Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).
Condition: Bile Duct Cancer; Biliary Cancer; Biliary Tract Neoplasms; Cholangiocarcinoma
MeSH terms: Cholangiocarcinoma; Bile Duct Neoplasms; Biliary Tract Neoplasms
Intervention: Trametinib; Hydroxychloroquine
Intervention description: orally 2 mg once a day; orally 600 mg twice a day-1,200 mg total dose
Intervention MeSH terms: Hydroxychloroquine; Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tumor Regression; Progression Free Survival; New Drug Combination

Summary:

      Background:

      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.

      Objective:

      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.

      Eligibility:

      Adults age 18 and older with BTC.

      Design:

      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 biopsy 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....
    

Eligibility criteria:

        -  INCLUSION 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 Kirsten rat sarcoma (KRAS) mutation(s) of clinical significance,
             confirmed by National Cancer Institute (NCI) Laboratory of Pathology or by Food and
             Drug Administration (FDA).

          -  Patients must have received or been intolerant of at least one line of chemotherapy.

          -  Patients must have at least 1 measurable lesion by Response Evaluation Criteria in
             Solid Tumors (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 Eastern Cooperative Oncology Group (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:

               -  absolute neutrophil count (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 upper limit of normal
                  (ULN)

               -  alanine aminotransferase (ALT) or aspartate aminotransferase (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

        Notes:

        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 estimated glomerular filtration rate (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.

        EXCLUSION CRITERIA:

          -  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 Common Terminology Criteria for Adverse Events (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.