Randomized Phase 2 Study Testing Two Conditioning Regimen With a Single Prophylaxis of Graft-versus-host Disease by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 82
- 试验地点
- 3
- 主要终点
- Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).
研究概览
简要总结
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-CSH).
Recently, in the context of semi-identical (=haploidentical) HLA donors, but also of compatible HLA donors, the use of cyclophosphamide (CY) administered in high doses at early post-transplant (PT) (=PTCY) (Days +3 and +4 or +5) has shown excellent control of acute and chronic GVH, even enabling the discontinuation of other immunosuppressive drugs administered after allo-CSH (ciclosporin, mycophenolate mofetyl (MMF) or Cellcept).
This step has already been taken in the context of allo-CSH with myeloablative conditioning (MAC), which is a minoritary conditioning in adults.
However, in the context of allo-CSH with reduced-intensity conditioning (RIC), which predominates in adults, this strategy seems insufficient to prevent the risk of GVHD.
The idea of reducing the use of immunosuppressants in the context of RIC/HLA-compatible transplants seems, however, still relevant, in order to reduce their adverse effects, improve patients' quality of life and enhance the reconstitution of the post-transplant immune system.
详细描述
For this reason, the investigators now wish to test the administration of a combination of a high dose of early post-transplant CY (PTCY) and methotrexate (MTX) on days (D) D+1, D+4, D+6, D+11 (doses already performed in MAC transplant prophylaxis), with anti-lymphocyte serum (ALS) with RIC conditioning, without ciclosporin or MMF.
The investigators hypothesize that administration of this PTCY+MTX combination will enable immunosuppressive drugs to be discontinued as early as D+11 post-transplant, compared with the usual average of 3 to 4 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: ≥ 18 and ≤ 70 years old
- •Patient with hematologic malignancy
- •Indication for HSC allograft with attenuated conditioning
- •Pluripotent stem cell (PSC) engraftment
- •Availability of a 10/10 familial or non-familial HLA compatible donor
- •Consent to the protocol
- •ECOG <=2
- •Woman of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for a period of 12 months after stopping MTX and CY
- •Man of childbearing age with highly effective contraception during treatment and for a period of 6 months after stopping MTX and CY and a period of 12 months after stopping MTX and CY if TBF conditioning regimen arm
- •Negative Hepatitis B, C, HIV serologies
- •Social security affiliation
排除标准
- •History of allograft
- •Patient eligible for myeloablative conditioning (MAC)
- •Bone marrow transplant
- •Other progressive cancerous disease, or antecedent of cancer in the last five years, with the exception of a carcinoma of the skin or a carcinoma in situ of the uterine cole treated and in remission.
- •Progressive psychiatric condition
- •Pregnant or breastfeeding woman,
- •Woman or man of childbearing age with lack of effective contraception
- •Serious and uncontrolled concomitant infection
- •Cardiac: systolic ejection fraction < 50% by transthoracic ultrasound or by isotopic method (isotope gamma angiography), NYHA II, III or IV heart failure, active rhythmic, valvular or ischemic heart disease or anteriority
- •Respiratory with EFR: DLCOc <40% of theoretical
- •Renal: creatinine clearance < 50 ml/min (assessment with MDRD method)
- •Urological: active urinary tract infection, history of acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy, known obstruction of urinary flow, pre-existing hemorrhagic cystitis
- •Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal
- •Person protected by law (major under guardianship, curatorship or legal protection)
- •Vaccination against yellow fever in the last year
- •Known or suspected hypersensitivity to rabbit proteins as well as to the active substance and excipients of all investigational and ancillary drugs administered during the study,
- •Contraindication to any of the investigational or adjuvant drugs administered during the study
- •Patient not speaking French
研究组 & 干预措施
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Anti-Thymoglobulin (Drug)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: total body irradiation (Radiation)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Methotrexate (Drug)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Post-Transplant Cyclophosphamide (Drug)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Fludarabine (Drug)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Cycophosphamide (Drug)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: hematopoietic stem cells (Other)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Graft nuclear cells (Other)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Donor Lymphocytes Injection (Other)
(CLO)-BALTIMORE
BALTIMORE conditioning regime for LYMPHOID HEMOPATHY CLO-BALTIMORE conditioning regime for MYELOID HEMOPATHY
干预措施: Clofarabine (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Methotrexate (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Post-Transplant Cyclophosphamide (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Anti-Thymoglobulin (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: hematopoietic stem cells (Other)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Graft nuclear cells (Other)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Donor Lymphocytes Injection (Other)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Thiotepa (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Busulfan (Drug)
TBF
Conditioning regimen for LYMPHOID AND MYELOID HEMOPATHY
干预措施: Fludarabine (Drug)
结局指标
主要结局
Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).
时间窗: Post-transplant through study completion, an average of 1 year
Estimation of the incidence of grade 3 and 4 acute GVHD following allo-CSH (excluding post-DLI\* acute GVHD) according to Mount Sinai criteria.
次要结局
- Disease-free survival (DFS)(Post-transplant through study completion, an average of 1 year)
- Incidence of non-relapse mortality (NRM)(Post-transplant through study completion, an average of 1 year)
- Chimerism(At Month1, Month2, Month3, Month6, Month12 post-transplant)
- Incidence of acute GVHD grade 2-4(Post-transplant through study completion, an average of 1 year)
- Overall survival (OS)(Post-transplant through study completion, an average of 1 year)
- Incidence of corticoresistant acute GVHD(Post-transplant through study completion, an average of 1 year)
- Grade 3 and 4 post-transplant adverse events(Post-transplant through study completion, an average of 1 year)
- Incidence of chronic GVHD(From month 3 post-transplant through study completion, an average of 1 year)
- GVHD and relapse-free survival (GRFS)(Post-transplant through study completion, an average of 1 year)
- Incidence of engraftment(Month 1 post-transplant)
- Incidence of relapse(Post-transplant through study completion, an average of 1 year)
- Immune reconstitution(At Month3, Month6, Month9, Month12 post-transplant)
- Incidence of viral, bacteriological, fungal and parasitic infections(Post-transplant through study completion, an average of 1 year)