Lenalidomide in Comb w/Rituximab for Pts w/CD5+/CD20+ Hem Malignancies Who Relapse/Progress After Rituximab

This phase II trial will use a Simon's two stage design enrolling a total of 28 subjects.
Ten will be accrued during stage 1 and 18 during stage 2. If 3 or fewer responses (CR+PR)
are observed during the first stage then the trial is stopped early. Given that the 'true'
response probability is 30%, there is a 64.96% probability of ending the trial during stage
1. However, if the 'true' response probability is 60% then there is a 5.48% probability that
the trial will be stopped in stage 1. If more than 3 responses are observed in stage 1,
another 18 patients will be accrued in stage 2. If 12 or fewer responses are observed by the
end of the trial, then no further investigation of the drug is warranted. Otherwise,
conclude that the drug is worthy of further investigation. The alpha level of the design is
0.04 and the power is 0.91.

Patients with confirmed CD5+/CD20+ MCL or CLL who have relapsed or progressed after
Rituximab therapy following a minimum of 6 months duration of response (SD, PR, or CR as
defined by Appendix D) will be eligible for this study. Baseline evaluation of patients
prior to enrollment in this study will include complete blood counts (CBCs), serum
chemistries, liver function tests, kidney function tests, lactate dehydrogenase (LDH); and
CT scans of the chest, abdomen and pelvis; and bone marrow biopsy. The exact values for the
status of organ function allowable on this protocol are included in the body of this
document. Bone marrow aspirates, biopsies and standard FISH evaluation for specific
cytogenetic abnormalities will be obtained by the clinical site. An adequate bone marrow
aspirate sample is required for a subject to be eligible to participate in this study. All
assessments will be completed according to Schedule of Study Assessments.

Patients who meet eligibility criteria and have signed the informed consents will have
further laboratory evaluation which will involve flow cytometry of the peripheral blood to
evaluate: 1) CD20 density on the leukemic cells (CLL patients only), 2) the percentage of
CD56+ cells to evaluate the baseline level of natural killer (NK) cell, 3) the density of
activation antigens (CD2, CD11a, CD31, CD38, and CD69) on CD56+ cells, and 4) CD38 (ZAP-70)
expression. Pretreatment serum baseline values for Interferon-alpha (IFN-alpha), Tumor
necrosis factor-alpha (TNF-A), granulocyte-macrophage colony-stimulating factor (GM-CSF),
IL-6, and soluble IL-2 receptor will be obtained. A baseline CBC, flow cytometry and
cytokine studies will be obtained on Day 1 prior to start of Lenalidomide.

All patients will have a full immunological evaluation on Day 15 of Lenalidomide therapy
prior to Rituximab administration. A bone marrow biopsy will be performed on all patients
(CLL and MCL) with prior documented bone marrow involvement once between Days 13- 15 to
assess the impact of the lenalidomide on the malignant cells and the surface density of CD20
for patients with CLL before the administration of Rituximab. Flow cytometry on the aspirate
specimen will be performed at Moffitt Cancer Center. The cytokine studies will be drawn on
Day 15, prior to the administration of Rituximab. Starting on Day 15 after collection of
specimens, the patients will receive four weekly doses of Rituximab (375 mg/m^2) concurrent
with lenalidomide as per the cycle schedule. Lenalidomide therapy will be continued until
progression of disease, unacceptable toxicity or patient withdrawal.

Patient assessment during the clinical trial will be performed by a physician and will occur
prior to the administration of each dose of Rituximab. The evaluation will include CBC,
routine chemistries, kidney function, liver function, and LDH. The impact of the treatment
on any lymphadenopathy or splenomegaly will be documented. Any toxicities noted during these
evaluations will be noted. After the four weekly doses of Rituximab, if the pretreatment
bone marrow biopsy was positive, the patient will have a repeat bone marrow biopsy to assess
response. If the patient had splenomegaly or lymphadenopathy prior to entry into the trial,
the patient will need repeat CT scans to assess response. The scans and bone marrow biopsies
should be performed two weeks after the patient's last dose of Rituximab.

Follow-up of patients after completing the Rituximab treatment for patients who have not
progressed while on therapy will involve a CBC, routine chemistries, liver function tests,
and LDH drawn according to the Schedule of Assessments.

