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

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.

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