Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).
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|ClinicalTrials.gov Identifier: NCT04566133|
Recruitment Status : Recruiting
First Posted : September 28, 2020
Last Update Posted : December 3, 2021
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 taken often.
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....
|Condition or disease||Intervention/treatment||Phase|
|Bile Duct Cancer Biliary Cancer Biliary Tract Neoplasms Cholangiocarcinoma||Drug: Trametinib Drug: Hydroxychloroquine||Phase 2|
- 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 rheumatoid arthritis.
- 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 BTC.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).|
|Estimated Study Start Date :||December 8, 2021|
|Estimated Primary Completion Date :||December 31, 2023|
|Estimated Study Completion Date :||December 31, 2023|
Experimental: 1/Arm 1
Trametinib + hydroxychloroquine (HCQ)
orally 2 mg once a day
orally 600 mg twice a day - 1,200 mg total dose
- To determine whether the 5-month PFS of the trametinib plus hydroxychloroquine (HCQ) combination in subjects with refractory bile tract carcinoma (BTC) with KRAS mutation exceeds 25% [ Time Frame: 5 months ]The fraction of patients who are able to not have progressive disease at 5 months will be reported along with a 95% confidence interval
- To evaluate the response rate (RR) (CR+PR) in patients with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ [ Time Frame: every 2 months ]the fraction of patients who experience a response (PR + CR) will be reported along with 80% and 95% two-sided confidence intervals
- To determine the safety, tolerability and feasibility of the trametinib plus HCQ combination in subjects with refractory BTC with KRAS mutation [ Time Frame: 90 days after treatment ]List of adverse event frequency
- To access overall survival (OS) [ Time Frame: death ]Kaplan-Meier method
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 ClinicalTrials.gov identifier (NCT number): NCT04566133
|Contact: Donna M Hrones, C.R.N.P.||(240) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Tim F Greten, M.D.||National Cancer Institute (NCI)|