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Fludarabine and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Lymphocytic Leukemia or Waldenstrom's Macroglobulinemia

20. juli 2017 opdateret af: German CLL Study Group

Pilot Study on Allogeneic Stem Cell Transplantation Following Conditioning With Fludarabine and an Alkylating Agent in Patients With High-Risk Chronic Lymphocytic Leukemia

RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal 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 methotrexate, cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

PURPOSE: This phase I/II trial is studying the side effects of giving fludarabine together with cyclophosphamide and to see how well they work in treating patients who are undergoing donor stem cell transplant for B-cell chronic lymphocytic leukemia or Waldenström's macroglobulinemia.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

OBJECTIVES:

Primary

  • Determine the feasibility and safety of induction therapy comprising fludarabine and cyclophosphamide followed by allogeneic stem cell transplantation in patients with high-risk B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia).

Secondary

  • Determine the incidence and kinetics of clinical and molecular remissions in patients treated with this regimen.
  • Determine event-free and overall survival of patients treated with this regimen.
  • Determine the duration of clinical and molecular remission in relation to the underlying cytogenetic deviation in patients treated with this regimen.
  • Determine the kinetics and extent of lympho-hematopoietic donor chimerism in patients treated with this regimen.

OUTLINE: This is a multicenter, open-label, nonrandomized, pilot study.

  • Cytoreductive therapy: Patients receive up to 3 courses of cytoreductive therapy comprising fludarabine IV and cyclophosphamide IV on days 1-3 (with or without rituximab IV on day 1). Patients refractory to fludarabine-containing therapy may receive alemtuzumab IV for 12 weeks OR any other cytotoxic salvage regimen for cytoreduction.
  • Conditioning regimen: Patients receive 1 of the following conditioning regimens*:

NOTE: *Patients who did not achieve partial response after cytoreductive therapy receive regimen 3.

  • Regimen 1: Patients receive fludarabine IV and cyclophosphamide IV on days -7 to -3. If stem cells are collected from an unrelated donor, patients also receive anti-thymocyte globulin (ATG) IV on days -4 to -1.
  • Regimen 2: Patients undergo total-body irradiation on day -9. Patients then receive alemtuzumab IV on days -8 to -4 and fludarabine IV and cyclophosphamide IV on days -6 to -2.

  • Regimen 3: Patients receive fludarabine IV on days -7 to -3, busulfan IV or orally on days -7 to -5, and cyclophosphamide IV on days -3 to -2. If stem cells are collected from an unrelated donor, patients also receive ATG on days -3 to -1.

    • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously daily starting on day 5 and continuing until blood count recover.
    • Graft-versus-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV beginning on day -1 and continuing until approximately day 100. Patients treated with conditioning regimen 1 or 3 also receive methotrexate IV on days 1, 3, and 6 OR oral mycophenolate mofetil twice daily on days 0-50. Patients with evidence of residual disease at least 4 weeks after completion of cyclosporine undergo donor lymphocyte infusion (DLI).
    • DLI: The donor T-lymphocytes are collected from the PBSCT donor without prior G-CSF mobilization. Patients receive DLI every 8 weeks in the presence of residual disease and the absence of GVHD.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

100

Fase

  • Fase 2
  • Fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Canada
    • Quebec
      • Montreal, Quebec, Canada, H1T 2M4
        • Maisonneuve-Rosemont Hospital
  • Tyskland
      • Berlin, Tyskland, 12200
        • Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
      • Essen, Tyskland, 45122
        • Universitaetsklinikum Essen
      • Goettingen, Tyskland, 37075
        • Universitaetsklinikum Goettingen
      • Hamburg, Tyskland, D-20099
        • Asklepios Klinik St. Georg
      • Hannover, Tyskland, 30625
        • Medizinische Hochschule Hannover
      • Heidelberg, Tyskland, D-69120
        • Universitaets-Kinderklinik Heidelberg
      • Homburg, Tyskland, 66421
        • Universitaetsklinikum des Saarlandes
      • Idar-Oberstein, Tyskland, D-55743
        • Clinic for Bone Marrow Transplantation and Hematology and Oncology
      • Kiel, Tyskland, 24116
        • University Hospital Schleswig-Holstein - Kiel Campus
      • Leipzig, Tyskland, 04103
        • University Hospital of Leipzig
      • Regensburg, Tyskland, 93053
        • Klinikum der Universitaet Regensburg
      • Ulm, Tyskland, 89081
        • Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 65 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

