Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation

Lymphoma Clinical Trial

Official title:

A Pilot Phase II Study of Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01116232
• Other study ID #: CDR0000671822
• Secondary ID: P30CA022453U4781
• Status: Terminated
• Phase: Phase 2
• Start date: August 2010
• Est. completion date: June 2013

Study information

• Verified date: March 2019
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This Phase II clinical trial was designed for patients with hematologic malignancies in need of donor peripheral blood stem cell transplant, and have no HLA matched donor. Therefore It will test the efficacy of combining sirolimus, tacrolimus, antithymocyte globulin, and rituximab in preventing graft versus host disease in transplants from HLA Haploidentical and partially mismatched donors.

Description:

OBJECTIVES:

Primary

• Determine the incidence and severity of acute graft-vs-host disease (GVHD) in patients with hematologic malignancies undergoing donor peripheral blood stem cell transplantation who are receiving sirolimus, tacrolimus, anti-thymocyte globulin, and rituximab as GVHD prophylaxis.

• Assess time to engraftment absolute neutrophil count (> 0.5 x 10^9/L for 3 consecutive days) and platelet count (> 20 x 10^9/L for 3 consecutive days) in these patients.

• Determine the safety, as defined by serious adverse events and adverse events related to this immunosuppressive regimen, in the first 6 months after treatment.

Secondary

• Assess the incidence of chronic GVHD measured within 2 years after transplantation.

• Assess overall and disease-free survival at 2 years after transplantation.

• Examine the incidence of opportunistic infections including fungal infections, pneumocystis carinii pneumonia, and viral infections (cytomegalovirus, varicella zoster virus, herpes simplex virus, BK virus, Epstein-Barr virus, and post-transplant lymphoproliferative disorder).

• Assess the incidence of thrombotic microangiopathy within 100 days of transplantation.

• Perform immunocorrelative studies, including T-cell, B-cell, NK-cell, regulatory cell, and allo-reactive T-cell measurement studies via flow cytometry, at 30, 60, 90, and 180 days after transplantation.

OUTLINE: Patients receive rituximab IV on days -7 and 3, tacrolimus IV continuously (may switch to orally when the patient is able to eat) and oral sirolimus beginning on day -3, and anti-thymocyte globulin IV over 6 hours on days -3 to -1. Tacrolimus and sirolimus are tapered at the discretion of the treating physician.

All patients also receive a standard transplant-preparative regimen and undergo transplantation on day 0.

Blood samples are collected before the preparative regimen and at 30, 60, 90, and 180 days after transplantation for correlative immunologic studies.

After completion of study treatment, patients are followed up for 2 years.

Other known NCT identifiers

• NCT01534767

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: June 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of a hematological malignancy, including:

• Non-Hodgkin lymphoma

• Hodgkin lymphoma

• Acute myeloid leukemia or acute lymphoblastic leukemia

• Myelodysplastic syndrome (treated or untreated)

• Chronic myelogenous leukemia

• Multiple myeloma

• Chronic lymphocytic leukemia

• Myelofibrosis and other myeloproliferative disorders

• No suitable related HLA-matched or unrelated HLA-matched (8/8 or 7/8 matched) donor

• Available suitable haploidentical or partial-matched unrelated donor (high-resolution molecular HLA typing is mandatory for HLA Class I and II)

• No more than 4/8 HLA allele or antigen mismatch for a haploidentical-related first-degree family member donor

• Only 6/8 or 5/8 allele or antigen match for an unrelated donor

• Scheduled to undergo peripheral blood stem cell transplantation

• Not receiving bone marrow or ex vivo engineered or processed graft (e.g., CD34+ enrichment, T-cell depletion)

• No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 70-100%

• ECOG PS 0-2

• Serum bilirubin < 3 times upper limit of normal (ULN)

• ALT and AST < 3 times ULN

• Creatinine clearance > 60 mL/min

• Ejection fraction > 50%

• Forced vital capacity, FEV_1, or DLCO > 50% predicted

• Negative pregnancy test

• Able to cooperate with oral medication intake

• Patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the past 6 months) are eligible provided they are cleared with a stress echo or nuclear myocardial perfusions stress test and a cardiology consult

• No ascites

• No HIV positivity

• No active hepatitis B or C virus infection

• No known contraindication to the administration of sirolimus, tacrolimus, anti-thymocyte globulin, or rituximab

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Not on home oxygen

Related Conditions & MeSH terms

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

Intervention

Biological:
• anti-thymocyte globulin
Infuse the first dose over a minimum of 6 hours, and subsequent doses over a minimum of 4 hours via a 0.22 micron in-line filter.
• rituximab
The total dose chosen for this protocol is 28 mg/kg divided in two doses (14 mg/kg on days -7 and +3). Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour. Subsequent infusions: If patient did not tolerate initial infusion follow initial infusion guidelines. If patient tolerated initial infusion, start at 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour. Note: If a reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate. In patients who tolerated the Rituximab well in the past, a rapid infusion rate can be used over 90 minutes with 20% of the dose administered in the first 30 minutes and the remaining 80% is given over 60 minutes.

Drug:
• sirolimus
For adults, Sirolimus will be administered at 12 mg orally loading dose on day -3, followed by 4 mg orally single morning daily dose (target serum level 3-12 ng/ml by HPLC).
• tacrolimus
Tacrolimus will be administered intravenously at a dose of 0.03 mg/kg (ideal body weight) q 24h by continuous infusion starting on Day -3. Intravenous Tacrolimus will be discontinued once the patient starts eating and the drug will then be given orally at a dose of approximately 4 times the intravenous dose.

Other:
• laboratory biomarker analysis
laboratory biomarker analysis

Procedure:
• allogeneic hematopoietic stem cell transplantation
allogeneic hematopoietic stem cell transplantation
• management of therapy complications
management of therapy complications
• peripheral blood stem cell transplantation
peripheral blood stem cell transplantation

Locations

Country	Name	City	State
United States	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-vs-host Disease (GVHD)		During the first six months post transplant
Primary	Time to Engraftment		During the first six months post transplant
Primary	Safety Assessment		During the first six months post transplant
Secondary	Incidence of Chronic GVHD		Within two years after transplant
Secondary	Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder		At one year
Secondary	Incidence of Thrombotic Microangiopathy		Within 100 days of HCT
Secondary	Overall and Disease-free Survival		At 1 year
Secondary	Immunocorrelative Studies Pre- and Periodically Post-transplantation		Using flow cytometry at 30, 60, 90, and 180 days post transplant.

External Links

•   Clinical trial summary from the National Cancer Institute's PDQ® database