Futibatinib Versus Gemcitabine-Cisplatin Chemotherapy as First-Line Treatment of Patients With Advanced Cholangiocarcinoma Harboring FGFR2 Gene Rearrangements

Inclusion Criteria:

A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study:

1. Provide written informed consent.
2. Is ≥18 years of age (or meets the country's regulatory definition for legal adult age).
3. The patient has histologically confirmed, locally advanced, or metastatic, or recurrent unresectable iCCA harboring FGFR2 gene rearrangements based on testing performed by the designated central laboratory.
4. Patient has radiographically measurable disease per RECIST 1.1.
5. Patients who have received treatment for locally advanced disease (for example, trans-arterial chemoembolization, selective internal radiation therapy, external beam radiation) must have evidence of radiographic progression with measurable disease outside the previously-treated lesions.
6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.

Adequate organ function as defined by the following criteria:

1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 ×upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN.
2. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert's syndrome.
3. White Blood Count (WBC) ≥ 2000/mm3 (≥ 2.0 × 109/L)
4. Absolute neutrophil count (ANC) ≥ 1000/mm3 (ie, ≥ 1.0 × 109/L by International Units [IU])
5. Platelet count ≥ 100,000/mm3 (IU: ≥ 100 × 109/L)
6. Hemoglobin ≥ 9.0 g/dL
7. Phosphorus ≤ 1.5 × ULN
8. Creatinine clearance: ≥ 60 mL/min
9. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to administration of the first dose of futibatinib. Female patients are not considered to be of child bearing potential if they have a history of hysterectomy or are post menopausal defined as no menses for 12 months without an alternative medical cause. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 6 months after the last dose.
10. Willing and able to comply with scheduled visits and study procedures.

Exclusion Criteria:

A patient will be excluded from this study if any of the following criteria are met:

Patient has received previous systemic anticancer therapy.

• Patients receiving adjuvant or neoadjuvant treatment and completed ≥6 months prior to randomization are eligible.

Patient has mixed hepatocellular carcinoma - iCCA disease.

History and/or current evidence of any of the following disorders:

1. Non-tumor related alteration of calcium-phosphorus homeostasis that is clinically significant in the opinion of the Investigator.
2. Ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator.
3. Retinal disorder confirmed by retinal examination and considered clinically significant in the opinion of the ophthalmologist.
4. History or current evidence of uncontrolled ventricular arrhythmias
5. Fridericia's corrected QT interval (QTcF) > 470 ms on electrocardiogram (ECG) conducted during Screening.

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:

1. Major surgery within the previous 4 weeks (the surgical incision should be fully healed prior to the first dose of study therapy).
2. 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.
3. Patients with locoregional therapy, e.g. transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT) or ablation within 4 weeks.
4. Any history of liver transplant.

A serious illness or medical condition(s) including, but not limited to, the following:

1. Brain metastases that are untreated or clinically or radiologically unstable (that is, have been stable for <1 month).
2. Known acute systemic infection.
3. Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months.
4. Chronic nausea, vomiting, or diarrhea considered to be clinically significant in the opinion of the Investigator.
5. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death.
6. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the judgment of the Investigator would make the patient inappropriate for entry into this study.
7. Patients with a history of another primary malignancy that is currently clinically significant, and has potential for metastases or currently requires active intervention.
8. Pregnant or breast-feeding female.
9. The patient is unable to take oral medication.