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

A Phase 3, Open-Label, Randomized Study of Futibatinib Versus Gemcitabine-Cisplatin Chemotherapy as First-Line Treatment of Patients With Advanced Cholangiocarcinoma Harboring FGFR2 Gene Rearrangements FOENIX-CCA3

This is an open-label, multinational, parallel 2-arm, randomized Phase 3 study evaluating the efficacy and safety of futibatinib versus gemcitabine-cisplatin chemotherapy as first-line treatment of participants with advanced, metastatic, or recurrent unresectable intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene rearrangements

Study TAS-120-301 is an open-label, multinational, parallel 2-arm, randomized Phase 3 study evaluating the efficacy and safety of futibatinib versus gemcitabine-cisplatin chemotherapy as first-line treatment of participants with advanced, metastatic, or recurrent unresectable iCCA harboring FGFR2 gene rearrangements. Eligible participants will be randomized on a 1:1 basis to the following study arms:

• Experimental Arm: Participants will receive futibatinib at an oral dose of 20 mg, administered daily (QD) on every day of a 21-day cycle.

• Control Arm: On Days 1 and 8 of a 21-day cycle, participants will receive:

  • Cisplatin 25 mg/m2 in 1000 mL 0.9% saline by intravenous (IV) infusion over 1 hour, followed by 500 millilliteres (mL) 0.9 percent (%) saline over 30 minutes; and
  • Gemcitabine 1000 mg/m2 in 250-500 mL 0.9% saline by IV infusion over 30 minutes, beginning after completion of the cisplatin and saline infusions.

Participants in the Experimental Arm may continue to receive continuous futibatinib until documentation of progressive disease (PD) per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1), or until other withdrawal criteria are met, whichever comes first. However, treatment may continue following PD per RECIST 1.1 if the participants is clinically stable and is considered by the Investigator to be deriving continued clinical benefit from futibatinib.

Participants in the Control Arm may receive gemcitabine-cisplatin chemotherapy for up to 8 cycles or until PD or other withdrawal criteria are met, whichever comes first. Participants who discontinue gemcitabine-cisplatin due to documented disease progression (by ICR) may receive treatment with futibatinib ("crossover"), if medically appropriate in the opinion of the Investigator and if criteria for futibatinib treatment are met.

Inclusion Criteria:

A participant 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 participant 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. Participant has radiographically measurable disease per RECIST 1.1.

5. Participants 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.

7. Adequate organ function as defined by the following criteria:

   • 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.
   • Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for participants with Gilbert's syndrome.
   • White Blood Count (WBC) ≥ 2000/mm3 (≥ 2.0 × 109/L)
   • Absolute neutrophil count (ANC) ≥ 1000/mm3 (ie, ≥ 1.0 × 109/L by International Units [IU])
   • Platelet count ≥ 100,000/mm3 (IU: ≥ 100 × 109/L)
   • Hemoglobin ≥ 9.0 g/dL
   • Phosphorus ≤ 1.5 × ULN
   • Creatinine clearance: ≥ 60 mL/min

8. 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 participants 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.

9. Willing and able to comply with scheduled visits and study procedures.

Exclusion Criteria:

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

1. Participant has received previous systemic anticancer therapy.

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

2. Participant has mixed hepatocellular carcinoma - iCCA disease.

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

   • Non-tumor related alteration of calcium-phosphorus homeostasis that is clinically significant in the opinion of the Investigator.
   • 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.
   • 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 milliseconds (ms) on electrocardiogram (ECG) conducted during Screening.

6. 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.
   • Participants with locoregional therapy, e.g. transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT) or ablation within 4 weeks.
   • Any history of liver transplant.

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

   • Brain metastases that are untreated or clinically or radiologically unstable (that is, have been stable for <1 month).
   • Known acute systemic infection.
   • Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months.
   • Chronic nausea, vomiting, or diarrhea considered to be clinically significant in the opinion of the Investigator.
   • Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death.
   • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the judgment of the Investigator would make the participant inappropriate for entry into this study.

8. Participants with a history of another primary malignancy that is currently clinically significant, and has potential for metastases or currently requires active intervention.

9. Pregnant or breast-feeding female.

10. The participant is unable to take oral medication.