Rituximab, Bendamustine Hydrochloride, and Lenalidomide in Treating Patients With Aggressive B-Cell Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cell-killing substances to them. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stop the growth of cancer by blocking blood flow to the tumor. Giving rituximab together with bendamustine hydrochloride and lenalidomide may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving rituximab together with bendamustine hydrochloride and lenalidomide in treating patients with aggressive B-cell lymphoma.

Detailed Description
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OBJECTIVES: Primary To determine the maximum-tolerated dose of the combination of rituximab, bendamustine hydrochloride, and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based first-line treatment or intensive regimens including high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in refractory or relapsing disease, or as treatment for patients relapsing after HDT with ASCT. (phase I). To identify the recommended dose of this regimen for a phase II study (phase I). To determine the efficacy and safety of this regimen in these patients (phase II). Secondary To assess the quality of life (QOL) of patients treated with this regimen (phase II). To evaluate the usefulness and feasibility of the SAKK Cancer-Specific Geriatric Assessment (C-SGA) in patients treated with this regimen (phase II). To assess the association between WHO performance status, QOL indicators, and SAKK C-SGA scores (phase II). To describe changes in SAKK C-SGA scores from pre- to post-treatment and in QOL (phase II). OUTLINE: This is a multicenter, phase I dose-escalation study of bendamustine hydrochloride and lenalidomide followed by a phase II study. Patients receive rituximab IV on day 1, bendamustine hydrochloride IV over 30-60 minutes on days 1-2, and oral lenalidomide on days 1-21. Courses repeat every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients on phase II study complete the SAKK Cancer-Specific Geriatric Assessment at baseline and after completion of course 1. Patients also complete quality-of-life questionnaires at baseline and periodically during study. After completion of study therapy, patients are followed for up to 2 years.

Official Title
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Rituximab, Bendamustine and Lenalidomide in Patients With Aggressive B-cell Lymphoma Not Eligible for High Dose Chemotherapy or Anthracycline-Based Therapy. A Phase I/II Trial.

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: bendamustine hydrochloride
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed aggressive B-cell non-Hodgkin lymphoma, including any of the following: Diffuse large B-cell lymphoma (variants, subgroups, and subtypes according to WHO criteria) Transformed follicular lymphoma Follicular lymphoma grade 3B Meets 1 of the following criteria: Not eligible for anthracycline-based first-line chemotherapy (e.g., R-CHOP) Refractory disease after at least 2 courses of anthracycline-based immune-chemotherapy (e.g., R-CHOP) and patient is not eligible for intensive salvage regimens including HDT with ASCT Relapsed disease after at least 1 treatment with curative intention and patient is not eligible for intensive salvage regimens including HDT with ASCT Relapsed disease after HDT with ASCT Measurable disease defined as ≥ 1 lesion ≥ 2 cm in greatest transverse diameter on cross-sectional imaging Must complete pre-treatment cancer-specific geriatric assessment and/or quality-of-life questionnaire (phase II only) No known CNS involvement Diagnostic procedures required only in case of specific symptoms PATIENT CHARACTERISTICS: WHO performance status (PS) 0-2 WHO PS 3 allowed in case of lymphoma-related impaired general condition (phase II only) ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT ≤ 2 times ULN Alkaline phosphatase 2 times ULN Creatinine clearance > 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 12 months after completion of study therapy EF ≥ 40% by echocardiography or MUGA scan Negative HIV test Able to comply with and geographic proximity to allow proper staging and study follow-up Agree to follow the special prescribing requirements for lenalidomide No other malignancy within the past 3 years except adequately treated cervical carcinoma in situ or localized nonmelanoma skin cancer No unstable cardiovascular disease No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or interfering with compliance for oral drug intake No serious underlying medical condition that, in the judgement of the investigator, could impair the ability of the patient to participate in the trial including, but not limited to, any of the following conditions: Acute or ongoing infection Uncontrolled diabetes mellitus Active autoimmune disease No known hypersensitivity to any component of the trial drugs PRIOR CONCURRENT THERAPY: See Disease Characteristics No experimental drugs within the past 30 days No concurrent drugs contraindicated with the trial drugs according to the Swissmedic-approved product information No other concurrent anticancer or investigational drugs or radiotherapy

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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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: Treatment with rituximab, bendamustine and lenalidomide<br> | Biological: rituximab<br>* day 1 at a fixed dose of 375mg/m2<br>* Other names: Rituxan;Drug: bendamustine hydrochloride<br>* Bendamustine at day 1 and 2 according to the dose escalation in phase I, and at the recommended dose in phase II: 70mg/m2.<br>* Other names: Cephalon;Drug: lenalidomide<br>* Lenalidomide at days 1-21 according to the dose escalation in phase I, and at the recommended dose in phase II: 10mg<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (phase I) |  | at 4 weeks. | 
| Maximum-tolerated dose (phase I) |  | at the end of phase I (31 August 2011) | 
| Objective response (complete and partial response) (phase II) |  | phase II (3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events according to NCI CTCAE v. 3.0 |  | All AEs will be assessed according to NCI CTCAE v3.0 until 30 days after trial therapy end. | 
| Event-free survival (phase II) |  | up to 30 months for each patient. | 
| Response duration (phase II) | From the time when criteria for response (CR/CRu or PR) are met, until documentation of relapse or progression thereafter. Only patients with a response (CR/ CRu or PR) shall be included in this analysis. Patients with no disease progression or relapse shall be censored at the last time they were known to be in remission | up to 30 months for each patient. | 
| Time to progression (phase II) | Defined as the time from registration until documented lymphoma progression or death as a result of lymphoma. Patients not experiencing an event will be censored at the last time they were known to be in remission | up to 30 months for each patient. | 
| Overall survival (phase II) |  | up to 30 months for each patient. | 
| Quality of life |  | approx. 5 months for each patient. | 
| Usefulness and feasibility of the SAKK C-SGA |  | End of phase II (excluding follow-up) at 3 years. | 
| Association between WHO performance status, QOL indicators, and SAKK C-SGA scores |  | End of phase II (excluding follow-up) at 3 years. | 
| Progression Free Survival (PFS) | Time from registration until one of the following events (whichever occurs first): Relapse or progression assessed according to the International Workshop NHL criteria (1999) Death of any cause | up to 30 months for each patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult diffuse large cell lymphoma, recurrent grade 3 follicular lymphoma