Clinical trial NCT04778618: Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation
Official title: Impact of Optimal Doses of Antithymocyte Globulin Conditioning on Graft-versus- Host Disease and Virus Reactivation in Haploidentical Hematopoietic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Haploidentical Hematopoietic Stem Cell Transplantation
Lead sponsor: Chinese PLA General Hospital
Sponsor class: OTHER
First posted: 2021-03-03
Enrollment: 63
Sex: ALL
Minimum age (years): 14
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the response and toxicity rate of two different dosages (Individualized dosage VS. fixed dosage) of ATG as a prophylaxis for acute GVHD in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT).

Detailed description: Acute graft-versus-host disease (aGvHD) is an important complication of haplo-HSCT. The Seattle group initially introduced the use of ATG as a treatment for acute graft-versus-host disease (aGVHD) in allogeneic hematopoietic stem cell transplantation (haplo-PBSCT) recipients. Presently, in both myeloablative and reduced-intensity conditioning (RIC) haplo-PBSCT, ATG is part of postengraftment immunosuppressive regimens.

The regimens for prophylaxis of GVHD based on 10mg/kg rabbit anti-human thymocyte immunoglobin (ATG, Thymoglobulin®, Genzyme Polyclonals S.A.S) effectively reduced the occurrence of grade II-IV aGvHD. However, the incidence of cytomegalovirus (CMV) and EB virus (EBV) reactivation were higher due to a slower immune reconstitution. The 100-day cumulative incidence of CMV and EBV viremia were both over 70% in our unmanipulated haplo-PBSCT program. The optimal dose of ATG balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation in haplo-PBSCT remains unknown.

Reports on the pharmacokinetics of Thymoglobulin in allo-HSCT revealed a high variability. Recent pharmacokinetic studies have shown that the half-life of total ATG after transplant is longer than the active ATG (which is available to bind to human lymphocytes and causes the desired immunological effects). And active ATG appears more associated with pharmacodynamics effects. The investigators found that virus reactivation and acute GVHD were highly affected by ATG exposure (area under the curve, AUC) in previous cohort study. The investigators have found an optimal range of active ATG exposure balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation. The incidence of CMV reactivation and III-IV aGVHD reduced to 60%, 6% respectively.

The results suggested that Individualized dosing of ATG has a potential advantage in balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation in haplo-PBSCT. This may improve the survival and quality of life of patients undergoing haplo-PBSCT. A prospective randomized trial is required to compare the efficacy of Individualized dosage of ATG as a prophylaxis for acute GVHD in haplo-PBSCT.

Eligibility criteria: Inclusion Criteria:

1. Confirmed diagnosis of hematological malignancies refer to the 2016 WHO classification.
2. Aged 14 to 60 years.
3. Karnofsky or Lansky performance status \[27\] ≥ 70%. Please refer to Appendix A.
4. First transplantation.
5. Adequate organ function
6. Patient and/or legal guardian must sign informed consent for HSCT.

Exclusion Criteria:

1. Ex-vivo T-cell depleted grafts.
2. Pregnancy or breast-feeding or unwilling to use proper contraception.
3. Unable to assess whether the malignancy is in complete remission.
4. History of hypersensitivity to any biological product.
5. Sensibility to rabbit proteins or previous treatment with Thymoglobuline®.
6. Subjects with uncontrollable systemic infection (viral, bacterial or fungal).
7. Participation in other trial in which the dose of Thymoglobuline® is fixed other than individualized dose.
8. Unable to sign the informed consent form.

Primary outcomes:
measure: The cumulative incidences of CMV reactivation
timeFrame: 180 days after transplantation
measure: The cumulative incidences of EBV reactivation
timeFrame: 180 days after transplantation
Secondary outcomes:
measure: Engraftment
timeFrame: 28 days after transplantation
measure: The cumulative incidences of aGVHD (refer to MAGIC criteria)
timeFrame: 100 days after transplantation
measure: The cumulative incidences of cGVHD (refer to NIH criteria)
timeFrame: 2 years after transplantation
measure: Relapse
timeFrame: 1 years after transplantation
measure: Nonrelapse mortality (NRM)
timeFrame: 1 years after transplantation
measure: Disease-free survival (DFS)
timeFrame: 1 years after transplantation
measure: Overall survival (OS)
timeFrame: 1 year after transplantation
Other outcomes:
Locations:
city: Beijing
country: China
facility: Chinese PLA General Hospital
state: Beijing
Study officials:
affiliation: Chinese PLA General Hospital
name: Dai-hong Liu, Dr.
role: STUDY_CHAIR
References:
citation: Call SK, Kasow KA, Barfield R, Madden R, Leung W, Horwitz E, Woodard P, Panetta JC, Baker S, Handgretinger R, Rodman J, Hale GA. Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):274-8. doi: 10.1016/j.bbmt.2008.11.027.
citation: Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. doi: 10.1016/S1470-2045(15)00462-3. Epub 2015 Dec 24.
citation: 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.
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. doi: 10.1182/blood.v98.10.2942.
citation: Remberger M, Svahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation. 2004 Jul 15;78(1):122-7.