Inclusion Criteria:
* Age ≥ 18 years at the time of consent.
* Histologically or cytologically confirmed unresectable locally advanced and/or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, and carcinoma of the Ampulla of Vater, that has progressed or recurred after prior therapy.
* Documented pathogenic RAS (KRAS, NRAS, or HRAS) mutations confirmed by a CAP or CLIA-certified assay from tumor tissue or plasma.
* Progression or intolerance of first-line systemic chemotherapy lines (with or without immunotherapy) for unresectable and/or advanced stage disease. Prior systemic therapy administered in the adjuvant or neoadjuvant context may be considered as a prior line of therapy if disease recurrence or progression occurred during or within 6 months after the last dose of the systemic therapy.
* Radiographically measurable or evaluable disease per RECIST v1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 prior to registration.
* Adequate organ function as defined by the following:
* Absolute neutrophil count (ANC) ≥ 1.5 × 10³/uL
* Platelet count ≥ 75 × 10³/uL
* Hemoglobin ≥ 8 g/dL
* Total bilirubin ≤ 2 × upper limit of normal (ULN) (except participants with Gilbert Syndrome who must have a total bilirubin level of ≤ 3.0 x ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN, or ≤ 5.0 × ULN in the presence of liver metastases
* Calculated creatinine clearance ≥ 45 mL/min (CKD-EPI equation or other equation per institutional guidelines, or based on 24-hour urine collection.)
Exclusion Criteria:
* Receipt of any systemic anti-cancer therapy for advanced BTC within 3 weeks of allocation/randomization or 5 half-lives of the drug (whichever is longer).
* Prior treatment with any RAS pathway inhibitor, including any KRAS, MEK, or receptor tyrosine kinase (RTK) inhibitor (or other RAS-pathway targeting agents).
* Concurrent use of strong CYP3A4 modulators or drugs that strongly inhibit/induce P-gp or BCRP, if alternatives are not feasible.
* Treatment with any of the following within the specified time frame prior to the first dose of study therapy, or failure to recover from side effects of these prior therapies:
* Major surgery within the previous 4 weeks (the surgical incision should be fully healed prior to the first dose of study therapy).
* Radiotherapy (any dose) for extended field within 4 weeks or limited-field radiotherapy within 2 weeks, and/or has not recovered from acute impact of radiotherapy. Note: evaluable lesion must be outside the treated field.
* Local-regional therapy (e.g., TACE, SIRT, or ablation) within 4 weeks. Note: evaluable lesion must be outside the treated field.
* Known CNS (central nervous system) metastases or history of uncontrolled seizures. Participants with treated CNS metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and without steroid requirement (with the exception of low-dose steroid use for reasons such as appetite stimulant).
* Known diagnosis of an additional malignancy that is progressing or requires active treatment, with the exception of individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as agreed upon by the Investigator (e.g., non-melanoma skin cancer, carcinoma in situ of the breast or cervix).
* Pregnant or breastfeeding.
