Clinical Trials /

Comparison of Triple GVHD Prophylaxis Regimens for Nonmyeloablative or Reduced Intensity Conditioning Unrelated Mobilized Blood Cell Transplantation

NCT03246906

Description:

This randomized phase II trial includes a blood stem cell transplant from an unrelated donor to treat blood cancer. The treatment also includes chemotherapy drugs, but in lower doses than conventional (standard) stem cell transplants. The researchers will compare two different drug combinations used to reduce the risk of a common but serious complication called "graft versus host disease" (GVHD) following the transplant. Two drugs, cyclosporine (CSP) and sirolimus (SIR), will be combined with either mycophenolate mofetil (MMF) or post-transplant cyclophosphamide (PTCy). This part of the transplant procedure is the main research focus of the study.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Chronic Myeloid Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Multiple Myeloma
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
  • Prolymphocytic Leukemia
  • T-Cell Prolymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Comparison of Triple GVHD Prophylaxis Regimens for Nonmyeloablative or Reduced Intensity Conditioning Unrelated Mobilized Blood Cell Transplantation
  • Official Title: A Randomized Phase II Study to Compare the Net Clinical Benefit of Cyclosporine and Sirolimus Combined With MMF or Post-Transplant Cyclophosphamide as GVHD Prophylaxis After HLA-Matched or HLA-Mismatched Unrelated G-CSF Mobilized Blood Cell Transplantation Using Nonmyeloablative or Reduced Intensity Conditioning for Patients With Hematologic Malignancies: A Multi-Center Trial

Clinical Trial IDs

  • ORG STUDY ID: 9816
  • SECONDARY ID: NCI-2017-01311
  • SECONDARY ID: 9816
  • SECONDARY ID: P01CA078902
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT03246906

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Aggressive Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Hematopoietic Cell Transplantation Recipient
  • Loss of Chromosome 17p
  • Mantle Cell Lymphoma
  • Myelodysplastic Syndrome
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Prolymphocytic Leukemia
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Recurrent Hodgkin Lymphoma
  • Recurrent Plasma Cell Myeloma
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm II (cyclosporine, sirolimus, cyclophosphamide)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaArm I (mycophenolate mofetil, cyclosporine, sirolimus)
Mycophenolate MofetilCellcept, MMFArm I (mycophenolate mofetil, cyclosporine, sirolimus)
SirolimusAY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217Arm I (mycophenolate mofetil, cyclosporine, sirolimus)

Purpose

This randomized phase II trial includes a blood stem cell transplant from an unrelated donor to treat blood cancer. The treatment also includes chemotherapy drugs, but in lower doses than conventional (standard) stem cell transplants. The researchers will compare two different drug combinations used to reduce the risk of a common but serious complication called "graft versus host disease" (GVHD) following the transplant. Two drugs, cyclosporine (CSP) and sirolimus (SIR), will be combined with either mycophenolate mofetil (MMF) or post-transplant cyclophosphamide (PTCy). This part of the transplant procedure is the main research focus of the study.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Compare chronic graft versus host disease (GVHD)-free and relapse-free survival (CRFS)
      after transplant between the 2 GVHD prophylaxis regimens.

      SECONDARY OBJECTIVES:

      I. Compare rates of acute (grades II-IV and III-IV) and moderate and severe chronic GVHD
      (based on National Institutes of Health [NIH] consensus criteria), relapse, non-relapse
      mortality, progression or relapse-free survival, and overall survival between the 2 regimens.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients undergo allogeneic hematopoietic stem cell transplant (HCT) at day 0.
      Patients with an HLA-matched unrelated donor receive mycophenolate mofetil orally (PO) on
      days 0 to 40, cyclosporine PO every 12 hours twice daily (BID) on days -3 to 96 then tapered
      to day 150, and sirolimus PO once daily (QD) on days -3 to day 150 then tapered to day 180.
      Patients with an HLA-mismatched donor receive mycophenolate mofetil PO on days 0-100 then
      tapered to day 150, cyclosporine PO BID on days -3 to 150 then tapered to day 180, and
      sirolimus PO QD on days -3 to 180 then tapered to day 365.

      ARM II: Patients undergo HCT at day 0. Patients with an HLA-matched unrelated donor receive
      cyclosporine PO BID on days 5-96 then tapered to day 150, sirolimus PO QD on days 5-150 then
      tapered to day 180, and cyclophosphamide intravenously (IV) on days 3 and 4. Patients with an
      HLA-mismatched donor receive cyclosporine PO BID on days 5-150 then tapered to day 180,
      sirolimus PO QD on days 5-180 then tapered to day 365, and cyclophosphamide IV on days 3 and
      4.

      After completion of study treatment, patients are followed up at 6 months and every year
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (mycophenolate mofetil, cyclosporine, sirolimus)ExperimentalPatients undergo allogeneic HCT at day 0. Patients with an HLA-matched unrelated donor receive mycophenolate mofetil PO on days 0 to 40, cyclosporine PO every 12 hours BID on days -3 to 96 then tapered to day 150, and sirolimus PO QD on days -3 to day 150 then tapered to day 180. Patients with an HLA-mismatched donor receive mycophenolate mofetil PO on days 0-100 then tapered to day 150, cyclosporine PO BID on days -3 to 150 then tapered to day 180, and sirolimus PO QD on days -3 to 180 then tapered to day 365.
  • Cyclosporine
  • Mycophenolate Mofetil
  • Sirolimus
Arm II (cyclosporine, sirolimus, cyclophosphamide)ExperimentalPatients undergo HCT at day 0. Patients with an HLA-matched unrelated donor receive cyclosporine PO BID on days 5-96 then tapered to day 150, sirolimus PO QD on days 5-150 then tapered to day 180, and cyclophosphamide IV on days 3 and 4. Patients with an HLA-mismatched donor receive cyclosporine PO BID on days 5-150 then tapered to day 180, sirolimus PO QD on days 5-180 then tapered to day 365, and cyclophosphamide IV on days 3 and 4.
  • Cyclophosphamide
  • Cyclosporine
  • 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
             hematopoietic cell transplant-comorbidity index (HCT-CI) score of > 3; transplants
             should be approved for these inclusion criteria by the principal investigators at the
             collaborating centers and at 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 with chronic lymphocytic leukemia (CLL)

