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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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT00589563
First received: December 21, 2007
Last updated: September 3, 2014
Last verified: September 2014

December 21, 2007
September 3, 2014
May 2007
February 2012   (final data collection date for primary outcome measure)
  • Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100 [ Time Frame: 100 Days Post Hematopoietic Stem Cell Transplant (HSCT) ] [ Designated as safety issue: No ]
    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.
  • Severity of Acute GVHD [ Time Frame: 100 Days Post HSCT ] [ Designated as safety issue: No ]
    All patients were considered for the evaluation of the severity of acute GVHD.
  • Cumulative Incidence of Chronic GVHD [ Time Frame: 2 year point estimate was provided. ] [ Designated as safety issue: No ]
    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.
  • Severity of Chronic GVHD [ Time Frame: Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT ] [ Designated as safety issue: No ]
    All Patients were considered for the evaluation of chronic GVHD severity.
  • Incidence and severity of acute and chronic graft-versus-host disease
  • Safety in the first 6 months post-transplant
Complete list of historical versions of study NCT00589563 on ClinicalTrials.gov Archive Site
  • Time to Absolute Neutrophil Count Recovery (Engraftment) [ Time Frame: Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT ] [ Designated as safety issue: Yes ]
    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
  • Time to Platelet Count Recovery (Engraftment) [ Time Frame: Patients were evaluated until platelet recovery, a median of 14 days ] [ Designated as safety issue: Yes ]
    Platelet recovery is defined as the first date of three consecutive laboratory values ≥ 25 x 10^9 L obtained on different days.
  • Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation [ Time Frame: Median Follow Up: 28 months (Range: 1-49 months) ] [ Designated as safety issue: Yes ]
    Participants were monitored throughout the trial (median of 28 months) for various infections/complications.
  • Occurrence of Thrombotic Microangiopathy [ Time Frame: Median Follow Up: 28 Months (Range: 1-49 months) ] [ Designated as safety issue: Yes ]
    Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed TMA.
  • Occurence of Sinusoidal Obstructive Syndrome (SOS) [ Time Frame: Median Follow Up: 28 Months (Range: 1-49 Months) ] [ Designated as safety issue: Yes ]
    Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed SOS.
  • Non-relapse Mortality at 100 Days Post HSCT [ Time Frame: 100 day point estimate was provided ] [ Designated as safety issue: Yes ]
    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.
  • Non-relapse Mortality at Two Years Post HSCT [ Time Frame: 2 year point estimate was provided. ] [ Designated as safety issue: No ]
    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.
  • Overall Survival at Two Years Post HSCT [ Time Frame: 2 year point estimate was provided. ] [ Designated as safety issue: No ]
    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.
  • Event Free Survival at Two Years Post HSCT [ Time Frame: 2 year point estimate was provided. ] [ Designated as safety issue: No ]
    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.
  • Incidence of Disease Relapse/Progression at 2 Years Post HSCT [ Time Frame: 2 year point estimate was provided. ] [ Designated as safety issue: No ]
    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.
  • Time to absolute neutrophil count recovery (engraftment)
  • Time to platelet count recovery (engraftment)
  • Time to first hospital discharge
  • Incidence of infections including cytomegalovirus and Epstein-Barr virus reactivation
  • Incidence of thrombotic microangiopathy
  • Non-relapse mortality at 100 days and one year past hematopoietic stem cell transplantation (HSCT)
  • Overall and disease-free survival at one year post HSCT
  • Incidence of disease relapse
  • Incidence of post-transplant lymphoproliferative disease
Not Provided
Not Provided
 
Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer
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 .

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.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
  • Chronic Myeloproliferative Disorders
  • Graft Versus Host Disease
  • Infection
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • Precancerous Condition
  • Secondary Myelofibrosis
  • Small Intestine Cancer
  • Biological: anti-thymocyte globulin
    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
  • Drug: cyclophosphamide
    60mg/kg on days -5 and -4 from stem cell transplant
  • Drug: etoposide
    60mg/kg on day -4 from stem cell transplant
  • Drug: fludarabine phosphate
    Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant
  • Drug: melphalan
    Melphalan 140 mg/m2 on day -4 from stem cell transplant
  • Drug: methotrexate
    For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant
  • Drug: sirolimus

    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

  • Drug: tacrolimus
    0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
  • Procedure: allogeneic hematopoietic stem cell transplantation
    The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
  • Procedure: hematopoietic stem cell transplantation
    The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
  • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    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
  • Procedure: peripheral blood stem cell transplantation
    The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
  • Radiation: total-body irradiation
    1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
  • Experimental: Fludarabine/Melphalan Conditioning

    Fludarabine/Melphalan Conditioning with

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

    Interventions:
    • Biological: anti-thymocyte globulin
    • Drug: fludarabine phosphate
    • Drug: melphalan
    • Drug: methotrexate
    • Drug: sirolimus
    • Drug: tacrolimus
    • Procedure: allogeneic hematopoietic stem cell transplantation
    • Procedure: hematopoietic stem cell transplantation
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: total-body irradiation
  • Experimental: FTBI/Cytoxan Conditioning
    FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
    Interventions:
    • Biological: anti-thymocyte globulin
    • Drug: cyclophosphamide
    • Drug: methotrexate
    • Drug: sirolimus
    • Drug: tacrolimus
    • Procedure: allogeneic hematopoietic stem cell transplantation
    • Procedure: hematopoietic stem cell transplantation
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: total-body irradiation
  • Experimental: FTBI/Etoposide Conditioning

    FTBI/Etoposide Conditioning with

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

    Interventions:
    • Biological: anti-thymocyte globulin
    • Drug: etoposide
    • Drug: methotrexate
    • Drug: sirolimus
    • Drug: tacrolimus
    • Procedure: allogeneic hematopoietic stem cell transplantation
    • Procedure: hematopoietic stem cell transplantation
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
    • Radiation: total-body irradiation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
32
February 2012
February 2012   (final data collection date for primary outcome measure)

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
Both
2 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00589563
06141, P30CA033572, CHNMC-06141, CDR0000579340
Yes
City of Hope Medical Center
City of Hope Medical Center
National Cancer Institute (NCI)
Study Chair: Ryotaro Nakamura, MD Beckman Research Institute
City of Hope Medical Center
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP