Combination of GNS561 and Trametinib in Patients With Advanced KRAS Mutated Cholangiocarcinoma

Inclusion criteria

• Histologically confirmed intrahepatic CCA with a documented KRAS mutation.
• Patients greater than or equal to 18 years of age.
• Patients must have disease progression that is not amenable to potentially curative treatment.
• Patients must have received one or two lines of chemotherapy.
• Patients must have at least one measurable disease by RECIST v1.1.
• Performance status (ECOG) 0-1.
• Adequate organ baseline function defined as follows: absolute neutrophil count ≥1000 cells/μL, platelet count ≥75,000 cells/μL, hemoglobin ≥9 g/dL, aspartate aminotransferase or alanine aminotransferase less than or equal to 3 × upper limit of normal, estimated glomerular filtration rate ≥60 mL/min, corrected QT interval by Fridericia's (QTcF) interval ≤470 msec.
• Women of childbearing potential must present with a negative serum pregnancy test and agree to use adequate contraception during the study and until 6 months after the end of treatment. Male patients with women partners of childbearing potential must agree with the contraception procedures of the study protocol.
• Patients must be able to understand and be willing to comply with the requirements of the study protocol.
• Patients participate voluntarily and sign informed consent form(s).

Exclusion criteria

• Previous treatment with a MEK inhibitor or autophagy inhibitor.
• Previous treatment with three or more lines of prior chemotherapy.
• Extrahepatic CCA with recent (within 6 weeks) placement of a stent or episodes of unstable biliary stents (manifest as obstruction, migration of the stent, infevtion or mechanical failure of the stent) within 6 weeks according to investigator's judgement.
• 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 2 or left ventricular ejection fraction (LVEF) <50%, arrythmias or cardiac conduction abnormalities. Uncontrolled arterial hypertension or inadequately controlled arterial hypertension, at the discretion of the investigator, based on an average of = >3 BP readings over = >2 sessions.
• Patients who have retinal condition (retinal tear, exudate, hemorrhage) or history of retinal vein occlusion or central serous retinopathy or retinal pigment epithelial detachment.
• History of interstitial lung disease or pneumonitis.
• Patients who have clinically significant pleural effusion or ascites.
• Patients who have neurological condition (e.g., tremor, ataxia, hypotension, confusion), history of seizures or active central nervous system metastases.
• Impairment of gastrointestinal function or gastrointestinal disease (e.g., diarrhea, active ulcer disease, history of gastrointestinal perforation/hemorrhage, malabsorption or other conditions that under the judgment of the principal investigator (PI) may impair absorption of study drugs).
• Patients who are taking antineoplastic drugs for concomitant cancer or history of malignancy other than CCA within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• Any other condition that would, in the Investigator s judgment, contraindicate the patients' participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection, unable to swallow medication, social/psychological issues, etc).
• Known active viral hepatitis, including HBV and HCV.
• Patients with known allergic reaction to quinoline derivatives (e.g., quinine, chloroquine, mefloquine) and/or hypersensitivity to study drugs.
• Patients who have not recovered for certain AEs due to previous lines of therpay.
• Female patients who are pregnant or lactating at the time of enrollment.