Meclizine for Hepatocellular Carcinoma

The constitutive androstane receptor (CAR, NR1I3) is a nuclear receptor that plays a central
role in hepatic detoxification of potentially toxic compounds, or xenobiotics. Chronic CAR
activation by specific agonists induces tumors in wild type mice, and strongly promotes
hepatocarcinogenesis in combination with initiating mutagens. Both effects are absent in CAR
null mice. These tumorigenic effects are associated with an acute induction of hepatocyte
proliferation in mice. Preliminary results using partially humanized mice demonstrate a very
similar proliferative effect of CAR activation in human hepatocytes.

The transcriptional activity of CAR can be reversed by specific inverse agonists. These
ligands are analogous to steroid receptor antagonists, converting the transcriptional
activation of the agonist bound receptor into transcriptional repression. These compounds are
termed inverse agonists because they do not depend on the presence of agonist ligands to
exert their repressive effects. Mouse and human CAR proteins are more divergent than other
nuclear receptors, and respond to quite different profiles of agonists and inverse agonists.
Preliminary results demonstrate that the specific mouse CAR inverse agonist androstanol
blocks proliferation and induces apoptosis in mouse liver tumors. This raises the possibility
that targeting CAR may represent a new modality of treatment for hepatocellular cancer (HCC)
analogous to estrogen and androgen receptor antagonists in breast and prostate cancers.
Meclizine, a widely used antihistamine medication for vertigo and motion sickness, is an
inverse agonist ligand of human CAR. Investigators hypothesize that reversing CAR function
with meclizine will have a beneficial therapeutic effect in patients with HCC by blocking
proliferation and inducing apoptosis.

Investigators therefore propose a novel window of opportunity trial in which biopsy proven
HCC patients will receive oral meclizine daily for 28 days while awaiting surgical resection,
radiofrequency ablation, or transarterial chemoembolization. The primary test of treatment
outcome will be the predicted decrease in expression of downstream CAR target genes (CYP2B6,
MYC and FOXM1) in pre and post treatment tumor specimens. Investigators will also measure the
change in tumor proliferation and apoptosis by measuring Ki-67 proliferation index and TUNEL
assays (terminal deoxynucleotidyl transferase dUTP Nick-End Labeling assay), serum levels of
AFP and GDF 15, and overall tumor response by imaging. HCC is the most rapidly increasing
cause of cancer mortality in the United States and medical treatment options are limited.
Successful completion of this study may identify a new approach to treatment of HCC.

Inclusion Criteria:

1. Patient must have imaging (MRI or CT abdomen liver protocol) confirmed Hepatocellular
carcinoma. Patients cannot have metastatic HCC.

2. Patients must have measurable disease, defined as tumor mass which is >10 mm with
spiral CT scan or MRI. Baseline imaging scan must be within 6 weeks of registration.

3. Patients must be greater than 18 years of age.

4. ECOG Performance status less than/equal to 2 (Karnofsky greater than 60%).

5. Patients must have normal organ and marrow function as defined below, within 21 days
of registration: Leukocytes greater than 3,000/mcL; ANC greater than 1,500/mcL;
Platelets greater than 50,000/mcL; Hemoglobin greater than/equal to 8 g/dL; ALT(SGPT)
less than/equal to 5X IULN and AST (SGOT) less than/equal to 5X IULN; Creatinine less
than/equal to 2X IULN or Creatinine clearance greater than 60 mL/min for patients with
creatinine levels greater than IULN; Child Pugh Class A (5-6 points) or B (7 points);
INR less than/equal to 2.3; Albumin greater than 2.8 g/dL; Total bilirubin less
than/equal to 3X IULN.

6. Patients must be candidate for surgical resection, ablation, and TACE.

7. Patients should have life expectancy greater than/equal to 10 weeks.

8. Willingness to Use Contraception: The effects of Meclizine on the developing human
fetus at the recommended therapeutic dose are unknown. Women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
treatment with meclizine. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately. If a male participant impregnates his partner he should inform his
treating physician immediately.

9. Subjects must be informed of the investigational nature of this study, and must sign
and give written informed consent in accordance with institutional and federal
guidelines.

10. Patients taking medications with a narrow therapeutic index including warfarin,
digoxin, phenobarbital, carbamazepine, and cyclosporine are not excluded but should be
monitored carefully.

11. Antiviral therapy for HCV and HBV is allowed, but patient should not be on interferon

Exclusion Criteria:

1. Patients must have no prior history of treatment for HCC (treatment naive).

2. Patients may not be receiving any other anti-cancer therapy.

3. Patients may not be receiving any other investigational agents.

4. Patients must not be taking Rifampin or St John's Wort.

5. Patient must not have a history of allergic reactions like anaphylaxis attributed to
compounds of similar chemical or biologic composition to Meclizine such as
antihistamine drugs.

6. Patient must not be a candidate for liver transplant.

7. Child Pugh Class B (8,9) and Class C are excluded

8. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with meclizine.

9. Patient must not have uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, myocardial infarction or cerebrovascular accident within 6 months prior to
registration, cardiac arrhythmia, glaucoma, asthma or psychiatric illness/social
situations that would limit compliance with study requirements.

10. Pregnant women are excluded from this study because meclizine is a Class B agent with
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with meclizine, breastfeeding should be discontinued if the mother is treated
with meclizine.