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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

3 сентября 2014 г. обновлено: 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 .

Обзор исследования

Подробное описание

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.

Тип исследования

Интервенционный

Регистрация (Действительный)

32

Фаза

  • Фаза 2

Контакты и местонахождение

В этом разделе приведены контактные данные лиц, проводящих исследование, и информация о том, где проводится это исследование.

Места учебы

    • Arizona
      • Phoenix, Arizona, Соединенные Штаты, 85006
        • Banner Good Samaritan Medical Center
    • California
      • Duarte, California, Соединенные Штаты, 91010-3000
        • City of Hope Comprehensive Cancer Center

Критерии участия

Исследователи ищут людей, которые соответствуют определенному описанию, называемому критериям приемлемости. Некоторыми примерами этих критериев являются общее состояние здоровья человека или предшествующее лечение.

Критерии приемлемости

Возраст, подходящий для обучения

2 года и старше (Ребенок, Взрослый, Пожилой взрослый)

Принимает здоровых добровольцев

Нет

Полы, имеющие право на обучение

Все

Описание

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

Учебный план

В этом разделе представлена ​​подробная информация о плане исследования, в том числе о том, как планируется исследование и что оно измеряет.

Как устроено исследование?

Детали дизайна

  • Основная цель: Поддерживающая терапия
  • Распределение: Нерандомизированный
  • Интервенционная модель: Одногрупповое задание
  • Маскировка: Нет (открытая этикетка)

Оружие и интервенции

Группа участников / Армия
Вмешательство/лечение
Экспериментальный: 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
Экспериментальный: 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
Экспериментальный: 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

Что измеряет исследование?

Первичные показатели результатов

Мера результата
Мера Описание
Временное ограничение
Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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

Вторичные показатели результатов

Мера результата
Мера Описание
Временное ограничение
Time to Absolute Neutrophil Count Recovery (Engraftment)
Временное ограничение: 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)
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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)
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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.

Соавторы и исследователи

Здесь вы найдете людей и организации, участвующие в этом исследовании.

Следователи

  • Учебный стул: Ryotaro Nakamura, MD, City of Hope Comprehensive Cancer Center

Даты записи исследования

Эти даты отслеживают ход отправки отчетов об исследованиях и сводных результатов на сайт ClinicalTrials.gov. Записи исследований и сообщаемые результаты проверяются Национальной медицинской библиотекой (NLM), чтобы убедиться, что они соответствуют определенным стандартам контроля качества, прежде чем публиковать их на общедоступном веб-сайте.

Изучение основных дат

Начало исследования

1 мая 2007 г.

Первичное завершение (Действительный)

1 февраля 2012 г.

Завершение исследования (Действительный)

1 февраля 2012 г.

Даты регистрации исследования

Первый отправленный

21 декабря 2007 г.

Впервые представлено, что соответствует критериям контроля качества

25 декабря 2007 г.

Первый опубликованный (Оценивать)

9 января 2008 г.

Обновления учебных записей

Последнее опубликованное обновление (Оценивать)

10 сентября 2014 г.

Последнее отправленное обновление, отвечающее критериям контроля качества

3 сентября 2014 г.

Последняя проверка

1 сентября 2014 г.

Дополнительная информация

Термины, связанные с этим исследованием

Ключевые слова

Дополнительные соответствующие термины MeSH

Другие идентификационные номера исследования

  • 06141
  • P30CA033572 (Грант/контракт NIH США)
  • CHNMC-06141
  • CDR0000579340 (Идентификатор реестра: NCI PDQ)

Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .

Клинические исследования anti-thymocyte globulin

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