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

Study Overview
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Brief Summary
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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 patients with advanced, metastatic, or recurrent unresectable iCCA harboring FGFR2 gene rearrangements

Detailed Description
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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 patients with advanced, metastatic, or recurrent unresectable iCCA harboring FGFR2 gene rearrangements. Eligible patients will be randomized on a 1:1 basis to the following study arms: Experimental Arm: Patients 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, patients will receive: Cisplatin 25 mg/m2 in 1000 mL 0.9% saline by intravenous (I.V.) infusion over 1 hour, followed by 500 mL 0.9% saline over 30 minutes; and Gemcitabine 1000 mg/m2 in 250-500 mL 0.9% saline by I.V. infusion over 30 minutes, beginning after completion of the cisplatin and saline infusions. Patients in the Experimental Arm may continue to receive continuous futibatinib until documentation of progressive disease (PD) per RECIST 1.1, or until other withdrawal criteria are met, whichever comes first. However, treatment may continue following PD per RECIST 1.1 if the patient is clinically stable and is considered by the Investigator to be deriving continued clinical benefit from futibatinib. Patients 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. Patients 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.

Official Title
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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

Conditions
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Advanced Cholangiocarcinoma, FGFR2 Gene Rearrangements

Intervention / Treatment
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* Drug: TAS-120
* Drug: Cisplatin/Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study: Provide written informed consent. Is ≥18 years of age (or meets the country's regulatory definition for legal adult age). 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. Patient has radiographically measurable disease per RECIST 1.1. 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. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 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 patients 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 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. 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: 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. History or current evidence of uncontrolled ventricular arrhythmias 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: 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. Patients with locoregional therapy, e.g. transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT) or ablation within 4 weeks. Any history of liver transplant. 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 patient inappropriate for entry into this study. Patients with a history of another primary malignancy that is currently clinically significant, and has potential for metastases or currently requires active intervention. Pregnant or breast-feeding female. The patient is unable to take oral medication.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAS-120<br>TAS-120 tablets, oral; 21-day cycle | Drug: TAS-120<br>* TAS-120 is an oral FGFR inhibitor<br>* Other names: Futibatinib;|
| Active Comparator: Cisplatin/Gemcitabine<br>• On Days 1 and 8 of a 21-day cycle, patients will receive: Cisplatin 25 mg/m2 in 1000 mL 0.9% saline by intravenous (I.V.) infusion over 1 hour, followed by 500 mL 0.9% saline over 30 minutes; and Gemcitabine 1000 mg/m2 in 250-500 mL 0.9% saline by I.V. infusion over 30 minutes, beginning after completion of the cisplatin and saline infusions. | Drug: Cisplatin/Gemcitabine<br>* Cisplatin/Gemcitabine is currently 1st line standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS: defined as the time from date of randomization to the date of documentation of disease progression by ICR per RECIST (version 1.1, 2009) or date of death, whichever comes first. | Response assessments will be made based on RECIST guidelines (version 1.1, 2009) for solid tumors | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | defined as the proportion of patients experiencing a best overall response of partial response (PR) or complete response (CR) (per RECIST 1.1), based on ICR. | up to12 months | 
| DCR | defined as the proportion of patients experiencing a best overall response of partial response (PR) or complete response (CR) (per RECIST 1.1), based on ICR. | up to 12 months | 
| OS | defined as the time from the date of randomization until the date of death due to any cause. | up to 12 months | 
| PFS per Investigator assessment | defined as the time from date of randomization to the date of disease progression based on Investigator assessment of radiographic images or death, whichever occurs first | up to 12 months | 
| Safety and Tolerability | Treatment-emergent adverse events (TEAEs) as assessed by CTCAE v5.0, including serious adverse events (SAEs) | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Futibatinib, Advanced Cholangiocarcinoma, FGFR2, Fusion, Rearrangement, TAS-120