Bendamustine and Rituximab for the Treatment of Splenic Marginal Zone Lymphoma

Phase 2

Completed

• Conditions: Marginal Zone B-cell Lymphoma
• Interventions: Drug: Bendamustine and Rituximab

• Registration Number: NCT02853370
• Lead Sponsor: International Extranodal Lymphoma Study Group (IELSG)

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those achieving a partial response (PR) received 3 additional cycles of R-Bendamustine; if less than PR patients were withdrawn from the study

Study Timeline

• Study Start: 2012-07
• Study First Submitted: 2016-07-26
• Study First Submitted QC: 2016-07-28
• Study First Posted: 2016-08-02
• Primary Completion: 2020-12
• Study Completion: 2020-12
• Results First Submitted: 2022-02-03
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-03
• Last Update Submitted: 2022-05-03
• Results First Posted: 2023-02-01
• Last Update Posted: 2023-02-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 78

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bendamustine and Rituximab	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)

Primary Outcome Measures

Name	Time	Method
Complete Response Rate (CRR)	At the end of treatment (After 24 weeks of treatment)	Percentage of patients with complete response. Complete response to be assessed by means of CT-scan, Immunophenotype in blood and bone marrow (PET-scan optional) Complete response (CR) requires the disappearance of all evidence of disease; 1. Regression to normal size on CT of organomegaly (splenomegaly, hepatomegaly and lymphoadenopathies); 2. Normalization of the blood counts (Hb \>12 g/dl; platelets \>100.000/mm3; neutrophils \>1.500/mm3 and no evidence of circulating clonal B-cells); 3. No evidence or minor (\<5%) BM infiltration detected by immunohistochemistry

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	At the end of treatment (After 24 weeks of treatment)	Percentage of patients with complete and partial response. Partial response (PR) requires regression of 50% or greater in the measurable disease manifestations and no new sites of disease.; This should include: resolution or decrease in spleen size, improvement on cytopenias and resolution or decrease in lymphadenopathy if present. Bone Marrow should show a decrease in the level of lymphoid infiltration and improvement of the haemopoietic reserve
3-year Progression Free Survival (PFS)	3 years after study entry	Percentage of patients free from disease progression after 3 years from study entry.; Progression is defined as reappearance of cytopenia or lymphoma relapse/ progression with enlarged lymph node(s) or spleen if present, histologic transformation or death as a result of any cause.
3-years Duration of Response (DOR)	3 years from study entry	Percentage of responding patients after 3 years from study entry. DOR is defined for all patients who achieved a response (CR and PR)
3-years Event Free Survival (EFS)	3 years after study entry	Percentage of patients free from events after 3 years from study entry. Events are defined as any treatment failure including disease progression, or discontinuation of treatment for any cause (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death).
3-years Overall Survival Rate	3 years after treatment start	Percentage of patients alive after 3 years from study entry
5 Years Progression Free Survival (PFS) -	Five years after study entry	Percentage of patients free from disease progression after 5 years from treatment start. Progression is defined as reappearance of cytopenia or lymphoma relapse/ progression with enlarged lymph node(s) or spleen if present, histologic transformation or death as a result of any cause.
5 Years Overall Survival (OS)	Five years after study entry	Percentage of patients alive after 5 years from study entry

Trial Locations

Locations (30)

Vandoeuvre-les-Nancy cedex (CHU Brabois); 🇫🇷 Nancy, France

A.O. Universitaria S. Martino Di Genova; 🇮🇹 Genova, Italy

Irccs Fondazione Centro S. Raffaele Del Monte Tabor; 🇮🇹 Milano, Italy

A.O. Universitaria Policlinico Di Modena; 🇮🇹 Modena, Italy

A.O. Universitaria Policlinico Giaccone; 🇮🇹 Palermo, Italy

Irccs Istituto Dermatologico S. Gallicano (Ifo); 🇮🇹 Roma, Italy

Ospedale Bianchi - Melacrino - Morelli; 🇮🇹 Reggio Calabria, Italy

Azienda Ospedaliera "S. Maria"; 🇮🇹 Terni, Italy

Créteil (Hôpital Henri Mondor); 🇫🇷 Creteil, France

Dijon (CHU de Dijon - Hôpital d'Enfants); 🇫🇷 Dijon, France

Le Kremlin Bicêtre (Hôpital Bicêtre); 🇫🇷 Le Kremlin Bicetre, France

Rouen (Centre Henri Becquerel); 🇫🇷 Rouen, France

Ospedale Civile Ss. Antonio E Biagio; 🇮🇹 Alessandria, Italy

Nantes cedex 01 (CHU de Nantes - Hôtel Dieu); 🇫🇷 Nantes, France

Pessac cedex (Centre François Magendie); 🇫🇷 Pessac, France

Grenoble cedex 9 (CHU Michallon); 🇫🇷 Grenoble, France

Paris cedex 10 (Hôpital Saint-Louis); 🇫🇷 Paris, France

Le Mans (C.H. Le Mans); 🇫🇷 Le Mans, France

A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona; 🇮🇹 Ancona, Italy

A.O. "V. Cervello"; 🇮🇹 Palermo, Italy

Ospedale S. Maria Delle Croci Di Di Ravenna; 🇮🇹 Ravenna, Italy

Lille cedex (CHRU Lille - Hôpital Claude Huriez); 🇫🇷 Lille, France

Pierre Bénite; 🇫🇷 Lyon Sud, France

Ospedale Armando Businco; 🇮🇹 Cagliari, Italy

Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Sede Di Meldola (Fc); 🇮🇹 Meldola, Italy

Ausl Di Piacenza; 🇮🇹 Piacenza, Italy

A.O. Universitaria Di Parma; 🇮🇹 Parma, Italy

Ospedale Di S. Maria Nuova-Irccs; 🇮🇹 Reggio Emilia, Italy

Irccs Centro Di Riferimento Oncologico Di Basilicata (Crob); 🇮🇹 Rionero, Italy

Ospedale Di Circolo E Fondazione Macchi; 🇮🇹 Varese, Italy