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Study to Compare Busulfan-fludarabine With Thiotepa-fludarabine Regimen in Allogeneic Transplantation for Myelofibrosis (GITMO-MF2010)

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ClinicalTrials.gov Identifier: NCT01814475
Recruitment Status : Completed
First Posted : March 20, 2013
Last Update Posted : June 23, 2017
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Trapianto di Midollo Osseo

Brief Summary:

This study will be performed as a prospective multicenter phase II trial for compare busulfan-fludarabine reduced-intensity conditioning (RIC) with thiotepa-fludarabine RIC regimen prior to allogeneic transplantation of hematopoietic cells for the treatment of myelofibrosis.

The primary endpoint for this study is to compare Progression Free Survival of two different RIC regimens for allogeneic stem cell transplantation in myelofibrosis.

Progression Free Survival is defined as the time from the date of randomization to the date of the first documented disease progression or relapse (according to the International Working Group Consensus Criteria) or death due to any cause. Patients who have neither progressed nor died at the time of study completion or who are lost to follow-up are censored at the data of the last follow up for progression of disease for this study.


Condition or disease Intervention/treatment Phase
Myelofibrosis Drug: A: Fludarabine + Busulphan Drug: B: Fludarabine + Thiotepa Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Phase II Randomized Study to Compare Busulfan-fludarabine Reduced-intensity Conditioning (RIC) With Thiotepa-fludarabine RIC Regimen Prior to Allogeneic Transplantation of Hematopoietic Cells for the Treatment of Myelofibrosis
Study Start Date : July 2011
Actual Primary Completion Date : December 31, 2016
Actual Study Completion Date : December 31, 2016


Arm Intervention/treatment
Active Comparator: A: Fludarabine + Busulphan
Conventional conditioning regimen with Fludarabine and Busulphan (Busilvex)for allogeneic stem cell transplantation in myelofibrosis
Drug: A: Fludarabine + Busulphan
Fludarabine 30 mg/m2/d, day -8 to day-3 and Busulphan (Busilvex) 0,8 mg/Kg/i.v. dose x 4 doses on days -5,-4 and x 2 doses on day -3, total dose 8 mg/Kg) prior allogenic transplant (day zero)
Other Name: BU-FLU

Experimental: B: Fludarabine + Thiotepa
Reduced-intensity conditioning with Fludarabine and Thiotepa for allogeneic stem cell transplantation in myelofibrosis
Drug: B: Fludarabine + Thiotepa
Fludarabine 30 mg/m2/d day -8 to day -3 Thiotepa 6 mg/Kg for 2 doses ( days -4, -3) prior allogeneic transplant (day zero)
Other Name: THIO-FLU




Primary Outcome Measures :
  1. Progression -free survival at one year [ Time Frame: Assessment at 1 year post randomization ]

    The primary endpoint for this study is to compare Progression Free Survival of two different RIC regimens for allogeneic stem cell transplantation in myelofibrosis.

    Progression Free Survival is defined as the time from the date of randomization to the date of the first documented disease progression or relapse (according to the International Working Group Consensus Criteria) or death due to any cause. Patients who have neither progressed nor died at the time of study completion or who are lost to follow-up are censored at the data of the last follow up for progression of disease for this study.



Secondary Outcome Measures :
  1. Safety and efficacy profile: The non relapse mortality [ Time Frame: Assessment at 1 year post randomization ]
    The non relapse mortality (NRM) is defined as death due to any other cause than progression of malignancy after allogeneic stem cell transplantation.

  2. Safety and efficacy profile: Overall survival [ Time Frame: Assessment at 1 year post randomization ]
    Overall survival is defined as the time between randomization and the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of the data cut-off for the final analysis

  3. Safety and efficacy profile: responses [ Time Frame: Assessment at 1 year post randomization ]
    Rate of clinical hematological and histological responses

  4. Safety and efficacy profile: molecular remissions [ Time Frame: Assessment at 1 year post randomization ]
    Rate of molecular remissions in patients having a molecular marker (according to IWG consensus criteria)

  5. Safety and efficacy profile: engraftment [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 30 days ]
    Cumulative incidence of engraftment. The day of engraftment is defined as the first 3 consecutive days on which the blood granulocyte count rises to 0.5 x 109/L

  6. Acute Graft-versus-Host Disease (aGvHD) [ Time Frame: from date of transplant to until the date of first event of aCGVD assessed up to 100 days post transplant ]
    The available information in the European Group for Blood and Marrow Transplantation (EBMT) data regard the date of onset and the maximum grade of aGvHD. It is therefore possible to estimate the probability of aGvHD in a competing risks setting (death is a competing event; whether relapse/progression is a competing event must be discussed with the physician). By definition, patients alive (relapse/progression-free) at day 100 without having experienced aGvHD are censored. If the dates of onset are missing for the majority of patients, the analysis can focus only on the occurrence of aGvHD, which is analyzed by a logistic regression model. This method would however be incorrect if there is a (non negligible) percentage of censored observations or if competing events occurred before day 100.

  7. Chronic Graft-versus-Host Disease (cGvHD) [ Time Frame: from day +100 post transplant to until the date of first event to cGVHD assessed up to 1 years post enrolment ]
    When possible, if information on the date of 1°occurrence of cGvHD is available, it should be analyzed as a time-to-event outcome, being death (and possibly relapse/progression) the competing event; data are censored for patients alive (relapse/progression-free) without episodes of cGvHD at last follow-up. Since cGvHD is defined only for patients surviving at least 100 days, the survival model should consider a left truncation at 100 days; alternatively, the time of occurrence of cGvHD must be computed from 100 days. If information on the timing of cGvHD is not available, the outcome considered is the occurrence, and the statistical model to be used is the logistic regression. Only patients surviving at least 100 days are considered to be at risk of developing cGvHD, therefore the analysis must be restricted to these patients. This analysis is of course not satisfactory because it does not take into account the occurrence of death and censoring.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 ≤ 70 years
  • Primary or secondary myelofibrosis after essential thrombocythemia or polycythemia vera
  • One of the following unfavourable prognostic factors: Hb < 10 g/dL or leukocytes >25x109/L or > 1% circulating blasts in the peripheral blood or constitutional symptoms
  • Performance Status (Karnofsky)≥ 60%
  • Hematopoietic Cell Transplantation Comorbidity Score ≤ 5
  • Written informed consent

Exclusion Criteria:

-≥ 20% blasts in peripheral blood and/or bone marrow

  • Positive serologic markers for human immunodeficiency virus (HIV)
  • Acute hepatitis B virus (HBV) or acute hepatic C virus (HCV) infection
  • Severe irreversible renal, hepatic, pulmonary or cardiac disease, such as: --total bilirubin, Serum Glutamate Oxaloacetate Transaminase (SGOT) or Serum Glutamate Pyruvate Transaminase (SGPT) > 5 the upper normal limit;

    • Left ventricular ejection fraction < 40%;
    • Clearance creatinine < 30 ml/min;
    • Diffusing Capacity of Lung for Carbon monoxide (DLCO) < 30% and/or receiving supplementary oxygen.
  • Pregnancy or lactation
  • Any active, uncontrolled infection

Donors:

  • Age ≥ 18 < 65 years
  • human leukocyte antigen (HLA)-identical sibling donor by high resolution DNA-based HLA-A, -B, -C, -DRB1, typing
  • human leukocyte antigen (HLA)-identical unrelated donor by high resolution DNA-based human leukocyte antigen-A, human leukocyte antigen-B, human leukocyte antigen-C, human leukocyte antigen-DRB1 typing. One allele mismatched (class I) can be accepted for recipients up to 60 years.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01814475


Locations
Show Show 21 study locations
Sponsors and Collaborators
Gruppo Italiano Trapianto di Midollo Osseo
Investigators
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Principal Investigator: Francesca Patriarca, MD Azienda Ospedaliera Santa Maria della Misericordia di Udine

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Responsible Party: Gruppo Italiano Trapianto di Midollo Osseo
ClinicalTrials.gov Identifier: NCT01814475    
Other Study ID Numbers: 2010-022052-23 GITMO - MF2010
First Posted: March 20, 2013    Key Record Dates
Last Update Posted: June 23, 2017
Last Verified: June 2017
Keywords provided by Gruppo Italiano Trapianto di Midollo Osseo:
myelofibrosis
unfavourable prognostic factors
Allogeneic stem cell transplantation
Progression Free Survival
thrombocythemia vera
polycythemia vera
Reduced-intensity conditioning
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Vidarabine
Fludarabine
Fludarabine phosphate
Busulfan
Thiotepa
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists