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

Study Overview
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Brief Summary
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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....

Detailed Description
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Background: 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 kirsten rat sarcoma (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 methyl ethyl ketone 1 (MEK1) and methyl ethyl ketone 2 (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 is 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. Objective: -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%. Eligibility: 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. At least two weeks washout period from previous therapy Eastern Cooperative Oncology Group (ECOG) less than or equal to 2 Adequate renal, hepatic and bone marrow function Design: -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.

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

Conditions
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Bile Duct Cancer, Biliary Cancer, Biliary Tract Neoplasms, Cholangiocarcinoma

Intervention / Treatment
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* Drug: Trametinib
* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1/Arm 1: Trametinib + Hydroxychloroquine (HCQ)<br>Trametinib + hydroxychloroquine (HCQ) | Drug: Trametinib<br>* orally 2 mg once a day<br>* Other names: Mekinist;Drug: Hydroxychloroquine<br>* orally 600 mg twice a day-1,200 mg total dose<br>* Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | Participants with refractory bile tract carcinoma (BTC) with KRAS mutation that exceed 25% who receive trametinib plus hydroxychloroquine (HCQ) combination who are able to not have progressive disease at 5 months will be reported along with a 95% confidence interval. Progression was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression). | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With a Response (Complete Response (CR) + Partial Response (PR) Reported With an 80% Confidence Interval | Response is defined as a Complete Response (CR) + Partial Response (PR) in participants with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters. | Every 2 months up to approximately 10 months | 
| Proportion of Participants With a Response (Complete Response (CR) + Partial Response (PR) Reported With an 95% Confidence Interval | Response is defined as a Complete Response (CR) + Partial Response (PR) in participants with refractory BTC with KRAS mutation treated with the combination of trametinib plus HCQ. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters. | Every 2 months up to approximately 10 months | 
| Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment | Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | 90 days after treatment | 
| Overall Survival | Overall survival is defined as the duration of time from start of treatment to death from any cause. | duration of time from the start of treatment to death from any cause, approximately 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor Regression, Progression Free Survival, New Drug Combination