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

Follicular Lymphoma Clinical Trial

— BENEFIT  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02008006
• Other study ID #: BENEFIT
• Secondary ID: 2013-000076-16
• Status: Terminated
• Phase: Phase 2
• Start date: July 9, 2014
• Est. completion date: July 12, 2018

Study information

• Verified date: January 2019
• Source: Centre Leon Berard
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 21
• Est. completion date: July 12, 2018
• Est. primary completion date: July 12, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

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

Locations

Country	Name	City	State
France	CHU Henri Mondor	Créteil	Val De Marne
France	CHU de Dijon - Hôpital Le Bocage	Dijon	Côte d'Or
France	CHU Grenoble - Hôpital Michallon	Grenoble	Isère
France	CHRU de Lille Hôpital Claude Huriez	Lille	Nord Pas De Calais
France	Centre Léon Bérard	Lyon	Rhône
France	CHRU de Montpellier, Hôpital Saint-Eloi	Montpellier	Hérault
France	CHU de Nantes Hôtel Dieu	Nantes	Loire Atlantique
France	AP-HP Hôpital Saint-Louis	Paris	Ile-de-France
France	APHP Hôpital Necker	Paris	Ile De France
France	CHU Lyon Sud	Pierre Bénite	Rhône
France	CHU de Rennes - Hôpital Pontchaillou	Rennes	Ille Et Vilaine
France	Centre Henri Becquerel	Rouen	Haute Normandie
France	CHU de Nancy	Vandoeuvre Lès Nancy	Meurthe Et Moselle

Sponsors (1)

Lead Sponsor	Collaborator
Centre Leon Berard

Country where clinical trial is conducted

France, 

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* Note: There are 55 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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