BENdamustine at Elevated Dose for Relapsed Follicular Lymphoma in Intensification Therapy and Transplantation (BENEFIT) (BENEFIT)

January 4, 2019 updated by: Centre Leon Berard

A Multicenter Phase II Study Evaluating BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Prior to Autologous Stem Cell Transplant for First and Second Chemosensitive Relapses in Patients With Follicular Lymphoma

The purpose of this study is to evaluate the efficacy and safety of BeEAM (bendamustine, etoposide, cytarabine and melphalan) regimen prior to autologous stem cell transplant for first and second chemosensitive relapses in patients with follicular lymphoma (World Health Organisation (WHO) grade 1, 2, 3a).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

The natural history of this follicular lymphoma (FL) is marked by multiple relapses. The prognosis of FL has improved with the use of effective sequential chemotherapy and the introduction of anti-cluster of differentiation antigen 20 (anti-CD20) monoclonal antibody. Based on the multiple phases II, high dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) appear to be an effective treatment in relapsed FL. At rituximab era, the 3-years EFS rate was 75% for relapsed transplanted patients treated in first line therapy in FL2000 protocol. Bendamustine that combines alkylating and antimetabolite activities had proven clinical activity in relapse and in first line therapy of FL. Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM regimen) is one of the most used schedule of HDT in non hodgkin lymphoma. Regarding the good safety profile of Bendamustine, Visani et al. proposed a phase I/II of bendamustine at day -7 and -6, followed by etoposide, cytarabine and melphalan with similar dose than BEAM regimen. The bendamustine maximal dose is 200 mg/m² day -7, -6. Data from engraftment showed closed results than those observed after BEAM. None of patients experienced a dose limiting toxicity. In this context, the investigators proposed to perform a multicentric phase II of this regimen with 200 mg/m² day-7 and -6 of bendamustine for first and second relapsed FL with a chemosensitive disease after salvage therapy. No FL was evaluated in Visani et al. study. In addition, the investigators can observe a shortage of the BCNU these last years that incline to evaluate new schedule of HDT.

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Côte d'Or
      • Dijon, Côte d'Or, France, 21000
        • CHU de Dijon - Hopital le Bocage
    • Haute Normandie
      • Rouen, Haute Normandie, France, 76038
        • Centre Henri Becquerel
    • Hérault
      • Montpellier, Hérault, France, 34295
        • CHRU de Montpellier, Hôpital Saint-Eloi
    • Ile De France
      • Paris, Ile De France, France, 75743
        • APHP Hopital Necker
    • Ile-de-France
      • Paris, Ile-de-France, France, 75475
        • AP-HP Hopital Saint-Louis
    • Ille Et Vilaine
      • Rennes, Ille Et Vilaine, France, 35033
        • CHU de Rennes - Hôpital Pontchaillou
    • Isère
      • Grenoble, Isère, France, 38043
        • CHU Grenoble - Hopital Michallon
    • Loire Atlantique
      • Nantes, Loire Atlantique, France, 44093
        • CHU de Nantes hotel Dieu
    • Meurthe Et Moselle
      • Vandoeuvre Lès Nancy, Meurthe Et Moselle, France, 54511
        • CHU de Nancy
    • Nord Pas De Calais
      • Lille, Nord Pas De Calais, France, 59037
        • Chru de Lille Hopital Claude Huriez
    • Rhône
      • Lyon, Rhône, France, 69473
        • Centre Leon Berard
      • Pierre Bénite, Rhône, France, 69495
        • CHU Lyon Sud
    • Val De Marne
      • Créteil, Val De Marne, France, 94010
        • CHU Henri Mondor

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

INCLUSION CRITERIA:

  • Histologically confirmed follicular lymphoma relapsed (WHO grade 1, 2, 3a)
  • Patients aged from 18 to 65 years
  • First or second chemosensitive relapses after salvage therapy (rituximab-chemotherapy) based on 2007 Cheson et al. international response criteria (CR and PR) before the decision of BeEAM (HDT) and ASCT (autologous stem cell transplantation) treatment
  • Eligible for ASCT
  • Autologous graft with a minimum of a number of cluster of differentiation 34 (CD34+) cells 3.0x106/kg.
  • Autologous transplantation will be performed in hematopoietic stem cell transplantation authorized centers.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2
  • Minimum life expectancy of 3 months
  • Cardiovascular baseline corrected QT interval F ( QTcF) ≤ 450 msec (male) or 470 msec (female)
  • Medications that may cause corrected QT interval (QTc) interval prolongation should be avoided by patients entering on trial
  • Normal organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1.5 G/l
    • Platelet count ≥ 100 G/l or > 75 G/l if the bone marrow is involved
    • Creatine clearance ≥ 50 ml/min
    • Serum Glutamate Oxaloacetate Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5 x ULN if liver metastasis
    • Total bilirubin ≤ 1.5 x ULN
  • Cardiac ejection fraction greater than 50% by echocardiogram or multiple gated acquisition scan (MUGA scan)
  • Negative serum pregnancy test for women of childbearing potential*
  • Pregnancy tests will include a negative serum pregnancy test (with a sensitivity of at least 25 mill-International Unit (mIU)/ml)
  • Women of childbearing potential* and men must agree to use adequate contraception prior to study entry, for the duration of study participation and until 6 months after the end of treatment

    • Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
    • ≥ 50 years old and naturally amenorrheic for ≥ 1 year
    • Permanent premature ovarian failure confirmed by a specialist gynecologist
    • Previous bilateral oophorectomy
    • XY genotype, Turner's syndrome or uterine agenesis
    • Female patients who do not meet at least of the above criteria are defined as women of childbearing potential
  • Ability to understand and willingness to sign a written informed consent document
  • Covered by a medical insurance
  • Signed informed consent

EXCLUSION CRITERIA:

  • Transformed follicular lymphoma
  • Prior autologous or allogeneic transplantation
  • Presence of a none chemosensitive disease before HDT according to 2007 Cheson et al. international response criteria (stable or progressive disease)
  • Contraindication to any drug contained in the chemotherapy regimens
  • Bone marrow infiltration > 25% before HDT+ASCT
  • Positive HIV, Hepatitis C Virus (HCV) and Hepatitis B (HBs)Ag serologies
  • Current bacterial, viral or fungal infection
  • Treatment with any investigational drug within 30 days before enrolment
  • Major surgery within 30 days before enrolment
  • Participation in another clinical trial within 30 days prior to enrolment in the study and during study
  • Any serious active disease or co-morbid medical conditions that would interfere with therapy
  • Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 5 years
  • Known or suspected hypersensitivity to any of the agents or excipients of the regime under evaluation
  • Concomitant treatment with chemotherapy or immunotherapy or radiotherapy
  • Yellow fever vaccination (attenuated virus vaccine )
  • Pregnant or lactating female
  • Abnormalities in cardiac function or clinically significant heart disease such as acute myocardial infarction or unstable angina within 6 months prior to the start of study treatment, heart failure New York Heart Association (NYHA) class III or IV, uncontrolled hypertension or a history of antihypertensive treatment poor compliance, uncontrolled arrhythmias with treatment, except extrasystoles or minor conduction disorders
  • Known involvement of the central nervous system by lymphoma
  • History of chronic liver disease
  • History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
  • Excessive alcohol use

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: BeEAM

High Dose Chemotherapy (HDT) containing :

  • Bendamustine
  • Etoposide
  • Cytarabine
  • Melphalan

HDT will be followed by an Autologous Stem Cell Transplantation

High Dose Chemotherapy (HDT) containing :

  • Bendamustine 160 mg/m2 for 2 days (D-8 and D-7)
  • Etoposide 200 mg/m2 and Cytarabine 400 mg/m2 for 4 days (D-6 to D-3)
  • Melphalan 140 mg/m2 on D-2

HDT will be followed by an Autologous Stem Cell Transplantation on D0

Other Names:
  • Cytarabine
  • Etoposide
  • Melphalan
  • Bendamustine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event Free Survival rate (EFS)
Time Frame: Evaluated by the time from inclusion to the time of event appearance with a time of observation of 2 years after inclusion
EFS will be measured from the date of inclusion to the date of event defined as : death due to any cause, relapse/progression, or changes in therapies. Patients with no event at the time of analysis will be censored at the date of the last contact
Evaluated by the time from inclusion to the time of event appearance with a time of observation of 2 years after inclusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety profile of BeEAM
Time Frame: Evaluated all along the 4 years study follow up for each patient
The safety analyzable population include all patients who received at least one dose of BeEAM regimen
Evaluated all along the 4 years study follow up for each patient
Overall Response Rate (ORR) according to Cheson at al. 2007
Time Frame: Evaluated at day 100 after graft

ORR is defined by the rate of patients in Complete Response (CR) and in Partial Response (PR) at time of evaluation.

ORR is assessed according to Cheson et al. 2007 criteria

Evaluated at day 100 after graft
Overall Response Rate (ORR) according to Cheson et al. 1999
Time Frame: Evaluated at day 100 after graft

ORR is defined by the rate of patients in Complete Response (CR) and in Partial Response (PR) at time of evaluation.

ORR assessed according to Cheson et al. 1999 criteria

Evaluated at day 100 after graft
Progression Free Survival (PFS)
Time Frame: Evaluated by the time from inclusion to the time of progression with a study duration of 5 years maximum

PFS will be measured from the date of inclusion to the date of event defined as : progression/relapse or death due to any cause. Patients with no event at the time of analysis will be censored at the date of the last contact.

PFS will be assessed among all included patients and in the subgroup of complete responders at the beginning of HDT.

Evaluated by the time from inclusion to the time of progression with a study duration of 5 years maximum
Overall Survival (OS)
Time Frame: Evaluated by the time from inclusion to the time of death with a study duration of 5 years maximum
OS will be measured from the date of inclusion to the date of death due to any cause and will be censored at the date of last contact for the patients alive at last contact
Evaluated by the time from inclusion to the time of death with a study duration of 5 years maximum

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Hervé Ghesquières, Dr, Centre Léon Bérard, Lyon

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 9, 2014

Primary Completion (Actual)

July 12, 2018

Study Completion (Actual)

July 12, 2018

Study Registration Dates

First Submitted

December 6, 2013

First Submitted That Met QC Criteria

December 10, 2013

First Posted (Estimate)

December 11, 2013

Study Record Updates

Last Update Posted (Actual)

January 8, 2019

Last Update Submitted That Met QC Criteria

January 4, 2019

Last Verified

January 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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