Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD)
研究概览
简要总结
Background:
Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells.
This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.
Objectives:
To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.
To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.
Eligibility:
People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.
Design:
All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.
All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.
Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:
- Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
- Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.
Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen.
Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.
A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.
...
详细描述
Background:
- The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immune depleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of human leukocyte-antigen (HLA)-matched unrelated donors in a pilot manner.
- A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus, methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition, neither of these regimens has been assessed for their effects on chronic GVHD using the National Institutes of Health (NIH) Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.
Objectives:
- Primary objectives:
- to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of cluster of differentiation 4 (CD4)+ T cell receptor V BETA repertoire by complementarity determining region 3 (CDR3) spectratyping at 3 months post-transplant.
- to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival.
- to determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials.
- Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities
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 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: Allogenic stem cell transplant (ASCT) (Drug)
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: Rituximab (Biological)
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: Conditioning Chemotherapy (Drug)
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: TMS (Drug)
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: FLAG (Drug)
A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
干预措施: EPOCH-F (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: Rituximab (Biological)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: Cyclosporine (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: Allogenic stem cell transplant (ASCT) (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: Conditioning Chemotherapy (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: FLAG (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: EPOCH-F (Drug)
B - Cyclosporine (AC) Arm
AC Arm
干预措施: Alemtuzumab (Biological)
结局指标
主要结局
Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD)
时间窗: 6 months
Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.
Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD)
时间窗: 2 years post transplant
Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria.
Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells
时间窗: Recipient recovery at 6, 12 and 24 months post transplant
The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry.
Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells
时间窗: Recipient recovery at 6, 12 and 24 months post transplant
The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry.
Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire
时间窗: Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant
Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.
Changes in CD8 T Cell Receptor Vbeta Repertoire
时间窗: Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant
Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.
次要结局
- Toxicities(103 months and 22 days)
- Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD)(6 months)
- Days to Engraftment of Neutrophils(2 years)
- Days to Engraftment of Platelets(2 years)
- Days to Engraftment of Lymphocytes(2 years)
- Overall Survival(Patients were followed for an average of up to 5 years.)
- Early Treatment Related Mortality(Less than or equal to 28 days after transplantation)
- Percentage of Participants With Late Treatment Related Mortality(Greater than 28 days after transplantation)
- Decline in Homeostatic Cytokine Interleukin 7 (IL-7) Post-Transplant(Day 0, 1 week and 2 weeks)
- Immune Reconstitution of Normal Killer (NK) Cells(2 weeks, and 1, 3, 6, 12, and 24 months post transplant)
- Immune Reconstitution of Cluster of Differentiation 4 (CD4) T Cell Populations(2 weeks, and 1, 3, 6, 12 and 24 months post transplant)
- Immune Reconstitution of Cluster of Differentiation 8 (CD8) T Cell Populations(2 weeks, 1, 3, 6, 12 and 24 months post transplant)
研究者
Steven Pavletic, M.D.
Principal Investigator
National Cancer Institute (NCI)