Phase 1 Trial for Patients With Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Determine the overall survival (OS) post-HCT ( Arm-B)
研究概览
简要总结
Reduced intensity conditioning (RIC) has emerged and been increasingly adopted as a modality to allow preparative conditioning pre transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study, we aim to use RIC followed by matched related/unrelated donor, 7/8 matched related/unrelated donor, or haploidentical donor peripheral blood stem cell transplantation. Standard strategies to control the alloreactivity following HCT utilize immunosuppressive or cytotoxic medications. In this study, we explore donor graft engineering to enrich for immmunoregulatory populations to facilitate post transplantation immune reconstitution while minimizing graft versus host disease (GVHD) with post-transplant immunosuppressive agents.
详细描述
The objectives for the study are listed below:
Primary Objectives
*Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg) in subjects undergoing allogeneic hematopoietic cell transplantation (HCT) with related/unrelated HLA-matched or mismatched donors, or haploidentical donors with reduced intensity conditioning preparative regimen.
Secondary Objectives
- To determine the GVHD-free relapse-free survival (GRFS) post-HCT
- To determine the overall survival (OS) post-HCT
- To measure the incidence and severity of acute and chronic GVHD
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Recipient Inclusion Criteria a. Patients with the following diseases that are histopathologically-confirmed are eligible
- •Acute myeloid, lymphoid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) or beyond first complete remission (CR1) without the presence of minimal residual disease
- •Acute myeloid, leukemia, or mixed phenotype leukemia that is either:
- •Not in morphologic CR with bone marrow infiltration by leukemic blasts of ≤10%, or
- •In morphologic CR with evidence of minimal residual disease positivity by either multiparametric flow cytometric analysis or by a nucleic acid-based technique
- •Primary refractory acute myeloid, lymphoid, or mixed phenotype leukemia
- •Chronic myelogenous leukemia (accelerated, blast or second chronic phase)
- •Myelodysplastic syndromes
- •Myeloproliferative syndromes b. Match to the patient as follows:
- •For Arm A1 (CLOSED):
- •Availability of a 8/8 or 7/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing.
- •If the donor is a 7/8 HLA-match, the mismatch must be a permissive allelic mismatch as assessed by an independent HLA and transplantation expert.
- •For Arm A1 and Arm A3:
- •Availability of a 8/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing.
- •For Arm B (CLOSED):
- •Availability of a haploidentical donor who is a ≥ 4/8 but <7/8 match at HLA-A, -B, -C, and -DRB1 (typed using DNA-based high-resolution methods), with at most one mismatch per locus
- •For Arm C1 (CLOSED) and C2:
- •Availability of a 8/8 HLA matched donor (related or unrelated) defined by Class I (HLA-A, B, C) serologic typing (or higher resolution) and Class II (HLA DRB1) molecular typing.
- •c. Age ≥ 18 and ≤75 years old at the time of enrollment. For Arm A4, age >/= 18 and </= 78 years of age.
- •d. Left ventricular ejection fraction (LVEF) ≥ 45% e. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50% f. Calculated creatinine clearance ≥ 50 mL/min or creatinine < 2.0 mg/dL g. SGPT and SGOT ≤ 3 x ULN, unless elevated secondary to disease Total bilirubin ≤ 2 x ULN (patients with Gilbert's syndrome may be included at the discretion of the PI or where hemolysis has been excluded h. Negative serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration i. Karnofsky performance status ≥ 70%
- •Donor Inclusion Criteria
- •Age ≥ 18 and ≤ 75 years of age
- •Karnofsky performance status of ≥ 70% defined by institutional standards
- •Seronegative for HIV-1 RNA PCR; HIV 1 and HIV 2 ab (antibody); HTLV-1 and HTLV-2 ab; PCR+ or sAg (surface antigen) hepatitis B ; or PCR or sAg negative for hepatitis C; negative for the Treponema palladum antibody Syphillis screen; and negative for HIV-1 and hepatitis C by nucleic acid testing (NAT) within 30 days of apheresis collection.
- •In the case that T palladum antibody tests are positive, donors must:
- •Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history, or Have completed effective antibiotic therapy to treat syphilis, or Have a documented negative non-treponemal test (such as RPR) or in the case of a positive non-treponemal test must be evaluated by an infectious disease expert to evaluate for alternative causes of test positivity and confirm no evidence of active syphilitic disease e. Match to the patient as follows: a. Arm A1(CLOSED):
- •Must be a related or unrelated, 8/8 or 7/8-HLA match to recipient at HLAA, -B, -C, and -DRB
- •If 7/8 HLA-matched, must be with permissive allelic HLA mismatch as assessed by an independent HLA and transplantation expert.
- •b. Arm A2 (CLOSED) and Arm A3 (CLOSED):
- •Must be a related or unrelated, 8/8 HLA match to recipient at HLA A, B, C, and DRB1
- •c. Arm B (CLOSED):
- •Must be a haploidentical donor who is ≥ 4/8 but < 7/8 match at HLA-A, -B,
- •C, and -DRB1, with at most one mismatch per locus.
