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Rituximab, Alemtuzumab, and GM-CSF As First-Line Therapy in Treating Patients With Early-Stage Chronic Lymphocytic Leukemia

30. marts 2020 opdateret af: Mayo Clinic

Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia

RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving monoclonal antibody therapy together with GM-CSF may be an effective treatment for early-stage chronic lymphocytic leukemia.

PURPOSE: This phase II trial is studying the side effects of giving rituximab and alemtuzumab together with GM-CSF and to see how well it works in treating patients with early-stage chronic lymphocytic leukemia.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

OBJECTIVES:

Primary

  • To assess the rate of complete and overall response in patients with high-risk, early-stage, chronic lymphocytic leukemia (CLL) treated with alemtuzumab, rituximab, and sargramostim (GM-CSF).
  • To monitor and assess toxicity of this regimen in these patients through clinical evaluation and serial monitoring of cytomegalovirus antigenemia by polymerase chain reaction (PCR).

Secondary

  • To determine the overall and progression-free survival, time to response, time to next treatment, and duration of response in patients treated with this regimen.
  • To assess the correlation between individual prognostic markers (i.e., 17p-, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+) and clinical outcome.

Correlative Studies

  • To assess response in these patients using an expanded definition of response, including minimal residual disease (MRD) by sensitive flow cytometry in patients in complete clinical remission.
  • To assess MRD status of responding patients using sensitive flow cytometry and molecular assays (i.e., spectral karyotype analysis of CLL cells) before treatment and at relapse to identify subpopulations that could contribute to disease resistance and relapse.
  • To detail the in vivo effect of this regimen on critical aspects of the immune system in CLL.
  • To determine if GM-CSF, β-glucan, and CpG7909 can increase antibody dependent cellular cytotoxicity to improve efficacy against CLL cells and clinical response to treatment.

OUTLINE: Patients receive rituximab IV over 30 minutes on day 3 of weeks 2-5, alemtuzumab subcutaneously (SC) on days 3, 4, and 5 in week 1 and on days 1, 3, and 5 in weeks 2-5, and sargramostim SC on days 1, 3, and 5 in weeks 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection for measurement of serum cytomegalovirus DNA copy number by polymerase chain reaction at baseline, weekly during treatment, and monthly for the 6 months after completion of treatment. Patients also undergo bone marrow biopsy and aspirate at two months and then again at 12 months (if in complete remission). Blood samples are collected periodically during study for evaluation of prognostic biomarkers (i.e., 11q-, 17p-, unmutated IgVH gene, VH3-21 gene segment use, and CD38 and ZAP-70 expression) by fluorescent in situ hybridization (FISH) and for immunophenotyping by flow cytometry. Blood samples are collected from patients at the Mayo Clinic Rochester site at baseline and periodically during study for immunological and other correlative studies, including minimal residual disease (in responding patients only).

After completion of study therapy, patients are followed periodically for up to 5 years.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

33

Fase

  • Fase 2

Kontakter og lokationer

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

Studiesteder

  • Forenede Stater
    • Arizona
      • Scottsdale, Arizona, Forenede Stater, 85259-5499
        • Mayo Clinic Scottsdale
    • Minnesota
      • Rochester, Minnesota, Forenede Stater, 55905
        • Mayo Clinic Cancer Center

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 120 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

DISEASE CHARACTERISTICS:

  • Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

    • Minimum threshold peripheral blood lymphocyte count 5 x 10^9/L

    • Monoclonality (light chain exclusion) of B lymphocytes detected by immunophenotyping (CD19-positive), demonstrating ≥ 3 of the following characteristics:

      • CD5-positive
      • CD23-positive
      • Dim surface light chain expression
      • Dim surface CD20 expression
    • Negative for IGH/CCND1 translocation AND/OR immunostaining is negative for cyclin D1 expression by fluorescent in-situ hybridization (FISH) analysis
    • Rai stage 0, I, or II disease that does not meet standard NCI-Working Group criteria for treatment of CLL

  • Poor prognosis as defined by ≥ 1 of the following factors:

    • Unmutated IgVH mutation status AND CD38 expression (i.e., ≥ 30% cells positive on flow cytometry)
    • Unmutated IgVH mutation status AND ZAP-70 expression (i.e., ≥ 20% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND CD38 expression (≥ 30% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND ZAP-70 expression (≥ 20% cells positive on flow cytometry)
    • 11q-negative*
    • 17p-negative* NOTE: *Determination of IgVH mutation status is not required in patients whose eligibility is based on 17p13- or 11q22- deletions

PATIENT CHARACTERISTICS:

  • ECOG performance status 0- 2
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 ULN
  • AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must practice effective contraception
  • Willing to provide mandatory blood samples (for patients at the Mayo Clinic in Rochester only) for research studies as required by the protocol

  • No comorbid conditions, including any of the following:

    • New York Heart Association Class III or IV heart disease
    • Myocardial infarction within the past month
    • Uncontrolled infection
    • HIV infection or AIDS
    • Serological evidence of active hepatitis B infection (i.e., serum antigen or e-antigen positivity) or positive hepatitis C serology
  • No other active primary malignancy requiring treatment or limiting survival to ≤ 2 years
  • No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia

PRIOR CONCURRENT THERAPY:

  • More than 4 weeks since prior major surgery
  • No prior chemotherapy or monoclonal antibody treatment for CLL
  • No concurrent corticosteroids

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: Alemtuzumab + Rituximab + GM-CSF
Biologisk: Alemtuzumab

Week 1 (dose escalation):

Day 3: 3mg subcutaneously; Day 4: 10mg subcutaneously; Day 5 30mg subcutaneously

Weeks 2-5:

30mg subcutaneously three times a week.

Biologisk: Rituximab

Weeks 2-5:

375 mg/m^2 by IV once weekly

Biologisk: Sargramostim

Week 1-6:

250 mcg subcutaneously three time as week

Andre navne:
  • GM-CSF

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Number of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months
Tidsramme: 6 months

Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months:

  • CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy
  • PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
6 months

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Progression Free Survival
Tidsramme: Time from registration to progression (up to 5 years)
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to the standard NCI-WG96 criteria. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time from registration to progression (up to 5 years)
Duration of Response
Tidsramme: time from start of response to progression (up to 5 years)

Duration of response (DOR) is defined as the time from documentation of response (CR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method.Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months:

  • CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy
  • PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
time from start of response to progression (up to 5 years)
Time to Next Treatment
Tidsramme: time from end of protocol treatment to subsequent treatment (up to 5 years)
Time to next treatment was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median and 95% CI was estimated using the Kaplan Meier method.
time from end of protocol treatment to subsequent treatment (up to 5 years)
Overall Survival
Tidsramme: Time from registration to death (up to 5 years)
Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method.
Time from registration to death (up to 5 years)

Samarbejdspartnere og efterforskere

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

Sponsor

Mayo Clinic

Samarbejdspartnere

National Cancer Institute (NCI)

Efterforskere

  • Studiestol: Clive S. Zent, MD, Mayo Clinic

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

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 (Faktiske)

1. januar 2008

Primær færdiggørelse (Faktiske)

5. februar 2010

Studieafslutning (Faktiske)

18. december 2014

Datoer for studieregistrering

Først indsendt

21. november 2007

Først indsendt, der opfyldte QC-kriterier

21. november 2007

Først opslået (Skøn)

22. november 2007

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

8. april 2020

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

30. marts 2020

Sidst verificeret

1. maj 2017

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • CDR0000574754
  • P30CA015083 (U.S. NIH-bevilling/kontrakt)
  • MC0785 (Anden identifikator: Mayo Clinic Cancer Center)
  • U4449s (Anden identifikator: Genentech)
  • 001.0888 (Anden identifikator: Bayer)
  • 07-002087 (Anden identifikator: Mayo Clinic IRB)

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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