Trial of Intracycle Sequential Ofatumumab and Lenalidomide for the Treatment of Chronic Lymphocytic Leukemia in Patients Previously Exposed to Rituximab

The purpose of this research is to evaluate the safety and effectiveness of the drugs lenalidomide and ofatumumab in the treatment of chronic lymphocytic leukemia (CLL).

Inclusion Criteria:

1. Subjects must have confirmed diagnosis of chronic lymphocytic leukemia (CLL) by flow cytometry, including simultaneous expression of CD5, CD20 and CD23 with at least 10,000 CLL cells/mm3 in the patient peripheral blood at the time of enrollment
2. Prior therapy with at least one regimen containing rituximab
3. Age > 18 years. Because no dosing or adverse event data are currently available on the use of ofatumumab in combination with lenalidomide in patients <18 years of age, children are excluded from this study.
4. Life expectancy greater than 12 months.
5. ECOG performance status <2

6. Patients must have normal organ function as defined below:

   • Total bilirubin <1.5 X normal institutional limits
   • AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal
   • Creatinine clearance >60 mL/min/1.73 m2 (Cockcroft-gault)

7. Patients must have adequate bone marrow function defined as:

   • Absolute neutrophil count ≥ 1000/mm3
   • Platelet count ≥ 50,000/mm3
   • Hemoglobin ≥ 8.0 g/dl
8. Ability to understand and the willingness to sign a written informed consent document.
9. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
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 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. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin.

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 4 weeks or received any monoclonal antibody within 6 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
2. Patients may not be receiving any other investigational agents or other anti-cancer agents or treatments.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ofatumumab or lenalidomide.
4. Uncontrolled concomitant illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
5. Pregnant women are excluded from this study because lenalidomide is believed to be teratogenic. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ofatumumab or lenalidomide , breastfeeding should be discontinued if the mother is treated with ofatumumab or lenalidomide.
6. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ofatumumab or lenalidomide. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive and/or potentially immunosuppressive therapy.
7. Prior treatment with lenalidomide
8. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome. Subjects may be enrolled upon correction of electrolyte abnormalities.

9. All patients will undergo screening for hepatitis B:

   • HbsAg positive- subject is excluded from the trial
   • HBsAg negative, HBcAb negative, HBsAb- subject is eligible.
   • HBsAg negative, HBcAb positive - HBV DNA must be performed
   • HBV DNA positive- subject is excluded
   • HBV DNA negative- subject is eligible, must undergo at least every 2 months HBV DNA PCR testing during treatment and at least every 3 months up to 6 months after the last treatment dose. Prophylactic antiviral therapy in addition to the monitoring described above, may be initiated at the discretion of the investigator.

• GlaxoSmithKline
• Celgene Corporation