Clinical Trials /

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

NCT01231412

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Completed

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2448.00
  • SECONDARY ID: NCI-2010-02035
  • SECONDARY ID: 2448.00
  • SECONDARY ID: P01CA018029
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01231412

Conditions

  • 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

Interventions

DrugSynonymsArms
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaArm I (MMF and CSP)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Arm I (MMF and CSP)
Mycophenolate MofetilCellcept, MMFArm I (MMF and CSP)
SirolimusAY 22989, RAPA, Rapamune, RAPAMYCIN, SILA 9268A, WY-090217Arm II (MMF, CSP, and Sirolimus)

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.

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 0: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day
      150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed
      as of 14-Sep-2011

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (MMF and CSP)Active ComparatorPatients 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.
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil
Arm II (MMF, CSP, and Sirolimus)ExperimentalPatients 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.
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil
  • Sirolimus
Arm 0 (CSP and Sirolimus)ExperimentalPatients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011
  • Cyclosporine
  • Fludarabine Phosphate
  • Sirolimus

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidences of Acute Grade II-IV GVHD, 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
Safety Issue:
Description:Number of patients who developed acute 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

Secondary Outcome Measures

Measure:Incidences of Chronic Extensive GVHD
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Incidences of Grade III-IV Acute GVHD
Time Frame:Up to 100 days
Safety Issue:
Description: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
Measure:Incidences of Non-relapse Mortality
Time Frame:Up to 1 year
Safety Issue:
Description:Number of subjects expired without disease progression/relapse.
Measure:Overall Survival
Time Frame:Up to 1 year
Safety Issue:
Description:Number of subjects surviving post-transplant.
Measure:Number of Participants With Relapse/Progression
Time Frame:Up to 1 year
Safety Issue:
Description: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%. AML, ALL, MDS >5% blasts by morphologic or flow cytometric evaluation of the BMA or appearance of extramedullary disease 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 numb

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Fred Hutchinson Cancer Research Center

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