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

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ClinicalTrials.gov Identifier: NCT02273362
Recruitment Status : Recruiting
First Posted : October 24, 2014
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cirrhosis Hepatocellular Carcinoma Drug: Erlotinib Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Phase 1 Phase 2

Detailed Description:

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Pilot Study of EGFR Inhibition With Erlotinib in Cirrhosis to Inhibit Fibrogenesis and Prevent Hepatocellular Carcinoma
Actual Study Start Date : November 24, 2014
Estimated Primary Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis

Arm Intervention/treatment
Experimental: Prevention (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD for 7 days (depending on the date of surgery, treatment range may be 5-14 days).
Drug: Erlotinib
Given PO

Drug: Erlotinib Hydrochloride
Given PO
Other Names:
  • Cp-358,774
  • OSI-774
  • Tarceva

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Minimum effective dose (MED) of erlotinib hydrochloride that inhibits EGFR signaling in the target organ (liver) as assessed by phospho-EGFR staining [ Time Frame: Up to day 7 ]
    The MED that achieves at least a 40% response rate, where a response is defined as an evaluable participant that achieves at least a 50% reduction in liver phospho-EGFR staining, defined as the percentage of positive pixels, from baseline after a 7-day intervention period with daily erlotinib hydrochloride will be evaluated.


Secondary Outcome Measures :
  1. Overall adverse event profile for erlotinib hydrochloride [ Time Frame: Up to the day of liver resection ]
    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4. The maximum grade for each type of adverse event will be recorded for each participant and frequency tables will be reviewed to determine the overall patterns. The number and severity of adverse events will be tabulated and summarized across all grades. Grade 3+ adverse events will be similarly described and summarized separately. Overall toxicity incidence, as well as toxicity profiles will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.


Other Outcome Measures:
  1. Changes in phospho-ERK levels in the liver [ Time Frame: Baseline to day 7 ]
    The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using analysis of variance (ANOVA) or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  2. Changes in PCNA levels in the liver [ Time Frame: Baseline to day 7 ]
    The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  3. Changes in EGF levels in the liver [ Time Frame: Baseline to day 7 ]
    The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  4. Changes in alphaSMA levels in the liver [ Time Frame: Baseline to day 7 ]
    The relationship between dose-level and staining of biomarkers in the liver will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  5. Modulation of gene expression signatures associated with prognosis in cirrhosis [ Time Frame: Baseline to day 7 ]
    The relationship between dose and modulation of a gene expression signature associated with prognosis in cirrhosis will be assessed. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  6. Change in viral load in participants with hepatitis C virus (HCV)+ [ Time Frame: Baseline to 7 days ]
    Whether erlotinib hydrochloride is associated with a measurable reduction in viral load in participants with HCV+ will be determined. The baseline biomarker expression levels across all the dose levels using ANOVA or the nonparametric equivalent will be compared. The changes in these biomarker values will be assessed using the Wilcoxon signed-rank test and compare these changes across dose levels using ANOVA. Graphical methods will be used to assess the differences in these biomarker values across dose levels. All categorical variables will be analyzed using chi-square or Fisher's exact tests.

  7. Erlotinib hydrochloride plasma level [ Time Frame: Day of liver resection ]
    The relationship between erlotinib hydrochloride dose-schedule and erlotinib hydrochloride plasma level on the day of liver resection will be determined.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02273362


Locations
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United States, Florida
Mayo Clinic in Florida Suspended
Jacksonville, Florida, United States, 32224-9980
United States, Massachusetts
Massachusetts General Hospital Cancer Center Suspended
Boston, Massachusetts, United States, 02114
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Sean P. Cleary    507-284-2511    cleary.sean@mayo.edu   
Principal Investigator: Sean P. Cleary         
United States, New York
Mount Sinai Hospital Suspended
New York, New York, United States, 10029
United States, Ohio
Case Western Reserve University Suspended
Cleveland, Ohio, United States, 44106
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Christopher T. Siegel    800-223-2273    siegelc2@ccf.org   
Principal Investigator: Christopher T. Siegel         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kenneth K Tanabe Mayo Clinic

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02273362     History of Changes
Other Study ID Numbers: NCI-2014-02170
NCI-2014-02170 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HHSN261201200042I
N01-CN-2012-00042
MAY2013-02-02 ( Other Identifier: Mayo Clinic )
MAY2013-02-02 ( Other Identifier: DCP )
N01CN00042 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: October 24, 2014    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: June 2019
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Liver Cirrhosis
Fibrosis
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Pathologic Processes
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action