- •d. Arm C1 (CLOSED) and Arm C2:
- •Must be a related or unrelated 7/8 HLA matched to recipient at HLA A, B, C, DRB1 or -DQB1
- •f. Must be willing to donate PBSC for up two consecutive days g. Female donors of child-bearing potential must have a negative serum or urine beta HCG test within 3 weeks of mobilization h. Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate i. Agreeable to 2nd donation of PBPC (or bone marrow harvest) in the event of graft failure j. The donor or legal guardian greater than 18 years of age, capable of signing an IRB approved consent form. k. Meets other criteria for donation as specified by standard NMDP guidelines (NMDP donors) or institutional standards (non-NMDP donors) l. Donors not meeting federal eligibility criterion, may nonetheless be included if either apply as follows per 21 CFR § 1271.65:
- •The donor is a first-degree or second-degree blood relative of the recipient, or
- •Documented urgent medical need (DUMN), meaning no comparable human cell product is available and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the Investigator or sub-investigator
排除标准
- •Recipient Exclusion Criteria
- •Seropositive for any of the following:
- •HIV antibodies; hepatitis B surface antigen (sAg); hepatitis C antibodies
- •Patients deemed candidates for fully myeloablative preparative conditioning regimens
- •d. Candidate for autologous transplant e. Hepatitis B or C with SGPT or SGOT > 3 x ULN f. HIV-positive g. Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms. h. Uncontrolled CNS disease involvement i. Pregnant or a lactating female j. Positive serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration k. Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow-up care l. Known allergy or hypersensitivity to, or intolerance of, tacrolimus m. Positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:
- •A positive crossmatch of any titer; or
- •The presence of anti-donor HLA antibody to any HLA locus n. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment o. Concurrent malignancies or active disease within 1 year, except nonmelanomatous skin cancers that have been curatively resected
- •Donor Exclusion Criteria
- •Evidence of active infection
- •Seropositive for HIV-1 or-2, HTLV-1 or -2
- •Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis
- •Lactating female
研究组 & 干预措施
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Fludarabine (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Tacrolimus (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Plerixafor (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Tacrolimus (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Thiotepa (Drug)
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Melphalan (Drug)
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Fludarabine (Drug)
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Tacrolimus (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Fludarabine (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Melphalan (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Tacrolimus (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Cyclophosphamide (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Fludarabine (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Tacrolimus (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Plerixafor (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Thiotepa (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: Plerixafor (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Mycophenolate Mofetil (MMF) (Drug)
Arm B: Haploidentical transplantation (closed)
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:
-. Fludarabine (160 mg/m2)
- Melphalan (100 mg/m2
- TBI (4Gy)
Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.
干预措施: CliniMACS CD34 Reagent System (Device)
Arm C1:7/8 mismatched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Purified regulatory T-cells (Treg) plus CD34+ HSPC (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Fludarabine (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm A4: 8/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (7.5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus
干预措施: Thiotepa (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Thiotepa (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Ruxolitinib (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Plerixafor (Drug)
Arm A2: Fully matched (8/8) related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (10 mg/kg)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Fludarabine (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Tacrolimus (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Plerixafor (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent (Drug)
Arm A3: Fully (8/8) matched related/unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy).
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Thiotepa (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Sirolimus (Drug)
Arm A1: Matched related/matched unrelated donor transplantation (closed)
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.
- Fludarabine (160 mg/m2)
- Melphalan (50 mg/m2)
- TBI (4Gy)
All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.
干预措施: Plerixafor (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Fludarabine (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Tacrolimus (Drug)
Arm C2: 7/8 mismatched related/unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:
- Fludarabine (160 mg/m2)
- Thiotepa (5 mg/kg)
- TBI (2-3 Gy)
All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.
干预措施: Plerixafor (Drug)
结局指标
主要结局
Determine the overall survival (OS) post-HCT ( Arm-B)
时间窗: 2 years
Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored.
Determine the GVHD-free relapse-free survival (GRFS) post-HCT ( Arm-A)
时间窗: 12 months
Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD symptoms, and relapse free survival is defined as survival at 12 months without relapse. The outcome will be measured in Arm A only.
Incidence of Grade III-IV acute GVHD
时间窗: At baseline, day +30, 60, 90, 180, year 1 and year 2
Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria.
The incidence and timing of primary graft failure
时间窗: 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion
Primary graft failure is defined as being alive with donor CD3 chimerism \<5% at day +30 after transplant without recovery of neutrophils (i.e. without achieving an absolute neutrophil count \[ANC\] ≥ 500/mm3 for 3 consecutive days) at Day+28
Donor CD3 chimerism at Day+60 post-HCT
时间窗: 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion)
Defined as a percentage on donor CD3 cells chimerism at day +60 after transplantation.
次要结局
- Overall survival(12 months)
- Treatment-emergent adverse events (TEAs)(from Day 0 through 100 days)
- Acute GVHD (all grades)(from Day 0 through 100 days)
- GVHD-relapse-free survival(12 months)
- Secondary graft failure(from Day 0 through 100 days)
- Steroid-refractory acute GVHD(within 3-5 days of therapy onset)
- Non-relapse mortality (NRM)(12 months)
- Disease-free survival (DFS)(12 months)
- Chronic GVHD (limited or extensive)(from Day 0 through Year 2)