This study will determine whether lenalidomide has activity in patients with advanced liver cancer that have had growth of their cancer after sorafenib.

This study will determine the response rate and toxicities of lenalidomide as second line treatment for patients with liver cancer who have progressed after sorafenib.

Inclusion Criteria:

1. Pathologically confirmed HCC or triple phase CT consistent with HCC in a patient with known cirrhosis and AFP > 200 ng/ml.

2. Disease not amenable to curative surgical resection

3. Patients must have been previously treated with sorafenib. Patients who are unable to receive sorafenib due to financial reasons are also eligible.

4. All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.

5. No previous thalidomide.

6. Patients must have radiologically assessable tumor.

7. ECOG performance status of 0-2 at study entry.

8. Understand and voluntarily sign an informed consent form.

9. Age >18 years at the time of signing the informed consent form.

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

11. Laboratory test results within these ranges:

    • Absolute neutrophil count > 1000/mm3
    • Platelet count > 60,000/mm3
    • Serum creatinine > 2.0 mg/dL
    • Total bilirubin > 4 mg/dL
    • AST (SGOT) and ALT (SGPT) > 5 x ULN.

12. 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. See Appendix: H Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, AND also Appendix: F Education and Counseling Guidance Document

13. 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. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
3. 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.
4. Use of any other experimental drug or therapy within 28 days of baseline.
5. Known hypersensitivity to thalidomide.
6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
7. Any prior use of lenalidomide.
8. Concurrent use of other anti-cancer agents or treatments.
9. Known positive for HIV. (The effect of immune modulation of lenalidomide on patients who are HIV positive is unknown).

From time of signing consent to approximately 30 days post last dose of drug, for a maximum of 4 years