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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 de septiembre de 2014 actualizado por: 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 .

Descripción general del estudio

Descripción detallada

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.

Tipo de estudio

Intervencionista

Inscripción (Actual)

32

Fase

  • Fase 2

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

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

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

2 años y mayores (Niño, Adulto, Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

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

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Cuidados de apoyo
  • Asignación: No aleatorizado
  • Modelo Intervencionista: Asignación de un solo grupo
  • Enmascaramiento: Ninguno (etiqueta abierta)

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Experimental: 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
Experimental: 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
Experimental: 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

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Time to Absolute Neutrophil Count Recovery (Engraftment)
Periodo de tiempo: 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)
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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)
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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.

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Investigadores

  • Silla de estudio: Ryotaro Nakamura, MD, City of Hope Comprehensive Cancer Center

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de mayo de 2007

Finalización primaria (Actual)

1 de febrero de 2012

Finalización del estudio (Actual)

1 de febrero de 2012

Fechas de registro del estudio

Enviado por primera vez

21 de diciembre de 2007

Primero enviado que cumplió con los criterios de control de calidad

25 de diciembre de 2007

Publicado por primera vez (Estimar)

9 de enero de 2008

Actualizaciones de registros de estudio

Última actualización publicada (Estimar)

10 de septiembre de 2014

Última actualización enviada que cumplió con los criterios de control de calidad

3 de septiembre de 2014

Última verificación

1 de septiembre de 2014

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • 06141
  • P30CA033572 (Subvención/contrato del NIH de EE. UU.)
  • CHNMC-06141
  • CDR0000579340 (Identificador de registro: NCI PDQ)

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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