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Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)

27. juli 2017 opdateret af: University Hospital, Tours

Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab in Patients Older Than 65 Years With Previously Untreated Chronic Lymphocytic Leukemia: a Phase III Trial of FILO

RATIONALE: Classical chemotherapy does not cure advanced chronic lymphocytic leukemia (CLL) despite new drugs. Rituximab is a monoclonal antibody directed against CD20 surface antigen on B lymphocytes and leads to apoptosis of CD20 positive B lymphocytes. The highest response rate yet published in the treatment of first-line CLL has been obtained by the association of fludarabine, cyclophosphamide and rituximab (FCR). Now, the question is whether this response can be improved, as some trials showed that eradication of minimal residual disease (MRD) in CLL is associated with a longer treatment-free and overall survival. Maintenance therapy using rituximab has been recently approved as a means of prolonging remission in patients with indolent non Hodgkin's lymphoma. Maintenance therapy with rituximab could be of interest in treatment of MRD in CLL and prolonging remission and survival times.

PURPOSE: The overall purpose of the study is to determine the value of immunotherapy maintenance with single agent rituximab in comparison with no further treatment (observation ) for previously untreated chronic lymphocytic leukaemia in elderly (>65 years) patients who respond to induction immunochemotherapy with FCR.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

OBJECTIVES:

Primary

  • To demonstrate superiority, in terms of 3-year progression-free survival (PFS), of rituximab maintenance over observation in patients who are in complete or partial response (CR or PR) after induction therapy comprising fludarabine, cyclophosphamide, and rituximab.

Secondary

  • To determine event-free survival, disease-free survival, overall survival, and time to next treatment, all from time of randomization.
  • To determine overall response rate (CR and PR) according to NCI and iwCLL criteria
  • To assess the rate of phenotypic response (minimal residual disease).
  • To assess duration of phenotypic and NCI and iwCLL clinical responses.
  • To determine response rates and time-related parameters in biological subgroups.
  • To determine rates of treatment-related adverse events.
  • To evaluate CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia.
  • To study pharmacokinetics of rituximab during induction and maintenance.
  • To evaluate the prognostic impact of the immunoglobulin FcγRIIIA genotype.
  • To assess quality of life.
  • To study pharmacoeconomics.

OUTLINE: This is a multicenter study. Randomization is stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IGHV mutational status, and 11q deletion.

Patients receive rituximab IV on days 1 and 14 of courses 1-2 and on day 1 of courses 3 and 4. Patients also receive oral fludarabine and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses are administered every 28 days. Patients achieving CR or PR are randomized 1:1 to maintenance arm or observation arm.

  • Arm A: Patients receive rituximab IV every 2 months in the absence of disease progression or unacceptable toxicity for a maximum duration of 24 months (12 infusions).
  • Arm B: Patients undergo observation only.

After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 2 years.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

542

Fase

  • Fase 3

Kontakter og lokationer

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

Studiesteder

  • Frankrig
      • TOURS Cedex, Frankrig, 37044
        • French Innovative Leukemia Organization

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

65 år og ældre (Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion criteria

  • B-CLL
  • Matutes score 4 or 5
  • Binet stages B or C
  • Age > 65 years old
  • No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy, except glucocorticoids < 1 month
  • Patient's written informed consent
  • Life expectancy > 6 months

Exclusion criteria

  • Binet stage A
  • ECOG performance status 2 or more
  • Presence of a 17p deletion by FISH (> 10% positive cores)
  • Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
  • Patients with a history of another malignancy in complete remission less than 5 years, except basal cell skin cancer or tumor treated curatively by surgery
  • Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
  • Any severe co-morbidities such as NYHA Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia, or uncontrolled diabetes mellitus.
  • CIRS (Cumulative Illness rating Scale) > 6
  • Known hypersensitivity to murine proteins or to any of the study drugs or to their components
  • Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma) or prolymphocytic leukemia
  • Active bacterial, viral or fungal infection
  • Seropositivity HIV, hepatitis C or hepatitis B (unless clearly due to vaccination)
  • Total bilirubin, alkaline phosphatases and aminotransferases > 2 x ULN
  • Creatinine clearance < 60 ml/min calculated according to the formula of Cockcroft and Gault
  • Any coexisting medical or psychological condition that would preclude participation to the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment

Inclusion criteria at randomization

  • Patients having received the full induction phase with 4 FC and 6 rituximab courses (with/without dose adjustments as per protocol)
  • Complete or partial response according to NCI and iwCLL criteria at the end of induction phase
  • Recovery from FCR toxicities
  • Patient willingness to continue on protocol

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: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Ingen indgriben: Observation
Observation every 8 weeks during 2 years
Eksperimentel: rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
Biologisk: Rituximab
rituximab :500 mg/m² every 8 weeks during 2 years
Andre navne:
  • Mabthera

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Progression-free survival
Tidsramme: randomization until disease progression or death
Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria
randomization until disease progression or death

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Event-free survival
Tidsramme: randomization until disease progression, death, new CLL treatment, and secondary cancer
Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
randomization until disease progression, death, new CLL treatment, and secondary cancer
Disease-free survival
Tidsramme: first documented CR until relapse
Disease-free survival is defined as the time from first documented CR to relapse
first documented CR until relapse
Overall survival
Tidsramme: randomization until death
Overall survival is defined as the time from randomization to death from any cause
randomization until death
Time to next treatment
Tidsramme: randomization until new CLL treatment
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
randomization until new CLL treatment
Overall response rate
Tidsramme: baseline up to approximately 66 months
Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
baseline up to approximately 66 months
Phenotypic response rate
Tidsramme: randomization up to approximately 60 months
Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
randomization up to approximately 60 months
Rates of treatment-related adverse events
Tidsramme: safety since baseline
Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
safety since baseline
Pharmacokinetics of rituximab
Tidsramme: baseline up to approximately 36 months
Pharmacokinetics of rituximab during induction and rituximab maintenance
baseline up to approximately 36 months
Quality of life
Tidsramme: baseline up to approximately 30 months
Change from baseline in EORTC Quality of Life Questionnaire Core 30
baseline up to approximately 30 months

Samarbejdspartnere og efterforskere

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

Sponsor

University Hospital, Tours

Samarbejdspartnere

Roche Pharma AG
French Innovative Leukemia Organisation

Efterforskere

  • Ledende efterforsker: Caroline Dartigeas, MD, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
  • Ledende efterforsker: Eric VAN DEN NESTE, MD PhD, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM

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

1. december 2007

Primær færdiggørelse (Faktiske)

1. februar 2014

Studieafslutning (Faktiske)

1. juli 2017

Datoer for studieregistrering

Først indsendt

26. marts 2008

Først indsendt, der opfyldte QC-kriterier

26. marts 2008

Først opslået (Skøn)

27. marts 2008

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

1. august 2017

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

27. juli 2017

Sidst verificeret

1. juli 2017

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • CDR0000589684
  • CHRUT-LLC-2007-SA (Anden identifikator: CHU Tours)
  • CHRUT-PHRN05-CD (Anden identifikator: CHU Tours)
  • INCA-RECF0497 (Anden identifikator: INCA)
  • 2007-001015-28 (EudraCT nummer)

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