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    Clinical Trial Results:
    Phase II Trial of Combined Immunochemotherapy with Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab (FMC-Alemtuzumab) in Patients with Previously Treated or Untreated T-Prolymphocytic Leukemia

    Summary
    EudraCT number
    2008-001421-34
    Trial protocol
    DE   AT  
    Global end of trial date
    29 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TPLL2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01186640
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    PEI: 962/01
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Information Desk, German CLL Study Group, 0049 22147888220, cll-studie@uk-koeln.de
    Scientific contact
    Information Desk, German CLL Study Group, 0049 22147888220, cll-studie@uk-koeln.de
    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
    02 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the T-PLL2-study is to assess remission rate, number of serious adverse events, number of life-threatening infections of simultaneous FMC-Alemtuzumab administration followed by Alemtuzumab-maintenance therapy in patients with T-PLL.
    Protection of trial subjects
    I. Premedication Patients should be treated with - Antihistamine (e.g. Diphenhydramine/Tavegil® 2mg i.v.) - Paracetamol/Acetaminophen (1000mg p.o.) - Prednisolone (e.g. Solu-Decortin® 100mg i.v.) 30 minutes before the administration of Alemtuzumab during the first cycle and on the first day of the subsequent cycles of A-FMC and Alemtuzumab-maintenance treatment, plus in cases this premedication is clinically indicated (e.g., when there are adverse effects due to an infusion). If a patient did not show any adverse effects, the premedication could be omitted on day 2 and 3 of each cycle. Any patient considered being at risk of an infusion related reaction and/or tumour lysis syndrome (pts. with a lymphocytosis > 100,000/l) should have received appropriate hydration, urine alkalisation with intravenous bicarbonate and allopurinol before the beginning of treatment and thereafter until the risk is ruled out. II. Infection prevention Patients should have received - Trimethoprim / Sulfamethoxazole (e.g. two tablets Cotrim forte® three times a week) - Valgancyclovir (. 2x 450mg p.o./day) or equivalent medications from the beginning until 4 months after the end of the treatment. Prophylactic antifungal medication, e.g., with 100 mg Fluco-nazole, and use of growth factors like G-CSF and Erythropo-etin could be administered according to institutional standards. No live vaccines should have been administered during the treatment; responses to inactivated, recombinant and cell wall-vaccines were unreliable and suboptimal in these patients.
    Background therapy
    As the median survival time of patients with T-PLL is less than 12 months, the treatment of T-PLL is a special challenge. The overall response rates with conventional chemotherapy or Deoxycoformycin were low (about 30% and 40%), with the monoclonal antibody Alemtuzumab response rates of 50% to 70% were achieved, but the duration of the response was short. In the previous trial (T-PLL 1), the efficacy of the FMC regi-men (FMC = Fludarabine, Mitoxantrone and Cyclophos-phamide) was tested, a preliminary analysis of 16 patients revealed a response rate of more than 60% after FMC-poly-chemotherapy and 83% after the subsequent administration of Alemtuzumab. The goal of the T-PLL2-protocol is to assess if the simulta-neous administration of FMC-polychemotherapy and -Alem-tuzumab with a subsequent Alemtuzumab-maintenance the-rapy is capable of improving the remission rate and the disease-free survival time in patients with T-PLL.
    Evidence for comparator
    n/a
    Actual start date of recruitment
    01 Jun 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    7
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    It was planned to enroll 16 patients. In total 18 patients were enrolled between 06/2010 and 05/2014

    Pre-assignment
    Screening details
    20 T-PLL patients were registered for the trial. The central screening was performed by the GCLLSG central study office in Cologne, Germany and included immunophenotyping, anaylsis of TCL1 signaling and cytogenetic analysis. Of those 20 patients, 2 patient were assessed as screening failure, 18 patients were enrolled.

    Pre-assignment period milestones
    Number of subjects started
    20 [1]
    Number of subjects completed
    18

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Protocol deviation: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All patients who meet the eligibility criteria for the study entry can be enrolled into the trial. To verify the eligibility of patients, a patient screening by a medical review of the pretherapeutic staging as well as a central immunophenotyping, analysis of the TCL1 signaling and the cytogenetics will be performed before randomization. 20 patients started pre-assignment period, 2 patient were assessed as screening failure, 18 patients were enrolled.
    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
    FMC-Alemtuzumab
    Arm description
    All patients received a combination therapy of Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab (A-FMC), followed by Alemtuzumab maintenance treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First treatment phase Chemoimmunotherapy A-FMC: 20 mg/m2 i.v., days 1-3; Repeat day 29, maximum 4 cycles.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    09393
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First treatment phase Chemoimmunotherapy A-FMC: 6 mg/m2 i.v., day 1; Repeat day 29, maximum 4 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    1001995601
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First treatment phase Chemoimmunotherapy A-FMC: 200 mg/m2 i.v., days 1-3; Repeat day 29, maximum 4 cycles.

    Investigational medicinal product name
    Alemtuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    First treatment phase Chemoimmunotherapy A-FMC Cycle 1+2: 10 mg s.c., days 1-3 Cycle 3+4: CR: 10 mg s.c., days 1-3 PR/SD: 30 mg s.c., days 1-3 Second treatment phase Maintenance-treatment with 30mg Alemtuzumab s.c. for patients in CR, PR or SD; The maintenance therapy started one month after the Final Staging and was administered monthly during the first six months plus once in month 10 and 13.

    Number of subjects in period 1
    FMC-Alemtuzumab
    Started
    18
    Completed
    0
    Not completed
    18
         Adverse event, serious fatal
    5
         Physician decision
    12
         non-cooperation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    18 18
    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)
    7 7
        From 65-84 years
    11 11
        85 years and over
    0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    68 (57.8 to 73.5) -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    10 10

    End points

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    End points reporting groups
    Reporting group title
    FMC-Alemtuzumab
    Reporting group description
    All patients received a combination therapy of Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab (A-FMC), followed by Alemtuzumab maintenance treatment.

    Primary: Overall response rate

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    End point title
    Overall response rate [1]
    End point description
    Remission rate (ocurence of CRs, CRis, nPRs and PRs)
    End point type
    Primary
    End point timeframe
    Overall response rate was analysed within the final analysis in 2014 (data cut-off was 03.09.2014) . This analysis was not repeated for the final clinical study.
    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 the hypothesis states that the efficacy of the TPLL2 regimen is assessed uninteresting if the ORR rate is less than 50% and is confirmed if the ORR is at least 50% and as there are no further comparisons between different treatment arms, a frequency tabulation with no further statistical analyses was sufficient. So there are no statistical values available to provide.
    End point values
    FMC-Alemtuzumab
    Number of subjects analysed
    18
    Units: percent
        number (confidence interval 95%)
    66.7 (44.0 to 89.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    FMC-A
    Reporting group description
    -

    Serious adverse events
    FMC-A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 18 (66.67%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    4
    Vascular disorders
    Shock haemorrhagic
    Additional description: Shock haemorrhagic
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Aplastic anaemia
    Additional description: Aplastic anaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
    Additional description: Pancytopenia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic inflammatory response syndrome
    Additional description: Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cystitis
    Additional description: Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus chorioretinitis
    Additional description: Cytomegalovirus chorioretinitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
    Additional description: Cytomegalovirus infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile infection
    Additional description: Febrile infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
    Additional description: Herpes zoster
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic infection
    Additional description: Neutropenic infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
    Additional description: Oesophageal candidiasis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia respiratory syncytial viral
    Additional description: Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection bacterial
    Additional description: Urinary tract infection bacterial
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
    Additional description: Tumour lysis syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    FMC-A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 18 (94.44%)
    Investigations
    Blood lactate dehydrogenase increased
    Additional description: Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    7 / 18 (38.89%)
         occurrences all number
    7
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    12 / 18 (66.67%)
         occurrences all number
    30
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    14 / 18 (77.78%)
         occurrences all number
    36
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    12 / 18 (66.67%)
         occurrences all number
    15
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Subileus
    Additional description: Subileus
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Tongue ulceration
    Additional description: Tongue ulceration
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    3
    Infections and infestations
    Aspergillus infection
    Additional description: Aspergillus infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Giardiasis
    Additional description: Giardiasis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Herpes virus infection
    Additional description: Herpes virus infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infection
    Additional description: Infection
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Lip infection
    Additional description: Lip infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Metapneumovirus infection
    Additional description: Metapneumovirus infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2010
    Amendment 1: - Change of the start of the trial - Reduction of the Alemtuzumab dosing and change in the treatment intervals - Changes in the recomennded CMV prophylaxis - Simplification of the Retreatment criteria and dose modification - Correction of the registration and screening process - Changes in the logisitic procedures of Alemtuzumab - Changes for the immunophenotypig samples

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30234404
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