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)

University of Wisconsin, Madison1 site in 1 country36 target enrollmentNovember 12, 2013

Overview

Brief Summary

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

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.

Registry

clinicaltrials.gov

Start Date

November 12, 2013

End Date

June 30, 2022

Last Updated

2 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

University of Wisconsin, Madison

Responsible Party

Sponsor

Eligibility Criteria

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

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

Arms & Interventions

Bendamustine, rituximab, lenalidomide

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.

Intervention: Bendamustine

Bendamustine, rituximab, lenalidomide

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.

Intervention: Rituximab

Bendamustine, rituximab, lenalidomide

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.

Intervention: Lenalidomide

Outcomes

Primary Outcomes

Time to Progression

Time Frame: At least 24 months following completion of therapy, an average of 5 years

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.