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

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Brief Title

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

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).

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....

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

        -  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 Phase

Phase 2

Study Type


Primary Outcome

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%

Secondary Outcome

 To evaluate the response rate (RR) (CR+PR) in patients with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ


Bile Duct Cancer



Study Arms / Comparison Groups

 1/Arm 1
Description:  Trametinib + hydroxychloroquine (HCQ)


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 15, 2022

Completion Date

December 31, 2025

Primary Completion Date

December 31, 2024

Eligibility Criteria


          -  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

          -  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

          -  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.




18 Years - N/A

Accepts Healthy Volunteers



Tim F Greten, M.D., (240) 858-3155, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Tim F Greten, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

October 3, 2022