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

March 13, 2019 updated by: Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Karmanos Cancer Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SUPPORTIVE_CARE
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Procedure: management of therapy complications
management of therapy complications
Other: laboratory biomarker analysis
laboratory biomarker analysis
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 Names:
  • 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 Names:
  • 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 Names:
  • Prograf
Procedure: allogeneic hematopoietic stem cell transplantation
allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
peripheral blood stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Incidence and Severity of Acute Graft-vs-host Disease (GVHD)
Time Frame: During the first six months post transplant
During the first six months post transplant
Time to Engraftment
Time Frame: During the first six months post transplant
During the first six months post transplant
Safety Assessment
Time Frame: During the first six months post transplant
During the first six months post transplant

Secondary Outcome Measures

Outcome Measure
Time Frame
Incidence of Chronic GVHD
Time Frame: Within two years after transplant
Within two years after transplant
Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder
Time Frame: At one year
At one year
Incidence of Thrombotic Microangiopathy
Time Frame: Within 100 days of HCT
Within 100 days of HCT
Overall and Disease-free Survival
Time Frame: At 1 year
At 1 year
Immunocorrelative Studies Pre- and Periodically Post-transplantation
Time Frame: Using flow cytometry at 30, 60, 90, and 180 days post transplant.
Using flow cytometry at 30, 60, 90, and 180 days post transplant.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Barbara Ann Karmanos Cancer Institute

Collaborators

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2010

Primary Completion (ACTUAL)

May 1, 2013

Study Completion (ACTUAL)

June 1, 2013

Study Registration Dates

First Submitted

May 3, 2010

First Submitted That Met QC Criteria

May 3, 2010

First Posted (ESTIMATE)

May 4, 2010

Study Record Updates

Last Update Posted (ACTUAL)

March 26, 2019

Last Update Submitted That Met QC Criteria

March 13, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000671822
  • P30CA022453 (U.S. NIH Grant/Contract)
  • U4781s (OTHER: Genentech)
  • 2009-150 (OTHER: Barbara Ann Karmanos Cancer Institute)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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