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

This study has been terminated.
(Lack of funding.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier:
NCT01116232
First received: May 3, 2010
Last updated: October 22, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Lymphoproliferative Disorder
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Biological: anti-thymocyte globulin
Biological: rituximab
Drug: sirolimus
Drug: tacrolimus
Other: laboratory biomarker analysis
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: management of therapy complications
Procedure: peripheral blood stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
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

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Myelodysplastic Syndromes Leukemia, Myeloid Chronic Myeloid Leukemia Multiple Myeloma Lymphosarcoma Mantle Cell Lymphoma B-cell Lymphomas Burkitt Lymphoma Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Acute Myelocytic Leukemia Acute Non Lymphoblastic Leukemia Follicular Lymphoma Lymphoma, Large-cell Acute Myeloid Leukemia, Adult Lymphoma, Small Cleaved-cell, Diffuse Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Hodgkin Lymphoma Lymphoma, Large-cell, Immunoblastic Plasmablastic Lymphoma Mycosis Fungoides Sezary Syndrome Cutaneous T-cell Lymphoma Leukemia, T-cell, Chronic Myelofibrosis Waldenstrom Macroglobulinemia Anaplastic Large Cell Lymphoma Chronic Myelomonocytic Leukemia Hairy Cell Leukemia Lymphomatoid Granulomatosis Angioimmunoblastic T-cell Lymphoma Angioimmunoblastic Lymphadenopathy With Dysproteinemia Hypereosinophilic Syndrome Chronic Myeloproliferative Disorders Myelodysplastic/myeloproliferative Disease Large Granular Lymphocyte Leukemia Chronic Neutrophilic Leukemia Homologous Wasting Disease Anaplastic Plasmacytoma
U.S. FDA Resources

Further study details as provided by Barbara Ann Karmanos Cancer Institute:

Primary Outcome Measures:
  • Incidence and Severity of Acute Graft-vs-host Disease (GVHD) [ Time Frame: During the first six months post transplant ] [ Designated as safety issue: No ]
  • Time to Engraftment [ Time Frame: During the first six months post transplant ] [ Designated as safety issue: No ]
  • Safety Assessment [ Time Frame: During the first six months post transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence of Chronic GVHD [ Time Frame: Within two years after transplant ] [ Designated as safety issue: No ]
  • Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder [ Time Frame: At one year ] [ Designated as safety issue: No ]
  • Incidence of Thrombotic Microangiopathy [ Time Frame: Within 100 days of HCT ] [ Designated as safety issue: No ]
  • Overall and Disease-free Survival [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • Immunocorrelative Studies Pre- and Periodically Post-transplantation [ Time Frame: Using flow cytometry at 30, 60, 90, and 180 days post transplant. ] [ Designated as safety issue: No ]

Enrollment: 1
Study Start Date: August 2010
Study Completion Date: June 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: anti-thymocyte globulin, rituximab, sirolimus, tacrolimus,

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.

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.
Biological: 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.

Other Name: Rituxan®
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).
Other Name: Rapamune®
Drug: 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 Name: Prograf
Other: laboratory biomarker analysis
laboratory biomarker analysis
Procedure: allogeneic hematopoietic stem cell transplantation
allogeneic hematopoietic stem cell transplantation
Procedure: management of therapy complications
management of therapy complications
Procedure: peripheral blood stem cell transplantation
peripheral blood stem cell transplantation

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01116232

Locations
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
Investigators
Principal Investigator: Zaid Al-Kadhimi, M.D. Barbara Ann Karmanos Cancer Institute
  More Information

No publications provided

Responsible Party: Zaid Al-Kadhimi, Principal Investigator, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT01116232     History of Changes
Obsolete Identifiers: NCT01534767
Other Study ID Numbers: CDR0000671822, P30CA022453, WSU-2009-150, GENENTECH-WSU-2009-150, 1002008107
Study First Received: May 3, 2010
Results First Received: October 22, 2013
Last Updated: October 22, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Barbara Ann Karmanos Cancer Institute:
contiguous stage II adult diffuse small cleaved cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
graft versus host disease
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)
atypical chronic myeloid leukemia, BCR-ABL negative
blastic phase chronic myelogenous leukemia
chronic myelomonocytic leukemia
chronic phase chronic myelogenous leukemia
meningeal chronic myelogenous leukemia
progressive hairy cell leukemia, initial treatment
prolymphocytic leukemia
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
recurrent adult T-cell leukemia/lymphoma
refractory chronic lymphocytic leukemia
refractory hairy cell leukemia
relapsing chronic myelogenous leukemia
stage I adult T-cell leukemia/lymphoma
stage I chronic lymphocytic leukemia

Additional relevant MeSH terms:
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Lymphoma
Leukemia
Disease
Syndrome
Graft vs Host Disease
Plasmacytoma
Myeloproliferative Disorders
Lymphoproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Precancerous Conditions
Lymphatic Diseases
Pathologic Processes
Rituximab
Sirolimus

ClinicalTrials.gov processed this record on September 18, 2014