Lenalidomide, Rituximab, Cyclophosphamide, and Dexamethasone in Treating Patients With Previously Untreated Low-Grade Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer 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 cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with rituximab, cyclophosphamide, and dexamethasone may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving lenalidomide together with rituximab, cyclophosphamide, and dexamethasone works in treating patients with previously untreated low-grade non-Hodgkin lymphoma.

Detailed Description
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OBJECTIVES: Primary To assess tumor response to lenalidomide, rituximab, cyclophosphamide, and dexamethasone in patients with symptomatic previously untreated low-grade non-Hodgkin lymphoma. Secondary To describe the adverse event profile of this regimen. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure associated with this regimen. To estimate tumor response to lenalidomide, rituximab, cyclophosphamide and dexamethasone in the subgroup of patients with lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia). OUTLINE: This is a multicenter study. Patients receive oral lenalidomide once daily on days 1-21, rituximab IV on day 1, oral cyclophosphamide once daily on days 1, 8, and 15, and oral dexamethasone once daily on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months for 5 years.

Official Title
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A Phase 2 Study of Lenalidomide, Rituximab, Cyclophosphamide and Dexamethasone (LR-CD) for Untreated Low Grade Non-Hodgkin Lymphoma Requiring Therapy

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: dexamethasone
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed symptomatic non-Hodgkin lymphoma by biopsy within the past 6 months Any of the following subtypes allowed: Grade 1 or 2 lymphoma Small lymphocytic lymphoma Marginal zone lymphoma Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]) Previously untreated disease that, in the investigator's opinion, requires treatment Measurable disease by CT or MRI scans with lymph nodes ≥ 2.0 cm in ≥ 1 dimension WM patients without lymphadenopathy must meet the following criteria: More than 10% lymphocytes, lymphoplasmacytic cells, or plasma cells on a bone marrow aspirate/biopsy Quantitative Immunoglobulin M ≥ 400 mg/dL NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of indolent or aggressive lymphoma will replace the former terminology of low, intermediate, or high grade lymphoma. However, this protocol uses the former terminology. PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,400/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine ≤ 2.0 mg/dL Total or direct bilirubin ≤ 1.5 mg/dL AST and ALT ≤ 2 times upper limit of normal (ULN) (5 times ULN if hepatic metastases are present) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception at least 28 days prior to, during, and for 28 days after completion of study therapy Able to take acetylsalicylic acid (ASA) 325 mg/day as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) No known hypersensitivity to thalidomide No development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would limit compliance with study requirements No myocardial infarction within the past 6 months No other active malignancy requiring treatment, except for localized nonmelanomatous skin cancer or any cancer that, in the judgement of the investigator, has been treated with curative intent and will not interfere with the study treatment plan and response assessment No co-morbid systemic illnesses or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into the study or would interfere significantly with the proper assessment of safety and toxicity of study treatment No known positivity for HIV or infectious hepatitis A, B, or C No serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent Willing to return to Mayo Clinic enrolling institution for follow up Registered into the RevAssist® program and willing and able to comply with the requirements of RevAssist® PRIOR CONCURRENT THERAPY: No prior lenalidomide No prior irradiation to ≥ 25% of the bone marrow More than 28 days since prior experimental drug or therapy No concurrent radiotherapy, chemotherapy, or immunotherapy No other concurrent anticancer agents or treatments, including thalidomide or investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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<br>Participants with symptomatic untreated low grade NHL will be treated according to a 28 day schedule for up to a maximum of 12 consecutive cycles: 375 mg/m^2 Rituximab IV on day 1. 20 mg Lenalidomide taken orally on days 1-21. 250 mg/m^2 Cyclophosphamide orally on days 1, 8, 15. 40 mg Dexamethasone orally on days 1, 8, 15, 22. | Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: dexamethasone<br> <br> Drug: lenalidomide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Tumor Response | The proportion of responses was determined by counting the number of complete responses and partial responses and dividing by the number of evaluable patients. Complete Response (CR): Disappearance of all evidence of disease and disease-related symptoms. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. Partial Response (PR): At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. No new sites of disease should be observed. | Up to 1 year from registration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response to Lenalidomide, Rituximab, Cyclophosphamide and Dexamethasone in the Subgroup of Patients With Lymphoplasmacytic Lymphoma (Waldenstrom's Macroglobulinemia). | The proportion of responses in Waldenstrom's macroglobulinemia was determined by counting the number of complete responses and partial responses and dividing by the number of evaluable patients. Complete Response (CR): Disappearance of all evidence of disease and disease-related symptoms. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. Partial Response (PR): At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. No new sites of disease should be observed. | Up to 1 year from registration. | 
| Survival Time | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Up to 1 year from registration. | 
| Progression-free Survival Time | Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. Progressive disease is defined as having one of the following: The appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size. At least a 50% increase from nadir in the sum of the product of the dimension (SPD) of any previously involved nodes. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis. | Up to 1 year from registration. | 
| Time to Treatment Failure | Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier. | Up to 1 year from registration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I grade 1 follicular lymphoma, contiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, stage III grade 1 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage I grade 2 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, stage III grade 2 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage I small lymphocytic lymphoma, contiguous stage II small lymphocytic lymphoma, noncontiguous stage II small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, Waldenstrom macroglobulinemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, stage I marginal zone lymphoma, contiguous stage II marginal zone lymphoma, noncontiguous stage II marginal zone lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma