The purpose of this trial is to investigate the efficacy (how well the drug works) of ofatumumab and lenalidomide in patients with lymphoma and to investigate if any possible unwanted side effects may occur. The purpose of the Phase I portion of this trial will be to determine the maximum dose of these medications that can be given with minimal side effects.

This trial will investigate the efficacy of ofatumumab and lenalidomide in patients with lymphoma and investigate if any possible unwanted side effects may occur. Ofatumumab is a human antibody (a type of protein) that binds specifically to a protein (CD20) on the surface of some of the white blood cells (B-cells). Research, so far, has shown that ofatumumab can destroy cancer cells which originate from B cells. Ofatumumab is approved for sale by the US Food and Drug Administration (FDA). The medicine has an approved indication for Chronic Lymphocytic Leukemia (CLL) but is not approved for Non-Hodgkin's Lymphoma (NHL).

Lenalidomide is a drug that affects the immune system. Lenalidomide can change the body's immune system and it may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, it may reduce or prevent the growth of cancer cells. Lenalidomide is approved by the FDA for treatment of multiple myeloma (MM) and myelodysplastic syndrome (MDS) and has been shown to be effective in lymphoma that does not respond to treatment or has come back after treatment. Lenalidomide has not been approved by the United States (US) Food and Drug Administration (FDA) and is experimental (investigational) in this study.

Inclusion Criteria:

• Histologically confirmed diagnosis of CD20+ non-Hodgkin's lymphoma that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available.

• Subject, age > or = 19 years

• Patients must have relapsed or refractory disease after at least one prior systemic therapy, with at least a 3 week interval from the completion of the most recent chemotherapy or radiotherapy regimen (unless the patient has had progressive disease prior to the 3 weeks). Patient has resolved all toxicities to ≤ grade 1, felt to be related to prior therapy.

• Patients must be ineligible or relapsed after an autologous or allogeneic stem cell transplant if clinically appropriate.

• Adequate Laboratory Parameters:

  • ANC ≥ 1500/μL
  • Platelet count ≥75,000/μL
  • Total bilirubin ≤ 1.5 times the institutional Upper Limit of Normal (ULN)- unless due to NHL
  • Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN - unless due to NHL
  • Serum Creatinine < 3.0 times the institutional ULN - unless due to NHL
  • Creatinine clearance ≥60ml/min during phase I (See Appendix A) Creatinine clearance ≥ 30ml/min during phase II and patients with creatinine clearance ≥ 30ml/min and < 60ml/min should start Lenalidomide at a reduced dose. See Section 5.3.1

• Females of child-bearing potential (FCBP) must agree to:

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. See Appendix B: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

Note: A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (i.e., amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Male patients must:

• Agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and 28 days after cessation of study therapy.
• Agree to not donate semen during study drug therapy and for a period after end of study drug therapy
• ECOG Performance status of 0-2 (See Appendix C)
• Signed written informed consent including HIPAA according to institutional guidelines

Exclusion Criteria:

• No malignancy [other than the one treated in this study] which required systemic treatment within the past 3 years.
• Patients not willing to take DVT prophylaxis
• Pregnant or lactating females
• Positive serology for hepatitis B (HB) defined as positive test of HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded. Patients with documented vaccination against Hepatitis B will not be considered positive.
• Known seropositive for active viral infection with human immunodeficiency virus (HIV), or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
• Patients with ≥ Grade 2 neuropathy
• Active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Known CNS involvement with lymphoma
• Significant concurrent, uncontrolled medical condition, that in the judgment of the investigator, may affect the patient's ability to sign the informed consent and comply with study procedures.

6 years