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Erlotinib for Chemoprevention in Trisomy 7 Positive Primary Sclerosing Cholangitis (PSC)

Primary Purpose

Primary Sclerosing Cholangitis, Trisomy 7, Cholangiocarcinoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Erlotinib (Tarceva)
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Primary Sclerosing Cholangitis focused on measuring Primary sclerosing cholangitis, Trisomy 7, Cholangiocarcinoma, Chemoprevention, Erlotinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female patients > 18 years of age, able to provide written informed consent.
  • Diagnosis of Primary Sclerosing Cholangitis.
  • Scheduled for an ERCP as part of their clinical care.
  • Diagnosed with trisomy 7 on cytologic testing.
  • Willingness to utilize adequate contraception (if female, evidenced by being postmenopausal for at least 6 months or using contraceptive pill; for both females and males, being surgically sterile, or using two forms of barrier contraception) from screening to at least one month after the trial.

Exclusion Criteria:

  • Cholangiocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma or other malignancy <=3 years of registration.
  • Other liver disease as determined by standard clinical, serological, imaging or histological criteria.
  • Secondary cause of sclerosing cholangitis (IgG cholangiopathy, autoimmune, post-surgical biliary stricture, radiation, human immunodeficiency syndrome).
  • Cholestasis with a bilirubin of > 1.6 mg/dl (normal range: 0.1 - 1.0 mg/dL).
  • Decompensated cirrhosis, Child-Pugh Class B or C.
  • Child A cirrhosis with portal hypertension (i.e., splenomegaly, esophageal or gastric varices, or platelet count < 100,000/µl [normal range: 150 - 450 x 103/µL]).
  • Transaminase (AST [norm.: 8-48 U/L], ALT [norm.: 7-55 U/L]) elevation of more than three times the upper limit of the normal range.
  • Pregnancy.
  • Nursing mothers.
  • Uncontrolled intercurrent illness.
  • Concurrent administration of CYP3A modulators, Antiepileptics, Rifampin, St. Johns wort, Ketoconazole, protonpump-inhibitors.
  • Men or women unwilling to employ adequate contraception.
  • Abnormalities of the cornea by history.
  • Moderate diarrhea defined as defecation frequency of equal or more than 4/d for those with their colon, equal or more than 8/d for patients with a pouch, and high ostomy output with those with ostomy.
  • Known interstitial lung disease

Sites / Locations

  • Mayo Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm A

Arm B

Arm Description

Erlotinib (Tarceva) 25 mg by mouth once daily.

Erlotinib (Tarceva) 50 mg by mouth once daily for 6 months

Outcomes

Primary Outcome Measures

To examine the safety and tolerability of Tarceva (Erlotinib) in patients with primary sclerosing cholangitis and trisomy 7 on biliary cytology.

Secondary Outcome Measures

To assess among patients with primary sclerosing cholangitis and trisomy 7 the resolution of this cytologic abnormality following treatment with Tarceva (Erlotinib).

Full Information

First Posted
August 5, 2009
Last Updated
January 9, 2014
Sponsor
Mayo Clinic
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00955149
Brief Title
Erlotinib for Chemoprevention in Trisomy 7 Positive Primary Sclerosing Cholangitis (PSC)
Official Title
An Open Label Pilot Trial of Erlotinib (Tarceva) in Primary Sclerosing Cholangitis With Trisomy 7
Study Type
Interventional

2. Study Status

Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
April 2013 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Mayo Clinic
Collaborators
Genentech, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary sclerosing cholangitis (PSC) is a chronic inflammatory condition of the bile ducts of unknown etiology. It is characterized by diffuse inflammation and stricturing of the entire biliary tree, eventually resulting in cirrhosis of the liver. Patients with PSC are at increased risk for the development of cholangiocarcinoma (CCA), a cancer arising from bile duct epithelium. This risk is estimated to be approximately 1 to 1.5% per year. It is postulated that chronic inflammatory changes in the biliary epithelium promote CCA formation. The prognosis of CCA is fatal. The only potentially curative therapy is surgical; however, only a minority of patients qualify for surgical treatment. Several studies have demonstrated overexpression of the epidermal growth factor receptor (EGFR) in CCA cells. EGFR is a type 1 tyrosine kinase promoting cell proliferation, migration and altered cell adhesion - typical characteristics of malignant neoplasias. In CCA cells, EGFR-activation is sustained resulting in cancer progression. In human CCA samples, EGFR-expression correlates with higher histologic grade, poor prognosis, and risk of recurrence. The EGFR gene is located on the short arm of chromosome 7 (7p12). Chromosomal abnormalities of the bile duct epithelium, particularly trisomy 7 (i.e. three copies of chromosome 7) can be detected in biliary epithelial samples obtained by endoscopic retrograde cholangiopancreatography (ERCP) in PSC patients. The finding of cells with trisomy 7 has preceded the development of aneuploidy and multiple chromosomal abnormalities in a number of patients, the latter chromosomal abnormalities are characteristic of CCA. Trisomy 7 amplifies the gene for EGFR thereby presumably promoting overexpression of this growth factor receptor. In a cohort of patients with Trisomy 7 and Primary Sclerosing Cholangitis patients followed for 1 year, the rate of development of Cholangiocarcinoma was 35% (n=37, Dr. Gores, unpublished observation). Patients without cytologic abnormalities were at minimal risk for the development of CCA. Erlotinib (Tarceva) is a human EGFR type 1 tyrosine kinase inhibitor. Tarceva received FDA approval as single agent treatment for patients with locally advanced or metastatic non-small cell lung cancer. In a randomized, double blind, placebo controlled trial of 731 patients, receiving 150 mg of Tarceva or placebo once daily, median survival was prolonged to 6.7 months from 4.7 months (p<0.001). Analysis of epidermal growth factor receptor expression (45% of total study patients) demonstrated greater survival benefit in EGFR positive patients. Tarceva in combination with Gemcitabine is also FDA approved as first line therapy in patients with locally advanced, unresectable or metastatic pancreatic cancer. Our central hypothesis is that patients with trisomy 7 will have carcinogenic changes including EGFR overexpression. EGFR blockade will inhibit a growth/survival advantage for these premalignant clones eliminating them from the biliary epithelium. As an initial step towards testing this hypothesis, the tolerability of Tarceva in this patient population needs to be established. This study will assist in determining the safety and tolerability of Tarceva in patients with primary sclerosing cholangitis. This study will be followed by a Phase 2 randomized controlled trial of Tarceva in patients with Primary Sclerosing Cholangitis with Trisomy 7.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Sclerosing Cholangitis, Trisomy 7, Cholangiocarcinoma, Chemoprevention
Keywords
Primary sclerosing cholangitis, Trisomy 7, Cholangiocarcinoma, Chemoprevention, Erlotinib

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
Erlotinib (Tarceva) 25 mg by mouth once daily.
Arm Title
Arm B
Arm Type
Experimental
Arm Description
Erlotinib (Tarceva) 50 mg by mouth once daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Erlotinib (Tarceva)
Intervention Description
Patients with PSC found to be positive for Trisomy 7 on biliary brushings will be treated with Erlotinib (Tarceva) at a dose of 25 mg or 50 mg by mouth once daily for 6 months.
Primary Outcome Measure Information:
Title
To examine the safety and tolerability of Tarceva (Erlotinib) in patients with primary sclerosing cholangitis and trisomy 7 on biliary cytology.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
To assess among patients with primary sclerosing cholangitis and trisomy 7 the resolution of this cytologic abnormality following treatment with Tarceva (Erlotinib).
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients > 18 years of age, able to provide written informed consent. Diagnosis of Primary Sclerosing Cholangitis. Scheduled for an ERCP as part of their clinical care. Diagnosed with trisomy 7 on cytologic testing. Willingness to utilize adequate contraception (if female, evidenced by being postmenopausal for at least 6 months or using contraceptive pill; for both females and males, being surgically sterile, or using two forms of barrier contraception) from screening to at least one month after the trial. Exclusion Criteria: Cholangiocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma or other malignancy <=3 years of registration. Other liver disease as determined by standard clinical, serological, imaging or histological criteria. Secondary cause of sclerosing cholangitis (IgG cholangiopathy, autoimmune, post-surgical biliary stricture, radiation, human immunodeficiency syndrome). Cholestasis with a bilirubin of > 1.6 mg/dl (normal range: 0.1 - 1.0 mg/dL). Decompensated cirrhosis, Child-Pugh Class B or C. Child A cirrhosis with portal hypertension (i.e., splenomegaly, esophageal or gastric varices, or platelet count < 100,000/µl [normal range: 150 - 450 x 103/µL]). Transaminase (AST [norm.: 8-48 U/L], ALT [norm.: 7-55 U/L]) elevation of more than three times the upper limit of the normal range. Pregnancy. Nursing mothers. Uncontrolled intercurrent illness. Concurrent administration of CYP3A modulators, Antiepileptics, Rifampin, St. Johns wort, Ketoconazole, protonpump-inhibitors. Men or women unwilling to employ adequate contraception. Abnormalities of the cornea by history. Moderate diarrhea defined as defecation frequency of equal or more than 4/d for those with their colon, equal or more than 8/d for patients with a pouch, and high ostomy output with those with ostomy. Known interstitial lung disease
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

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Erlotinib for Chemoprevention in Trisomy 7 Positive Primary Sclerosing Cholangitis (PSC)

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