Phase II Study of Age-Adjusted Rituximab, Bendamustine, Cytarabine as Induction Therapy in Older Patients With MCL

Study Overview
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Brief Summary
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A phase 2 study of standard R-BAC (rituximab 375 mg/m2, bendamustine 70 mg/m2, ara-c 800 mg/m2) has been recently ultimated at the Vicenza Hematology Department involving several regional centers on both untreated and previously treated patients with Mantle Cell Lymphoma (MCL). An interim analysis conducted on 30 patients showed that rituximab + bendamustine + ara-c combination had very good clinical activity, but a quite relevant hematological toxicity, especially in previously treated and older patients (Visco C, ICML 2011 Lugano Conference, Poster 236). Objectives: The primary objective is to determine the activity (complete remission rate according to Cheson 2007 criteria) and safety of age-adjusted Rituximab-Bendamustine-Cytarabine (RBAC500) regimen at the end of treatment in older untreated patients with MCL. The secondary objectives are to determine: The rate of molecular response (characterized by labs of the FIL) The progression-free survival (PFS) The overall survival (OS) The duration of responses (DOR) The rate of patients that complete the expected treatment schedule (6 courses) The rate of patients that are subject to dose reductions or delays

Detailed Description
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Study End points Primary efficacy end point of the study is the proportion of CR defined according to Cheson criteria (2007) at the end of treatment (6 or 4 cycles). Primary safety end point is the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity, as above defined. Secondary end points are MRD defined response, OS, PFS and DOR (Cheson 2007). Molecular response is the proportion of patients with molecular rearrangements at baseline that become negative during treatment, measured by qualitative and quantitative PCR. OS is measured from enrollment until death from any cause. PFS is measured from the time of enrollment until disease progression, relapse or death from any cause. DOR is measured from the first assessment that documents response (CR or PR) to the date of disease relapse or progression. Minimum follow up required for all patients will be 24 months.

Official Title
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Phase II Study of Age-Adjusted R-BAC (Rituximab, Bendamustine, Cytarabine) as Induction Therapy in Older Patients With Mantle Cell Lymphoma (MCL)

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Rituximab, Bendamustine, Cytarabine.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated patients with MCL aged > 65 years if they are FIT according to the geriatric CGA assessment. age 60-65 years not eligible to high-dose chemotherapy plus transplantation, FIT or UNFIT according to the geriatric CGA assessment. ECOG performance status ≤ 2. Positivity for cyclin D1 and SOX11 [the latter being mandatory in cases lacking cyclin D1- or t(11;14)-negative], CD20 and CD5. Adequate renal function (Creatinine clearance > 40 mL/min), with preserved diuresis. Adequate liver function: alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) value, total bilirubin < 2 mg/dL, unless directly attributable to the patient's tumor. Hepatitis B core antibody (HBcAb) positive/HBsAg negative/HBV-DNA negative patients may be enrolled if correct antiviral prophylaxis is administered at least 2 weeks before initiating protocol treatment. Written informed consent. Exclusion Criteria: Human immunodeficiency virus (HIV) positive. Previous treatment for lymphoma Medical conditions or organ injuries that could interfere with administration of therapy. Active bacterial, viral, or fungal infection requiring systemic therapy. Seizure disorders requiring anticonvulsant therapy. Severe chronic obstructive pulmonary disease with hypoxemia. History of severe cardiac disease: New York Heart Association (NYHA) functional class III-IV, myocardial infarction within 6 months, ventricular tachyarrhythmias, dilatative cardiomyopathy, or unstable angina. Uncontrolled diabetes mellitus. Active secondary malignancy. Known hypersensitivity or anaphylactic reactions to murine antibodies and proteins, to Bendamustine or mannitol. Major surgery within 4 weeks of study Day 1. HBsAg+ HCVAb+ patients with active viral replication (HCV-RNA+ with AST > 2 x normal limit) Any co-existing medical or psychological condition that would preclude participation in the study or compromise the patient's ability to give informed consent, or that may affect the interpretation of the results, or render the patient at high risk from treatment complications. CNS involvement (a diagnostic lumbar puncture will be performed in patients with the blastoid variant of MCL)

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: One arm for all patients.<br>Rituximab, Bendamustine, Cytarabine | Drug: Rituximab, Bendamustine, Cytarabine.<br>* 6 cycles of 28 days with Rituximab, Bendamustine and Cytarabine (R-BAC). Rituximab 375mg/mq; Bendamustine 70mg/mq; Cytarabine 500mg/mq.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete remission rate at the end of treatment | The primary objective is to determine the activity [complete remission rate (CR) according to Cheson 2007 criteria] | 6 months | 
| Toxicity will be represented by the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity | Relevant toxicity: Grade 4 cytopenia lasting for more than 6 days or Grade 3-4 non-hematologic toxicity or Febrile neutropenia lasting for more than 3 consecutive days. Stop treatment criteria: Occurrence of relevant toxicity for two subsequent or consecutive cycles. Grade 3-4 hematological or non-hematological toxicity on day +28 of a cycle not resolving within two weeks. Grade 3-4 hematological or non-hematological toxicity on day +28 of a cycle after 25% dose reduction. Patient refusal to procede with further cycles due to perceived excessive toxicity. Any unpredictable drug related event that suggests against study continuation | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the rate of molecular response | the rate of molecular response (characterized by labs of the FIL) | 6 months | 
| the progression-free survival (PFS) | the progression-free survival (PFS)is defined as the time from enrollment to complete remission with disappearance of all evidence of disease, disease progression or relapse or death from any cause. | 30 months | 
| the overall survival (OS) | the overall survival (OS) is defined as the time from enrollment to death from any cause | 30 months | 
| the duration of responses (DOR) | the duration of responses (DOR) | 30 months | 
| the rate of completion of treatment | the rate of patients that complete the expected treatment schedule (6 courses) | 6 months | 
| the rate of dose reductions or delays | the rate of patients that are subject to dose reductions or delays | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MCL, Mantle Cell Lymphoma, Older