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

Inclusion criteria:

1. Histologically confirmed intrahepatic CCA with a documented KRAS mutation.

2. Patients greater than or equal to 18 years of age.

3. Patients must have disease progression that is not amenable to potentially curativetreatment.

4. Patients must have received one or two lines of chemotherapy.

5. Patients must have at least one measurable disease by RECIST v1.1.

6. Performance status (ECOG) 0-1.

7. Adequate organ baseline function defined as follows: absolute neutrophil count ≥1000cells/μL, platelet count ≥75,000 cells/μL, hemoglobin ≥9 g/dL, aspartateaminotransferase or alanine aminotransferase less than or equal to 3 × upper limitof normal, estimated glomerular filtration rate ≥60 mL/min, corrected QT interval byFridericia's (QTcF) interval ≤470 msec.

8. Women of childbearing potential must present with a negative serum pregnancy testand agree to use adequate contraception during the study and until 6 months afterthe end of treatment. Male patients with women partners of childbearing potentialmust agree with the contraception procedures of the study protocol.

9. Patients must be able to understand and be willing to comply with the requirementsof the study protocol.

10. Patients participate voluntarily and sign informed consent form(s).

Exclusion criteria:

1. Previous treatment with a MEK inhibitor or autophagy inhibitor.

2. Previous treatment with three or more lines of prior chemotherapy.

3. Extrahepatic CCA with

4. Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

5. Cardiovascular disorders: congestive heart failure New York Heart Association ≥class 2 or left ventricular ejection fraction (LVEF) <50%, arrythmias orcardiac conduction abnormalities. Uncontrolled arterial hypertension orinadequately controlled arterial hypertension, at the discretion of theinvestigator, based on an average of = >3 BP readings over = >2 sessions.

6. Patients who have retinal condition (retinal tear, exudate, hemorrhage) orhistory of retinal vein occlusion or central serous retinopathy or retinalpigment epithelial detachment.

7. History of interstitial lung disease or pneumonitis.

8. Patients who have clinically significant pleural effusion or ascites.

9. Patients who have neurological condition (e.g., tremor, ataxia, hypotension,confusion), history of seizures or active central nervous system metastases.

10. Impairment of gastrointestinal function or gastrointestinal disease (e.g.,diarrhea, active ulcer disease, history of gastrointestinalperforation/hemorrhage, malabsorption or other conditions that under thejudgment of the principal investigator (PI) may impair absorption of studydrugs).

11. Patients who are taking antineoplastic drugs for concomitant cancer or historyof malignancy other than CCA within 5 years prior to screening, with theexception 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 thecervix, non-melanoma skin carcinoma, localized prostate cancer, ductalcarcinoma in situ, or Stage I uterine cancer.

12. Any other condition that would, in the Investigator s judgment, contraindicatethe patients' participation in the clinical study due to safety concerns orcompliance with clinical study procedures (e.g., infection, unable to swallowmedication, social/psychological issues, etc).

13. Known active viral hepatitis, including HBV and HCV.

14. Patients with known allergic reaction to quinoline derivatives (e.g., quinine,chloroquine, mefloquine) and/or hypersensitivity to study drugs.

15. Patients who have not recovered for certain AEs due to previous lines of therpay.

16. Female patients who are pregnant or lactating at the time of enrollment.