Clinical trial NCT00691015: Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant
Official title: A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin®, as Graft-versus-Host- Disease Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: 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 Hodgkin lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic 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 Hodgkin lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic 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
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone 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
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
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)
chronic phase chronic myelogenous leukemia
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
de novo myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
primary myelofibrosis
atypical chronic myeloid leukemia, BCR-ABL negative
chronic eosinophilic leukemia
chronic myelomonocytic leukemia
chronic neutrophilic leukemia
Lead sponsor: Barbara Ann Karmanos Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-06-05
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop 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, and antithymocyte globulin before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with tacrolimus and antithymocyte globulin and to see how well it works in preventing graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem cell transplant.

Detailed description: OBJECTIVES:

Primary

* To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
* To determine the safety of this regimen in these patients at 6 months after PBSCT.

Secondary

* To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen.
* To determine the length of hospital stay of these patients within 100 days after PBSCT.
* To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen.
* To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen.
* To determine the incidence of chronic GVHD in patients treated with this regimen.
* To determine the overall and disease-free survival of these patients at 2 years after PBSCT.
* To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT.
* To conduct immunocorrelative studies prior to and at various time points after PBSCT.

OUTLINE:

* Conditioning regimen: Patients receive 1 of 6 conditioning regimens (standard of care treatment) between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity.

  * Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
  * Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
  * Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
  * Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
  * Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
  * Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI.
* Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.
* Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.

Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution.

After completion of study therapy, patients are followed periodically for up to 2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of a hematological malignancy, including any of the following:

  * Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR)
  * Hodgkin lymphoma in CR or PR
  * Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria:

    * In CR
    * Not in CR and meets the following criteria:

      * Bone marrow blast \< 20% within 4 weeks of transplantation
      * Peripheral blood absolute blast count \< 500 per microliter on the day of initiating conditioning therapy
  * Myelodysplastic syndromes, treated or untreated
  * Chronic myeloid leukemia in chronic phase or accelerated phase
  * Multiple myeloma in CR or PR
  * Chronic lymphocytic leukemia in second or greater CR or PR
  * Myelofibrosis or other myeloproliferative disorders meeting the following criteria:

    * Bone marrow blasts \< 20% within 4 weeks of transplantation
    * Peripheral blood absolute blast count \< 500 per microliter on the day of initiating conditioning therapy
    * Patients with ascites not allowed
* No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc)
* Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician

  * High resolution molecular HLA typing is required for HLA class I and II
  * No more than one antigen or allele mismatch
* No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

* ECOG performance status (PS) 0-2
* Karnofsky PS 60-100%
* Creatinine clearance \> 50 mL/min
* Bilirubin \< 3 times upper limit of normal (ULN)
* ALT and AST \< 3 times ULN
* LVEF \> 50%
* FVC, FEV_1, or DLCO \> 50% predicted

  * Patients on home oxygen not allowed
* Able to cooperate with oral medication intake
* HIV negative
* No active hepatitis B or hepatitis C
* No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics

Primary outcomes:
measure: Incidence of Acute Graft-versus-host Disease (GVHD)
timeFrame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
measure: Severity of Acute Graft-versus-host Disease (GVHD)
timeFrame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
measure: Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment.
timeFrame: Within 6 months after PBSCT
Secondary outcomes:
measure: Incidence of Chronic GVHD.
timeFrame: Within 2 years after PBSCT
measure: Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] )
timeFrame: post transplant, up to 4 weeks
measure: Overall Survival.
timeFrame: At 2 years after PBSCT
measure: Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders)
timeFrame: Within 6 months after PBSCT
measure: Karnofsky Performance Status Performance Status
timeFrame: At 90 days after PBSCT
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Zaid Al-Kadhimi, MD
role: STUDY_CHAIR
References: