T&B Depletion Non Malignant

NCT01810926 | Unknown Phase 2 DMC

• 2 other identifiers: OPBG_361.112011-004730-34
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 4

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.

Conditions

Graft Versus Host Disease

Keywords

indication for HSCT; matched related donor; MRD; Matched Unrelated Donor; MUD

Outcome Measures

Primary Outcomes (1)

• 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.

  From date of randomization assessed up to 100 months

Secondary Outcomes (3)

• Chronic graft-versus-host disease (cGVHD)

  From date of randomization assessed up to 100 months

• Treatment related mortality (TRM)

  From date of randomization assessed up to 100 months

• Overall survival (OS)

  From date of randomization assessed up to 100 months

Study Arms (4)

MRD-Regimen&Polyclonal antibody

EXPERIMENTAL

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; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate

MRD-Regimen

SHAM COMPARATOR

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; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate

MUD-Regimen & Rituximab

EXPERIMENTAL

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; Drug: Rituximab; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate

MUD-Regimen

SHAM COMPARATOR

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; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate

Interventions

polyclonal antibody BIOLOGICAL

iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)

Also known as: ATG S Fresenius

MRD-Regimen&Polyclonal antibody; MUD-Regimen; MUD-Regimen & Rituximab

Rituximab DRUG

single infusion of200 mg/m2 on day -1

Also known as: Mabthera

MUD-Regimen & Rituximab

Treosulfan DRUG

iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)

Also known as: Medac

MRD-Regimen; MRD-Regimen&Polyclonal antibody; MUD-Regimen; MUD-Regimen & Rituximab

Fludarabine DRUG

iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan

Also known as: Fludara

MRD-Regimen; MRD-Regimen&Polyclonal antibody; MUD-Regimen; MUD-Regimen & Rituximab

Thiotepa DRUG

iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals

Also known as: Tepadina

MRD-Regimen; MRD-Regimen&Polyclonal antibody; MUD-Regimen; MUD-Regimen & Rituximab

Cyclosporine A DRUG

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

Also known as: Neoral

MRD-Regimen; MRD-Regimen&Polyclonal antibody; MUD-Regimen; MUD-Regimen & Rituximab

Methotrexate DRUG

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

MRD-Regimen; MRD-Regimen&Polyclonal antibody

Eligibility Criteria

• Age: 28 Days - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Franco Locatelli: lead
• University of Milano Bicocca: collaborator
• medac GmbH: collaborator
• Fresenius AG: collaborator

Study Sites (4)

University of Cagliari

Cagliari, Italy, 09126, Italy

ACTIVE NOT RECRUITING

San Raffaele Scientific Institute

Milan, Italy, 20132, Italy

ACTIVE NOT RECRUITING

University of Milano-Bicocca San Gerardo Hospital

Monza, Italy, 20052, Italy

ACTIVE NOT RECRUITING

Bambino Gesù Hospital and Research Institute

Rome, Italy, 00165, Italy

RECRUITING

Related Publications (9)

• 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. doi: 10.1016/j.bbmt.2005.12.034.

  PMID: 16635791 BACKGROUND

• 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. doi: 10.1182/blood.v98.10.2942.

  PMID: 11698275 BACKGROUND

• Ballet JJ, Griscelli C, Coutris C, Milhaud G, Maroteaux P. Bone-marrow transplantation in osteopetrosis. Lancet. 1977 Nov 26;2(8048):1137. doi: 10.1016/s0140-6736(77)90592-x. No abstract available.

  PMID: 73050 BACKGROUND

• 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.

  PMID: 19167683 BACKGROUND

• 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. doi: 10.1016/j.bbmt.2007.09.015.

  PMID: 18158965 BACKGROUND

• 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. doi: 10.1038/sj.bmt.1704957.

  PMID: 15821768 BACKGROUND

• 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.

  PMID: 18986389 BACKGROUND

• 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. doi: 10.1182/blood-2007-03-079665. Epub 2007 Jul 2.

  PMID: 17606762 BACKGROUND

• Chiesa R, Cappelli B, Crocchiolo R, Frugnoli I, Biral E, Noe 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.

  PMID: 19963071 BACKGROUND

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

Rituximab; treosulfan; fludarabine; fludarabine phosphate; Thiotepa; Cyclosporine; Methotrexate

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Franco Locatelli, Prof

  Bambino Gesù Hospital and Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director Department of Pediatric Hematology and Oncology

Study Record Dates

• First Submitted: January 16, 2012
• First Posted: March 14, 2013
• Study Start: September 1, 2011
• Primary Completion: August 1, 2015
• Study Completion: October 1, 2016
• Last Updated: March 14, 2013

Record last verified: 2013-03

Locations

IT (4)