Fase II Study With BRB for Non-Hodgkin Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia's

Study Overview
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Brief Summary
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This is a prospective, multicenter phase II trial designed to determine efficacy and safety of Bortezomib plus Rituximab plus Bendamustine in patients with relapsed/refractory Waldenstrom's Macroglobulinemia.

Detailed Description
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The progression free survival (PFS) expected for lymphoplasmacytic/lymphoplasmocytoid lymphoma/Waldenstrom macroglobulinemia with the same characteristics indicated into the study and treated with standard Rituximab plus chemotherapy may be estimated to be 50% at 18 months. The Investigators would consider a positive result to increase 18 months-PFS rate from 50 to 65%.

Official Title
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Fase II Study With Bortezomib, Rituximab and Bendamustin-BRB- for Non-Hodgkin Lymphoplasmocytic Lymphoma/Waldenstrom Macroglobulinemia's Patients at First Relapse

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Bortezomib-Rituximab-Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological proven diagnosis of Lymphoplasmacytic/cytoid lymphoma/Waldenstrom macroglobulinemia according to REAL/WHO Classification Relapsed/refractory disease after receiving one line chemotherapy (rituximab). If patients received bortezomib or bendamustine and have obtained a partial response lasting at least two years. Age >= 18 Presence of at least one of the following criteria for the definition of active disease: Systemic symptoms or Hemoglobin less than 10 g/dL (due to lymphoma) or Platelets less than 100 x 109/L (due to lymphoma) or symptomatic splenomegaly or Bulky disease (>7 cm) or Hyperviscosity syndrome, peripheral neuropathy up to grade 1 (Waldenstrom's disease-related), hemolytic anemia, and immune complex vasculitis Life expectancy >6 months Eastern Cooperative Oncology Group (ECOG) performance status 0-2 left ventricular ejection fraction (LVEF) ≥45% or FS ≥37% Creatinine up to 1.5 x upper limit of normal Conjugated bilirubin up to 2 x upper limit of normal Alkaline phosphatase and transaminases up to 2 x upper limit of normal Written informed content Exclusion Criteria: Patients who received bortezomib or bendamustine first-line therapy, that or haven't obtained at least partial response nor partial response lasting at least two years. Patients not agreeing to take adequate contraceptive precautions during and for at least 6 months after cessation of therapy History of other malignancies within 3 years prior to study entry except for: adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage, localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent Medical condition requiring long term use (>1 months) of systemic corticosteroids Active bacterial, viral, or fungal infection requiring systemic therapy Peripheral neuropathy of any grade ≥ 2 [see Appendix Section A] Concurrent medical condition which might exclude administration of therapy Cardiac insufficiency (NYHA grade III/IV) Myocardial infarction within 6 months of entry on study Severe chronic obstructive pulmonary disease with hypoxemia Severe diabetes mellitus difficult to control with adequate insulin therapy Hypertension that is difficult to control Impaired renal function with creatinine clearance <30 ml/min HIV positivity HBV positivity with the exception of patients HbsAg and HBV-DNA negative and Ab anti-HB core positive (these patients need to receive prophylaxis with Lamivudine) HCV positivity with the exception of patients with HCV RNA negative Participation at the same time in another study in with investigational drugs are used Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent. Women in pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib-Rituximab-Bendamustine<br>Bortezomib-Rituximab-Bendamustine (BRB) combination in patients with relapsed/refractory lymphoplasmocytic/lymphoplasmocytoid lymphoma/Waldenstrom macroglobulinemia after one line of therapy. | Drug: Bortezomib-Rituximab-Bendamustine<br>* Bortezomib-Rituximab-Bendamustine Bortezomib: 1.3 mg/mq sc days 1, 8, 15, 22* Rituximab: 375 mg/sqm i.v. day 1** Bendamustine: 90 mg/sqm iv days 1-2 or days 2-3 according to institutional/physician choice Repeat cycles every 28 days for a total of 6 cycles *In case of toxicity is omitted **In cycles 1, in order to avoid tumor lysis syndrome, Rituximab will be given on day 8<br>* Other names: BRB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | This is a prospective, multicenter phase II trial designed to determine efficacy and safety of Bortezomib plus Rituximab plus Bendamustine in patients with relapsed/refractory Waldenstrom's Macroglobulinemia. Primary Objective is to assess whether the experimental treatment achieves an absolute increase of PFS rate from 50 to 65% at 18 months with respect to the standard treatment. PFS is measured from the beginning of therapy to the date of disease progression, relapse or death from any cause. Patients without any relapse at the end of the follow-up will be censored at their last assessment date. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate (ORR): a patient is defined as a responder if he has a complete or very good partial or partial response, evaluated in based on Waldenstrom macroglobulinemia consensus recommendations of the 6th International Workshop on Waldestrom's macroglobulinemia. | 2 years | 
| Overall Survival (OS) | Overall survival (OS): measured from the beginning of therapy to the date of death from any cause. Patients alive at the time of the final analysis will be censored at the date of the last contact. Minimum follow up time required for all patients will be 2 years. | 2 years | 
| Toxicity | Toxicity: severe, life- threatening, fatal (grade 3, 4 and 5) | 2 years | 
| Number of serious adverse events | Number of serious adverse events are defined according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 | 2 years |