Summary

This phase II trial evaluates lenvatinib for the treatment of hepatocellular carcinoma (HCC) that has come back (recurrent) after a liver transplant. HCC is a cancer of the liver and is the second leading cause of cancer-related deaths in the world. Liver transplants are a curative option for HCC, however, up to 20% of patients develop recurrent disease and prognosis remains poor. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Systemic treatments for HCC have not been studied in patients with recurrent disease after liver transplantation, so there is no established therapy for these patients. This phase II trial evaluates lenvatinib for this purpose.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate anti-tumor activity of the lenvatinib by assessing the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of lenvatinib in patients with recurrent HCC after liver transplantation.
II. To evaluate the anti-tumor activity of the lenvatinib by assessing progression-free survival (PFS) and overall survival (OS) and duration of response.

TERTIARY/EXPLORATORY OBJECTIVE:
I. To assess the effects of the lenvatinib on circulating tumor deoxyribonucleic acid (DNA) and biomarkers.

OUTLINE:
Patients receive lenvatinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression, unacceptable toxicity, or patient withdrawal.

After completion of study treatment, patients are followed for 30 days and then every 90 days until death or 2 years from registration.

Eligibility

1. Male or female
2. Age >= 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
4. Patients must have recurrent histologically or cytologically confirmed hepatocellular carcinoma that has recurred after liver transplantation and not amenable for surgical resection
5. Child Pugh class A
6. Prior orthotropic liver transplantation for curative intent
7. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
8. Life expectancy > 12 weeks as determined by the investigator
9. Hemoglobin >= 8.0 g/dl (within 28 days of cycle 1 day 1)
10. Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of cycle 1 day 1; after at least 7 days without growth factor support or transfusion)
11. Platelets >= 75,000/mcL (within 28 days of cycle 1 day 1)
12. International normalized ratio (INR) =< 2.3 (within 28 days of cycle 1 day 1)
13. Total bilirubin =< 3 times the institutional upper limit of normal (ULN) (within 28 days of cycle 1 day 1)
14. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5.0 times the ULN (within 28 days of cycle 1 day 1)
15. Albumin >= 2.8 g/dL (within 28 days of cycle 1 day 1)
16. Serum creatinine =< 1.5 x ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN; creatinine clearance should be calculated per institutional standard (within 28 days of cycle 1 day 1)
17. Urinary protein =< 1+ on dipstick or routine urinalysis or 24-hour urine demonstrating < 1 gram of protein (within 28 days of cycle 1 day 1)
18. The effects of lenvatinib on the developing human fetus are unknown. For this reason females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test 72 hours prior to starting protocol therapy. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution. * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago
19. FCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 60 days after the last dose of protocol therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study or for 60 days after the last dose of protocol therapy, she should inform the principal investigator immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 60 days after last dose of protocol therapy.
20. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) functional classification. To be eligible for this trial, patients should be class 2B or better.
21. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions.
22. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.