          -  Ages =< 50 years 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

          -  Aggressive nonHodgkin 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 1) failed to meet National Cancer Institute (NCI) Working Group
             criteria for complete or partial response after therapy with a regimen containing
             fludarabine (FLU) (or another nucleoside analog, e.g. cladribine [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; or 4) 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; 5) patients failing to achieve a
             response to ibrutinib as first-line therapy; 6) patients not responding to ibrutinib,
             idelalisib, or venetoclax as salvage therapy or intolerant of these agents as salvage
             therapy due to side effects; all CLL patients must have received prior
             myelosuppressive chemotherapy

          -  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 CP1 must have failed or be intolerant of
             tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they have <
             5% marrow blasts at time of transplant

          -  Myelodysplasia (MDS)/myeloproliferative syndrome (MPS)/chronic myelomonocytic leukemia
             (CMML) - patients must have < 5% marrow blasts at time of transplant

          -  Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy

          -  HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1;
             unrelated donors who are prospectively:

               -  Matched for 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

          -  HLA-MATCHED UNRELATED 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

          -  HLA-MATCHED UNRELATED 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

          -  HLA-MATCHED UNRELATED DONOR: Only granulocyte colony-stimulating factor (G-CSF)
             mobilized PBSC will be permitted as a HSC source on this protocol

          -  HLA-MISMATCHED UNRELATED DONOR: Unrelated volunteer donors who are mismatched with the
             recipient within one of the following limitations:

               -  Mismatch for one HLA class I antigen with or without an additional mismatch for
                  one HLA-class I allele, but matched for HLA-DRB1 and HLA-DQ, OR

               -  Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ

               -  HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1
                  and/or DQB1 antigen/allele mismatch

          -  HLA-MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high
             resolution typing at HLA-A, -B, -C, - DRB1, and -DQ

          -  HLA-MISMATCHED UNRELATED DONOR: If the patient is homozygous at the mismatch HLA class
             I locus or II locus, the donor must be heterozygous at that locus and one allele must
             match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous
             A*01:01, A*02:01); this mismatch will be considered a one-antigen mismatch for
             rejection only

        Exclusion Criteria:

          -  Patients with rapidly progressive intermediate or high grade NHL

          -  Patients with a diagnosis of chronic myelomonocytic leukemia (CMML) who have not
             received induction chemotherapy

          -  Patients with refractory anemia with excess blasts (RAEB) who have not received
             myelosuppressive chemotherapy i.e. induction chemotherapy and will receive
             conditioning Regimen C (fludarabine and total body irradiation [TBI]) will be
             excluded; patients with RAEB who have not received myelosuppressive chemotherapy but
             who will receive conditioning Regimen A or B are eligible for this study as long as
             other inclusion and exclusion criteria are met

          -  CNS involvement with disease refractory to intrathecal chemotherapy

          -  Presence of circulating blasts (in the blood) detected by standard pathology for
             patients with AML, ALL or CML

          -  Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard
             pathology for patients with MDS/MPS/CMML

          -  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

          -  Organ dysfunction

               -  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

               -  Pulmonary:

                    -  Diffusing capacity of the lungs for carbon monoxide (DLCO) < 40%, total lung
                       capacity (TLC) < 40%, forced expiratory volume in the first second of breath
                       (FEV1) < 40% and/or receiving supplementary continuous oxygen

                    -  The FHCRC PI of the study must approve of 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, 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

          -  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 peripheral blood stem cell (PBSC)

          -  DONOR: Patients who are homozygous at the mismatched HLA class I or II locus, the
             donor is excluded if homozygous at the mismatched locus (i.e., patient is homozygous A
             *01:01 and donor is homozygous A *02:01); this type of mismatch is considered a
             two-antigen mismatch and is not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Chronic graft versus host disease (GVHD)-free, relapse-free survival (CRFS)
Time Frame:At 1 year post- hematopoietic cell transplantation (HCT)
Safety Issue:
Description:Composite time-to-event outcome in which events include moderate or severe chronic GVHD based on National Institute of Health consensus criteria, relapse, or death from any cause.

Secondary Outcome Measures

Measure:Grades II-IV and III-IV acute graft versus host disease (GVHD)
Time Frame:At day 100 post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods. Grading is based on "Graft-vs-host disease" Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas, K. Blume, S. Forman, Blackwell Sciences; 1999, pages 518-519.
Measure:Late graft versus host disease (GVHD) not meeting National Institute of Health (NIH) consensus criteria for chronic GVHD
Time Frame:At 1 year post-HCT
Safety Issue:
Description:GVHD occurring after day 100 and not meeting NIH consensus criteria for chronic GVHD. Estimated by cumulative incidence methods.
Measure:Moderate and severe chronic graft versus host disease
Time Frame:At 1 year post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods. Based on NIH consensus criteria.
Measure:Relapse
Time Frame:At 1 year post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods.
Measure:Non-relapse mortality
Time Frame:At 1 year post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods.
Measure:Progression or relapse-free survival
Time Frame:At 1 year post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods.
Measure:Overall survival
Time Frame:At 1 year post-HCT
Safety Issue:
Description:Estimated by cumulative incidence methods.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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