Clinical trial NCT03395860: Low Dose ATG Plus Low Dose PTCy as GVHD Prophylaxis in Haplo-HSCT
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Graft-versus-host-disease
Prophylaxis
Keywords: GVHD
ATG
PTCy
halo-HSCT
Lead sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
First posted: 2018-01-10
Enrollment: 100
Sex: ALL
Minimum age (years): 14
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: drug: rATG drug: PTCy
Primary purpose: TREATMENT

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

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 .

Eligibility 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.

Primary outcomes:
measure: The cumulative incidences of acute GVHD
timeFrame: 100 days after transplantation
Secondary outcomes:
measure: Leukocyte engraftment
timeFrame: 1 MONTH
measure: Platelet engraftment
timeFrame: 1 MONTH
measure: Donor chimerism
timeFrame: 2 YEARS
measure: Relapse incidence (RI)
timeFrame: 2 YEARS
measure: chronic GVHD
timeFrame: 2 year
measure: infection
timeFrame: 6 month
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai First People's HOSPITAL
state: Shanghai
Study officials:
affiliation: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
name: xinpeng wang, doctor
role: STUDY_CHAIR
References: