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
  Purpose

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 .


Condition Intervention Phase
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
Drug: cyclophosphamide
Drug: etoposide
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
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin, as Graft-versus-Host Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia, Childhood Acute Myelocytic Leukemia Acute Myeloid Leukemia, Adult Acute Myeloid Leukemia, Childhood Acute Non Lymphoblastic Leukemia Anaplastic Large Cell Lymphoma Anaplastic Plasmacytoma Angioimmunoblastic Lymphadenopathy With Dysproteinemia Angioimmunoblastic T-cell Lymphoma B-cell Lymphomas Burkitt Lymphoma Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Chronic Myelomonocytic Leukemia Chronic Myeloproliferative Disorders Cutaneous T-cell Lymphoma Follicular Lymphoma Hodgkin Lymphoma Hodgkin Lymphoma, Childhood Homologous Wasting Disease Juvenile Myelomonocytic Leukemia Leukemia, B-cell, Chronic Leukemia, Myeloid Leukemia, T-cell, Chronic Lymphoblastic Lymphoma Lymphoma, Large-cell Lymphoma, Large-cell, Immunoblastic Lymphoma, Small Cleaved-cell, Diffuse Lymphomatoid Granulomatosis Lymphosarcoma Mantle Cell Lymphoma Multiple Myeloma Myelodysplastic Syndromes Myelodysplastic/myeloproliferative Disease Myelofibrosis Plasmablastic Lymphoma Small Intestine Cancer Small Non-cleaved Cell Lymphoma
U.S. FDA Resources

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 32
Study Start Date: May 2007
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Fludarabine/Melphalan Conditioning

Fludarabine/Melphalan Conditioning with

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

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: 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: FTBI/Cytoxan Conditioning
FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
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: 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: FTBI/Etoposide Conditioning

FTBI/Etoposide Conditioning with

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

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: etoposide
60mg/kg 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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00589563

Locations
United States, Arizona
Banner Good Samaritan Medical Center
Phoenix, Arizona, United States, 85006
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Study Chair: Ryotaro Nakamura, MD Beckman Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT00589563     History of Changes
Other Study ID Numbers: 06141, P30CA033572, CHNMC-06141, CDR0000579340
Study First Received: December 21, 2007
Results First Received: July 21, 2014
Last Updated: September 3, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:
graft versus host disease
infection
adult favorable prognosis Hodgkin lymphoma
adult unfavorable prognosis Hodgkin lymphoma
childhood favorable prognosis Hodgkin lymphoma
childhood unfavorable prognosis Hodgkin lymphoma
cutaneous B-cell non-Hodgkin lymphoma
recurrent adult Hodgkin lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent/refractory childhood Hodgkin lymphoma
stage I adult Hodgkin lymphoma
stage I childhood Hodgkin lymphoma
stage I cutaneous T-cell non-Hodgkin lymphoma
stage II adult Hodgkin lymphoma
stage II childhood Hodgkin lymphoma
stage II cutaneous T-cell non-Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage III childhood Hodgkin lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
stage IV childhood Hodgkin lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
Burkitt lymphoma
contiguous stage II adult Burkitt lymphoma
contiguous stage II adult diffuse large cell lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
contiguous stage II adult diffuse small cleaved cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma

Additional relevant MeSH terms:
Graft vs Host Disease
Infection
Leukemia
Lymphoma
Multiple Myeloma
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasm Metastasis
Neoplasms
Neoplasms, Plasma Cell
Plasmacytoma
Precancerous Conditions
Preleukemia
Primary Myelofibrosis
Syndrome
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Disease
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplastic Processes
Paraproteinemias

ClinicalTrials.gov processed this record on October 23, 2014