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

Phase 3

Terminated

• Conditions: Advanced Cholangiocarcinoma; FGFR2 Gene Rearrangements
• Interventions: Drug: Futibatinib; Drug: Cisplatin; Drug: Gemcitabine

• Registration Number: NCT04093362
• Lead Sponsor: Taiho Oncology, Inc.

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2019-09-16
• Study First Submitted QC: 2019-09-16
• Study First Posted: 2019-09-18
• Study Start: 2021-01-06
• Primary Completion: 2024-04-22
• Study Completion: 2024-04-22
• Results First Submitted: 2025-01-15
• Status Verified: 2025-02
• Results First Submitted QC: 2025-02-06
• Last Update Submitted: 2025-02-06
• Results First Posted: 2025-03-25
• Last Update Posted: 2025-03-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 10

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Futibatinib	Futibatinib	Participants received futibatinib at an oral dose of 20 milligrams (mg), administered once daily (QD) on every day of a 21-day cycle up to disease progression.
Cisplatin/Gemcitabine	Cisplatin	Participants received cisplatin 25 milligrams per square meter (mg/m\^2) IV infusion followed by gemcitabine 1000 mg/m\^2 IV infusion on Days 1 and 8 of each 21-day cycle up to 8 cycles.
Cisplatin/Gemcitabine	Gemcitabine	Participants received cisplatin 25 milligrams per square meter (mg/m\^2) IV infusion followed by gemcitabine 1000 mg/m\^2 IV infusion on Days 1 and 8 of each 21-day cycle up to 8 cycles.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Up to approximately 28 months	PFS was defined as the time from date of randomization to the date of documentation of disease progression by independent central review (ICR), or date of death, whichever occurs first. Response assessments were made based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1, 2009)

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 28 months	ORR was defined as the proportion of participants experiencing a best overall response of partial response (PR) or complete response (CR) as per RECIST 1.1, based on ICR. PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. CR was defined as disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to less than (\<)10 millimeters (mm) and disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10-mm short axis)
Disease Control Rate (DCR)	Up to approximately 28 months	DCR was defined as the proportion of participants experiencing a best overall response of stable disease (SD), PR or CR as per RECIST 1.1, based on central assessment of radiologic images. PR was defined as at least a 30% decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. CR was defined as disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to \<10 mm and disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10-mm short axis).
Overall Survival (OS)	Up to approximately 28 months	OS was defined as the time from the date of randomization until the date of death due to any cause.
Progression-Free Survival (PFS) Per Investigator Assessment	Up to approximately 28 months	PFS per investigator assessment is 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs)	Up to approximately 28 months	An adverse event (AE) was defined as any untoward medical condition in clinical investigation participant administered drug; it does not necessarily have to have causal relationship with this treatment. A TEAE was defined as an AE that started or worsened at the time of or after first dose of study drug administration and within 30 days after last dose of study drug and does not necessarily have a causal relationship to use of the study drug. TEAEs were assessed by Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0). SAE was any untoward medical occurrence that at any dose: results in death, is life-threatening, required in participant hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is congenital anomaly/birth defect, important medical event. TEAEs included any clinically significant changes in clinical laboratory tests, vital signs, ophthalmological exams, and 12-lead electrocardiogram (ECG).

Trial Locations

Locations (102)

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Norton Cancer Institute Audubon Hospital Campus Medical Plaza; 🇺🇸 Louisville, Kentucky, United States

New Mexico Cancer Care Alliance; 🇺🇸 Albuquerque, New Mexico, United States

Utah Cancer Specialists; 🇺🇸 Salt Lake City, Utah, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

Medical Oncology Associates, PS - Summit Cancer Centers; 🇺🇸 Spokane, Washington, United States

Carbone Comprehensive Cancer Center; 🇺🇸 Madison, Wisconsin, United States

Medical College of Wisconsin - Froedtert Hospital; 🇺🇸 Milwaukee, Wisconsin, United States

Fundacion Favaloro para la Docencia e Investigacion Medica; 🇦🇷 Buenos Aires, Caba, Argentina

Hospital de Gastroenterologia Dr. C. Bonorino Udaondo; 🇦🇷 Buenos Aires, Caba, Argentina

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