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Optimized Donor Selection, Nonmyeloablative BMT for B-cell Lymphomas With Post-transplantation Cy and Rituximab

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ClinicalTrials.gov Identifier: NCT00946023
Recruitment Status : Terminated (Funding was unavailable to complete the study as originally planned.)
First Posted : July 24, 2009
Results First Posted : July 24, 2018
Last Update Posted : August 27, 2018
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description
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Brief Summary:
This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation and rituximab works in treating patients with B-cell lymphoma or chronic lymphocytic leukemia who are undergoing an allogeneic (donor) bone marrow transplant. The type of bone marrow transplant is a less intensive or "mini" transplant using a relative as the bone marrow donor. The donated bone marrow stem cells may replace the patient's immune system cells and help destroy any remaining cancer (graft-versus-tumor effect). Patients undergoing this type of transplant often have more than one relative who could be a donor. The trial is also studying a new way of choosing amongst possible donors which might improve how the rituximab works.

Condition or disease Intervention/treatment Phase
Lymphoma B-cell Lymphoma Non Hodgkin Lymphoma Chronic Lymphocytic Leukemia Drug: Fludarabine Drug: Cyclophosphamide Radiation: Total body irradiation Drug: Tacrolimus Drug: Mycophenolate Mofetil Drug: Rituximab Biological: Allogeneic Bone Marrow Transplant (BMT) Phase 2

Detailed Description:
This phase II for relapsed or refractory B-cell malignancies builds on the platform of nonmyeloablative, related-donor, HLA (human leukocyte antigen)-matched or HLA-haploidentical BMT with post-transplantation high-dose cyclosphosphamide administered for prophylaxis of graft-versus-host disease and graft rejection. Rituximab is added to the transplant regimen with the goal of augmenting anti-tumor activity. In patients with B-cell lymphomas, specific polymorphisms in the immunoglobulin Fc receptor have been associated with greater sensitivity to rituximab or rituximab-based therapies, translating in some series into higher response rates and improved progression-free survival. This raises the possibility of selecting donors who carry this permissive polymorphism. This trial identifies and selects donors who have the favorable polymorphism at FcgammaR3A-158, thereby potentially conferring greater sensitivity to rituximab in the host after BMT.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 135 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonmyeloablative BMT With Post-transplant Cyclophosphamide, Rituximab and Optimized Donor Selection for B-cell Lymphomas
Actual Study Start Date : July 2009
Actual Primary Completion Date : July 2013
Actual Study Completion Date : July 17, 2013

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Transplant
Non-myeloablative allogeneic bone marrow transplant (BMT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD (graft vs host disease) prophylaxis. Rituximab will be given as post-transplant maintenance.
 Drug: Fludarabine
Days -6 through -2: 30 mg/m^2 IV daily
Other Name: Fludara

Drug: Cyclophosphamide
Days -6 and -5: 14.5 mg/kg IV daily; Days 3 and 4: 50 mg/kg IV daily
Other Names:
  • Cytoxan
  • CTX
  • Cy

Radiation: Total body irradiation
Day -1: 200 centigray (cGy) in a single fraction
Other Name: TBI

Drug: Tacrolimus
Start on Day 5 through Day 180
Other Names:
  • FK-506
  • FK506
  • Prograf

Drug: Mycophenolate Mofetil
Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
Other Names:
  • MMF
  • CellCept

Drug: Rituximab
Day 30 and every week after for 8 total doses: 375 mg/m^2 IV
Other Name: Rituxan

Biological: Allogeneic Bone Marrow Transplant (BMT)
Day 0: Donor bone marrow infusion


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: 1 year post-intervention ]
    Percentage of participants alive and without relapse or disease progression.


Secondary Outcome Measures :
  1. Progression-free Survival [ Time Frame: 2 years post-intervention ]
    Percentage of participants alive with and without relapse.

  2. Overall Survival [ Time Frame: 1 year post intervention ]
    Percentage of participants alive.

  3. Overall Survival [ Time Frame: 2 years post intervention ]
    Percentage of participants alive.

  4. Relapse [ Time Frame: 1 year post intervention ]
    Percentage of participants alive with relapse or disease progression.

