We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02273362
Recruitment Status : Active, not recruiting
First Posted : October 24, 2014
Results First Posted : February 25, 2022
Last Update Posted : February 25, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 22, 2014
First Posted Date  ICMJE October 24, 2014
Results First Submitted Date  ICMJE August 12, 2021
Results First Posted Date  ICMJE February 25, 2022
Last Update Posted Date February 25, 2022
Actual Study Start Date  ICMJE November 24, 2014
Actual Primary Completion Date February 11, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 24, 2022)
Response (at Least a 50% Reduction in Liver Phospho-EGFR Staining) [ Time Frame: Up to day 7 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 22, 2014)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2022)
Adverse Event Profile [ Time Frame: Up to day 7 ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 22, 2014)
Overall adverse event profile for erlotinib hydrochloride graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4 [ Time Frame: Up to the day of liver resection ]
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.
Current Other Pre-specified Outcome Measures
 (submitted: February 24, 2022)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: October 22, 2014)
  • Changes in phospho-ERK, PCNA, EGF, and 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 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.
  • Modulation of a gene expression signature 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.
  • Change in viral load in participants with 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.
  • 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.
 
Descriptive Information
Brief Title  ICMJE Erlotinib Hydrochloride in Preventing Liver Cancer in Patients With Cirrhosis of the Liver
Official Title  ICMJE Pilot Study of EGFR Inhibition With Erlotinib in Cirrhosis to Inhibit Fibrogenesis and Prevent Hepatocellular Carcinoma
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.
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Cirrhosis
  • Hepatocellular Carcinoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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).
Interventions:
  • Drug: Erlotinib
  • Drug: Erlotinib Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 26, 2020)
25
Original Estimated Enrollment  ICMJE
 (submitted: October 22, 2014)
65
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date February 11, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02273362
Other Study ID Numbers  ICMJE 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 in Rochester )
MAY2013-02-02 ( Other Identifier: DCP )
N01CN00042 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party National Cancer Institute (NCI)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kenneth K Tanabe Mayo Clinic
PRS Account National Cancer Institute (NCI)
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP