Follicular Lymphoma
Conditions
Keywords
Follicular Lymphoma, Chemosensitive relapse, High Dose Chemotherapy, Bendamustine, BeEAM, Autologous Stem Cell Transplantation, Safety, Event Free Survival, Overall Response Rate, Progression Free Survival, Overall Survival, Phase II, World Health Organization (WHO) 1 grade, WHO 2 grade, WHO 3a grade
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).
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.
Interventions
DRUGBeEAM
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
Sponsors
Centre Leon Berard
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
France
Outcome results
None listed