Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

January 17, 2020 updated by: Fred Hutchinson Cancer Center

A Multi-Center Study of Nonmyeloablative Conditioning With TBI or Fludarabine/TBI for HLA-matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies With Post Grafting Immunosuppression With Tacrolimus and Mycophenolate Mofetil

This phase II trial studies how well tacrolimus and mycophenolate mofetil works in preventing graft-versus-host disease in patients who have undergone total-body irradiation (TBI) with or without fludarabine phosphate followed by donor peripheral blood stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and TBI before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system 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 and mycophenolate mofetil after the transplant may stop this from happening.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the incidence of grade III/IV graft-versus-host disease (GVHD) after conditioning with 200 centigray (cGy) TBI alone or Fludarabine (fludarabine phosphate)/200 cGy TBI followed by tacrolimus (Tac)/mycophenolate mofetil (MMF) immunosuppression in patients with hematologic malignancies.

II. To estimate the incidence of chronic extensive GVHD.

SECONDARY OBJECTIVES:

I. To estimate the incidences of graft rejection.

II. To estimate overall survival 1-year after conditioning.

III. To evaluate the incidences of grades II-IV acute GVHD.

IV. To evaluate the rates of disease progression and/or relapse-related mortality.

V. To estimate the rate and duration of steroid use for the treatment of chronic GVHD.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM I (nonmyeloablative conditioning with fludarabine phosphate and TBI): Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.

ARM II (nonmyeloablative conditioning with TBI): Patients undergo TBI on day 0.

All patients then undergo allogeneic peripheral blood stem cell transplantation on day 0 and receive tacrolimus orally (PO) every 12 hours on days -3 to 180, with taper on day 56, or tacrolimus IV if unable to tolerate PO; and mycophenolate mofetil PO every 12 hours on days 0-27 or mycophenolate mofetil IV if unable to tolerate PO.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 3 years.

Study Type

Interventional

Enrollment (Actual)

150

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

  • Italy
      • Torino, Italy, 10126
        • University of Torino
  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Huntsman Cancer Institute/University of Utah
      • Salt Lake City, Utah, United States, 84143
        • LDS Hospital
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
      • Seattle, Washington, United States, 98101
        • VA Puget Sound Health Care System

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

No older than 74 years (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patient must be not eligible for conventional allogeneic hematopoietic cell transplantation (HCT) and must have disease expected to be stable for at least 100 days without chemotherapy; patients with hematologic malignancies treatable with HCT or with a B cell malignancy except those curable with autologous transplant will be included; patients not eligible for active disease specific protocols may be enrolled in this protocol; patients will include the following
  • Diffuse large B cell non-Hodgkin lymphoma (NHL) and other aggressive lymphomas - not eligible for conventional myeloablative HCT or after autologous HCT
  • Low grade NHL- with < 6 months duration of complete response (CR) between courses of conventional therapy
  • Mantle cell NHL- may be treated in first CR
  • Chronic lymphocytic leukemia (CLL) - must have either 1) failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog, e.g. 2-chlorodeoxyadenosine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or 3) have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) or a diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
  • Hodgkin lymphoma (HL) - must have received and failed frontline therapy; patients must have failed or were not eligible for autologous transplant
  • Multiple myeloma (MM) - following a planned autologous transplant or equivalent high-dose therapy without a graft, or following a failed prior autograft
  • Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
  • Acute lymphoblastic leukemia (ALL) - must have < 5% marrow blasts at the time of transplant
  • Chronic myelogenous leukemia (CML) - patients will be accepted beyond first chronic phase (CP1) if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
  • Myelodysplastic syndromes/myeloproliferative disorders (MDS/MPD) - must have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
  • Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy
  • Myelosuppressive chemotherapy must be discontinued three weeks prior to conditioning with the exception of hydroxyurea or imatinib
  • Patients < 12 years old must be approved by both the participating institutions' patient review committee such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator
  • Patient who refused to be treated on a conventional HCT protocol; for this inclusion criterion, transplants must be approved by both the participating institution's patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigators
  • Patients with human leukocyte antigen (HLA)-matched related donors
  • Patients with renal failure are eligible; however, patients with renal compromise (serum creatinine > 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum tacrolimus levels
  • DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
  • DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
  • DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion Criteria:

  • Eligible for a high priority curative autologous transplant
  • Patient with rapidly progressive, aggressive NHL unless in minimal disease state
  • Patients with chronic myelomonocytic leukemia (CMML)
  • Life expectancy severely limited by diseases other than malignancy
  • Any current central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
  • Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment
  • Female patients who are pregnant or breastfeeding
  • Human immunodeficiency virus (HIV)-positive patients
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
  • Karnofsky score < 50 for adult patients
  • Lansky-Play performance score < 50 for pediatric patients
  • Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • Poorly controlled hypertension
  • Diffusing capacity of the lung for carbon monoxide (DLCO) < 30%, total lung capacity (TLC) < 30%, forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC principal investigator (PI) of the study must approve enrollment of all patients with pulmonary nodules
  • Liver function abnormalities: Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
  • Patients with active bacterial or fungal infections unresponsive to medical therapy
  • DONOR: Age less than 12 years
  • DONOR: Identical twin
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Known allergy to filgrastim (G-CSF)
  • DONOR: Current serious systemic illness that would result in increased risk for G-CSF mobilization and harvest of peripheral blood stem cells (PBSC)

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: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Arm I (nonmyeloablative conditioning with fludarabine and TBI)
Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
Other: laboratory biomarker analysis
Correlative studies
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Radiation: total-body irradiation
Undergo radiotherapy
Other Names:
  • TBI
EXPERIMENTAL: Arm II (nonmyeloablative conditioning with TBI)
Patients undergo TBI on day 0. All patients then undergo allogeneic peripheral blood stem cell transplantation on day 0 and receive tacrolimus PO every 12 hours on days -3 to 180, with taper on day 56, or tacrolimus IV if unable to tolerate PO; and mycophenolate mofetil PO every 12 hours on days 0-27 or mycophenolate mofetil IV if unable to tolerate PO.
Other: laboratory biomarker analysis
Correlative studies
Drug: tacrolimus
Given IV or PO
Other Names:
  • Prograf
  • FK 506
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
Radiation: total-body irradiation
Undergo radiotherapy
Other Names:
  • TBI
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Grade III/IV GVHD
Time Frame: Day 180 post-transplantation

Number of patients who developed acute/chronic GVHD post-transplant. aGVHD Stages

Skin:

a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with desquamation

Liver:

bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL

Gut:

Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

aGVHD Grades Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Day 180 post-transplantation
Incidence of Chronic Extensive GVHD
Time Frame: Day 180 post-transplantation
Number of patients who developed chronic extensive GVHD post-transplant. The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
Day 180 post-transplantation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidences of Graft Rejection
Time Frame: Day 180 post-transplantation
Number of patients who rejected their graft. Rejection is defined as the inability to detect or loss of detection of greater than 5% donor T cells (CD3+) as a proportion of the total T cell population, respectively, after nonmyeloablative HCT.
Day 180 post-transplantation
Overall Survival
Time Frame: At 1 year after conditioning
Number of patients surviving post-transplant.
At 1 year after conditioning
Incidences of Grades II-IV Acute GVHD
Time Frame: Day 180 post-transplantation

Number of patients who developed acute/chronic GVHD post-transplant. aGVHD Stages

Skin:

a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with desquamation

Liver:

bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL

Gut:

Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

aGVHD Grades Grade II: Stage 1 - 3 skin and/or stage 1 gut involvement and/or stage 1 liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Day 180 post-transplantation
Rates of Disease Progression
Time Frame: Up to 5 years

Relapse/Progression criteria:

CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever >38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%.

CMML, AML, ALL >30% BM blasts w/ deteriorating performance status, or worsening of anemia, neutropenia, or thrombocytopenia.

CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation.

NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions.

MM

≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.
Up to 5 years
Rates of Relapse-related Mortality
Time Frame: Up to 5 years
Number of patients who expired with relapsed/progressive disease.
Up to 5 years
Rate and Duration of Steroid Use for the Treatment of Chronic GVHD
Time Frame: Up to 5 years
Number of patients that received prednisone treatment of chronic GVHD, and number of days for which they received prednisone.
Up to 5 years

Collaborators and Investigators

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

Sponsor

Fred Hutchinson Cancer Center

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.

General Publications

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 (ACTUAL)

April 1, 2004

Primary Completion (ACTUAL)

March 1, 2014

Study Completion (ACTUAL)

July 1, 2018

Study Registration Dates

First Submitted

August 4, 2004

First Submitted That Met QC Criteria

August 4, 2004

First Posted (ESTIMATE)

August 5, 2004

Study Record Updates

Last Update Posted (ACTUAL)

January 29, 2020

Last Update Submitted That Met QC Criteria

January 17, 2020

Last Verified

December 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1898.00 (OTHER: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium)
  • P30CA015704 (U.S. NIH Grant/Contract)
  • P01CA078902 (U.S. NIH Grant/Contract)
  • NCI-2010-00267 (REGISTRY: CTRP (Clinical Trial Reporting Program))

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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