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T&B Depletion Non Malignant

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ClinicalTrials.gov Identifier: NCT01810926
Recruitment Status : Unknown
Verified March 2013 by Franco Locatelli, Bambino Gesù Hospital and Research Institute.
Recruitment status was:  Recruiting
First Posted : March 14, 2013
Last Update Posted : March 14, 2013
Sponsor:
Collaborators:
University of Milano Bicocca
medac GmbH
Fresenius AG
Information provided by (Responsible Party):
Franco Locatelli, Bambino Gesù Hospital and Research Institute

Brief Summary:

• The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients.

The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.


Condition or disease Intervention/treatment Phase
Graft Versus Host Disease Biological: polyclonal antibody Drug: Rituximab Drug: Treosulfan Drug: Fludarabine Drug: Thiotepa Drug: Cyclosporine A Drug: Methotrexate Phase 2

Detailed Description:

For patients transplanted from a MRD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

  • primary and secondary graft failure,
  • aGVHD II-IV,
  • cGVHD,
  • death, whichever occurs first.

For patients transplanted from a MUD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

  • aGVHD II-IV,
  • EBV viremia, whichever occurs first.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase II Multicentre, Randomized, Controlled Open-label Study on the Use of Anti-thymocyte Globulin and Rituximab for Immunomodulation of Graft-versus-host Disease in Allogeneic Matched Transplants for Non Malignancies
Study Start Date : September 2011
Estimated Primary Completion Date : August 2015
Estimated Study Completion Date : October 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MRD-Regimen&Polyclonal antibody
Patients MRD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 & ATG-Fresenius S® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2
Biological: polyclonal antibody
iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)
Other Name: ATG S Fresenius

Drug: Treosulfan
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
Other Name: Medac

Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Name: Fludara

Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Name: Tepadina

Drug: Cyclosporine A
iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL
Other Name: Neoral

Drug: Methotrexate
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

Sham Comparator: MRD-Regimen
Patients receiving stem cell transplantation from a matched related donors (MRD) will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²) + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 (total dose of 150 mg/m²) after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals (total dose of 8 mg/kg)+ Cyclosporine A iv at a starting dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL (In the absence of GvHD CSA will be tapered after day + 180 and stopped at 9-12 months) + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6
Drug: Treosulfan
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
Other Name: Medac

Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Name: Fludara

Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Name: Tepadina

Drug: Cyclosporine A
iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL
Other Name: Neoral

Drug: Methotrexate
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

Experimental: MUD-Regimen & Rituximab
Patients MUD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 & Rituximab in a single infusion of 200 mg/m2 on day -1
Biological: polyclonal antibody
iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)
Other Name: ATG S Fresenius

Drug: Rituximab
single infusion of200 mg/m2 on day -1
Other Name: Mabthera

Drug: Treosulfan
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
Other Name: Medac

Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Name: Fludara

Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Name: Tepadina

Drug: Cyclosporine A
iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL
Other Name: Neoral

Drug: Methotrexate
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11

Sham Comparator: MUD-Regimen
Patients MUD will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2
Biological: polyclonal antibody
iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)
Other Name: ATG S Fresenius

Drug: Treosulfan
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
Other Name: Medac

Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Name: Fludara

Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Name: Tepadina

Drug: Cyclosporine A
iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL
Other Name: Neoral

Drug: Methotrexate
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11




Primary Outcome Measures :
  1. Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD [ Time Frame: From date of randomization assessed up to 100 months ]

    For patients transplanted from a MRD

    The cumulative incidence of a combined end-point defined as the time from randomization to:

    • primary and secondary graft failure,
    • aGVHD II-IV,
    • cGVHD,
    • death, whichever occurs first.

    For patients transplanted from a MUD

    The cumulative incidence of a combined end-point defined as the time from randomization to:

    • aGVHD II-IV,
    • EBV viremia, whichever occurs first.


Secondary Outcome Measures :
  1. Chronic graft-versus-host disease (cGVHD) [ Time Frame: From date of randomization assessed up to 100 months ]
    The cumulative incidence and severity of cGVHD

  2. Treatment related mortality (TRM) [ Time Frame: From date of randomization assessed up to 100 months ]
    The incidence of TRM

  3. Overall survival (OS) [ Time Frame: From date of randomization assessed up to 100 months ]
    The overall survival probability



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 64 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • non malignant haematological and inherited metabolic disorders benefiting from an allogeneic HSCT conditioned with a myeloablative regimen
  • Availability of a matched related donor (MRD) or Matched Unrelated Donor (MUD)
  • Lansky or Karnofsky Index ≥ 60
  • Inherited metabolic disorders: DQ ≥ 70 (+ MRI Loes score ≤ 9 for adrenoleukodystrophy)
  • Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
  • Heart shortening fraction (left-ventricle) > 28 % or LVEF > 55%
  • Serum bilirubin ≤ 1.5 × ULN (except for Wolman disease),
  • AST and ALT ≤ 2.5 × ULN (except for thalassemic syndromes and Wolman disease)
  • Pulmonary function: if cooperative: FEV1 and FVC on pulmonary function testing > 60 %; if non cooperative: pulse oximetry > 95 % in room air
  • Availability of autologous back up marrow (> 2 x 108 TNC+ cells/kg or > 2 x 106 CD34+ cells/kg) for MUD
  • Adequate contraception in female patients of child-bearing potential
  • Signed informed consent

Exclusion Criteria:

  • Any malignancy
  • Liver cirrhosis evidenced on liver histology (performed in suspicious cases or in case of Wolman disease)
  • HIV- positivity
  • Clinically significant pleural effusion or ascites
  • Pregnancy or lactation
  • Known hypersensitivity to trial drugs
  • Participation in another experimental drug trial in the 2 months preceding enrollment
  • Non-cooperative behaviour or non-compliance
  • Previous HSCT

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): NCT01810926


Locations
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Italy
University of Cagliari Active, not recruiting
Cagliari, Italy, 09126
San Raffaele Scientific Institute Active, not recruiting
Milano, Italy, 20132
University of Milano-Bicocca San Gerardo Hospital Active, not recruiting
Monza, Italy, 20052
Bambino Gesù Hospital and Research Institute Recruiting
Rome, Italy, 00165
Contact: Maria Ester Bernardo, MD       mebernardo@gmail.com   
Principal Investigator: Franco Locatelli         
Sponsors and Collaborators
Franco Locatelli
University of Milano Bicocca
medac GmbH
Fresenius AG
Investigators
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Principal Investigator: Franco Locatelli, Prof Bambino Gesù Hospital and Research Institute

Publications:

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Responsible Party: Franco Locatelli, Director Department of Pediatric Hematology and Oncology, Bambino Gesù Hospital and Research Institute
ClinicalTrials.gov Identifier: NCT01810926     History of Changes
Other Study ID Numbers: OPBG_361.11
2011-004730-34 ( EudraCT Number )
First Posted: March 14, 2013    Key Record Dates
Last Update Posted: March 14, 2013
Last Verified: March 2013
Keywords provided by Franco Locatelli, Bambino Gesù Hospital and Research Institute:
indication for HSCT
matched related donor
MRD
Matched Unrelated Donor
MUD
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Cyclosporine
Rituximab
Methotrexate
Fludarabine
Fludarabine phosphate
Thiotepa
Treosulfan
Busulfan
Antibodies
Immunoglobulins
Cyclosporins
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Anti-Infective Agents