Erlotinib for Chemoprevention in Trisomy 7 Positive Primary Sclerosing Cholangitis (PSC)
| Status: | Completed |
|---|---|
| Conditions: | Liver Cancer, Cancer, Gastrointestinal |
| Therapuetic Areas: | Gastroenterology, Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 1/1/2014 |
| Start Date: | August 2009 |
| End Date: | May 2013 |
An Open Label Pilot Trial of Erlotinib (Tarceva) in Primary Sclerosing Cholangitis With Trisomy 7
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 Gores, unpublished observation).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.
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.
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
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