Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

ATG Based Conditioning Regimen in HLA Related HSCT for Aggressive T-cell Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02938741
Recruitment Status : Recruiting
First Posted : October 19, 2016
Last Update Posted : October 25, 2016
Sponsor:
Information provided by (Responsible Party):
Yang Jun, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Tracking Information
First Submitted Date  ICMJE October 16, 2016
First Posted Date  ICMJE October 19, 2016
Last Update Posted Date October 25, 2016
Study Start Date  ICMJE October 2016
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2016)
relapse free survival(RFS) [ Time Frame: 2 year ]
PFS were defined as the time from stem-cell infusion to relapse, disease progression from any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02938741 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2016)
  • Progress free survival (PFS) rate [ Time Frame: 2 years ]
    PFS were defined as the time from stem-cell infusion to relapse, disease progression,or death from any cause
  • Overall survival rate [ Time Frame: 2 years ]
    OS were defined as the time from stem-cell infusion to death from any cause
  • Leukocyte engraftment [ Time Frame: one month ]
    Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul.
  • Platelet engraftment [ Time Frame: one month ]
    Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >50000/ul.
  • Donor chimerism: [ Time Frame: 2 year ]
    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.
  • Transplant related mortality [ Time Frame: up to 2 year ]
    TRM were defined as death within 100 days of high-dose therapy not related to the disease,relapse or progression
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ATG Based Conditioning Regimen in HLA Related HSCT for Aggressive T-cell Tumors
Official Title  ICMJE Hematology , Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, China
Brief Summary ATG based conditioning regimen in HLA related allogeneic hematopoietic stem cell transplantation for aggressive T-cell tumors: multi-center, open, randomized controlled clinical study
Detailed Description

Aggressive T-cell lymphomas (ATCLs), including peripheral T-cell lymphoma and T lymphoblastoid cell lymphoma/leukemia, represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults(1). ATCLs show a worse prognosis than that of B-cell lymphomas. Myeloablative allogeneic stem cell transplantation (allo-SCT) may be the only way to cure these patients, but the recurrence of the primary disease after transplantation is still an important prognostic factor (2). Optimizing the conditioning regimen is always the research hot topics in hematology fields. Polyclonal antithymocyte globulin (rabbit anti-thymocyte globulin, r-ATG) are currently used to prevent graft-versus -host(GVHD) disease in allogeneic stem cell transplantation, and also widely used for the prevention and treatment of acute rejection after solid organ transplant because of its strong immunomodulatory effects. ATG is used in allogeneic SCT for the prophylaxis of graft versus host disease by in vivo T cell depletion, including the complement-dependent cytotoxic response, antibody-dependent cell-mediated cytotoxicity, the opsonophagocytic role of phagocytic cells and induced apoptosis(3). But some scholars reported the ATG delayed immune reconstitution and hematologic reconstitution and leaded to the increase of the incidence of virus and fungal infections after transplantation. But it is often curable and does not affect the overall survival and quality of life of the patients (4). Because of its strong immune suppression and regulation, also on the basis of the above facts, ATG as GVHD prophylaxis is generally limited to the unrelated donor, or human leukocyte antigen(HLA)-mismatched related donor transplantation. But There are many issues still need to be studied. ATG has shown efficacy in preventing acute GVHD(aGVHD) in allo-SCT, but its efficacy in chronic GVHD (cGVHD) and long-term outcomes remains controversial. A systematic review and meta-analysis from Du k et al(5) reported that prophylactic use of ATG exerted a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat. Does the ATG also have the killing effect on the tumor cells of the lymphatic system? The vitro studies have confirmed this point recently. Grüllich(6) et al and the investigators study(7) both found that ATG can inhibit the proliferation and induce high level of apoptosis in the human lymphoblastic cell lines, such as Jurkat, Daudi, DG-75 , and myeloblastic cell lines K562, HL-60, KG1, and U937. ATG also has pro-apoptotic activity against the majority of primary leukemia cells, particularly those cells from lymphatic origin. In addition, ATG will not result in apoptosis of normal hematopoietic cells. Low-dose ATG can also stimulate normal hematopoietic colony growth. Therefore, ATG may be used as anti-lymphocyte tumor bio-therapeutics (such as rituximab) to increase the role of chemo-radiotherapy in the conditioning regimen. And ATG can remove the residual tumor lesions, which reduced the rate of tumor recurrence after transplantation. The result of our retrospective study in our hospital had already be published in blood cancer journal. We used the ATG as the part of the conditioning regimen and to evaluate the long-term antileukemia effect, the safety and complication in the patients with highly aggressive T-cell lymphomas. Twenty-three patients were enrolled into this study. At the time of transplant, six patients reached first or subsequent complete response, three patients had a partial remission and 14 patients had relapsed or primary refractory disease. The conditioning regimen consisted of ATG, total body irradiation, toposide and cyclophosphamide. The complete remission rate after transplant was 95.7%. At a median follow-up time of 25 months, 16 (69.6%) patients are alive and free from diseases, including nine patients in refractory and progressive disease. Seven patients died after transplant, five from relapse and two from treatment-related complications. The incidence of grades II-IV acute graft-vs-host disease (GvHD) was 39.1%. The maximum cumulative incidence of chronic GvHD was 30%. The most frequent and severe conditioning-related toxicities observed in 8 out of 23 patients were grades III/IV infections during cytopenia. Thus, ATG based conditioning is a feasible and effective alternative for patients with highly aggressive T-cell tumors(8). In view of this convincing result, we designed a multi-center, open, randomized controlled clinical study.

