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    Clinical Trial Results:
    A phase II multicentric study in adults with acute myelogenous leukaemia (AML) in first complete remission (CR1) using IV BuCy2 in a once daily Bu regimen targeting a narrow therapeutic window prior to hematopoietic stem cell transplantation.

    Summary
    EudraCT number
    		 2009-016601-42
    Trial protocol
    		 FR   ES   IT  
    Global end of trial date
    19 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2017
    First version publication date
    09 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F60002 IN 202 G0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PIERRE FABRE MEDICAMENT
    Sponsor organisation address
    45 Place Abel Gance, Boulogne, France, 92654
    Public contact
    Ta Thanh Minh Christine, PIERRE FABRE MEDICAMENT, 33 0149108000, christine.ta.thanh.minh@pierre-fabre.com
    Scientific contact
    Ta Thanh Minh Christine, PIERRE FABRE MEDICAMENT, 33 0149108000, christine.ta.thanh.minh@pierre-fabre.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 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To target the upper range of the busulfan therapeutic window (AUC from 4400 to 6000 μM.min) from a once daily myeloablative regimen in adult patients with AML in CR1 receiving the IV BuCy2 regimen.
    Protection of trial subjects
    Before enrolment in the study trial, the patient was examined by an experienced physician in charge of the study; some routine tests, including usual blood tests for pre-transplant check-up, a chest X-ray, echocardiogram and pulmonary tests function were carried out in order to assess vital functions and monitor the disease. Results of these tests were documented by the physician and the specialized team in charge of performing the hematopoietic stem cell transplantation. The patient was hospitalized 8 days before the transplantation in a bone marrow unit. The entire procedure of transplantation including administration of the conditioning regimen was supervised by a specialized physician. The patient was isolated in a sterile environment. The conditioning regimen consisted of intravenous busulfan over 4 days followed by a day of rest and followed by infusion of cyclophosphamide over 2 days (60 mg/kg/d); there was a day of rest after the last day of cyclophosphamide, then on the following day (Day0) the graft was infused to the patient. During the administration of the conditioning therapy, the dose level of intravenous busulfan were adjusted as it was an objective of the trial . Twelve plasma samples were collected over 4 days. The duration of the initial hospitalization lasted between four and six weeks until complete recovery. The follow-up, the treatments, the transplantation procedure were performed by the physician in charge of the study. He was also responsible of reviewing the patient information sheet and obtaining the patient's agreement. Women of childbearing potential had to have negative serum or urine pregnancy test within 72 hours prior to the start of study treatment. Fertile men and women of childbearing potential were expected to use an effective method of contraception during the 2 months preceding the start of study treatment, during treatment and at least 6 months following the last dose of study treatment.
    Background therapy
    		 Allogeneic Hematopoietic Stem Cell transplantation (HSCT) is a curative therapy and is widely used in the treatment of various haematological and non-haematological malignancies. The conditioning therapy is a key point in this procedure. Apart from the conditioning regimen, during the allogeneic procedure, many concomitant treatments are usually administered before or after infusion of the graft as prophylaxis to prevent occurrence of side effects or as part of supportive care. The graft was administered after the end of the conditioning therapy. Oral phenytoin was used as seizure prophylaxis. The prophylaxis to prevent the occurrence of veno-occlusive disease was based on heparin. The prophylaxis for prevention of the graft-versus-host-disease could have combined antithymoglobuline (if indicated) and ciclosporin and methotrexate. The recommended doses and duration of the graft-versus-host-disease prophylaxis was to be adapted based on local institutional guidelines. Hydration with glucose serum or chloride serum, uromitexan and anti-emetic therapies were recommended and adjusted according to the local institutional guidelines. Others medications such as blood transfusions, platelet transfusions, growth factor, antibiotics, antifungal treatment were given according to institutional guidelines.
    Evidence for comparator
    		 not applicable. The study was a phase multicentric study, open-label
    Actual start date of recruitment
    17 May 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 patients were enrolled from 8 active centers in 3 countries. The patient's eligibilty was assessed by an experienced physician within four weeks before the start of conditioning regimen. First patient enrolled on the 17th May 2010; last patient enrolled on the 21th May 2012.

    Pre-assignment
    Screening details
    		 Patient eligibility was assessed from Day-36 to Day-9 (the period before the day of transplantation was counted as negative). Patient's informed consent was signed. Parameters: demographics, disease, organ functions, laboratory tests, eligibility for transplantation, compatible donor, no exclusion criteria. Assignement of patient number.

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Intermediate milestone: Number of subjects
    pre study screeening period: 30
    Number of subjects completed
    		 30

    Period 1
    Period 1 title
    study treatment period-follow-up periods (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Arm title
    		 overall cohort-study treatment period and follow-up periods
    Arm description
    		 The study was split in study treatment period and study follow-up periods. The reference day was Day0 the day of transplantation. After Day0 the number of days was counted as positive. Before Day0, the days was counted as negative. The study treatment period started from Day-8 up to Day+28: 30 patients (overall cohort) were enrolled and treated with IV BuCy2 as conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. During this period, in-patients evaluations for safety and efficacy were done until Day+28. Follow-up period 1 : Day+29 up to Day+100; Follow-up period 2: Day+101 up to Day+365; Follow-up period 3: Day+366 up to Day+730. During the 3 study follow-up periods, the patients could have received additional therapies as part of the transplantation procedure, and the clinical evaluations with safety and efficacy parameters were collected. All 30 patients were evaluable for pharmacokinetic, safety and efficacy analysis.
    Arm type
    		 Investigational arm

    Investigational medicinal product name
    Busilvex
    Investigational medicinal product code
    F60002
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First administered dose (Day-8) was 3.2 mg/kg according to either actual body weight (ABW) for normal patients or to adjusted ideal body weight (AIBW) for obese patients. Then subsequent doses (Day-7 to Day-5) were adjusted according to the targeted AUC (i.e.: 5200 μM.min), corresponding to the middle of the therapeutic window (i.e.: 4400-6000 μM.min) and based on prior PK information collected from the dose before. One-day rest (Day-4) followed the last administration of IV Bu before cyclophosphamide treatment.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    cyclophosphamide
    Other name
    Cytoxan; Endoxan
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    One-day rest (Day-4) followed the last administration of IV Bu before cyclophosphamide administered at a dose of 60 mg/kg over two to four hours for two consecutive days (total dose 120 mg/kg) (Day-3 toDay-2). One-day rest (Day-1) followed the IV BuCy2 regimen before Stem Cell Infusion on Day0.

    Number of subjects in period 1
    		overall cohort-study treatment period and follow-up periods
    Started
    30
    Completed
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    study treatment period-follow-up periods
    Reporting group description
    		 Overall cohort: 30 adult patients diagnosed with acute myelogenous leukemia in first complete remission. The characteristics of patients at baseline (diagnosis, prior medical history, prior treatment, clinical and biological tests for eligibility) were collected during visits before enrolment and start of the conditioning therapy.

    Reporting group values
    		 study treatment period-follow-up periods Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 30
    Age continuous
    Units: years
        median (full range (min-max))
    		 43.5 (19.3 to 55.5) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 21 21
    disease
    AML in first complete remission
    Units: Subjects
        disease
    		 30 30
    height
    Units: centimeter
        median (full range (min-max))
    		 174.5 (155 to 186) -
    Weight
    Units: kilo units
        median (full range (min-max))
    		 75.5 (47 to 99) -
    karnofsky performance status
    General status score
    Units: score
        median (full range (min-max))
    		 100 (90 to 100) -

    End points

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    End points reporting groups
    Reporting group title
    overall cohort-study treatment period and follow-up periods
    Reporting group description
    		 The study was split in study treatment period and study follow-up periods. The reference day was Day0 the day of transplantation. After Day0 the number of days was counted as positive. Before Day0, the days was counted as negative. The study treatment period started from Day-8 up to Day+28: 30 patients (overall cohort) were enrolled and treated with IV BuCy2 as conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. During this period, in-patients evaluations for safety and efficacy were done until Day+28. Follow-up period 1 : Day+29 up to Day+100; Follow-up period 2: Day+101 up to Day+365; Follow-up period 3: Day+366 up to Day+730. During the 3 study follow-up periods, the patients could have received additional therapies as part of the transplantation procedure, and the clinical evaluations with safety and efficacy parameters were collected. All 30 patients were evaluable for pharmacokinetic, safety and efficacy analysis.

    Primary: Number of patients in Bu therapeutic window

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    End point title
    		 Number of patients in Bu therapeutic window [1]
    End point description
    To target the upper range of the busulfan therapeutic window (AUC from 4400 to 6000 μM.min) from a once daily myeloablative regimen in adult patients with AML inCR1 receiving the IV BuCy2 regimen. A daily PK guided dose adjustment from Day-7 (Dose 2) to Day-5 (Dose 4) of Bu treatment was expected to enable the same targeting performance (≥ 70 to 80% ofpatients within the therapeutic window) as that achieved for the larger therapeutic window (i.e.: 3600 – 6000 μM.min) without dose adjustment. The endpoint value was expressed by the number of subjects within the Bu therapeutic window (AUC from 4400 to 6000 μM.min).
    End point type
    Primary
    End point timeframe
    Blood sampling for pharmacokinetic analysis performed over 4 days from Day-8 (dose 1) to Day-5 (dose 4) in order to calculate daily busulfan plasma exposure (AUC). Doses were ajusted from Day-7 (dose 2) to Day-5 (dose 4).
    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: The endpoint number of patients in Bu therapeutic window was calculated and reported as absolute count. No statistical test was performed for this endpoint
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    27
    No statistical analyses for this end point

    Secondary: intrapatient variability of clearance

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    End point title
    		 intrapatient variability of clearance
    End point description
    To confirm the narrow intra-patient variability of once daily busulfan pharmacokinetics already demonstrated on a q.i.d. dosing regimen.
    End point type
    Secondary
    End point timeframe
    For once-daily busulfan infusion over four days of treatment from Day-8 to Day-5 (dose 1 to dose 4)
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: percentage
        number (not applicable)
    14
    No statistical analyses for this end point

    Secondary: number of patients alive during study treatment period

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    End point title
    		 number of patients alive during study treatment period
    End point description
    proportion of patients alive at the end of the study treatment period (Day+28).
    End point type
    Secondary
    End point timeframe
    from Day-8 up to Day+28
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    30
    No statistical analyses for this end point

    Secondary: number of patients with engraftment during study treatment period

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    End point title
    		 number of patients with engraftment during study treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    from Day-8 up to Day+28
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    30
    No statistical analyses for this end point

    Secondary: Number of patients alive at Day+100

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    End point title
    		 Number of patients alive at Day+100
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+28 (study treatment period) and Day+29 up to Day+100 (Follow-up period 1)
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    30
    No statistical analyses for this end point

    Secondary: Number of patients with TRM at Day+100

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    End point title
    		 Number of patients with TRM at Day+100
    End point description
    TRM: transplant-related mortality; TRM was expressed as a number of patients who died from causes other than relapse of the underlying hematological malignancy.
    End point type
    Secondary
    End point timeframe
    Study treatment period and follow-up period 1 ( Day-8 up to Day+28 and Day+29 up to Day+100)
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of patients alive at Day+365

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    End point title
    		 Number of patients alive at Day+365
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+365: study treatment period, follow-up period 1 and follow-up period 2
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    22
    No statistical analyses for this end point

    Secondary: Number of patients with TRM at Day+365

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    End point title
    		 Number of patients with TRM at Day+365
    End point description
    TRM: transplant-related mortality; TRM was expressed as a number of patients who died from causes other than relapse of the underlying hematological malignancy.
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+365: study treatment period, follow-up period 1 and follow-up period 2
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    4
    No statistical analyses for this end point

    Secondary: Number of patients alive at Day+730

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    End point title
    		 Number of patients alive at Day+730
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+730: study treatment period and the 3 follow-up periods.
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    19
    No statistical analyses for this end point

    Secondary: Number of patients with TRM at Day+730

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    End point title
    		 Number of patients with TRM at Day+730
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+730: study treatment period and the 3 follow-up periods
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    5
    No statistical analyses for this end point

    Secondary: Number of patients with relapse at Day+365

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    End point title
    		 Number of patients with relapse at Day+365
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+365: study treatment period, follow-up period 1 and follow-up period 2
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    5
    No statistical analyses for this end point

    Secondary: Number of patients with relapse at Day+730

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    End point title
    		 Number of patients with relapse at Day+730
    End point description
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+730: study treatment period, and the 3 follow-up periods.
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    6
    No statistical analyses for this end point

    Secondary: Number of patients with VOD

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    End point title
    		 Number of patients with VOD
    End point description
    VOD: veno-occlusive disease. Diagnosis defined by Jones criteria and severity according to McDonald criteria. Overall 3 episodes of VOD in 2 patients.
    End point type
    Secondary
    End point timeframe
    From Day-8 up to Day+365
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    2
    No statistical analyses for this end point

    Secondary: number of patients with acute GVHD grade III-IV at Day+100

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    End point title
    		 number of patients with acute GVHD grade III-IV at Day+100
    End point description
    GVHD: graft-versus-host-disease. Grading according to Glucksberg criteria. No patient developed acute GVHD of grade IV.
    End point type
    Secondary
    End point timeframe
    From Day0 up to Day+100: study treatment period and follow-up period 1
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subjects
    2
    No statistical analyses for this end point

    Secondary: Myeloablation

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    End point title
    		 Myeloablation
    End point description
    Expected effect of conditioning regimen. number of patients with profound cytopenia after administration of the conditioning regimen (Bucy2)
    End point type
    Secondary
    End point timeframe
    study treatment period (Day-8 to D+28) post-HSCT
    End point values
    		 overall cohort-study treatment period and follow-up periods
    Number of subjects analysed
    30
    Units: subject
    30
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day-8 to Day+365
    Adverse event reporting additional description
    Grading of severity according NCI-CTC v.3 for AEs except for VOD, GVHD, infections and febrile neutropenia. Assessment by physician, collected through the case report form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13
    Reporting groups
    Reporting group title
    overall cohort-study treatment period-follow-up periods
    Reporting group description
    		 Reporting period for SAEs and non serious AEs: from Day-8 up to Day+365. Reported: related SAEs by patient and related non serious AEs (grade 4) by patient during the period defined above.

    Serious adverse events
    		 overall cohort-study treatment period-follow-up periods
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    1
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    veno-occlusive disease
    Additional description: diagnosis according to Jones criteria and grading according to McDonald criteria
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Haemorrgagic cystitis with BK virus
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
    Additional description: Gastro intestinal-clostridium difficile
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
    Additional description: sepsis
         subjects affected / exposed
    1 / 30 (3.33%)
         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
    		 overall cohort-study treatment period-follow-up periods
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2011
    The end of the period of inclusion was extended to Q2 2012.
    21 Jun 2011
    The amendment modified the planned list of centers and investigators with addition of new center as the accrual was slow. The procedure of IV Bu administration was modified to allow more flexibility to each participating center.
    18 Nov 2011
    Update of the manufacturer site for Busilvex.There was no consequence for the certification of the finished product. The corresponding section in the protocol was updated.

    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.
    not applicable
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    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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