Combination Therapy Using Lenalidomide (Revlimid)- Low Dose Dexamethasone and Rituximab for Treatment of Rituximab-Resistant, Non-Aggressive B-Cell Lymphomas

Study Overview
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Brief Summary
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Pre-clinical data and recently published clinical data suggest a synergistic effect between lenalidomide and dexamethasone. We hypothesize that a combination of lenalidomide-dexamethasone can overcome rituximab resistance. To determine the response rate to lenalidomide and dexamethasone plus rituximab therapy in subjects with recurrent small B-cell non-Hodgkin lymphoma who have had lymphoma progression within 6 months of being treated with rituximab alone or with a rituximab-containing regimen, we propose initial treatment with both drugs for two 28-day treatment cycles (Part I). After response assessment following two cycles of lenalidomide-dexamethasone, patients will enter Part II of the study. In Part II, patients will receive lenalidomide-dexamethasone and rituximab to evaluate the potential reversal of rituximab resistance as measured by response to rituximab and progression-free survival following rituximab.

Official Title
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Phase 2 Trial of Lenalidomide (Revlimid)-Dexamethasone + Rituximab in Recurrent Small B-Cell Non-Hodgkin Lymphomas (NHL) Resistant to Rituximab

Conditions
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Follicular Lymphoma, Marginal Zone B-Cell Lymphoma, MALT Lymphoma, Lymphoma of Mucosa-Associated Lymphoid Tissue, Lymphoma, Small Lymphocytic, Waldenstrom Macroglobulinemia, Mantle-Cell Lymphoma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated, histologically confirmed follicular lymphoma (grade 1, 2, 3a), marginal zone lymphoma, small lymphocytic lymphoma with less than <5000 lymphocytes/mm3 or lymphoplasmacytic lymphoma with <3g/mL IgM, mantle cell lymphoma by WHO classification Flow cytometry or immunohistochemistry must document CD20 antigen expression. Past documentation of CD20 antigen expression is admissible. Subjects must have been treated with rituximab in combination with chemotherapy or as monotherapy and must have refractory or progressive disease <6 months from the first rituximab dose of previous rituximab containing regimen At least 18 years of age ECOG performance status 0-2 Measurable disease must be present on physical examination or imaging studies. Any tumor mass >2cm is considered measurable. Lesions that are considered non-measurable, but assessable include the following: bone lesions, ascites, pleural/pericardial effusion, lymphangitis cutis/pulmonis, bone marrow Patients with a history of intravenous drug abuse or any behavior associated with increased risk of HIV infection should be tested for exposure to the HIV virus Understand and voluntarily sign an informed consent Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant of ASA may use warfarin or low molecular weight heparin) Laboratory test results within these ranges: absolute neutrophil count greater than or equal to 1500/mm3; platelet count greater than or equal to 75,000/mm3; serum creatinine less than or equal to 2.0mg/dL; total bilirubin less than or equal to 1.5mg/dL (unless due to Gilbert's syndrome); AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN or less than or equal to 5 x ULN if hepatic metastases are present Disease free of prior malignancies for greater than or equal to 5 years with the exception of currently treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from following study procedure Pregnant or breast-feeding females Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study Use of any other experimental drug or therapy within 28 days of baseline Known hypersensitivity to thalidomide The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs Any prior use of lenalidomide Known positivity for HIV or active infectious Hepatitis, type A, B, or C. Patients who test positive or who are known to be infected are not eligible due to an increased risk of infection with this regimen. HIV testing is not required for study entry, but is required if the patient is perceived to be at risk. Known central nervous system involvement by lymphoma

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: Lenalidomide plus rituximab with dexamethasone<br>Lenalidomide-low dose dexamethasone plus rituximab | Drug: Lenalidomide<br>* Lenalidomide: 10mg capsules, orally, once daily for each 28 day cycle for the duration of the study<br>* Other names: Revlimid (lenalidomide);Drug: Dexamethasone<br>* Dexamethasone: 8mg tablets, orally, once weekly on days 3, 10, 17, 24 of each 28 day cycle for the duration of the study;<br>* Other names: Decadron (dexamethasone);Drug: Rituximab<br>* Rituximab: 375mg/m2 IV (in the vein), once weekly on days 1, 8, 15, 22 during month 3 of therapy<br>* Other names: Rituxan (rituximab);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate to Lenalidomide-dexamethasone + Rituximab Therapy in Relapsed Small B-cell Lymphoma With Rituximab Resistance | Response rate is defined as a complete response or partial response using anatomic criteria of the International Workshop Response Critieria (Cheson, 1999). | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Until Progression After Lenalidomide-dexamethasone + Rituximab Therapy in Relapsed Small B-cell Lymphomas With Rituximab Resistance | Progression free survival time in months | 9 years from enrollment of first subject | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Revlimid, Celgene brand of lenalidomide, lenalidomide, Rituxan, CD20 antibody, rituximab, rituximab, Follicular Lymphoma, Marginal Zone B-Cell Lymphoma, Lymphoma, Small Lymphocytic, Waldenstrom Macroglobulinemia, Mantle-Cell Lymphoma, Antigens, CD20, refractory, resistantRefractory/progressive lymphoma less than 6 months from first rituximab dose of previous rituximab-containing regimen, Previously treated, Treated with rituximab