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Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer

2014年9月3日 更新者:City of Hope Medical Center

A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin, as Graft-versus-Host Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, antithymocyte globulin, and methotrexate before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well sirolimus, tacrolimus, and antithymocyte globulin work in preventing graft-versus-host disease in patients undergoing a donor stem cell transplant for hematological cancer .

研究概览

详细说明

OBJECTIVES:

Primary

  • To determine the incidence and severity of acute- and chronic-graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor hematopoietic peripheral blood transplantation in patients with hematologic malignancies scheduled to receive immunosuppressive combination of sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
  • To determine the safety of this combination in the first six months post-transplant.

Secondary

  • To determine the time-to-engraftment, non-relapse mortality rate, overall and disease-free survival, incidence of disease relapse, and incidence of opportunistic infections with this GVHD prophylaxis.

OUTLINE: Patients are stratified according to conditioning regimen (fludarabine phosphate and melphalan vs fractionated total-body irradiation [FTBI] and etoposide vs FTBI and cyclophosphamide) and degree of donor/recipient HLA mismatch (high-risk vs low-risk).

  • Conditioning regimen: Patients receive 1 of 3 standard conditioning regimens beginning on day -9 or -8 and continuing to day -1 or 0.
  • Peripheral blood stem cell transplantation: Patients receive HLA-matched or mismatched unrelated donor peripheral blood stem cells on day 0.
  • Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -3 and then orally when tolerated, oral sirolimus on days -3 and -2, anti-thymocyte globulin IV over 4-8 hours on days -3 to 0, and methotrexate* IV on days 1, 3, and 6. Tacrolimus and sirolimus continue for 3-6 months (with taper).

NOTE: *Only patients with high-risk HLA mismatch receive treatment with methotrexate.

After completion of study therapy, patients are followed periodically for up to 2 years.

研究类型

介入性

注册 (实际的)

32

阶段

  • 阶段2

联系人和位置

本节提供了进行研究的人员的详细联系信息,以及有关进行该研究的地点的信息。

学习地点

    • Arizona
      • Phoenix、Arizona、美国、85006
        • Banner Good Samaritan Medical Center
    • California
      • Duarte、California、美国、91010-3000
        • City of Hope Comprehensive Cancer Center

参与标准

研究人员寻找符合特定描述的人,称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

2年 及以上 (孩子、成人、年长者)

接受健康志愿者

有资格学习的性别

全部

描述

DISEASE CHARACTERISTICS:

  • Diagnosis of hematological malignancy including any of the following:

    • Non-Hodgkin lymphoma (NHL) in any complete remission (CR) or partial response (PR)
    • Hodgkin lymphoma in any CR or PR
    • Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in any CR

      • Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation of conditioning for patients with non-CR AML or ALL
    • Myelodysplastic syndromes (MDS) treated or untreated
    • Chronic myelogenous leukemia (CML) in chronic or accelerated phase
    • Multiple myeloma in any CR or PR
    • Chronic lymphocytic leukemia in CR or PR 2 or greater
    • Myelofibrosis and other myeloproliferative disorders

      • Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation
  • High-risk disease defined as AML or ALL > CR1, accelerated phase CML, recurrent aggressive lymphoma, or active lymphoproliferative disease at transplant
  • Low-risk disease defined as AML or ALL in CR1, chronic phase CML, or low-grade lymphoproliferative disorder with controlled disease at transplant
  • Must be planning to receive 1 of the following conditioning regimens at City of Hope:

    • Fludarabine phosphate and melphalan for patients with hematological malignancies and contraindications for conventional myeloablative regimens due to age, co-morbidity, or previous transplant
    • Fractionated total-body irradiation (FTBI) and etoposide for patients with AML and ALL or CML in accelerated phase
    • FTBI and cyclophosphamide for patients with NHL, AML, CML, and MDS
  • Suitable unrelated donor available

    • HLA-matched or mismatched
    • Peripheral blood stem cells available
    • No bone marrow or ex vivo-engineered or processed graft (e.g., CD34-positive, T-cell depletion)
  • No uncontrolled CNS disease

PATIENT CHARACTERISTICS:

  • Karnofsky performance status (PS) 70-100% or ECOG PS 0-2
  • Creatinine < 1.3 mg/dL or creatinine clearance ≥ 70 mL/min
  • Ejection fraction > 45%
  • Direct bilirubin < 3 times upper limit of normal (ULN)
  • ALT and AST < 3 times ULN
  • Forced vital capacity, FEV1, and DLCO > 45% of predicted
  • Able to cooperate with oral medication intake
  • No active donor or recipient serology positive for HIV
  • No known contraindication to administration of sirolimus, tacrolimus, or anti-thymocyte globulin
  • No active hepatitis B or C
  • Negative pregnancy test

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Concurrent participation in other clinical trials for prevention or treatment of viral, bacterial, or fungal disease allowed provided agents do not interact with agents used in the current study

学习计划

本节提供研究计划的详细信息,包括研究的设计方式和研究的衡量标准。

研究是如何设计的?