  5. Relapse [ Time Frame: 2 years post intervention ]
    Percentage of participants alive with relapse or disease progression.

  6. Non-relapse Mortality [ Time Frame: 1 year post intervention ]
    Percentage of participants who died due to BMT-related reasons.

  7. Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD) [ Time Frame: 1 year post intervention ]
    Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.

  8. Incidence of Grades III-IV Acute GVHD [ Time Frame: 1 year post intervention ]
    Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.

  9. Incidence of Chronic GVHD [ Time Frame: 1 year post intervention ]
    Percentage of participants who experienced chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria.

  10. Engraftment [ Time Frame: Day 60 ]
    Percentage of patients who engrafted neutrophils and platelets.

  11. Graft Failure [ Time Frame: Day 60 ]
    Percentage of participants who failed to engraft.


Eligibility Criteria
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Ages Eligible for Study:   1 Year to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Poor-risk CD20+, B-cell lymphoma, as follows:

    • Low grade B-cell lymphoma that has failed at least two prior therapies (excluding single agent rituximab), or undergone histologic conversion (if histologic conversion, PR or CR is required):

      1. Follicular grade 1 or 2 lymphoma
      2. Follicular lymphoma not otherwise specified
      3. Marginal zone (or MALT) lymphoma
      4. Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia
      5. Hairy cell leukemia
      6. Small lymphocytic lymphoma / chronic lymphocytic leukemia (SLL/CLL)
      7. Low grade B-cell lymphoma, unspecified
      8. Nodular lymphocyte-predominant Hodgkin lymphoma
  • Poor-risk small lymphocytic lymphoma or chronic lymphocytic leukemia, defined by a 17p deletion, 11q deletion, or histologic conversion (if histologic conversion, PR or CR is required)

  • Aggressive B-cell non-Hodgkin's lymphoma that has failed at least one prior regimen of multiagent chemotherapy, is in PR (partial remission) or CR (complete remission), and patient is either ineligible for autologous hematopoietic BMT or autologous BMT is not recommended:

    1. Follicular grade 3 lymphoma
    2. Histoconversion of low-grade B-cell lymphoma (including SLL/CLL) to aggressive B-cell non-Hodgkin's lymphoma
    3. Mantle cell lymphoma
    4. Diffuse large B-cell lymphoma (excluding primary CNS [central nervous system] lymphoma)
    5. "Gray zone" or composite lymphomas with combined features of primary mediastinal large B-cell and Hodgkin's lymphoma
    6. Burkitt's lymphoma/leukemia
    7. Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma)
  • Must have a related donor who is at least HLA haploidentical
  • Any previous BMT must have occurred at least 3 months prior
  • Left ventricular ejection fraction at least 35%
  • Bilirubin no more than 3.0 mg/dL (unless due to Gilbert's syndrome), and ALT (alanine aminotransferase) and AST (aspartate aminotransferase) no more than 5 x upper limit of normal
  • FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) at least 40% of predicted
  • Absence of uncontrolled infection

Exclusion Criteria:

  • More than 20% involvement of bone marrow by chronic lymphocytic leukemia
  • Active central nervous system lymphoma
  • ECOG (Eastern Cooperative Oncology Group) performance status greater than 1 (2,3, and 4)
  • HIV positive
  • Pregnant or breastfeeding
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00946023


Locations
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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
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Principal Investigator: Yvette L Kasamon, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
More Information
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Publications of Results:

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00946023    
Other Study ID Numbers: J0941
NA_00025589 ( Other Identifier: Johns Hopkins Medicine Institutional Review Board )
First Posted: July 24, 2009    Key Record Dates
Results First Posted: July 24, 2018
Last Update Posted: August 27, 2018
Last Verified: July 2018
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
lymphoma
non hodgkin lymphoma
allogeneic
bone marrow transplantation
 nonmyeloablative
cyclophosphamide
rituximab
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid
Leukemia
Leukemia, B-Cell
Mycophenolic Acid
Cyclophosphamide
 Rituximab
Fludarabine
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Calcineurin Inhibitors
Enzyme Inhibitors