Erlotinib Hydrochloride in Preventing Liver Cancer in Patients With Cirrhosis of the Liver

PRIMARY OBJECTIVES:

I. Determine the safe and minimum effective dose (MED) of daily erlotinib (erlotinib
hydrochloride) that inhibits epidermal growth factor receptor (EGFR) signaling in the target
organ (liver) as assessed by phosphorylated (phospho)-EGFR staining.

SECONDARY OBJECTIVES:

I. Determine the relationship between erlotinib dose-schedule and side effects in
participants with cirrhosis.

TERTIARY OBJECTIVES:

I. Determine the relationship between erlotinib dose-schedule and immuno-histochemical
staining pattern of phospho-ERK, proliferating cell nuclear antigen (PCNA), epidermal growth
factor (EGF), and alpha smooth muscle actin (alphaSMA) in the liver.

II. Determine the relationship between erlotinib dose-schedule and gene expression signature
associated with prognosis in cirrhosis participants following hepatocellular carcinoma (HCC)
resection.

III. Determine the relationship between erlotinib dose-schedule and viral load in
participants with hepatitis C virus (HCV) positive (+).

IV. Determine the relationship between erlotinib dose-schedule and erlotinib plasma level on
day of liver resection.

OUTLINE: This is a phase I, dose-escalation/de-escalation study followed by a phase II study.

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) for 7 days (depending on
the date of surgery, treatment range may be 5-14 days).

Inclusion Criteria:

- PRE-REGISTRATION INCLUSION:

- Individuals with a clinical diagnosis fibrosis or cirrhosis of the liver (no more than
Child-Pugh classification A; Child-Pugh-Turcotte score of 6 or less) who have:

- An indication for surgical liver resection, OR

- A clinical liver biopsy (with research tissue specimens available for analysis)
=< 3 months prior to pre-registration

- Willingness to discontinue smoking during the study two weeks prior to beginning the
study and willingness to not smoke while taking study medication

- Not pregnant or breast feeding; 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 participation; should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her study physician immediately

- Willingness to use adequate contraception to avoid pregnancy or impregnation until 2
weeks after discontinuing study agent

- Willingness to provide mandatory blood specimens

- Able to undergo:

- Percutaneous or transjugular biopsy of cirrhotic liver at least 7 days prior to
liver resection (surgical cohort), OR

- A biopsy of the cirrhotic liver (non-surgical cohort)

- Willingness to authorize collection of tissue from surgically-resected liver or
clinical liver biopsy for analyses

- Ability to understand and the willingness to sign a written informed consent document

- REGISTRATION INCLUSION:

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- International normalized ratio (INR) =< 1.5

- Platelets >= 50 B/L (10^9/L)

- Total bilirubin =< 3 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x
institutional ULN

- Creatinine =< 1.5 x institutional ULN

- Non-surgical cohort only: positive phospho-EGFR assessment (>= 100 stained pixels)
from tissue obtained from previous clinical liver biopsy

- Pre-intervention biopsy sample collected

Exclusion Criteria:

- PRE-REGISTRATION EXCLUSION:

- Any prior treatment with erlotinib or other agent whose primary mechanism of action is
known to inhibit EGFR

- Participants with a known diagnosis of human immunodeficiency virus (HIV); Note: an
HIV screening test does not have to be performed to evaluate this criterion

- Participants who regularly (>= 2 times per week) use drugs that alter the pH of the
gastrointestinal (GI) tract, such as proton pump inhibitors (PPI) and antacids;
exceptions: individuals who use prescription PPIs and have approval from their primary
health care provider to discontinue for the duration of clinical trial participation
may be enrolled; an alternate drug to control gastroesophageal reflux disease
(GERD)/peptic ulcer disease (PUD) symptoms will be suggested

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Use of potent CYP3A4 inhibitors, such as ketoconazole, atazanavir, clarithromycin,
indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin, voriconazole, and grapefruit or grapefruit juice

- Use of CYP3A4 inducers such as rifampicin, rifabutin, rifapentine, phenytoin,
carbamazepine, phenobarbital, and St. John's wort

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to erlotinib (Tarceva)

- Participants who cannot have their warfarin, Lovenox, Plavix, or other comparable
medications held for percutaneous or transjugular liver biopsy and surgery if so
indicated

- Non-surgical cohort only: pathology report from clinical liver biopsy (=< 3 months
prior to pre-registration) demonstrates no histologic abnormalities associated with
chronic hepatitis, steatohepatitis, fibrosis, or cirrhosis

- REGISTRATION EXCLUSION:

- Receiving any other investigational agents =< 6 months prior to registration

- Surgical cohort (cohort A only): percutaneous or transjugular biopsy incomplete or not
performed