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Low Dose ATG Plus Low Dose PTCy as GVHD Prophylaxis in Haplo-HSCT (ATG/PTCy)

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ClinicalTrials.gov Identifier: NCT03395860
Recruitment Status : Recruiting
First Posted : January 10, 2018
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
Xianmin Song, MD, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Brief Summary:
Low dose Rabbit Antithymocyte Globulin plus Low-dose post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplantation for patients with hematologic malignancies

Condition or disease Intervention/treatment Phase
Graft-versus-host-disease Prophylaxis Drug: ATG Phase 2

Detailed Description:
A novel regimen, which is composed of a low dose of ATG (5 mg/kg) and low-dose PTCy (one dose of PTCy, 50mg/kg) for GVHD prophylaxis in haplo-HSCT for patients with hematologic malignancies, is going to be evaluated in the prospective, randomized control, phase II clinical trial. It is theoretically feasible because the mechanisms of ATG and Cyclophosphamide on T lymphocyte are different. ATG plays the immunosuppressive activity on the depletion of peripheral T lymphocytes through complement dependent lysis or activation-associated apoptosis. ATG also modulates cell-surface expression of surface adhesion molecules or chemokine receptors. In addition, ATG can also affect or interfere with the function of different immune cells such as B lymphocytes, regulatory T lymphocytes (Treg), natural killer (NK)-T lymphocytes and dendritic cells (DC).Cyclophosphamide is nontoxic to hematopoietic stem cells and can selectively deplete the alloreactive T cells. Therefore, we hypothesis that ATG followed by PTCy have the synergistic effect on GVHD prophylaxis. (2) Luznik et al also showed that there was no difference in the incidence of severe acute GVHD between one or two doses of PTCy. Furthermore, there was a trend toward a lower incidence of extensive cGVHD among patients of two doses of PTCy compared with one dose PTCy. One dose of PTCy might preserve the GVL effect without influencing the incidence of the severe aGVHD. (3) Y Wang et al reported a randomized clinical trial comparing two different doses of ATG (6 and 10mg/kg) as GVHD prophylaxis for Haplo-HSCT. There was no difference in the median myeloid and platelet engraftment time and the rate of graft failure. The results showed that the incidence of grade III-IV acute GVHD was higher in the ATG-6 group than in the ATG-10 group. But the EBV reactivation occurred more frequently in the ATG-10 group than in the ATG-6 group. The higher rate of infection and NRM may influence the transplant outcomes in this GVHD prophylaxis strategy. We speculated that low dose of ATG (5 mg/kg) will ensure the engraftment and decrease infection frequency. But the optimal timing of ATG administration still needed to be considered. The immunosuppressive activity of ATG is not only dose-dependent but also rely on the timing of drug administration, especially when the lower dose of ATG was used as GVHD Prophylaxis. So we designed a randomized control phase II study to evaluate the efficacy and toxicity with low dose ATG followed by low dose PTCy as GVHD prophylaxis .

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: drug: rATG drug: PTCy
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low Dose Rabbit Antithymocyte Globulin Plus Low-dose Post-transplantation Cyclophosphamide as GVHD in Hapl-HSCT for Patients With Hematologic Malignancies: a Phase II Trial
Actual Study Start Date : May 30, 2017
Estimated Primary Completion Date : May 20, 2020
Estimated Study Completion Date : December 20, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: group A
low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-3-d-2 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3
Drug: ATG
group A:low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-3-d-2 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3 group B:low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-2-d-1 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3
Other Name: PTCY

Experimental: group B
low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-2-d-1 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3
Drug: ATG
group A:low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-3-d-2 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3 group B:low dose antithymocyte globulin rATG(2.5mg/kg/d) used at d-2-d-1 low dose post-transplant cyclophosphamide PTCy (50mg/kg/d) use at d+3
Other Name: PTCY




Primary Outcome Measures :
  1. The cumulative incidences of acute GVHD [ Time Frame: 100 days after transplantation ]
    The cumulative incidences of aGvHD was defined as the number and the ratio of the participants with aGVHD


Secondary Outcome Measures :
  1. Leukocyte engraftment [ Time Frame: 1 MONTH ]
    Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul.

  2. Platelet engraftment [ Time Frame: 1 MONTH ]
    Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >50000/ul.

  3. Donor chimerism [ Time Frame: 2 YEARS ]
    Quantitative chimerism analyzes were performed using short-tandem-repeat-based polymerase chain reaction technique sat regular intervals for every 4 weeks after allografting in bone marrow.

  4. Relapse incidence (RI) [ Time Frame: 2 YEARS ]
    RI was defined as the number and ratio of the participants with relapse after transplantation

  5. chronic GVHD [ Time Frame: 2 year ]
    cGvHD was diagnosed and graded according to the 2014 National Institutes of Health (NIH) consensus criteria: mild, moderate or severe respectively.The number and ratio of participants with cGVHD after transplatation

  6. infection [ Time Frame: 6 month ]
    CMV and EB infections(The number and ration of participants with infection after transplantaton)



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Ages Eligible for Study:   14 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients diagnosed with hematologic malignancies (AML, ALL, high-risk MDS, lymphoma, CML) were enrolled in this study. Diagnosis was according to the criteria of 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues.
  • Family members selected as donors were typed at the HLA-A, -B, -DQB1, -C and -DRB1 locus at high-resolution level. Haplo was defined as recipient-donor number of HLA mismatches > 2.(20)
  • 14 to 70 years old.
  • Performance status scores no more than 3 (ECOG criteria).
  • Adequate organ function as defined by the following criteria: alanine transaminase (ALT), aspartate transaminase(AST) and total serum bilirubin <2×ULN (upper limit of normal). Serum creatinine and blood urea nitrogen (BUN) <1.25×ULN.
  • Adequate cardiac function without acute myocardial infarction, arrhythmia or atrioventricular block, heart failure, active rheumatic heart disease and cardiac dilatation(the patients has been improved after treatment of the disease and are not expected to affect transplant can include in the study).
  • Absence of any other contraindications of stem cell transplantation. Willingness and ability to perform HSCT.
  • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

  • Presence of any condition inappropriate for HSCT.
  • Life expectancy < 3 months because of other severe diseases.
  • Presence of any fatal disease, including respiratory failure, heart failure, liver or kidney function failure.
  • Uncontrolled infection.
  • Pregnancy or breastfeeding.
  • Has enrolled in another clinical trials.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03395860


Contacts
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Contact: yang, master 18001890183 yangjuan74@hotmail.com
Contact: xianming song, doctor 13501672508 shongxm@sjtu.edu.cn

Locations
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China, Shanghai
Shanghai First People's HOSPITAL Recruiting
Shanghai, Shanghai, China, 200127
Contact: YANG JUN, master    18001890183    yangjuan74@hotmail.com   
Contact: song xianmin, doctor    13501672508    shongxm@sjtu.edu.cn   
Sponsors and Collaborators
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Investigators
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Study Chair: xinpeng wang, doctor Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Responsible Party: Xianmin Song, MD, Head of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
ClinicalTrials.gov Identifier: NCT03395860    
Other Study ID Numbers: SHSYXY-ATG/PTCy
NSFC ( Other Grant/Funding Number: 81370601 )
First Posted: January 10, 2018    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Xianmin Song, MD, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine:
GVHD
ATG
PTCy
halo-HSCT
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases