Clinical trial NCT00589563: Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer
Official title: A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin, as Graft-versus-Host Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Keywords: 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
contiguous stage II adult lymphoblastic lymphoma
contiguous stage II grade 1 follicular lymphoma
contiguous stage II grade 2 follicular lymphoma
contiguous stage II grade 3 follicular lymphoma
contiguous stage II mantle cell lymphoma
contiguous stage II marginal zone lymphoma
contiguous stage II small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent childhood anaplastic large cell lymphoma
recurrent childhood grade III lymphomatoid granulomatosis
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent grade I lymphomatoid granulomatosis
recurrent grade II lymphomatoid granulomatosis
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
small intestine lymphoma
splenic marginal zone lymphoma
stage I adult Burkitt lymphoma
stage I adult diffuse large cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage I adult lymphoblastic lymphoma
stage I adult T-cell leukemia/lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III adult T-cell leukemia/lymphoma
stage III childhood anaplastic large cell lymphoma
stage III childhood lymphoblastic lymphoma
stage III childhood small noncleaved cell lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult T-cell leukemia/lymphoma
stage IV childhood anaplastic large cell lymphoma
stage IV childhood lymphoblastic lymphoma
stage IV childhood small noncleaved cell lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
adult acute myeloid leukemia in remission
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
childhood acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
secondary acute myeloid leukemia
adult acute lymphoblastic leukemia in remission
childhood acute lymphoblastic leukemia in remission
recurrent adult acute lymphoblastic leukemia
recurrent childhood acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
refractory chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
childhood myelodysplastic syndromes
de novo myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia, BCR-ABL negative
chronic myelomonocytic leukemia
juvenile myelomonocytic leukemia
primary myelofibrosis
secondary myelofibrosis
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-01-09
Enrollment: 32
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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 .

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 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

Primary outcomes:
measure: Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100
timeFrame: 100 Days Post Hematopoietic Stem Cell Transplant (HSCT)
measure: Severity of Acute GVHD
timeFrame: 100 Days Post HSCT
measure: Cumulative Incidence of Chronic GVHD
timeFrame: 2 year point estimate was provided.
measure: Severity of Chronic GVHD
timeFrame: Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT
Secondary outcomes:
measure: Time to Absolute Neutrophil Count Recovery (Engraftment)
timeFrame: Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT
measure: Time to Platelet Count Recovery (Engraftment)
timeFrame: Patients were evaluated until platelet recovery, a median of 14 days
measure: Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation
timeFrame: Median Follow Up: 28 months (Range: 1-49 months)
measure: Occurrence of Thrombotic Microangiopathy
timeFrame: Median Follow Up: 28 Months (Range: 1-49 months)
measure: Occurence of Sinusoidal Obstructive Syndrome (SOS)
timeFrame: Median Follow Up: 28 Months (Range: 1-49 Months)
measure: Non-relapse Mortality at 100 Days Post HSCT
timeFrame: 100 day point estimate was provided
measure: Non-relapse Mortality at Two Years Post HSCT
timeFrame: 2 year point estimate was provided.
measure: Overall Survival at Two Years Post HSCT
timeFrame: 2 year point estimate was provided.
measure: Event Free Survival at Two Years Post HSCT
timeFrame: 2 year point estimate was provided.
measure: Incidence of Disease Relapse/Progression at 2 Years Post HSCT
timeFrame: 2 year point estimate was provided.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner Good Samaritan Medical Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
Study officials:
affiliation: City of Hope Comprehensive Cancer Center
name: Ryotaro Nakamura, MD
role: STUDY_CHAIR
References: