T&B Depletion Non Malignant
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
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.
Study Design
Arms and Interventions
| 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 Names:
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 Names:
Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Names:
Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Names:
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 Names:
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 Names:
Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Names:
Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Names:
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 Names:
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 Names:
Drug: Rituximab
single infusion of200 mg/m2 on day -1
Other Names:
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 Names:
Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Names:
Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Names:
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 Names:
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 Names:
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 Names:
Drug: Fludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
Other Names:
Drug: Thiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
Other Names:
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 Names:
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
|
Outcome Measures
Primary Outcome Measures
- Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD [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
- Chronic graft-versus-host disease (cGVHD) [From date of randomization assessed up to 100 months]
The cumulative incidence and severity of cGVHD
- Treatment related mortality (TRM) [From date of randomization assessed up to 100 months]
The incidence of TRM
- Overall survival (OS) [From date of randomization assessed up to 100 months]
The overall survival probability
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Cagliari | Cagliari | Italy | 09126 | |
| 2 | San Raffaele Scientific Institute | Milano | Italy | 20132 | |
| 3 | University of Milano-Bicocca San Gerardo Hospital | Monza | Italy | 20052 | |
| 4 | Bambino Gesù Hospital and Research Institute | Rome | Italy | 00165 |
Sponsors and Collaborators
- Franco Locatelli
- University of Milano Bicocca
- medac GmbH
- Fresenius AG
Investigators
- Principal Investigator: Franco Locatelli, Prof, Bambino Gesù Hospital and Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
- Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Sacchi N, van Lint MT, Bosi A; Gruppo Italiano Trapianti Midollo Osseo (GITMO). Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006 May;12(5):560-5.
- Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001 Nov 15;98(10):2942-7.
- Ballet JJ, Griscelli C, Coutris C, Milhaud G, Maroteaux P. Bone-marrow transplantation in osteopetrosis. Lancet. 1977 Nov 26;2(8048):1137.
- Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, Egeler M, Lankester AC, Egberts AC, Zwaveling J, Boelens JJ. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):231-41. doi: 10.1016/j.bbmt.2008.11.022.
- Bartelink IH, Bredius RG, Ververs TT, Raphael MF, van Kesteren C, Bierings M, Rademaker CM, den Hartigh J, Uiterwaal CS, Zwaveling J, Boelens JJ. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008 Jan;14(1):88-98.
- Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A, Huber C, Fauser AA, Schwerdtfeger R. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant. 2005 May;35(10):1011-8.
- Bernardo ME, Zecca M, Piras E, Vacca A, Giorgiani G, Cugno C, Caocci G, Comoli P, Mastronuzzi A, Merli P, La Nasa G, Locatelli F. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major. Br J Haematol. 2008 Nov;143(4):548-51. doi: 10.1111/j.1365-2141.2008.07385.x.
- Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier JP, Yakouben K, Thuret I, Bordigoni P, Fischer A, Lutz P, Stephan JL, Dhedin N, Plouvier E, Margueritte G, Bories D, Verlhac S, Esperou H, Coic L, Vernant JP, Gluckman E; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. Epub 2007 Jul 2.
- Chiesa R, Cappelli B, Crocchiolo R, Frugnoli I, Biral E, Noè A, Evangelio C, Fossati M, Roccia T, Biffi A, Finizio V, Aiuti A, Broglia M, Bartoli A, Ciceri F, Roncarolo MG, Marktel S. Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy. Biol Blood Marrow Transplant. 2010 May;16(5):622-8. doi: 10.1016/j.bbmt.2009.11.024. Epub 2009 Dec 4.
- OPBG_361.11
- 2011-004730-34