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

Sponsor

Centre Leon Berard (Other)

Overall Status

Terminated

CT.gov ID

NCT02008006

Collaborator

(none)

Enrollment

Locations

Arm

48.1

Actual Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma	Drug: BeEAM	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 9, 2014

Actual Primary Completion Date :

Jul 12, 2018

Actual Study Completion Date :

Jul 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BeEAM High Dose Chemotherapy (HDT) containing : Bendamustine Etoposide Cytarabine Melphalan HDT will be followed by an Autologous Stem Cell Transplantation	Drug: BeEAM 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: Bendamustine Etoposide Cytarabine Melphalan

Arm

Intervention/Treatment

Experimental: BeEAM

High Dose Chemotherapy (HDT) containing : Bendamustine Etoposide Cytarabine Melphalan HDT will be followed by an Autologous Stem Cell Transplantation

Drug: BeEAM

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:

Bendamustine

Etoposide

Cytarabine

Melphalan

Outcome Measures

Primary Outcome Measures

Event Free Survival rate (EFS) [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

Secondary Outcome Measures

Safety profile of BeEAM [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
Overall Response Rate (ORR) according to Cheson at al. 2007 [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
Overall Response Rate (ORR) according to Cheson et al. 1999 [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
Progression Free Survival (PFS) [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.
Overall Survival (OS) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHU de Dijon - Hôpital Le Bocage	Dijon	Côte d'Or	France	21000
2	Centre Henri Becquerel	Rouen	Haute Normandie	France	76038
3	CHRU de Montpellier, Hôpital Saint-Eloi	Montpellier	Hérault	France	34295
4	APHP Hôpital Necker	Paris	Ile De France	France	75743
5	AP-HP Hôpital Saint-Louis	Paris	Ile-de-France	France	75475
6	CHU de Rennes - Hôpital Pontchaillou	Rennes	Ille Et Vilaine	France	35033
7	CHU Grenoble - Hôpital Michallon	Grenoble	Isère	France	38043
8	CHU de Nantes Hôtel Dieu	Nantes	Loire Atlantique	France	44093
9	CHU de Nancy	Vandoeuvre Lès Nancy	Meurthe Et Moselle	France	54511
10	CHRU de Lille Hôpital Claude Huriez	Lille	Nord Pas De Calais	France	59037
11	Centre Léon Bérard	Lyon	Rhône	France	69473
12	CHU Lyon Sud	Pierre Bénite	Rhône	France	69495
13	CHU Henri Mondor	Créteil	Val De Marne	France	94010