T&B Depletion Non Malignant

Graft Versus Host Disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01810926
• Other study ID #: OPBG_361.11
• Secondary ID: 2011-004730-34
• Status: Recruiting
• Phase: Phase 2
• First received: January 16, 2012
• Last updated: March 12, 2013
• Start date: September 2011
• Est. completion date: October 2016

Study information

• Verified date: March 2013
• Source: Bambino Gesù Hospital and Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: October 2016
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 64 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease

Intervention

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

Drug:
• Rituximab
single infusion of200 mg/m2 on day -1
• 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 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
• 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

Locations

Country	Name	City	State
Italy	University of Cagliari	Cagliari
Italy	San Raffaele Scientific Institute	Milano
Italy	University of Milano-Bicocca San Gerardo Hospital	Monza
Italy	Bambino Gesù Hospital and Research Institute	Rome

Sponsors (4)

Lead Sponsor	Collaborator
Franco Locatelli	Fresenius AG, medac GmbH, University of Milano Bicocca

Country where clinical trial is conducted

Italy, 

References & 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. — View Citation

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. — View Citation

Ballet JJ, Griscelli C, Coutris C, Milhaud G, Maroteaux P. Bone-marrow transplantation in osteopetrosis. Lancet. 1977 Nov 26;2(8048):1137. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Chronic graft-versus-host disease (cGVHD)	The cumulative incidence and severity of cGVHD	From date of randomization assessed up to 100 months	Yes
Secondary	Treatment related mortality (TRM)	The incidence of TRM	From date of randomization assessed up to 100 months	Yes
Secondary	Overall survival (OS)	The overall survival probability	From date of randomization assessed up to 100 months	Yes