophosphamide and Thalidomide We would like to retract the dispensing labels for Fludarabine, Cyclophosphamide and Thalidomide that were submitted. Regarding the IV drugs (Fludarabine, Cyclophosphamide and Thalidomide), we propose not to apply IMP labelling to them as we believe their use falls under the remit of Regulation 46(2) of the Medicines for Human Use (Clinical Trials) Regulations, for the following reasons: 1) The IMPs are marketed products, used broadly within their authorisations (i.e. cancer). 2) The IMPs will be dispensed to subjects in accordance with a prescription given by an authorised health care professional 3) The IMPs will be labelled in accordance with the requirements of Schedule 5 to the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 that apply in relation to dispensed relevant medicinal products Regarding the oral drugs (Fludarabine, Cyclophosphamide and Thalidomide), abridged labels will be used.
    28 Jun 2011
    Sponsor decided to modify the indemnity wording based on comments made by the National Research Ethics Service Committee. Therefore, following amendment was made to protocol version 5.0: • The original wording of the Indemnity section of the protocol, section 22.2, was reinstated.

    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.
    AE line listings were not reported in the final publication for this study, and are therefore not provided on the results database.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27001186
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