Inclusion Criteria:

- Have histologically or cytologically confirmed CD5+/CD20+ B-Cell Chronic Lymphocytic
Leukemia or Mantle Cell Lymphoma

- Meet the following CLL criteria to participate in this study:

- Absolute lymphocyte count > 5000/μL

- CD20+ and CD5+

- Atypical cells representing < 55% on the peripheral smear

- Bone marrow lymphocytes ≥ 30%

- Or previous confirmed diagnosis of CLL/small lymphocytic lymphoma (SLL) with
less than 5000/μl or less than 30% lymphocytes in BM

- CLL Patients are eligible if they have stage III or IV disease. Patients with stage
0, I or II disease will be eligible if they have evidence of active disease defined
as one or more of the following signs/symptoms:

- Documented weight loss of ≥ 10% over a six month period

- Febrile episodes of 38 degrees Celsius (100.5 degrees F) or greater for greater
than 2 weeks without evidence of infection

- Massive or progressive splenomegaly defined as > 6 cm below the left costal
margin

- Massive (> 10 cm in longest diameter) or progressive lymphadenopathy

- Patients with progressive lymphadenopathy will need a biopsy of the lymphadenopathy
within the previous six months to ensure that the disease entity remains chronic
lymphocytic leukemia. Lymph node biopsy can be deferred if the patient does not have
superficial lymphadenopathy that is easily accessible by surgery or by CT guided
biopsy.

- The diagnosis of MCL is based upon the National Comprehensive Cancer Network (NCCN)
guidelines. The patient's will have biopsy proven CD5+/CD20+/CD23- mantle cell
lymphoma with the characteristic cytogenetic abnormality t(11;14) or a cyclin D1
positive immunophenotype. If malignancy is CD23+ but FISH positive for t(11;14),
diagnosis of mantle cell lymphoma can be made. Patients with mantle cell lymphoma
require appropriate staging which would include upper and lower endoscopy within 2
months of enrollment per NCCN guidelines without additional treatment since the
endoscopies.

- Patients with MCL and CLL will be eligible if they have relapsed or progressive
disease after Rituximab therapy or a combination therapy including Rituximab. Any
other number of previous treatments is allowed including autologous or allogeneic
bone marrow transplantation. Patients who are younger than age 65 who have not had a
bone marrow transplant must be ineligible or have declined a bone marrow (BM)
transplant to participate in this study. Although a transplant is not the standard of
care for this patient population, it does provide the best opportunity for a cure.

- Anticipated life expectancy of > 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Baseline organ and marrow function as follows:

- Absolute neutrophil count ≥1,500/µL

- Platelets ≥50,000/µL

- Total bilirubin ≤2.0 mg/dL (34 µmol/L)

- aspartic transaminase (AST)/alanine transaminase (ALT) ≤2.5 X institutional
upper limit of normal(ULN)

- Creatinine < institutional ULN OR

- Creatinine clearance ≥60 mL/min/m² for patients with creatinine levels above
institutional ULN

- All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®. Women of
childbearing potential, and men with a partner of childbearing potential must follow
pregnancy test and birth control guidelines outlined for this study.

- Ability to understand and the willingness to sign a written informed consent document

- Able to adhere to the study visit schedule and other protocol requirements

- Patients with uric acid levels > ULN at baseline must be corrected to ≤ULN prior to
the initiation of study therapy.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering study or those who have not recovered
from adverse events due to agents administered more than 4 weeks earlier.

- May not be receiving any other investigational agents

- Known brain metastases

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lenalidomide and/or thalidomide

- Prior desquamating (blistering) rash with thalidomide

- Neuropathy ≥ grade 2

- Uncontrolled intercurrent illness including (not limited to) ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, psychiatric illness/social situations that would limit compliance with
study requirements.

- Women currently pregnant or breastfeeding

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are
seropositive because of hepatitis B virus vaccine are eligible.

- History of another malignancy besides CLL or MCL who have been disease-free ≤ 3 years
with exception of basal cell or squamous cell carcinoma of skin or carcinoma in situ
of cervix or breast

- Any serious medical condition or psychiatric illness that will prevent patient from
signing the informed consent form or will place the patient at unacceptable risk if
he/she participates in the study

- Prior use of lenalidomide

- Prior severe hypersensitivity to Rituximab or other murine products