This is a single-site prospective study to describe efficacy endpoints of single agent memantine in patients with unresectable, locally advanced, or metastatic HCC otherwise not deemed candidates for intensive systemic therapy. In addition to the primary endpoint and multiple secondary efficacy endpoints, we will describe changes in quality of life on treatment over time.

Inclusion Criteria:

1. Age 18 or older.
2. Patients have newly diagnosed and previously untreated, histologically or radiologically confirmed hepatocellular carcinoma with at least one lesion that is measurable by RECIST 1.1 criteria. A prior HCC lesion that was treated surgically or by radiation is allowed as long as it was at least 2 years or more from the current HCC diagnosis.
3. Patient's cancer must be deemed locally advanced and unresectable as per the consensus of the Inova Multidisciplinary Cancer Care Conference.
4. Patients must have a Child-Pugh cirrhosis score of B7 or greater and deemed not a candidate for aggressive systemic treatment.
5. Eastern Cooperative Oncology Group Performance Status of 0-2.
6. Patients must have adequate blood counts and organ function.
7. Memantine is harmful to the human fetus. For this reason, sexually active males with partners of childbearing potential must agree to use an accepted and effective method of contraception prior to study entry and for the duration of the study. Women of child bearing potential must have a negative serum pregnancy test result within 24 hours prior to initiation of study treatment. They must also agree to use agree to use an accepted and effective method of contraception prior to study entry and for the duration of the study.
8. Patients must demonstrate ability to understand and the willingness to sign a written informed consent document.
9. Men and women, regardless of race, ethnic group or sexual orientation are eligible for this study.

Exclusion Criteria:

1. Patients with Child-Pugh A cirrhosis.
2. Female patients who are pregnant or breast-feeding.
3. Concomitant illness or history that would prevent adequate patient assessment or in the investigators' opinion pose an added risk for study participants.
4. Life-threatening intercurrent illness.
5. Anticipated poor compliance.
6. Subject is enrolled in a separate interventional clinical trial.
7. Active tuberculosis.
8. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
9. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
10. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry for at least 10 days prior to study entry.
11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment.
12. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
13. Patients undergoing other anti-cancer treatment. Palliative radiation for symptom control will be allowed while on protocol.