Clinical Trials /

Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT00104858

Description:

This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Related Conditions:
  • B-Cell Prolymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
  • Official Title: Nonmyeloablative Conditioning With Pre- and Post-Transplant Rituximab Followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients With Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial

Clinical Trial IDs

  • ORG STUDY ID: 1840.00
  • SECONDARY ID: NCI-2009-01594
  • SECONDARY ID: 1840.00
  • SECONDARY ID: P01CA018029
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT00104858

Conditions

  • Chronic Lymphocytic Leukemia
  • Prolymphocytic Leukemia
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Stage III Chronic Lymphocytic Leukemia
  • Stage III Small Lymphocytic Lymphoma
  • Stage IV Chronic Lymphocytic Leukemia
  • Stage IV Small Lymphocytic Lymphoma
  • T-Cell Large Granular Lymphocyte Leukemia

Interventions

DrugSynonymsArms
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (chemotherapy and rituximab followed by HCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586Treatment (chemotherapy and rituximab followed by HCT)
Mycophenolate MofetilCellcept, MMFTreatment (chemotherapy and rituximab followed by HCT)
RituximabBI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar BI 695500, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, RTXM83Treatment (chemotherapy and rituximab followed by HCT)

Purpose

This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine whether nonmyeloablative conditioning and allogeneic hematopoietic cell
      transplantation (HCT) improves survival at 18 months for patients with fludarabine
      (fludarabine phosphate)-refractory, fludarabine/cyclophosphamide/rituximab (FCR)-failed, or
      del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H
      (alemtuzumab).

      SECONDARY OBJECTIVES:

      I. Estimate the overall response rate (complete remission [CR] + partial remission [PR]) by
      standard morphologic, flow cytometric, and molecular techniques.

      II. Assess the rate of relapse/progression.

      III. Define incidences of regimen-related toxicities (RRT) and infections within the first
      100 days and the incidence of transplant-related mortality (TRM) within the first year.

      IV. Estimate incidences of grade II-III and III-IV acute graft-versus-host disease (GVHD) and
      chronic GVHD.

      V. Determine whether the addition of rituximab to the nonmyeloablative conditioning and
      allogeneic HCT improves survival at 18 months over our historical data (57% at 18 months).

      VI. Determine the incidence of serious adverse events with the addition of rituximab in
      comparison to historical data of unrelated nonmyeloablative HCT.

      VII. Evaluate the pharmacokinetics of rituximab.

      VIII. Evaluate B-cell and T-cell immune reconstitution in comparison to historical data of
      unrelated nonmyeloablative HCT.

      IX. Describe donor and host polymorphisms of the FCgammaRIIIa receptor and cluster of
      differentiation (CD)32 and evaluate their impact on disease response and relapse.

      X. Investigate the mechanism of disease resistance in relapsed/nonresponding patients.

      XI. Isolate donor cytotoxic T lymphocytes specific for host minor histocompatibility
      antigens.

      OUTLINE:

      Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV)
      on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38.

      Patients undergo single fraction low-dose total-body irradiation (TBI) on day 0. After
      completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation (HSCT)
      on day 0. Patients then receive rituximab IV on days 10, 24, and 38.

      Patients receive an immunosuppressive regimen comprising cyclosporine orally (PO) twice daily
      (BID) on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to
      100 followed by a taper to day 180 (unrelated recipients). Patients also receive
      mycophenolate mofetil PO BID on days 0-27 (related recipients) or three times daily (TID) on
      days 0-40 followed by a taper to day 96 (unrelated recipients).

      After completion of study treatment, patients are followed up at 6 months, 1 year, 18 months,
      2 years, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy and rituximab followed by HCT)ExperimentalPatients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients).
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to
             prolymphocytic leukemia (PLL)

          -  Patients with B-Cell CLL or PLL who:

               -  Failed to meet National Cancer Institute (NCI) Working Group criteria 2 for
                  complete or partial response after 2 cycles of therapy with regimen containing
                  fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin)
                  or with disease relapse within 12 months after completing therapy with a
                  fludarabine (or another nucleoside analog) containing regimen

               -  Failed FCR or pentostatin/cyclophosphamide/rituximab (PCR) combination
                  chemotherapy at any time point

               -  Patients with novo or acquired "17p deletion" cytogenetic abnormality; patients
                  should have received induction treatment but could be transplanted in 1st CR

          -  Patients who have suitable human leukocyte antigen (HLA)-matched related or unrelated
             donors willing to receive filgrastim (G-CSF), undergo leukapheresis to collect
             peripheral blood mononuclear cell (PBMC), and to donate stem cells

          -  RELATED DONORS: When more than one potential donor exists, priority should be given to
             donors based on HLA identity > cytomegalovirus (CMV) seronegativity > ABO
             compatibility > sex matching

               -  Donor who is HLA phenotypically or genotypically identical at the allele level at
                  HLA-A, -B, -C, -DRB1, and -DQB1

               -  Must consent to G-CSF administration and leukapheresis;

               -  Must have adequate veins for leukapheresis or agree to placement of central
                  venous catheter (femoral, subclavian);

               -  Only G-CSF mobilized PBMC only will be permitted as a hematopoietic stem cell
                  (HSC) source on this protocol

          -  UNRELATED DONORS:

               -  Fred Hutchinson Cancer Research Center (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

          -  UNRELATED DONORS: 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; recommended procedure
             for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
             reactive antibody screens to class I and 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

          -  UNRELATED DONORS: 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

          -  UNRELATED DONORS: Only G-CSF mobilized PBMC will be permitted as a HSC source on this
             protocol

        Exclusion Criteria:

          -  Infection with human immunodeficiency virus (HIV)

          -  Active diagnosis of central nervous system (CNS) involvement with CLL

          -  Patients unwilling to use contraceptive techniques before and for 12 months after HCT

          -  Pregnant women or females who are breastfeeding

          -  The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine
             kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose
             cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the
             initiation of conditioning

          -  Active bacterial or fungal infections unresponsive to medical therapy

          -  Performance status: Karnofsky score < 60 for adult patients

          -  Cardiac ejection fraction < 40%; ejection fraction is required if age > 50 years or
             there is a history of prior transplant, anthracycline exposure or history of cardiac
             disease; and poorly controlled hypertension despite multiple antihypertensives

          -  Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity
             (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or requiring
             continuous supplementary oxygen, or severe deficits in pulmonary function testing as
             defined by pulmonary consultant service; and the FHCRC principal investigator (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,
             hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a
             history of bleeding esophageal varices or hepatic encephalopathy, uncorrectable
             hepatic synthetic dysfunction evidenced 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, or
             symptomatic biliary disease

          -  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

          -  DONOR: Age < 12 years

          -  DONOR: Identical twin

          -  DONOR: Pregnancy

          -  DONOR: Infection with HIV

          -  DONOR: Inability to achieve adequate venous access

          -  DONOR: Known allergy to filgrastim (G-CSF)

          -  DONOR: Current serious systemic illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Survival
Time Frame:At 18 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Comparison of survival, serious adverse events, and B-cell and T-cell immune reconstitution with historical data
Time Frame:At 18 months
Safety Issue:
Description:
Measure:Donor and host polymorphisms of the FCgammaRIIIa receptor and CD32 and their impact on disease response and relapse
Time Frame:Day 84
Safety Issue:
Description:
Measure:Graft-versus-leukemia analysis by mechanism of disease resistance in relapsed or non-responding patients and isolation of donor cytotoxic T lymphocytes specific for host minor histocompatibility antigens
Time Frame:Day 84
Safety Issue:
Description:
Measure:Incidence of grade II-III and III-IV acute GVHD and chronic GVHD
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence of regimen-related toxicity and infections
Time Frame:Within the first 100 days
Safety Issue:
Description:Reported using the adapted National Cancer Institute Common Toxicity Criteria.
Measure:Incidence of treatment-related mortality
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Pharmacokinetics of rituximab
Time Frame:Days 60, 84, 180, and 1 year
Safety Issue:
Description:
Measure:Proportion of patients achieving complete response and partial response (overall response rate)
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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