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Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04566133
Recruitment Status : Recruiting
First Posted : September 28, 2020
Last Update Posted : June 24, 2022
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


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

Detailed Description:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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).
Actual Study Start Date : February 15, 2022
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Arm Intervention/treatment
Experimental: 1/Arm 1
Trametinib + hydroxychloroquine (HCQ)
Drug: Trametinib
orally 2 mg once a day

Drug: Hydroxychloroquine
orally 600 mg twice a day-1,200 mg total dose

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. 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

  2. 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

  3. To access overall survival (OS) [ Time Frame: death ]
    Kaplan-Meier method

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

    • biliary tract carcinoma (BTC) OR carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of BTC

Note: The term BTC includes intra- or extra- hepatic cholangiocarcinoma (CCA), gallbladder cancer or ampullary cancer.

  • The tumor must have KRAS mutation(s) of clinical significance, confirmed by NCI Laboratory of Pathology or by FDA approved test.
  • Patients must have received or been intolerant of at least one line of chemotherapy.
  • Patients must have at least 1 measurable lesion by RECIST version 1.1
  • Patients must have disease that is not amenable to potentially curative resection, ablation or transplantation.
  • Age greater than or equal to 18 years.
  • Performance status (ECOG) 0-2
  • If liver cirrhosis is present, patient must have a Child-Pugh score <7 (Class A)
  • Patients must have adequate organ and marrow function as defined below:

    • ANC greater than or equal to 1,500/mcL
    • platelets greater than or equal to 100,000/mcL
    • hemoglobin greater than or equal to 9 g/dL
    • total bilirubin if cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: bilirubin should be less than or equal to 1.5 x ULN
    • ALT or AST less than or equal to 5 x ULN.
    • Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)*** : < 1.5x institution upper limit of normal OR greater than or equal to 30 mL/min/1.73 m^2 for participant with creatinine levels greater than or equal to 1.5 X institutional ULN


ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);

GFR=glomerular filtration rate; ULN=upper limit of normal.

***Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.

  • Patients must have at least 1 focus of disease that is amenable to mandatory tumor biopsies and be willing to undergo this. Ideally, the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators.
  • The study drugs are harmful for developing human fetus. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study treatment and up to 4 months after the last dose of the study drug(s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patients must be able to understand and be willing to sign a written informed consent.


  • Patients who have had standard-of-care anti-cancer therapy within 2 weeks of treatment initiation or therapy with investigational agents (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents), large field radiotherapy, or major surgery within 4 weeks of treatment initiation.
  • Any unresolved toxicity NCI CTCAE v.5 Grade greater than or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade greater than or equal to 2 neuropathy will be evaluated on a case-by-case basis.
  • Has biliary duct obstruction, unless a treatable, clinically relevant obstruction has been relieved by internal endoscopic drainage/stenting, palliative by-pass surgery or percutaneous drainage prior to treatment initiation.
  • Patients with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Patients with signs of liver failure, e.g. clinically significant ascites, encephalopathy, or variceal bleeding within six months before treatment initiation.
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyper viscosity or hypercoagulability syndromes)
  • Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders: Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias, stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before treatment initiation
    • History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
    • History of seizures
    • Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma creatine kinase (CK) levels should be avoided while on study treatment
    • Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
    • Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the principal investigator (PI) may impair absorption of study drugs)
    • Any other condition that would, in the Investigator s judgment, contraindicate the patient s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication (patients may not receive drug through a feeding tube), social/psychological issues, etc.
  • Screening corrected QT interval by Fridericia's (QTcF) > 500 msec
  • Known infection with human immunodeficiency virus (HIV), unless patient is on effective anti-retroviral therapy with undetectable viral load within 6 months of treatment initiation
  • Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is undetectable.
  • Known history of hepatitis C virus (HCV) infection, unless completed treatment and cured with undetectable HCV viral load.
  • Known prior severe hypersensitivity to study drugs or any component in its formulations (CTCAE v5.0 grade >= 3).
  • Pregnant women are excluded from this study because study therapy can cause fetal harm. Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated with study drugs.

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): NCT04566133

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Contact: Donna M Hrones, C.R.N.P. (240) 858-3155
Contact: Tim F Greten, M.D. (240) 760-6114

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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      
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Tim F Greten, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT04566133    
Other Study ID Numbers: 200152
First Posted: September 28, 2020    Key Record Dates
Last Update Posted: June 24, 2022
Last Verified: April 29, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Tumor Regression
Progression Free Survival
New Drug Combination
Additional relevant MeSH terms:
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Bile Duct Neoplasms
Biliary Tract Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents
Antineoplastic Agents
Protein Kinase Inhibitors