As noted earlier, a higher relapse rate may be a major threat after ATG use(5).In China, the conventional dose of 2.5mg/kg/day, 2-3 days of Thymoglobulin is commonly used as GVHD prophylaxis in the unrelated donor, or HLA-mismatched related donor transplantation but not in the HLA matched related donor transplantation (9). In order to observe the anti-tumor effect of this conditioning regimen in the aggressive T-cell lymphomas patients(complete remission, partial remission), we designed a multi-center, open, randomized controlled clinical study. The donors are all HLA matched related donors. In the therapy group, we added in the Thymoglobulin dose in the conditioning regimen for four days 10mg/kg. We expect that this ATG based conditioning regimen does play anti-tumor effect, reduce primary disease recurrence after transplantation, improve disease-free survival (DFS) and overall survival rate (OS) , as well as reduce the incidence and severity of GVHD, but the incidence of infection need to be observed.

Reference:1. Rudiger T, Weisenburger DD, Anderson JR et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 2002; 13:140-149.

2. Armitage J, Vose J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124-4130 3. Mohty M .Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007 Jul;21(7):1387-94. Epub 2007 Apr 5 4. Baumann H, JudithD, Zey C et al. Antithymocyte globulin Fresenius or San gstat (Genzyme) as part of the conditioning for unrelated donor HSCT: emerging differences in posttransplant immune reconstitution. Bone Marrow Transplant, 2004; 33: S51.

5. Du K, Hu Y, Wu K, Huang H et al. Long-term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis.Clin Transplant. 2013 Mar;27(2):E91-E100.

6. Grullich G, Ziegler C, Finke J et al. Rabbit Anti T-Lymphocyte Globulin Induces Apoptosis in Peripheral Blood Mononuclear Cell Compartments and Leukemia Cells, While Hematopoietic Stem Cells Are Apoptosis Resistant. Biol Blood Marrow Transplant, 2009, 15:173-182.

7. Huixia Liu, chun wang, Youwen Qin,et al. Polyclonal Rabbit Antithymocyte Globulin induces apoptosis and has Cytotoxic Effects on human Leukemic Cells.Clinical Lymphoma, Myeloma & Leukemia 2012,12: 345-54 8. J Yang, C wang, Y Cai,et al.Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors.Blood Cancer Journal (2015) 5, e332; doi:10.1038/bcj.2015.54 9. Jacobsen ED, Kim HT, Ho VT,et al. A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome. Annals of Oncology 2011( 22): 1608-1613

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Lymphoblastic Lymphoma
Intervention  ICMJE
  • Drug: Anti-human Thymoglobulin
    r-ATG 2.5MG/KG*4days were used in the conditioning
    Other Name: (r-ATG )
  • Drug: Placebo
    r-ATG 2.5MG/KG*4days were not used in the conditioning
Study Arms  ICMJE
  • Experimental: r-ATG Immunosuppressive agents

    Rabbit Anti-human Thymoglobulin (r-ATG 2.5 mg/kg×4 days) were extra used in the treatment group.

    The conditioning include of Busulfex 3.2mg/kg*4d,CTX 60mg/kg *4d.

    Intervention: Drug: Anti-human Thymoglobulin
  • Placebo Comparator: placebo

    Rabbit Anti-human Thymoglobulin (r-ATG) were not used as intervention in the treatment group.

    The conditioning include of Busulfex 3.2mg/kg*4d,CTX 60mg/kg *4d.

    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 18, 2016)
130
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • According to the World Health Organization (WHO) classification, diagnosis of T cell tumor of lymphatic system sources (T lymphoblastoid cell lymphoma/leukemia) confirmed by pathological examination,morphology, cytochemistry, immunophenotyping and chromosome examination, molecular biology including complete remission, partial remission.

Performance status scores no more than 2 (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 et al.

Uncontrolled infection. Pregnancy or breastfeeding. Has enrolled in anther 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: jun yang, master 18001890183 yangjuan74@hotmail.com
Contact: chun wang, doctor 13386259777 wangchun2@medmail.com.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02938741
Other Study ID Numbers  ICMJE 2016KY148
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Yang Jun, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Study Sponsor  ICMJE Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: xipeng wang, doctor Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
PRS Account Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP