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T&B Depletion Non Malignant

Primary Purpose

Graft Versus Host Disease

Status
Unknown status
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
polyclonal antibody
Rituximab
Treosulfan
Fludarabine
Thiotepa
Cyclosporine A
Methotrexate
Methotrexate
Sponsored by
Franco Locatelli
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Graft Versus Host Disease focused on measuring indication for HSCT, matched related donor, MRD, Matched Unrelated Donor, MUD

Eligibility Criteria

28 Days - 64 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Cagliari
  • San Raffaele Scientific Institute
  • University of Milano-Bicocca San Gerardo Hospital
  • Bambino Gesù Hospital and Research InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Sham Comparator

Experimental

Sham Comparator

Arm Label

MRD-Regimen&Polyclonal antibody

MRD-Regimen

MUD-Regimen & Rituximab

MUD-Regimen

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD
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

Chronic graft-versus-host disease (cGVHD)
The cumulative incidence and severity of cGVHD
Treatment related mortality (TRM)
The incidence of TRM
Overall survival (OS)
The overall survival probability

Full Information

First Posted
January 16, 2012
Last Updated
March 12, 2013
Sponsor
Franco Locatelli
Collaborators
University of Milano Bicocca, medac GmbH, Fresenius AG
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1. Study Identification

Unique Protocol Identification Number
NCT01810926
Brief Title
T&B Depletion Non Malignant
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 Type
Interventional

2. Study Status

Record Verification Date
March 2013
Overall Recruitment Status
Unknown status
Study Start Date
September 2011 (undefined)
Primary Completion Date
August 2015 (Anticipated)
Study Completion Date
October 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Franco Locatelli
Collaborators
University of Milano Bicocca, medac GmbH, Fresenius AG

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease
Keywords
indication for HSCT, matched related donor, MRD, Matched Unrelated Donor, MUD

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
MRD-Regimen&Polyclonal antibody
Arm Type
Experimental
Arm Description
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
Arm Title
MRD-Regimen
Arm Type
Sham Comparator
Arm Description
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
Arm Title
MUD-Regimen & Rituximab
Arm Type
Experimental
Arm Description
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
Arm Title
MUD-Regimen
Arm Type
Sham Comparator
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
polyclonal antibody
Other Intervention Name(s)
ATG S Fresenius
Intervention Description
iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
single infusion of200 mg/m2 on day -1
Intervention Type
Drug
Intervention Name(s)
Treosulfan
Other Intervention Name(s)
Medac
Intervention Description
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
Tepadina
Intervention Description
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Intervention Type
Drug
Intervention Name(s)
Cyclosporine A
Other Intervention Name(s)
Neoral
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
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 Measure Information:
Title
Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD
Description
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.
Time Frame
From date of randomization assessed up to 100 months
Secondary Outcome Measure Information:
Title
Chronic graft-versus-host disease (cGVHD)
Description
The cumulative incidence and severity of cGVHD
Time Frame
From date of randomization assessed up to 100 months
Title
Treatment related mortality (TRM)
Description
The incidence of TRM
Time Frame
From date of randomization assessed up to 100 months
Title
Overall survival (OS)
Description
The overall survival probability
Time Frame
From date of randomization assessed up to 100 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
28 Days
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, Prof
Organizational Affiliation
Bambino Gesù Hospital and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Cagliari
City
Cagliari
ZIP/Postal Code
09126
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
San Raffaele Scientific Institute
City
Milano
ZIP/Postal Code
20132
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
University of Milano-Bicocca San Gerardo Hospital
City
Monza
ZIP/Postal Code
20052
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Bambino Gesù Hospital and Research Institute
City
Rome
ZIP/Postal Code
00165
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Ester Bernardo, MD
Email
mebernardo@gmail.com
First Name & Middle Initial & Last Name & Degree
Franco Locatelli

12. IPD Sharing Statement

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T&B Depletion Non Malignant

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