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

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. Identifier: NCT00955149
Recruitment Status : Completed
First Posted : August 7, 2009
Last Update Posted : January 10, 2014
Genentech, Inc.
Information provided by:
Mayo Clinic

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.

Condition or disease Intervention/treatment Phase
Primary Sclerosing Cholangitis Trisomy 7 Cholangiocarcinoma Chemoprevention Drug: Erlotinib (Tarceva) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: An Open Label Pilot Trial of Erlotinib (Tarceva) in Primary Sclerosing Cholangitis With Trisomy 7
Study Start Date : August 2009
Actual Primary Completion Date : April 2013
Actual Study Completion Date : April 2013

Arm Intervention/treatment
Experimental: Arm A
Erlotinib (Tarceva) 25 mg by mouth once daily.
Drug: Erlotinib (Tarceva)
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.

Experimental: Arm B
Erlotinib (Tarceva) 50 mg by mouth once daily for 6 months
Drug: Erlotinib (Tarceva)
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 Measures :
  1. 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 Measures :
  1. 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 ]

Information from the National Library of Medicine

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

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

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 identifier (NCT number): NCT00955149

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United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Genentech, Inc.

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Responsible Party: Principal investigator: Gregory J. Gores, M.D., Mayo Clinic, Dept. of Gastroenterology and Hepatology Identifier: NCT00955149     History of Changes
Other Study ID Numbers: 09-000516
First Posted: August 7, 2009    Key Record Dates
Last Update Posted: January 10, 2014
Last Verified: January 2014
Keywords provided by Mayo Clinic:
Primary sclerosing cholangitis
Trisomy 7
Additional relevant MeSH terms:
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Cholangitis, Sclerosing
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Chromosome Aberrations
Pathologic Processes
Chromosome Duplication
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action