设计细节

  • 主要用途:支持治疗
  • 分配:非随机化
  • 介入模型:单组作业
  • 屏蔽:无(打开标签)

武器和干预

参与者组/臂
干预/治疗
实验性的:Fludarabine/Melphalan Conditioning

Fludarabine/Melphalan Conditioning with

Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis

0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant
Melphalan 140 mg/m2 on day -4 from stem cell transplant
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant

Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.

Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose

0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
实验性的:FTBI/Cytoxan Conditioning
FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant

Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.

Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose

0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
60mg/kg on days -5 and -4 from stem cell transplant
实验性的:FTBI/Etoposide Conditioning

FTBI/Etoposide Conditioning with

Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis

0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant

Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.

Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose

0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
60mg/kg on day -4 from stem cell transplant

研究衡量的是什么?

主要结果指标

结果测量
措施说明
大体时间
Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100
大体时间:100 Days Post Hematopoietic Stem Cell Transplant (HSCT)
Patients were evaluated for the development of acute GVHD within the first 100 days post HSCT. The cumulative incidence of grade II-IV acute GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death and nonengraftment.
100 Days Post Hematopoietic Stem Cell Transplant (HSCT)
Severity of Acute GVHD
大体时间:100 Days Post HSCT
All patients were considered for the evaluation of the severity of acute GVHD.
100 Days Post HSCT
Cumulative Incidence of Chronic GVHD
大体时间:2 year point estimate was provided.
Patients were evaluated for the development of chronic GVHD from 101 days post HSCT to last contact or documented evidence of the disease. The cumulative incidence of chronic GVHD was determined using competing risk analysis. Competing risks for GVHD were death and nonengraftment.
2 year point estimate was provided.
Severity of Chronic GVHD
大体时间:Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT
All Patients were considered for the evaluation of chronic GVHD severity.
Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT

次要结果测量

结果测量
措施说明
大体时间
Time to Absolute Neutrophil Count Recovery (Engraftment)
大体时间:Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT
Absolute neutrophil count (ANC) recovery is defined as an ANC of ≥ 0.5 x 10^9/L (500/mm3) for three consecutive laboratory values obtained on different days
Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT
Time to Platelet Count Recovery (Engraftment)
大体时间:Patients were evaluated until platelet recovery, a median of 14 days
Platelet recovery is defined as the first date of three consecutive laboratory values ≥ 25 x 10^9 L obtained on different days.
Patients were evaluated until platelet recovery, a median of 14 days
Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation
大体时间:Median Follow Up: 28 months (Range: 1-49 months)
Participants were monitored throughout the trial (median of 28 months) for various infections/complications.
Median Follow Up: 28 months (Range: 1-49 months)
Occurrence of Thrombotic Microangiopathy
大体时间:Median Follow Up: 28 Months (Range: 1-49 months)
Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed TMA.
Median Follow Up: 28 Months (Range: 1-49 months)
Occurence of Sinusoidal Obstructive Syndrome (SOS)
大体时间:Median Follow Up: 28 Months (Range: 1-49 Months)
Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed SOS.
Median Follow Up: 28 Months (Range: 1-49 Months)
Non-relapse Mortality at 100 Days Post HSCT
大体时间:100 day point estimate was provided
Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.
100 day point estimate was provided
Non-relapse Mortality at Two Years Post HSCT
大体时间:2 year point estimate was provided.
Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.
2 year point estimate was provided.
Overall Survival at Two Years Post HSCT
大体时间:2 year point estimate was provided.
Patients were evaluated for survival (OS) throughout the study. Kaplan Meier estiamtes were calculated for overall survival using time from HSCT to death of any cause or for surviving patients last contact date.
2 year point estimate was provided.
Event Free Survival at Two Years Post HSCT
大体时间:2 year point estimate was provided.
Patients were evaluated for event free survival (EFS) throughout the study. Events were defined as death, relapse, progression, or nonengraftment. Kaplan Meier estimates were calculated as time from HSCT to event.
2 year point estimate was provided.
Incidence of Disease Relapse/Progression at 2 Years Post HSCT
大体时间:2 year point estimate was provided.
Patients were evaluated for relapse/progression post transplant throughout the study. The cumulative incidence of relapse/progression was determined using competing risk analysis. Competing risks for relapse were non-relapse mortality and nonengraftment.
2 year point estimate was provided.

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

调查人员

  • 学习椅:Ryotaro Nakamura, MD、City of Hope Comprehensive Cancer Center

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查,以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始

2007年5月1日

初级完成 (实际的)

2012年2月1日

研究完成 (实际的)

2012年2月1日

研究注册日期

首次提交

2007年12月21日

首先提交符合 QC 标准的

2007年12月25日

首次发布 (估计)

2008年1月9日

研究记录更新

最后更新发布 (估计)

2014年9月10日

上次提交的符合 QC 标准的更新

2014年9月3日

最后验证

2014年9月1日

更多信息

与本研究相关的术语

关键字

其他研究编号

  • 06141
  • P30CA033572 (美国 NIH 拨款/合同)
  • CHNMC-06141
  • CDR0000579340 (注册表标识符:NCI PDQ)

此信息直接从 clinicaltrials.gov 网站检索,没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求,请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改,我们的网站上也会自动更新.

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