T&B Depletion Non Malignant

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

• 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.

Study Overview

• Status: Unknown
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Biological: polyclonal antibody; Drug: Treosulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclosporine A; Drug: Methotrexate; Drug: Methotrexate; Drug: Rituximab

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 Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Cagliari, Italy, 09126
    • Active, not recruiting
    • University of Cagliari
  • Milano, Italy, 20132
    • Active, not recruiting
    • San Raffaele Scientific Institute
  • Monza, Italy, 20052
    • Active, not recruiting
    • University of Milano-Bicocca San Gerardo Hospital
  • Rome, Italy, 00165
    • Recruiting
    • Bambino Gesù Hospital and Research Institute
    • Contact: Maria Ester Bernardo, MD; Email: mebernardo@gmail.com
    • Principal Investigator: Franco Locatelli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 64 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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: 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 Names: Medac; Drug: Fludarabine; iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan; Other Names: Fludara; Drug: Thiotepa; iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals; Other Names: 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 Names: 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; 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: 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: Medac; Drug: Fludarabine; iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan; Other Names: Fludara; Drug: Thiotepa; iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals; Other Names: 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 Names: 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; 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
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: 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 Names: Medac; Drug: Fludarabine; iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan; Other Names: Fludara; Drug: Thiotepa; iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals; Other Names: 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 Names: 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; 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; Drug: Rituximab; single infusion of200 mg/m2 on day -1; Other Names: Mabthera
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: 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 Names: Medac; Drug: Fludarabine; iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan; Other Names: Fludara; Drug: Thiotepa; iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals; Other Names: 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 Names: 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic graft-versus-host disease (cGVHD)	The cumulative incidence and severity of cGVHD	From date of randomization assessed up to 100 months
Treatment related mortality (TRM)	The incidence of TRM	From date of randomization assessed up to 100 months
Overall survival (OS)	The overall survival probability	From date of randomization assessed up to 100 months

Collaborators and Investigators

• Sponsor: Franco Locatelli
• Collaborators: Fresenius AG; University of Milano Bicocca; medac GmbH
• Investigators: Principal Investigator: Franco Locatelli, Prof, Bambino Gesù Hospital and Research Institute

Publications and helpful links

General 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. doi: 10.1016/j.bbmt.2005.12.034.
• 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.
• 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.
• 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. doi: 10.1016/j.bbmt.2007.09.015.
• 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.
• 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. doi: 10.1182/blood-2007-03-079665. Epub 2007 Jul 2.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Anticipated): August 1, 2015
• Study Completion (Anticipated): October 1, 2016

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: March 12, 2013
• First Posted (Estimate): March 14, 2013

Study Record Updates

• Last Update Posted (Estimate): March 14, 2013
• Last Update Submitted That Met QC Criteria: March 12, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: MRD; indication for HSCT; matched related donor; Matched Unrelated Donor; MUD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Antibodies; Rituximab; Fludarabine; Methotrexate; Thiotepa; Cyclosporine; Cyclosporins; Treosulfan
• Other Study ID Numbers: OPBG_361.11; 2011-004730-34 (EudraCT Number)