DISEASE CHARACTERISTICS:

  • Diagnosis of B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia)

    • Must have poor prognostic features and low probability of successful autografting, defined by one of the following criteria:

      • Progressive disease with unfavorable cytogenetics (deletion or mutation of critical regions on chromosomes 11q and/or 17p [p53]; and/or unmutated status of the immunoglobulin V_H gene region; and/or usage of the V_H 3-21 gene), defined as 1 of the following:

        • Doubling of lymphocyte count or nodal involvement within 3 months or less
        • Progressive decline of platelet count and/or hemoglobin values defining Binet stage C disease (or to 50% or less of baseline values within 3 months) not due to immune mechanisms
        • Symptomatic splenomegaly
        • Discomfort or imminent complications due to large tumor masses
        • B symptoms
      • Refractory disease or early relapse (within 12 months) after treatment with a fludarabine-containing regimen
      • Relapsed after autologous stem cell transplant (SCT)
      • Insufficient stem cell harvest for intended autologous SCT
  • Presence of a clonal CDR III rearrangement detected by polymerase chain reaction
  • No Richter's syndrome
  • HLA-identical sibling or unrelated donor available

PATIENT CHARACTERISTICS:

  • ECOG performance status ≤ 1
  • Creatinine clearance > 60 mL/min
  • SGOT, SGPT, and bilirubin < 2 times normal
  • Normal cardiac function determined by ECG and echocardiographic examination
  • Inspiratory vital capacity, FEV_1, and DLCO > 50% of predicted
  • No serious localized or systemic infections
  • No other concurrent malignant disease
  • No impaired organ function
  • No uncontrolled diabetes
  • No uncontrolled hypertension
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • No HIV infection
  • No hepatitis B or C infection
  • No concurrent alcohol or drug abuse
  • No dementia or altered mental status that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

  • Not specified

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Allogeneic stem cell transplantation

  1. Cytoreductive therapy for inducing a state of partial remission:

    FC or FC-R or alternative salvage regimens (e.g. Alemtuzumab)

  2. Conditioning regimen:

    FC +/- ATG (Arm A) or FC/Busulfan +/- ATG (Arm C: refractory patients only)

  3. allogeneic-PBSCT (from HLA-identical donor)
  4. GVHD prophylaxis: CSA + MTX or MMF
  5. +/- DLI (Donor lymphocyte infusions)
Medicin: cyclophosphamid
Stråling: strålebehandling
Medicin: methotrexat
Biologisk: anti-thymocyt globulin
Biologisk: terapeutiske allogene lymfocytter
Medicin: fludarabin fosfat
Medicin: busulfan
Procedure: perifer blodstamcelletransplantation
Biologisk: filgrastim
Biologisk: rituximab
Biologisk: alemtuzumab
Medicin: cyclosporin
Medicin: mycophenolatmofetil

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Feasibility as measured by the proportion of eligible patients completing the transplant procedure successfully
Safety as measured by a treatment-related mortality of < 25% at 2 years following transplant

Sekundære resultatmål

Resultatmål
Clinical remission rate by NIH criteria at 12 months following transplant
Minimal residual disease negativity rate as measured by high-resolution flow or CDR PCR at 12 months following transplant
Chimerism as measured by STR-PCR at 12 months following transplant
Event-free and overall survival at 5 years following transplant

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

German CLL Study Group

Efterforskere

  • Studiestol: Peter Dreger, Universitaets-Kinderklinik Heidelberg

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Hjælpsomme links

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. juni 2000

Studieafslutning (Faktiske)

1. juli 2010

Datoer for studieregistrering

Først indsendt

24. januar 2006

Først indsendt, der opfyldte QC-kriterier

24. januar 2006

Først opslået (Skøn)

25. januar 2006

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

24. juli 2017

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

20. juli 2017

Sidst verificeret

1. april 2007

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • CLL3X
  • EU-20554
  • MEDAC-FLUD.10/CLL

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

INGEN

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