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

Study Overview
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Brief Summary
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This pilot phase I/II trial studies the best dose of erlotinib hydrochloride and to see how well it works in preventing liver cancer in patients with scarring (cirrhosis) of the liver. Erlotinib hydrochloride may help to inhibit the development of fibrous tissue and prevent liver cancer from forming in patients with cirrhosis of the liver.

Detailed Description
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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. TRANSLATIONAL 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).

Official Title
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Pilot Study of EGFR Inhibition With Erlotinib in Cirrhosis to Inhibit Fibrogenesis and Prevent Hepatocellular Carcinoma

Conditions
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Cirrhosis, Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Erlotinib Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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. Note: The effects of erlotinib (Tarceva) on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (erlotinib hydrochloride)<br>Patients receive erlotinib hydrochloride PO QD for 7 days (depending on the date of surgery, treatment range may be 5-14 days). | Drug: Erlotinib<br>* Given PO<br>Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (at Least a 50% Reduction in Liver Phospho-EGFR Staining) | A response is defined as having at least a 50% reduction in liver phospho-EGFR staining (50% reduction in the percentage of positive pixels).> > For each dose level, we report the number of participants achieving a response (at least 50% reduction in liver phospho-EGFR staining). > > The Minimum effective dose (MED) is defined as the dose which at least a 40% of patients report a response. | Up to day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event Profile | Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4. For this endpoint, we are reporting the number of participants with Grade 3 or higher as their worst reported adverse event. | Up to day 7 |