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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: BeEAM


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BeEAM<br>High Dose Chemotherapy (HDT) containing : Bendamustine Etoposide Cytarabine Melphalan HDT will be followed by an Autologous Stem Cell Transplantation | Drug: BeEAM<br>* 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<br>* Other names: Melphalan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival rate (EFS) | 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 | 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 | 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 | 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) | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Overall Survival, Follicular Lymphoma, Chemosensitive relapse, High Dose Chemotherapy, Bendamustine, BeEAM, Autologous Stem Cell Transplantation, Safety, Event Free Survival, Overall Response Rate, Progression Free Survival, Phase II, World Health Organization (WHO) 1 grade, WHO 2 grade, WHO 3a grade