- 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
- 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 by the Laboratory of Pathology of the NCI
- 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.
- INCLUSION CRITERIA:
- Histopathological confirmation by the NCI Laboratory of Pathology 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.
- 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
- 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.