Phase II Trial of Revlimid® and Rituximab for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

The Chronic Lymphocytic Leukemia (CLL) Research Consortium (CRC) is conducting a two-arm, multi-center phase II trial of Revlimid® and rituximab for Relapsed or Refractory CLL for patients under the age of 65 and patients 65 years and older.

Lenalidomide (Revlimid) is an immunomodulatory agent with promising clinical activity in CLL and is FDA approved for treatment of relapsed multiple myeloma and 5q-myelodysplastic syndrome. Rituximab (Rituxan) is a monoclonal antibody to CD20 that is approved for the treatment of CLL.

The primary objective of this study is to determine the overall response rate of the combination of Revlimid® and rituximab in previously treated CLL patients. All patients will receive treatment with Revlimid® starting at a low dose that will be dose escalated based on individual patient tolerability. The combination of Revlimid and Rituximab will be administered for a maximum of 7 cycles. Patients with residual leukemia following seven cycles of treatment with the combination may elect to continue on protocol for an additional 6 cycles of single agent Revlimid® consolidation.

The Chronic Lymphocytic Leukemia (CLL) Research Consortium (CRC) is conducting a two-arm, multicenter phase II trial of Revlimid® and rituximab for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) for patients under the age of 65 and patients 65 years and older.

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 both previously treated and treatment naive CLL in early clinical trials. However, the mechanism(s) whereby Revlimid® is active in CLL is unknown. Rituximab (Rituxan®) is a monoclonal antibody that binds to CD20 expressed on normal and leukemia B cells. Rituximab is approved for the treatment of CLL.

In preclinical models of lymphoma Revlimid improved the activity of Rituximab. In clinical studies of relapsed and/or refractory CLL the combination Revlimid and Rituximab was associated with better therapeutic effects compared with what was historically observed with either agent alone.

The purpose of this study is to evaluate the safety and activity of the combination of Revlimid® and rituximab in relapsed or refractory CLL, elucidate the mechanism of action of Revlimid® in CLL, and to assess whether prognostic factors might predict those patients likely to benefit from this therapy in the future.

The primary objective of this study is to determine the overall response rate (ORR) of the combination of Revlimid® and rituximab in previously treated CLL patients for those age 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, the significance of the tumor flare reaction and to compare the activity of this regimen when administered to previously treated patients to our protocol in the front line setting and to compare these outcomes for both arms of the study.

All patients will receive treatment with Revlimid® starting at a low dose that will be slowly dose escalated based on individual patient tolerability. The combination of Revlimid and Rituximab will be administered for a maximum of 7 cycles. Patients with residual leukemia following seven cycles of treatment with the combination may elect to continue on protocol for an additional 6 cycles of single agent Revlimid® consolidation.

All patients will have baseline assessment of known CLL prognostic factors 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.

Eligibility Criteria:
Inclusion Criteria:

1. Diagnosis of chronic lymphocytic leukemia (CLL).
2. Subjects must have active disease appropriate for therapy.
3. Previous treatment for CLL
4. Understand and voluntarily sign an informed consent form.
5. Age ≥18 years at the time of signing the informed consent form.
6. Able to adhere to the study visit schedule and other protocol requirements.
7. ECOG performance status of ≤ 2 at study entry (see Appendix B).
8. Laboratory test results within these ranges: Absolute neutrophil count ≥ 1.0 x 109/L,Platelet count ≥ 50 x 109/L, Total bilirubin ≤ 1.5 mg/dL, AST (SGOT) and ALT (SGPT) ≤ 2 x ULN, Creatinine clearance estimated to be ≥ 30 ml/min
9. Disease free of prior malignancies for ≥ 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ" of the cervix or breast.
10. 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 Revlimid® 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 Revlimid®. 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. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, AND also Appendix: Education and Counseling Guidance Document.

Exclusion Criteria:

1. Known Hepatitis B Ag positive, Hepatitis C positive patients.
2. Known HIV positive patients.
3. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP).
4. Inability to provide informed consent.
5. Concurrent malignancy (excluding basal and squamous cell skin cancers).
6. Active fungal, bacterial, and/or viral infection.
7. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
8. Pregnant or breast-feeding females. (Lactating females must agree not to breast feed while taking Revlimid®).
9. 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.
10. Use of any other experimental drug or therapy within 28 days of baseline.
11. Known hypersensitivity to thalidomide.
12. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
13. Concurrent use of other anti-cancer agents or treatments.
14. Patients with history of deep venous thrombus or pulmonary embolism. Patients who are at increased risk of thrombosis during treatment with Revlimid® including those taking concurrent erythropoietin, darbepoetin or high-dose corticosteroids are also excluded.
15. Patients with a history of embolic events (e.g. TIA) from arrhythmia or peripheral arterial disease or of recent mycocardial infarction whether or not treated with anti-platelet drugs.