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

Graft-versus-host-disease Clinical Trial

— ATG/PTCy  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03395860
• Other study ID #: SHSYXY-ATG/PTCy
• Secondary ID: NSFC
• Status: Recruiting
• Phase: Phase 2
• Start date: May 30, 2017
• Est. completion date: December 20, 2021

Study information

• Verified date: May 2018
• Source: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Contact: yang, master
• Phone: 18001890183
• Email: yangjuan74[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 .

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 20, 2021
• Est. primary completion date: May 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease
• Graft-versus-host-disease
• Prophylaxis

Intervention

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

Locations

Country	Name	City	State
China	Shanghai First People's HOSPITAL	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The cumulative incidences of acute GVHD	The cumulative incidences of aGvHD was defined as the number and the ratio of the participants with aGVHD	100 days after transplantation
Secondary	Leukocyte engraftment	Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul.	1 MONTH
Secondary	Platelet engraftment	Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >50000/ul.	1 MONTH
Secondary	Donor chimerism	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.	2 YEARS
Secondary	Relapse incidence (RI)	RI was defined as the number and ratio of the participants with relapse after transplantation	2 YEARS
Secondary	chronic GVHD	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	2 year
Secondary	infection	CMV and EB infections(The number and ration of participants with infection after transplantaton)	6 month