Bendamustine and Rituximab Induction Therapy and Maintenance Rituximab and Lenalidomide in Previously Untreated CLL/SLL

Study Overview
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Brief Summary
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The investigators propose a treatment strategy where patients are treated with induction chemoimmunotherapy consisting of rituximab + bendamustine for 6 cycles, followed by initiation of maintenance rituximab and lenalidomide among patients achieving an objective response (i.e., at least stable disease with some tumor shrinkage) to induction therapy. The goal of maintenance therapy will be to capitalize on the cytoreduction following induction chemotherapy with a maintenance regimen that has also shown promising activity in CLL, in order to allow for improved PFS in this population.

Detailed Description
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This is a phase II single arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and rituximab followed by maintenance therapy with rituximab and lenalidomide in subjects with CLL or SLL who have not received any prior cytotoxic chemotherapy for their disease (i.e., prior single-agent rituximab is permitted). The study will be carried out at the University of Wisconsin Carbone Cancer Center (UWCCC). The subject participation will include a screening period, treatment period, and a follow-up period. The treatment period will extend from the first dose of study drug treatment (day 1, cycle 1 of induction chemoimmunotherapy) until any of the following: completion of the entire course of induction and maintenance therapy; progressive disease (PD); an unacceptable adverse event (AE); the initiation of alternate anti-neoplastic therapy; or a decision by the subject or by the investigator to discontinue treatment; or death. The induction chemoimmunotherapy regimen consists of bendamustine and rituximab for 6 cycles, followed by initiation of maintenance therapy with rituximab and lenalidomide among subjects achieving an objective response to induction therapy (i.e., complete or partial response; stable disease with objective evidence of tumor shrinkage). Subjects with objective response after 4 cycles of bendamustine + rituximab (BR) are eligible to proceed to maintenance therapy if toxicities are limiting further BR induction therapy, or if the treating physician determines that further BR induction therapy would be associated with excessive risk for additional toxicities. To minimize toxicity with induction chemotherapy, we have chosen a dose of bendamustine at 90 mg/m2/day on days 1 & 2 every 28 days for a total of 6 cycles. Rituximab will be administered at a dose of 500 mg/m2 IV on day 1 of each cycle of induction chemoimmunotherapy (375 mg/m2 cycle 1 only); however, patients at high-risk for cytokine release syndrome may receive rituximab on day 2 of induction therapy. In select circumstances in subjects at high risk for cytokine release syndrome and/or tumor lysis syndrome, rituximab may be administered as late as day 5 of cycle 1 (this alternative dosing of rituximab applies to cycle 1 of induction therapy only). Lenalidomide and rituximab maintenance will be initiated 6-12 weeks after the 6th cycle of chemotherapy, and continued for a total of 24 cycles. Maintenance therapy will continue for a maximum of 24 cycles or until unacceptable toxicity or progression of disease. Maintenance therapy will begin once there has been adequate hematologic recovery (ANC ≥1000/µL and platelets ≥50,000/µL) and other criteria as outlined in Section 7.5 have been met. Rituximab will be administered at a dose of 375 mg/m2 IV on day 1 of every odd-numbered 28 day cycle (cycles 1,3,5,7,9,11,13,15,17,19,21,23) for a maximum of 12 doses during the maintenance phase. Subjects will receive concurrent lenalidomide 5 mg orally daily on days 1-21 of cycles 1-24 (28 day cycles). If subjects do not experience adverse effects from lenalidomide, dose escalation up to 10 mg orally daily on days 1-21 of each 28 day cycle will be allowed at the start of cycle 2 or at the start of any subsequent cycle (see Section 9.2.3 and 9.2.5 for criteria required to escalate the dose of lenalidomide to 10 mg/day on days 1-21). Lenalidomide dose escalation is only allowed at the start of a new cycle to a maximum dose of 10 mg/day on days 1-21. Subjects entering maintenance with reduced renal function (i.e., creatinine clearance ≥40 but <60 mL/min) will start lenalidomide at a dose of 5 mg every other day. There is no dose modification of rituximab based on reduced renal function. Among subjects without excessive toxicity or evidence of progression, treatment with lenalidomide will continue for up to 24 cycles (cycle 1-24) and treatment with rituximab will continue for up to 12 doses (administered every odd-numbered cycle during cycles 1,3,5,7,9,11,13,15,17,19,21,23). If subjects have excessive toxicity from lenalidomide, ongoing maintenance therapy with rituximab alone is permitted after lenalidomide is discontinued. After completing 24 cycles of maintenance therapy, subjects will then be observed for evidence of PD with clinical assessments every 3 months for at least 2 years.

Official Title
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Phase II Study of Bendamustine and Rituximab Induction Chemoimmunotherapy Followed by Maintenance Rituximab and Lenalidomide in Previously Untreated Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Conditions
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Lymphoid Leukemia, Small Lymphocytic Lymphoma, Lymphoma, Non-Hodgkin

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) No prior cytotoxic chemotherapy for their disease; prior therapy with single-agent rituximab is permitted Understand and voluntarily sign an informed consent document In cases of SLL, subjects must have at least one bidimensionally measurable lesion at least >= 1.5 cm measured in one dimension Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry Absolute neutrophil count >= 1500/uL Platelet count >= 100,000/uL Subjects with neutrophils < 1500/uL or platelets < 100,000/uL with splenomegaly or extensive bone marrow involvement as the etiology for their cytopenias are eligible Subjects must have adequate renal function with a creatinine clearance of >= 40 mL/min as determined by the Cockcroft-Gault calculation Total bilirubin =< 2 x upper limit laboratory normal (ULN); subjects with non-clinically significant elevations of bilirubin due to Gilbert's disease are not required to meet these criteria Serum transaminases aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x ULN Serum alkaline phosphatase =< 5 x ULN Disease-free of prior malignancies for >= 2 years with the exception of basal or squamous cell skin carcinoma, carcinoma in situ of the breast or cervix, or localized prostate cancer (treated definitively with hormone therapy, radiotherapy, or surgery) Life expectancy of at least 3 months All study participants must be willing to be registered into the mandatory Revlimid REMS program after completion of induction chemoimmunotherapy and prior to maintenance therapy, and be willing and able to comply with the requirements of the Revlimid REMS program Subjects must not have a known history of hypersensitivity to mannitol Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory disease Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects intolerant to aspirin may use warfarin or low molecular weight heparin) if clinically indicated 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 and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be filled within 7 days as required by the Revlimid REMS® program) 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 signing the informed consent document or complying with the protocol treatment Pregnant or breast-feeding females; lactating females must agree not to breast-feed while taking lenalidomide 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 Subjects are not eligible if there is a prior history or current evidence of central nervous system or leptomeningeal involvement Known hypersensitivity to thalidomide Concurrent use of other anti-cancer agents or treatments Known to be positive for human immunodeficiency virus (HIV) or infectious hepatitis (type B or C) Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or breast cancer, or other cancer from which the subject has been disease free for at least 2 years Severe or life-threatening anaphylaxis or hypersensitivity reaction when previously exposed to rituximab or other monoclonal antibody therapy Chronic hepatitis B or hepatitis C infection New York Heart Association class 3-4 heart failure More than one grade 2 or higher transaminase elevation

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: Bendamustine, rituximab, lenalidomide<br>INDUCTION: Bendamustine 90mg/m2 IV D1&2 and rituximab IV D1 (up to day 5 of course 1) every 28 days for 6 cycles. Patients with objective response move to maintenance therapy. Patients with objective response after 4 courses are eligible to for maintenance therapy if ongoing induction therapy is associated w/unacceptable toxicity. MAINTENANCE: At 6-12 wks post induction therapy, patients receive rituximab IV on day 1 of odd-numbered cycles for 24 cycles; lenalidomide 5mg PO daily on days 1-21 of each cycle (28 day cycles). Dose escalation to 10mg daily on days 1-21 allowed at start of cycle 2 or at start of subsequent cycles in subjects w/acceptable toxicities. Lenalidomide dose escalation only allowed at start of a new cycle up to a max dose of 10 mg/day on days 1- 21. Subjects entering maintenance with CrCl ≥40 & <60mL/min will begin dosing at 5mg every other day on days 1-21. Patients with excessive toxicity from lenalidomide may continue maintenance therapy with rituximab alone. | Drug: Bendamustine<br>* Given IV<br>Drug: Rituximab<br>* Given IV<br>Drug: Lenalidomide<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | The primary objective is progression-free survival (PFS). Tumor measurements and disease assessments will be performed at the time of screening, following cycles 3 and 6 of induction chemotherapy, every 4 cycles during the maintenance portion of treatment, and at the end of treatment (EOT). Subjects with clinical evidence of progression prior to a planned disease assessment will be evaluated at the time of clinically suspected progression. Follow-up visits for disease assessment will occur every 3 months after the EOT visit until PD, initiation of alternate anti-neoplastic therapy, decision by the subject to withdraw from the study, or death. The follow-up period will begin after the EOT visit, and all subjects will be followed for at least 2 years after completion of therapy or until death or progression and until the last patient has been followed for at least 1 year following completion of therapy. | At least 24 months following completion of therapy, an average of 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates | To determine objective response rates (CR + PR). As described in the primary objective, formal disease assessments including imaging will be performed after cycles 3 and 6 of induction chemotherapy and every 4 cycles during the maintenance portion of treatment. Response and progression in cases of SLL will be evaluated using the International Working Group Criteria30 for response in lymphoma. Response and progression in cases of CLL will be evaluated in this study using the Revised IWCLL Criteria31 for response in CLL. Radiological methodologies, techniques and/or physical examination, established at baseline for the assessment and measurement of each identified lesion will be used for all subsequent assessments. | Up to 30 months | 
| Count of Events Related to Toxicity | To determine toxicities observed with induction chemotherapy and maintenance therapy. Safety evaluations will be based on the incidence, intensity, and type of adverse events (AEs) and clinical laboratory results. Drug doses will be modified as required based on toxicity as assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | Up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Small Lymphocytic Lymphoma, Lymphoid Leukemia, Bendamustine, Rituximab