Study Examining the Combination of Lenalidomide and Azacitidine for Relapsed/Refractory CLL and SLL

• 1. Assess for treatment related toxicity following administration of lenalidomide/ azacitidine. [ Designated as safety issue: Yes ]
• 2. Estimate the progression free survival and overall survival of patients treated with the combination of lenalidomide and azacitidine [ Designated as safety issue: Yes ]
• 3. Bank tumor samples for planned correlative analyses to identify epigenetically silenced, clinically relevant genes in CLL. [ Designated as safety issue: Yes ]

To determine the response to the combination of azacitidine + lenalidomide in patients with relapsed/refractory CLL and SLL

Hypothesize - lenalidomide's activity in combination with azacitidine may further enhance its activity and the durability of treatment response.

A promising and untested combination in CLL is the combination of lenalidomide with the DNA methyltransferase inhibitor azacitidine. The combination of lenalidomide and azacitidine is novel to CLL, but has been tested in a phase I clinical trial involving patients with MDS and has been found to be safe with promising activity in that disease. Studying the activity of this combination in CLL may allow us to shift the CLL treatment paradigm from cytotoxic chemo-immunotherapies therapies towards an epigenetic-immunomodulatory approach and offers the unique opportunity to further understand the complex biology of this disease, mechanisms of resistance and its interaction with its microenvironment.

• Drug: Revlimid
  Lenalidomide PO daily Day 1-21. For patients with baseline calculated creatinine clearance ≥ 30 ml/min and < 60 ml/min the starting dose is 5 mg every other day (odd numbered days during Days 1-21). For patients with baseline calculated creatinine clearance ≥ 60 ml/min the starting dose is 5 mg daily on Days 1-21).
  Other Name: Lenalidomide
• Drug: Azacitidine
  Azacitidine 75 mg/m2 IV or SC D 1-5
  Other Name: Vidaza

Inclusion Criteria:

1. Patients must be age ≥ 18.
2. Patients must have an ECOG PS ≤ 2.
3. Patients must understand and voluntarily sign informed consent.
4. Able to adhere to the study visit schedule and other protocol requirements.
5. Patients must carry the diagnosis of B-CLL/SLL as per WHO diagnostic criteria.

6. SLL/CLL must be defined as relapsed or refractory disease as defined by the NCI-sponsored IWG criteria.

   • Relapsed CLL/SLL: Relapse is defined as a patient who has previously achieved CR or PR, but after a period of 6 or more months, demonstrates evidence of disease progression.
   • Refractory CLL/SLL: Refractory disease is defined as treatment failure or disease progression within 6 months to the last antileukemic therapy.
7. Patients must have received and failed at least one purine-based treatment regimen (ie. FCR, FR, PCR, Fludarabine) or alemtuzumab-based regimen or bendamustine-based regimen prior to study enrollment.
8. Serum bilirubin levels <1.5 times the upper limit of the normal range for the laboratory (ULN). Higher levels are acceptable if these can be attributed to active hemolysis, ineffective erythropoiesis or Gilbert's disease.
9. Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels <2 x ULN. (or <5 x ULN if hepatic metastases are present)
10. Subjects must have calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula. See section below, "Dosing Regimen", regarding lenalidomide dose adjustment for calculated creatinine clearance > 30ml/min and < 60ml/min
11. Absolute neutrophil count > 1.0 x 109 / L
12. Platelet count > 50x 109 / L (unless bone marrow is heavily infiltrated with underlying disease (50% or more)
13. Disease free of prior malignancies for > 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast.
14. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
15. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

16. 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 prior to prescribing lenalidomide (prescriptions must be filled within 7 days) 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. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

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Exclusion Criteria:

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

2. 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.

3. Patients must be lenalidomide / azacitidine naïve prior to study enrollment. 4. Patient's must not carry a diagnosis of HIV, Hepatitis B or Hepatitis C. Patients who are seropositive because of hepatitis B virus vaccine are eligible.

5. Patients must not have received chemotherapy, immunotherapy or any experimental study drug for CLL or SLL at least 4 weeks prior to study enrollment and initiation of treatment.

6. Patients with history of B-CLL and the development of prolymphocytic leukemia or Richter's transformation.

7. Known or suspected hypersensitivity to azacitidine, mannitol, thalidomide or lenalidomide.

8. Pregnant or breast feeding females. Lactating females must agree not to breast feed while taking lenalidomide.

9. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome. Subjects may be enrolled upon correction of electrolyte abnormalities.

10. Patients with advanced malignant hepatic tumors. 11. Concurrent use of other anti-cancer agents or treatments. 12. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment);

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