Multi-center Trial of Revlimid® and Rituximab, for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)

The CLL Research Consortium (CRC) is conducting a two-arm, multi-center phase II trial of
Revlimid® and rituximab for the first-line treatment of patients with CLL.

Revlimid® (lenalidomide) a derivative of thalidomide with immune-modulating properties.
Revlimid® is FDA approved for treatment of relapsed multiple myeloma and 5q- myelodysplastic
syndrome. Revlimid® has promising clinical activity in relapsed CLL in two early clinical
trials. However, the mechanism(s) whereby Revlimid® is active in CLL is unknown. Rituximab
(Rituxan®) is a protein that binds to CD20 expressed on normal and leukemia B cells.
Rituximab is FDA approved for the treatment of lymphoma and is used commonly for the
treatment of CLL. The purposes of this study are to evaluate the safety and activity of the
combination of Revlimid® and rituximab in CLL, elucidate the mechanism of Revlimid® in CLL,
and to assess whether prognostic factors might predict those patients likely to benefit from
this therapy in the future.

As older patients are commonly under-represented in CLL clinical trials and are less
tolerable of frontline therapy that utilizes combinations of fludarabine and
cyclophosphamide the trial has two arms; one to specifically assess for the tolerability of
the regimen in older subjects.

The primary objective of this study is to determine the response rate of the combination of
Revlimid® and Rituximab in previously untreated CLL patients in two arms- those aged 65
years and above and those younger than 65. Secondary objectives will evaluate the safety of
the combination of Revlimid® and Rituximab, response duration, improvement in hematologic
parameters, activity of the combination in high-risk CLL subsets, and the significance of
the tumor flare reaction.

All patients will have baseline assessment of known CLL prognostic factors including:
immunoglobulin variable heavy chain (IgVH) gene mutational status, interphase cytogenetics,
intracellular ZAP-70 expression, and CD38 expression through the CRC tissue core. These
known prognostic features in CLL together with novel prognostic factors will be evaluated
for the ability to predict response to treatment with Revlimid® and the combination of
Revlimid® and Rituximab. Extensive biologic corollary studies are designed to evaluate the
mechanism of Revlimid® in CLL, the impact of Revlimid® on the CLL microenvironment, and
Revlimid®'s impact on and rituximab mediated cytotoxicity.

All patients will receive the same treatment. Revlimid® will be started at a low dose and
slowly escalated based on patient tolerability. Rituximab will be administered following 21
days of Revlimid® monotherapy. Patients will continue treatment for up to 7 cycles unless
there is toxicity or progressive disease. There are three planned response assessments for
the subjects: a single agent Revlimid® response assessment prior to the addition of
rituximab, after 3 cycles of treatment, and following all the therapy.

Inclusion Criteria:

1. Diagnosis of chronic lymphocytic leukemia with no history of previous treatments with
monoclonal antibodies or chemotherapy.

2. Subjects must have an indication for treatment as defined by the NCI Working Group
Guidelines

3. Understand and voluntarily sign an informed consent form.

4. Age ≥18 years at the time of signing the informed consent form.

5. Able to adhere to the study visit schedule and other protocol requirements.

6. ECOG performance status of ≤ 2 at study entry (see Appendix A).

7. Laboratory test results within these ranges: Absolute neutrophil count ≥ 1.0 x 109/L,
Platelet count ≥ 50 x 109/L, Serum creatinine ≤ 1.5 mg/dL, Total bilirubin ≤ 1.5
mg/dL, AST & ALT ≤ 2 x ULN

8. 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 prior to
and again within 24 hours of starting lenalidomide 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. All patients
must be counseled at a minimum of every 28 days about pregnancy precautions and risks
of fetal exposure.

9. Disease free of prior malignancies for ≥ 2 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix
or breast

Exclusion Criteria:

1. Previous treatment for CLL with chemotherapy or monoclonal antibodies

2. Known Hepatitis B Ag positive, Hepatitis C positive patients

3. Known HIV positive patients

4. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune
thrombocytopenia (ITP).

5. Inability to provide informed consent.

6. Concurrent malignancy (excluding basal and squamous cell skin cancers).

7. Active fungal, bacterial, and/or viral infection.

8. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

9. Pregnant or breast-feeding females. (Lactating females must agree not to breast feed
while taking lenalidomide).

10. 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.

11. Use of any other experimental drug or therapy within 28 days of baseline.

12. Known hypersensitivity to thalidomide.

13. The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs.

14. Any prior use of lenalidomide.

15. Concurrent use of other anti-cancer agents or treatments.

16. Patients with history of deep venous thrombus or pulmonary embolism. Patients who are
at increased risk of thrombosis during treatment with lenalidomide including those
taking concurrent erythropoietin, darbepoetin or high-dose corticosteroids are also
excluded.

17. Patients with a history of embolic events (e.g. TIA) from arrhythmia or peripheral
arterial disease or of recent MI whether or not treated with anti-platelet drugs