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

Barbara Ann Karmanos Cancer Institute

Status and phase

Terminated

Phase 2

Conditions

Graft Versus Host Disease

Multiple Myeloma and Plasma Cell Neoplasm

Lymphoproliferative Disorder

Chronic Myeloproliferative Disorders

Lymphoma

Leukemia

Myelodysplastic Syndromes

Myelodysplastic/Myeloproliferative Neoplasms

Treatments

Biological: anti-thymocyte globulin

Drug: tacrolimus

Biological: rituximab

Drug: sirolimus

Procedure: management of therapy complications

Procedure: allogeneic hematopoietic stem cell transplantation

Other: laboratory biomarker analysis

Procedure: peripheral blood stem cell transplantation

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01116232

CDR0000671822

2009-150 (Other Identifier)

P30CA022453 (U.S. NIH Grant/Contract)

U4781s (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

4 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose

Supportive Care

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

4 participants in 1 patient group

anti-thymocyte globulin, rituximab, sirolimus, tacrolimus,

Experimental group

Description:

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; 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 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.

Treatment: