Bendamustine and Rituximab for the Treatment of Splenic Marginal Zone Lymphoma

NCT ID: NCT02853370

Last Updated: 2023-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2020-12-31

Brief Summary

Splenic Marginal Zone Lymphoma (SMZL) is a well-defined low-grade B-cell lymphoma,considered as a rare neoplasm accounting for about 2% of all non-Hodgkin's lymphomas (NHL) and represents for most cases of otherwise unclassifiable chronic lymphoid B-cell cluster of differentiation antigen 5 (CD5)-lymphoproliferative disorders. SMZL is characterized by an almost exclusive involvement of the spleen and bone marrow and in about 25% of cases the disease pursues an aggressive course and most patients die of lymphoma progression within 3-4 years.

Retrospective studies have indicated that purine analogous achieved very high response rates in both naïve and pre-treated patients. Moreover, the introduction of the anti-cluster of differentiation antigen 20 (CD20) humanized antibody rituximab, either used alone or in combination with chemotherapy has been reported to be very effective in producing a rapid clearance of neoplastic cells.

Detailed Description

Prospective, multicenter, open-label, phase II study, designed to determine efficacy and safety of a Chemo-immunotherapy with the combination of bendamustine + rituximab in patients with splenic marginal zone lymphoma.

Study Population: previously untreated (except for splenectomy and/or antiviral therapy for Hepatitis C Virus (HCV) infection) and symptomatic Splenic Marginal Zone patients.

Objectives: evaluation of the efficacy and the safety of R-Bendamustine in symptomatic Splenic Marginal Zone Lymphoma patients.

Primary Objective: efficacy of R-Bendamustine measured by Complete Response rate. Complete response rate defined as regression to normal size on CT of organomegaly (spleen, liver, lymph nodes); normalization of the blood counts and no evidence of circulating clonal cells, and no evidence or minor (≤ 5%) Bone Marrow (BM) infiltration detected by immunohistochemistry (IHC).

Treatment: The R-Bendamustine regimen consisted of 28-day cycle. Patients achieving a complete response (CR) after 3 cycles received only one more cycle of R-Bendamustine, while those achieving a partial response (PR) received 3 additional cycles of R-Bendamustine; if less than PR patients were withdrawn from the study

Conditions

Marginal Zone B-cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bendamustine and Rituximab

Induction Phase (Cycle 1 to Cycle 3 ):

Bendamustine 90 mg/sqm i.v. d1 & d2* Rituximab 375 mg/m2 i.v. d1**

Extended Phase (Cycle 4 to Cycle 6):

Bendamustine 90 mg/sqm i.v. d1 & d2* Rituximab 375 mg/m2 i.v. d1

From Cycle 4 to Cycle 6, every 4 weeks, depending on the response after the first 3 Cycles

*Or days 2-3 according to institutional/patient/physician preference

**Administration of Rituximab during cycle 1 and cycle 2 can be postponed to day 8 or 14 in case of risk of tumor lysis syndrome (TLS)

Group Type: EXPERIMENTAL

Bendamustine and Rituximab

Intervention Type: DRUG

Interventions

Bendamustine and Rituximab

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Initial diagnosis of CD20+ Splenic Marginal Zone Lymphoma morphology confirmed by histology, cytology, immunophenotype (chromosomal abnormalities by quantitative multiplex Polymerase Chain Reaction (PCR) of short fluorescent fragments (QMPSF) is optional) according to World Health Organization (WHO) 2008 classification of Lymphoma criteria or according to the recommendation of the Splenic Lymphoma Group for non splenectomized patient.

1. If patients not splenectomised: diagnosis on bone marrow biopsy (histology and immunohistochemistry), and blood (cytology, immunophenotype), chromosomal abnormalities by QMPSF optional.

2. If patients splenectomised diagnosis on spleen, bone marrow biopsy (histology and immunohistochemistry), and blood (cytology, immunophenotype) chromosomal abnormalities by QMPSF optional.

• No previous treatment with immunotherapy or chemotherapy or radiotherapy unless pretreatment by mono corticotherapy.
• Patients requiring a treatment with at least one of the following situation:

1. Symptomatic SMZL in not splenectomized patients

1. Bulky (arbitrarily defined as ≥6 cm below left costal margin) or progressive or painful splenomegaly, without enlarged lymphoadenopathy, with or without cytopenia, not eligible for splenectomy or not willing splenectomy

2. One of the following symptomatic/progressive cytopenias: Hb <10 g/dL, or Plat <80.000/mm3, or ANC <1.000/mm3, whatever the reason (autoimmune or hypersplenism or bone marrow infiltration) not eligible for splenectomy or not willing splenectomy

3. SMZL with enlarged lymphoadenopathy or involvement of extranodal sites with or without cytopenia

2. Symptomatic disease in SMZL splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites.

3. SMZL with concomitant hepatitis C infection who have not responded or are relapsed after Interferon and/or Ribavirin.

• Clinically and/or radiologically confirmed measurable disease before treatment start.
• Aged ≥ 18 yo at time of initial diagnosis and ≤ 80 yo.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Minimum life expectancy of >6 months.
• Voluntary signed informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• The following laboratory values at screening:

1. Absolute neutrophil count (ANC) ≥1.000/mm3 and Platelets ≥100.000/mm3, unless these abnormalities are related to bone marrow infiltration or to hypersplenism.

2. Aspartate transaminase (AST) ≤2 x upper limit of normal (ULN); Alanine transaminase (ALT) ≤2 x ULN; total bilirubin ≤1.5 x ULN.

3. Creatinine clearance ≥ 10 ml/min (as calculated by the Cockcroft-Gault formula)

All patients must:

1. Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy.

2. Agree not to share study medication with another person.

3. Agree to use an adequate method of contraception for women of childbearing potential during the study treatment and until 12 months after the end of the study treatment.

4. Agree to use an adequate method of contraception for men during the study treatment and until 6 months after the end of the study treatment

Exclusion Criteria

1. Any type of lymphoma other than SMZL.

2. Patients with proven biopsy of histological transformation.

3. Contraindication to any drug contained in the chemotherapy regimen.

4. Myocardial infarction during last 3 months or unstable coronary disease or uncontrolled chronic symptomatic congestive heart insufficiency NYHA III - IV.

5. Uncontrolled hypertension.

6. Uncontrolled diabetes mellitus as defined by the investigator.

7. Active systemic infection requiring treatment.

8. Previously known HIV positive serology.

9. Active hepatitis B virus infection (presence of antigen HBS+; in case of presence of antibody anti HBC+ and anti HBS+, controls should be organized according to guidelines of AASLD and l'EASL).

10. Active and previously untreated HCV infection.

11. Prior history of malignancies other than lymphoma within 3 years (except for complete resection of basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy). Patients previously diagnosed with prostate cancer are eligible if (1) their disease was T1-T2a, N0, M0, with a Gleason score </=7, and a prostate specific antigen(PSA) </=10 ng/mL prior to initial therapy, (2) they had definitive curative therapy (ie, prostatectomy or radiotherapy) >/=2 years before Day 1 of Cycle 1, and (3) at a minimum 2 years following therapy they had no clinical evidence of prostate cancer, and their PSA was undetectable if they underwent prostatectomy or <1 ng/mL if they did not undergo prostatectomy.

12. Major surgery within 30 days before the inclusion in the study

13. A positive Coombs test without haemolysis or an autoimmune hemolytic anemia is not an exclusion criterion.

14. Impaired renal function with creatinine clearance <10 ml/min.

15. Severe chronic obstructive pulmonary disease with hypoxemia.

16. Medical condition requiring long-term use (>1 months) of systemic corticosteroids.

17. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

18. Prior participation in another study with experimental drug during the last 4 months.

19. Pregnant or currently breast-feeding woman.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Extranodal Lymphoma Study Group (IELSG)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emilio Iannitto, MD

Role: STUDY_CHAIR

Presidio ospedaliero G. Moscati; UOC di Ematologia - Taranto

Locations

Créteil (Hôpital Henri Mondor)

Créteil, , France

Dijon (CHU de Dijon - Hôpital d'Enfants)

Dijon, , France

Grenoble cedex 9 (CHU Michallon)

Grenoble, , France

Le Kremlin Bicêtre (Hôpital Bicêtre)

Le Kremlin-Bicêtre, , France

Le Mans (C.H. Le Mans)

Le Mans, , France

Lille cedex (CHRU Lille - Hôpital Claude Huriez)

Lille, , France

Pierre Bénite

Lyon Sud, , France

Vandoeuvre-les-Nancy cedex (CHU Brabois)

Nancy, , France

Nantes cedex 01 (CHU de Nantes - Hôtel Dieu)

Nantes, , France

Paris cedex 10 (Hôpital Saint-Louis)

Paris, , France

Pessac cedex (Centre François Magendie)

Pessac, , France

Rouen (Centre Henri Becquerel)

Rouen, , France

Ospedale Civile Ss. Antonio E Biagio

Alessandria, , Italy

A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona

Ancona, , Italy

Ospedale Armando Businco

Cagliari, , Italy

A.O. Universitaria S. Martino Di Genova

Genova, , Italy

Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Sede Di Meldola (Fc)

Meldola, , Italy

Irccs Fondazione Centro S. Raffaele Del Monte Tabor

Milan, , Italy

A.O. Universitaria Policlinico Di Modena

Modena, , Italy

A.O. "V. Cervello"

Palermo, , Italy

A.O. Universitaria Policlinico Giaccone

Palermo, , Italy

A.O. Universitaria Di Parma

Parma, , Italy

Ausl Di Piacenza

Piacenza, , Italy

Ospedale S. Maria Delle Croci Di Di Ravenna

Ravenna, , Italy

Ospedale Bianchi - Melacrino - Morelli

Reggio Calabria, , Italy

Ospedale Di S. Maria Nuova-Irccs

Reggio Emilia, , Italy

Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob)

Rionero Sannitico, , Italy

Irccs Istituto Dermatologico S. Gallicano (Ifo)

Roma, , Italy

Azienda Ospedaliera "S. Maria"

Terni, , Italy

Ospedale Di Circolo E Fondazione Macchi

Varese, , Italy

Countries

France; Italy

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IELSG 36

Identifier Type: -

Identifier Source: org_study_id