The following datasets contain the data available for EPPT MAY2013-02-02. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 36 datasets contain the raw form data received, excluding PII.

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Trial Summary

The purpose of this pilot phase I/II trial was to find the safe and minimum effective dose (MED) of daily erlotinib that can inhibit epidermal growth factor receptor (EGFR) signaling (based on phospho-EGFR immunohistochemical [IHC] staining) in the liver of participants with fibrosis or cirrhosis. Participants were assigned to self-administer either 75 mg, 50 mg, or 25 mg of erlotinib for 7 days. Liver tissue was obtained before and after the drug administration period. The trial also examined the relationship between erlotinib dose-schedule and side effects in participants with cirrhosis.

The starting dose level was erlotinib (75 mg/day) a dose less than that prescribed for treatment of cancer (150 mg/day) and the human equivalent of a dose demonstrated to have efficacy in a rat model of cirrhosis and hepatocellular carcinoma (HCC) (7). It was considered ideal to choose a starting dose with room for both escalation and de-escalation depending upon reported adverse events and efficacy. If the endpoint (reduction of phospho-EGFR staining) was not achieved at this initial dose level, and the dose level was deemed safe, the next dose level would consist of a higher dose of erlotinib. Conversely, if the primary endpoint was achieved at the initial dose level, and the dose level was deemed safe, then the next dose level would consist of a lower dose of erlotinib. It was deemed probable that this algorithm would determine the minimum effective dose (MED) with fewer participants than alternative algorithms of starting at the lowest dose and escalating or starting at the highest dose and de-escalating. Once the MED requirements were met, the cohort was expanded.

Scheduled dose levels

• Dose level +2 = 150 mg/day
• Dose level +1 = 100 mg/day
• Dose level 0 = 75 mg/day (starting dose level)
• Dose level -1 = 50 mg/day
• Dose level -2 = 25 mg/day

Enrollment Statistics

Target Enrollment: 65

Actual Enrollment: 46

Actual Registration: 65

• 65 were evaluated for eligibility
• 19 were excluded for not meeting inclusion/exclusion criteria
• 46 were registered for 7 days of daily erlotinib
• 23 completed study
• 20 were Ineligible (includes screen failures)
• 1 withdrew due to adverse events
• 1 died
• 1 Physician decision

Participant Statistics

• Age
  • Mean: 59
  • Median: 60
  • Range: 28-81
• Sex
  • Female: 15 (32.6%)
  • Male: 31 (67.4%)
• BMI
  • Mean: 34.4
  • Median: 27.4
  • Range: 18.5-48.6, (135.3)

Eligibility Criteria

Inclusion Criteria

• Pre-Registration Inclusion:
• Individuals with a clinical diagnosis fibrosis or cirrhosis of the liver:
• an indication for surgical liver resection, OR
• a clinical liver biopsy (with research tissue specimens available for analysis) ≤ 3 months prior to pre-registration.
• Age ≥18 years.
• 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.
• Willingness to use adequate contraception to avoid pregnancy or impregnation until 2 weeks after discontinuing study agent.
• Willingness to provide mandatory blood specimens as specified in the protocol.
• 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 specified in the protocol.
• Ability to understand and the willingness to sign a written informed consent document.
• Registration Inclusion:
• ECOG performance status 0 or 1.
• Participants must have normal organ and marrow function as defined below:
• INR ≤ 1.5
• Platelets ≥ 50 B/L (10₉/L)
• Total bilirubin ≤ 3 × institutional ULN
• AST (SGOT) and ALT (SGPT) ≤ 5 × institutional ULN
• Creatinine ≤ 1.5 × institutional ULN
• Non-surgical cohort only:
• Positive phospho-EGFR assessment
• 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 HIV.
• Participants who regularly (≥ 2 times per week) use drugs that alter the pH of the 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.
• Uncontrolled intercurrent illness.
• Use of potent CYP3A4 inhibitors or grapefruit juice.
• Use of CYP3A4 inducers or 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.

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Biospecimen Report

Research Blood Specimens

Research blood will be drawn at baseline and after the final dose of erlotinib immediately prior to surgery. It will be processed according to the instructions in the blood specimen kit provided by BAP (Biospecimen Accessioning and Processing Core Facility). Specimens will be processed (centrifuged, aliquoted, labeled per instructions in research blood kit), packaged, and shipped to BAP for accessioning and storage (See Section 10.1). Upon request, they will be shipped in batches for analyses.

Research Tissue Specimens

Surgical Cohort - Pre-Intervention

The pre-intervention percutaneous or transjugular liver biopsy may be conducted under ultrasound guidance following institutional standards of care before, during, and after the procedures. The collected specimens will consist of 4 specimens, of which 2 will be placed in RNAlater (Qiagen), and the other two will be placed in formalin. All four samples will be clearly labeled with study number, participant ID, specimen type, and date and time of collection. The RNAlater samples will be stored in a refrigerator at the participating site until shipped to the BAP Lab. The BAP Lab will store samples in a -80°C freezer until sent to the lab.

The formalin samples will be embedded in paraffin within 24 hours. The date and time of collection as well as paraffin embedding will be recorded on the Specimen Submission: Tissue case report form. Paraffin blocks will be shipped on a cool pack to the Mayo Clinic (CPN PC Office) for accessioning. The PC office will forward blocks and cores to the Mayo Clinic PRC in one batch at the end of enrollment for each cohort.

Surgical Cohort - Post-Intervention

After the liver resection surgery, a portion of the liver specimen that does not contain tumor (≥ 1 cm from negative margin) and consists of at least 1 gram of liver tissue will be placed in RNAlater (Qiagen). One other section of non-tumor bearing liver tissue measuring at least 1 cm x 1 cm x 0.5 cm will be placed in formalin, clearly labeled, and stored in the refrigerator until shipment. The formalin samples will be embedded in paraffin within 24 hours.

Paraffin blocks will be shipped refrigerated to Mayo Clinic (CPN PC Office) for accessioning and then forwarded to the Mayo Clinic PRC in one batch at the end of enrollment for each cohort.

If an institution cannot provide blocks, one 3 mm to 4 mm core should be taken from each block and placed into individual 2 mL tubes. Alternatively, sites may submit ten 5-micron slides plus one H&E.

Notes:

• Analysis for the study endpoints requires all slides for both time points for all participants to be sectioned at the same time.

Non-Surgical Cohort - Pre-Intervention

After informed consent and pre-registration, specimens from the clinical biopsy (paraffin block or ten []) 5-micron unstained slides and 1 H&E) will be obtained and submitted to the CPN Pathology Coordinator for accessioning. The pathology coordinator will ship immediately to Mayo Clinic PRC for real-time (≤ 21 days from collection) phospho-EGFR assessment to determine eligibility. At this time, one or two slides will be cut from the block for the purposes of determining eligibility. The rest of the block will remain intact and be cut at the time of dose-level efficacy analyses (post-intervention). Results will be returned to CPN PC for entry into the database. If the assessment of the pre-intervention specimen is positive, the participant will be allowed to continue the screening process.

Non-Surgical Cohort - Post-Intervention

The post-intervention percutaneous or transjugular liver biopsy may be conducted following institutional standards of care before, during, and after the procedures. The collected specimens will consist of 4 samples. Two will be placed in RNAlater (Qiagen), and the other two will be placed in formalin. All specimens will be clearly labeled with study number, participant ID, specimen type, and date and time of collection. The RNAlater samples will be stored in a refrigerator at the participating sites until shipped to the BAP Lab. The BAP Lab will store samples in a -80°C freezer until sent to the lab (upon request).

The fresh formalin samples will be embedded in paraffin within 24 hours. The date and time of collection as well as paraffin embedding will be recorded on the Specimen Submission: Tissue case report form. Paraffin blocks will be shipped refrigerated to the Mayo Clinic (CPN PC Office) for accessioning.

At the same time, the paraffin block containing the specimen used to establish initial eligibility at baseline will be submitted to the CPN PC Office. Additional sections are required because it is critical that specimens used for efficacy analysis at the end of each dose level be cut for both time points and for all participants at the same time.

Institutions unable to submit paraffin blocks may submit one 3.0mm to 4.0mm core taken from each block and placed into individual 2mL tubes. If cores cannot be provided, cut one H&E and 10 sections at 5 microns and mount on charged slides.

A 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib.

Sources:

• Epidermal Growth Factor Receptor Inhibition With Erlotinib in Liver: Dose De-Escalation Pilot Trial as an Initial Step in a Chemoprevention Strategy
  Tanabe, K. K., Zahrieh, D., Strand, C. A., Hoshida, Y., Flotte, T. J., Della’Zanna, G., Umar, A., Chavin, K. D., Cleary, S., Kubota, N., Llovet, J. M., Patel, T., Siegel, C., & Limburg, P. J.
  Gastro Hep Advances. 2024 Jan 29; Volume 3 (Issue 3): Pages 426-439