Bile duct cancer is cancer of the slender tubes of the biliary tract. These tubes carry bile
through the liver. Such cancer tumors often have an abnormal or mutated gene. Researchers
think a mix of drugs can slow the progression of gene-mutated cancers of the biliary tract.
To see if using a combination of trametinib and hydroxychloroquine (HCQ) increases the period
of time it takes for a person s bile tract carcinoma (BTC) to get worse.
Adults age 18 and older with BTC.
Participants will be screened with a physical exam, medical history, and cancer history.
Their ability to do their normal activities will be assessed. They will have blood and urine
tests. They will give a tumor sample. They will have heart tests. They may talk with a heart
doctor. They may have an eye exam. They may have a tuberculosis test. They will have computer
tomography (CT) scans of the chest, abdomen, and pelvis. They may have magnetic resonance
imaging (MRI) scans of the chest, abdomen, pelvis.
Participants will repeat some screening tests throughout the study.
Participants will take HCQ and trametinib tablets by mouth daily in 28-day cycles. They will
have study visits once a month. They will take the drugs until they have bad side effects or
the drugs stop working.
Participants will have one more tumor biopsies during the treatment. They will have blood
One month after treatment ends, participants will have a safety follow-up visit. Then they
will be called or emailed every 6 months for the rest of their life....
Among the new cases of bile tract carcinoma (BTC) that are diagnosed every year in the
United States, there are approximately 6,500 cases of gallbladder carcinoma, 3,000 cases
of extrahepatic cholangiocarcinoma, and 3,000 cases of intrahepatic cholangiocarcinoma.
Current treatment options for patients with cholangiocarcinoma are limited and take no
account of the known biological and genetic heterogeneity in these diseases. Median
survival for advanced disease remains poor at approximately 1 year.
Activating KRAS mutations are frequently detected in all subtypes of BTC and can be
found in up to 40% of BTC, predominantly in perihilar and distal cholangiocarcinoma
(CCA). However, pharmacological inhibition of mutated KRAS has demonstrated little
clinical benefit in general.
Trametinib is a reversible, highly selective allosteric inhibitor of mitogen-activated
extracellular signal regulated kinases MEK1 and MEK2. Tumor cells with KRAS mutations
commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in which
activated MEK is a critical component. However, tumors are able to overcome MEK
signaling inhibition by trametinib through upregulation of autophagy pathway.
Hydroxychloroquine (HCQ) inhibits lysosomal acidification and prevents the degradation
of autophagosomes, to suppress autophagy.
Trametinib has been approved by FDA for the treatment of melanoma as a single agent or
for the treatment of other cancers if tumors carry BRAF mutation. Hydroxychloroquine are
approved for the treatment of malaria, lupus erythematosus and acute or chronic
Preclinical studies have shown that combined treatment of trametinib plus HCQ elicited
striking tumor regression in animal model.
-To determine whether the 5-month progression free survival (PFS) of the trametinib plus
hydroxychloroquine (HCQ) combination in subjects with refractory bile tract carcinoma (BTC)
with KRAS mutation exceeds 25%.
Histopathological confirmation of BTC or carcinoma highly suggestive of a diagnosis of
Tumor must have KRAS mutation.
Patients must have disease that is not amenable to potentially curative resection,
transplantation or ablation.
Age greater than or equal to 18 years
Patients must have measurable lesion by RECIST 1.1.
At least two weeks washout period from previous therapy
ECOG less than or equal to 2
Adequate renal, hepatic and bone marrow function
-The study is open-labeled phase 2 study. It is designed to enroll total 30 patients with
refractory BTC, to test the hypothesis that treatment with a combination of HCQ and
trametinib prevents cancer progression/recurrence. We propose that this combination will have
relative safety profile and antitumor efficacy in BTC patients with KRAS mutation.
Bile duct carcinoma,
Neoplasm of unspecified nature of digestive system,
cancer of the bile duct,
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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