Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00691015
• Other study ID #: CDR0000597130
• Secondary ID: P30CA022453WSU-2
• Status: Active, not recruiting
• Phase: Phase 2
• First received: June 4, 2008
• Last updated: August 6, 2012
• Start date: May 2008
• Est. completion date: January 2014

Study information

• Verified date: August 2012
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Chronic Myeloproliferative Disorders
• Graft vs Host Disease
• Leukemia
• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Neoplasms
• Neoplasms, Plasma Cell
• Plasmacytoma
• Preleukemia

Intervention

Biological:
• rituximab
Given IV

Drug:
• busulfan
Given IV
• carmustine
Given IV
• cyclophosphamide
Given IV
• cytarabine
Given IV
• etoposide
Given IV
• fludarabine phosphate
Given IV
• melphalan
Given IV

Radiation:
• total-body irradiation
Given once or twice daily

Locations

Country	Name	City	State
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Barbara Ann Karmanos Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of acute graft-versus-host disease (GVHD)		Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria	No
Primary	Safety, as defined by serious adverse events and adverse events related to study treatment.		Within 6 months after PBSCT	Yes
Secondary	Incidence of chronic GVHD.		Within 2 years after PBSCT	No
Secondary	Time to engraftment (i.e., absolute neutrophil recovery [ANC > 1,500/mm³] and platelet recovery [platelet count > 25,000/mm³])		At screening, post transplant, 30, 60, 90 & 180 days after PBSCT	No
Secondary	Overall and disease-free survival.		At 2 years after PBSCT	No
Secondary	Length of hospital stay.		Within 100 days after PBSCT	No
Secondary	Incidence of infections, including bacterial, fungal, and viral infections (i.e., CMV and EBV reactivation, including post-transplant lymphoproliferative disorders)		Within 6 months after PBSCT	No
Secondary	Incidence of thrombotic microangiopathy		Within 100 days after PBSCT	No
Secondary	Karnofsky performance status		At baseline and at 100 days, 6 months, 1 year, and 2 years after PBSCT	No
Secondary	Biomarkers and immunocorrelative studies (i.e., T-cell, B-cell, NK-cell, regulatory T-cell, and allo-reactive T-cell quantitation studies by flow cytometry)		At 30, 60, 90, and 180 days after PBSCT	No