Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2016 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01231412
First received: October 28, 2010
Last updated: June 27, 2016
Last verified: June 2016
  Purpose
This randomized phase III trial studies how well graft-vs-host disease (GVHD) prophylaxis works in treating patients with hematologic malignancies undergoing unrelated donor peripheral blood stem cell transplant. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant (PBSCT) helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving total-body irradiation (TBI) together with fludarabine phosphate (FLU), cyclosporine (CSP), mycophenolate mofetil (MMF), or sirolimus before transplant may stop this from happening.

Condition Intervention Phase
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Aggressive Non-Hodgkin Lymphoma
Chronic Lymphocytic Leukemia
Diffuse Large B-Cell Lymphoma
Hematopoietic and Lymphoid Cell Neoplasm
Indolent Non-Hodgkin Lymphoma
Mantle Cell Lymphoma
Myelodysplastic Syndrome
Myeloproliferative Neoplasm
Prolymphocytic Leukemia
Recurrent Chronic Lymphocytic Leukemia
Recurrent Plasma Cell Myeloma
Refractory Chronic Lymphocytic Leukemia
Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Refractory Hodgkin Lymphoma
Small Lymphocytic Lymphoma
T-Cell Chronic Lymphocytic Leukemia
Waldenstrom Macroglobulinemia
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Cyclosporine
Drug: Fludarabine Phosphate
Drug: Mycophenolate Mofetil
Procedure: Peripheral Blood Stem Cell Transplantation
Drug: Sirolimus
Radiation: Total-Body Irradiation
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD After Unrelated Donor Hematopoietic Cell Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies: A Multi-center Trial

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Rate of acute grade II-IV GHVD, exclusive of GVHD that occurs as a result of alterations to immunosuppressive therapy in response to relapse or progression [ Time Frame: At day 100 post-transplant ] [ Designated as safety issue: No ]
    The actual analysis will be a time-to-event analysis using a log-rank statistic. Patients dying or relapsing within the first 100 days post-transplant will be censored at that time. Skin involvement will be assessed by biopsy with percentage of body surface area involved recorded. Gastrointestinal (GI) symptoms suspicious for GVHD will be evaluated by biopsy as indicated. Acute GVHD will be graded according to established criteria by an independent reviewer blinded to study arm and patient identity.


Secondary Outcome Measures:
  • Chronic extensive GVHD [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Grade III-IV acute GVHD [ Time Frame: Up to 100 days ] [ Designated as safety issue: No ]
    Skin involvement will be assessed by biopsy with percentage of body surface area involved recorded. GI symptoms suspicious for GVHD will be evaluated by biopsy as indicated. Acute GVHD will be graded according to established criteria by an independent reviewer blinded to study arm and patient identity.

  • Non-relapse mortality [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Relapse [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: November 2010
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (chemo, radiation, transplant, GVHD prophylaxis)
Patients receive FLU IV over 30 minutes on days -4 to -2. Patients also receive CSP PO BID on days -3 to 96 with taper to day 150 and MMF PO TID daily on days 0-29 and then BID on days 30-150 with taper to day 180. Patients undergo allogeneic PBSCT on day 0 following the TBI.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • allogeneic stem cell transplantation
  • HSC
  • HSCT
Drug: Cyclosporine
Given PO or IV
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Experimental: Arm II (chemo, radiation, transplant, GVHD prophylaxis)
Patients receive FLU and CSP as in Arm I and sirolimus PO QD on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs. Patients undergo allogeneic PBSCT on day 0 following the TBI.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • allogeneic stem cell transplantation
  • HSC
  • HSCT
Drug: Cyclosporine
Given PO or IV
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Drug: Sirolimus
Given PO
Other Names:
  • AY 22989
  • RAPA
  • Rapamune
  • RAPAMYCIN
  • SILA 9268A
  • WY-090217
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the effectiveness of 2 GVHD prophylaxis regimens in preventing acute grades II-IV GVHD.

SECONDARY OBJECTIVES:

I. Compare non-relapse mortality in the 2 arms. II. Compare survival and progression-free survivals in the 2 arms.

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

All patients receive FLU intravenously (IV) over 30 minutes on days -4 to -2 followed by 2-3 Gy TBI on day 0.

ARM I: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.

ARM II: Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 following the TBI.

After completion of study treatment, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic cell transplant (HCT)
  • Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (> 40% risk of transplant related mortality [TRM]); this criterion can include patients with a HCT-comorbidity index (CI) score of >= 1; transplants should be approved for these inclusion criteria by the principal investigators at the collaborating centers and at the Fred Hutchinson Cancer Research Center (FHCRC); all children < 12 years must be discussed with the FHCRC principal investigator (PI) prior to registration
  • Ages =< 50 years of age with chronic lymphocytic leukemia (CLL)
  • Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who refuse a high-dose HCT; transplants must be approved for these inclusion criteria by the principal investigators at the collaborating centers and at FHCRC
  • The following diseases will be permitted although other diagnoses can be considered if approved by Patient Care Conference (PCC) or the participating institutions' patient review committees and the principal investigators

    • Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell NHL: not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT
    • Mantle cell NHL: may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)
    • Low grade NHL: with < 6 month duration of CR between courses of conventional therapy
    • CLL: must have either:

      • Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing 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);
      • Failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or
      • Have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; or
      • Patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
    • Hodgkin lymphoma: must have received and failed frontline therapy
    • Multiple myeloma: must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
    • Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant
    • Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant
    • Chronic myeloid leukemia (CML): patients in 1st chronic phase (CP1) must have failed or be intolerant of tyrosine-kinase inhibitors (TKI); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant
    • Myelodysplasia (MDS)/myeloproliferative syndrome (MPS): patients must have < 5% marrow blasts at time of transplant
    • Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy
  • DONOR: FHCRC matching allowed will be grades 1.0 to 2.1: Unrelated donors who are prospectively:

    • Matched for human leukocyte antigen (HLA)-A, B, C, DRB1 and DQB1 by high resolution typing
    • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
  • DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
  • DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
  • DONOR: Only filgrastim (G-CSF) mobilized PBSC only will be permitted as a hematopoietic stem cell (HSC) source on this protocol

Exclusion Criteria:

  • Patients with rapidly progressive intermediate or high grade NHL
  • Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
  • Patients with refractory anemia with excess blasts (RAEB) who have not received myelosuppressive chemotherapy i.e. induction chemotherapy
  • 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
  • Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with MDS/MPS
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Females who are pregnant or breast-feeding
  • Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
  • Cardiac ejection fraction < 35% (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
  • Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or receiving supplementary continuous oxygen
  • The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules
  • 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, 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
  • Karnofsky scores < 60 or Lansky Score < 50
  • Patient has poorly controlled hypertension and on multiple antihypertensives
  • Human immunodeficiency virus (HIV) positive patients
  • Active bacterial or fungal infections unresponsive to medical therapy
  • All patients receiving antifungal therapy voriconazole, posaconazole, or fluconazole and who are then randomized to ARM 2 must have sirolimus reduced according to the Standard Practice Antifungal Therapy Guidelines
  • The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
  • DONOR: Donor (or centers) who will exclusively donate marrow
  • DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC
  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: NCT01231412

Locations
United States, Colorado
University of Colorado Active, not recruiting
Denver, Colorado, United States, 80217-3364
Presbyterian - Saint Lukes Medical Center - Health One Recruiting
Denver, Colorado, United States, 80218
Contact: Michael B. Maris    720-754-4800    kgeisen@co-cancerresearch.org   
Principal Investigator: Michael B. Maris         
United States, Georgia
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Amelia A. Langston    404-778-4189    Amelia_Langston@emoryhealthcare.org   
Principal Investigator: Amelia A. Langston         
United States, Utah
Huntsman Cancer Institute/University of Utah Active, not recruiting
Salt Lake City, Utah, United States, 84112
United States, Washington
VA Puget Sound Health Care System Recruiting
Seattle, Washington, United States, 98101
Contact: Thomas R. Chauncey    206-762-1010    thomas.chauncey@va.gov   
Principal Investigator: Thomas R. Chauncey         
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Brenda M. Sandmaier    206-667-4961    bsandmai@fredhutch.org   
Principal Investigator: Brenda M. Sandmaier         
Denmark
Aarhus University Hospital Recruiting
Arhus, Denmark, 8200
Contact: Gitte Olesen    45 78 46 1152    gitte.olesen@rh.regionh.dk   
Principal Investigator: Gitte Olesen         
Rigshospitalet University Hospital Recruiting
Copenhagen, Denmark, 2100
Contact: Søren L. Petersen    45 35 45 1134      
Principal Investigator: Søren L. Petersen         
Germany
Medizinische Univ Klinik Koln Recruiting
Koln, Germany, 50924
Contact: Kai Huebel    0221-4785133    kai.huebel@uni-koeln.de   
Principal Investigator: Kai Huebel         
University of Leipzig Recruiting
Leipzig, Germany, 04109
Contact: Georg-Nikolaus Franke    0341-97-13842    nikolaus.franke@wu.ac.at   
Principal Investigator: Georg-Nikolaus Franke         
University of Tuebingen-Germany Recruiting
Tuebingen, Germany, D-72076
Contact: Wolfgang A. Bethge    49-7071-2982711    wolfgang.bethge@med.uni-tuebingen.de   
Principal Investigator: Wolfgang A. Bethge         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Brenda Sandmaier Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01231412     History of Changes
Other Study ID Numbers: 2448.00  NCI-2010-02035  2448.00  P01CA018029  P30CA015704 
Study First Received: October 28, 2010
Last Updated: June 27, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Waldenstrom Macroglobulinemia
Lymphoma
Leukemia
Neoplasms
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Hodgkin Disease
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, Large B-Cell, Diffuse
Myeloproliferative Disorders
Leukemia, Prolymphocytic
Multiple Myeloma
Neoplasms, Plasma Cell
Hematologic Neoplasms
Leukemia, Prolymphocytic, T-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases

ClinicalTrials.gov processed this record on July 26, 2016